Human Physiology and Mechanisms of Disease [6 ed.] 0721632998, 9780721632995

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GUYTON

and HALL

and JVlechanisms » lsease

ixth

edition

^Wk

lA^nM^

Human

I hysiology

and JVlechanisms of

Disease

Digitized by the Internet Archive in

2011

http://www.archive.org/details/humanphysiologymOOguyt

Human

Physiology and JVlechanisms

ofDilsease sixth

edition Arthur C. Guyton,

MD

Professor of Physiology and Biophysics

Department of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi

and

John

E. Hall,

Professor and

Department

PhD

Chairman

of Physiology

and Biophysics

University of Mississippi Medical Center Jackson, Mississippi

W.B. A

SAUNDERS COMPANY

Division of Harcourt Brace

Philadelphia

London

Toronto

& Company

Montreal

Sydney

Tokyo

W.B.

A

SAUNDERS COMPANY & Company

Division of Harcourt Brace

The Curtis Center Independence Square West Philadelphia, Pennsylvania 19106

Library of Congress Cataloging -in -Publication Data

Guyton, Arthur C. Human physiology and mechanisms of disease/Arthur and John E. Hall.— 6th ed. p.

C Guyton

cm.

Includes bibliographical references and index.

ISBN 0-7216-3299-8

Human physiology. 2. Physiology, Pathological. I. Hall, John (John Edward). II. Title. [DNLM: 1. Physiology. 2. Disease. QT 104 G992b 1997]

1.

E.

QP34.5.G87 1997

612— dc20

DNLM/DLC




A Figure

.

B E

c

addition to the pressure difference, several other factors affect the rate of gas diffusion in a fluid. Most important of all is the solubility of the gas. Carbon dioxide is especially soluble in water; therefore the relative diffusion rates for different gases of respiratory importance in the body fluids are as follows: ids. In

28-1 Net diffusion of oxygen from one end of a chamber

to the other.

mm

Hg. This partial the gas mixture is also 47 pressure, like the other partial pressures, is desig-

Oxygen

nated Ph 2 o.

Nitrogen

depends entirely on the temperature of the water. At normal room temHg. perature, the vapor pressure is about 20 But the most important value to remember is the Hg; vapor pressure at body temperature, 47

The vapor pressure

Diffusion of

mm

value will appear in

many

The gases

of our subsequent

Gases Through

Fluids

Pressure Difference Causes Net Diffusion

Now, let us return to the problem of diffusion. From the preceding discussion it is already clear

when the pressure of a gas is greater in one area than in another area, there will be net diffuthat

sion from the high pressure area toward the

low

pressure area. For instance, in Figure 28-1, one can readily see that the molecules in the area of high pressure at the left end of the chamber, because of their greater number, have a greater statistical chance of moving randomly into the area of low pressure than do molecules attempting to go in the other direction. However, some molecules do bounce randomly from the area of low pressure toward the area of high pressure. Therefore, the net diffusion of gas from the area of high pressure to the area of low pressure is equal to the number of molecules bouncing in this forward direction minus

Gases Through Tissues

that are of respiratory

Atmospheric Air*

{mm 597.0

2

COMPOSITION OF ALVEOLAR AIR ITS RELATION TO ATMOSPHERIC AIR Alveolar air does not have the same concentra-

by any means, which can readily be seen by comparing the alveolar air composition in column 5 of Table 28-1 with the composition of atmospheric air in column 1. tions of gases as atmospheric air

There are several reasons for the differences.

co H2

2

TOTAL

Alveolar Air

Expired Air

(mm Hg)

(mm Hg)

(mm Hg)

563.4 149.3

3.7

760.0

(100.00%)

0.3

566.0

47.0

(74.9%) (13.6%) (5.3%) (6.2%)

47.0

(74.5%) (15.7%) (3.6%) (6.2%)

760.0

(100.0%)

760.0

(100.0%)

569.0 104.0

47.0

(74.09%) (19.67%) (0.04%) (6.20%)

760.0

(100.00%)

0.3

First,

(AT SEA LEVEL)

Humidified Air

Hg)

(78.62%) (20.84%) (0.04%) (0.50%)

159.0

importance are

highly soluble in lipids and, consequently, are highly soluble in cell membranes. Because of this, these gases diffuse through the cell membranes with very little impediment. Instead, the major limitation to the movement of gases in tissues is the rate at which the gases can diffuse through the tissue water instead of through the cell membranes. Therefore, diffusion of gases through the tissues, including through the respiratory membrane, is almost equal to the diffusion of gases through water, as given in the preceding list. Note especially that carbon dioxide diffuses 20 times as rapidly as oxygen because of its high solubility in tissue fluids.

TABLE 28 -1 PARTIAL PRESSURES OF RESPIRATORY GASES AS THEY ENTER AND LEAVE THE LUNGS

N

0.53

all

discussions.

Diffusion of

20.3

of water

mm

this

1.0

Carbon dioxide

40.0

120.0 27.0

326

Respiration

VII

Upper

limit of

maximum

ventilation

Oxygen Concentration and Pressure

in

the Alveoli

Oxygen is continually being absorbed into the blood of the lungs, and new oxygen is continually being breathed into the alveoli from the atmosThe more rapidly oxygen

phere.

absorbed, the

is

lower becomes its concentration in the alveoli; on the other hand, the more rapidly new oxygen is breathed into the alveoli from the atmosphere, the 10

15

20

Alveolar ventilation Figure

40

25 (Lmin)

on the alveolar Po, caused by different levels two different rates of oxygen absorp250 ml/min and 1000 ml/min. 28-2

Effect

of alveolar ventilation at tion,

the alveolar air is only partially replaced by atmospheric air with each breath. Second, oxygen is constantly being absorbed from the alveolar air. Third, carbon dioxide is constantly diffusing from the pulmonary blood into the alveoli. And, fourth, dry atmospheric air that enters the respiratory passages is humidified even before it reaches the alveoli. Humidification of the Air As It Enters the Respiratory Passages. Column 1 of Table 28-1 shows that atmospheric air is composed almost entirely of nitrogen and oxygen; it normally contains almost no carbon dioxide and little water vapor. However, as soon as the atmospheric air enters the respiratory passages, it is exposed to the fluids covering the respiratory surfaces. Even before the air enters the alveoli, it becomes totally humidified. The partial pressure of water vapor at normal body temperature of 37° C is 47 Hg, which, therefore, is

higher becomes its concentration. Figure 28-2 illustrates the effect both of alveolar ventilation and of rate of oxygen absorption into the blood on the alveolar pressure of oxygen (Pa o ). The solid curve represents oxygen absorption at a rate of 250 ml/min, and the dotted curve at 1000 ml/min. At a normal ventilatory rate of 4.2 hters/min and an oxygen consumption of 250 ml/min, the normal operating point in Figure 28-2 is point A. The figure also shows that when 1000 milliliters of oxygen is being absorbed each minute, as occurs during moderate exercise, the rate of tain the alveolar

mm

increase fourfold to mainthe normal value of 104

Hg. Another effect illustrated in Figure 28-2 is that an extremely marked increase in alveolar ventilation can never increase the alveolar Po 2 above 149 Hg as long as the person is breathing normal

mm

atmospheric air, for this is the maximum Po 2 of oxygen in humidified atmospheric air. However, if the person breathes gases containing pressures of oxygen higher than 149 Hg, the alveolar Po, can approach these higher pressures.

mm

mm

the partial pressure of water in the alveolar

must Po 2 at

alveolar ventilation

C0 2

Concentration and Pressure

in

the Alveoli

air.

Carbon dioxide is continually being formed in the body, then discharged into the alveoli; and it is Rate at Which Alveolar Air Is

Renewed by Atmospheric

In Chapter 27,

it

was pointed out

Air 175

that the funcamount of

150-

tional residual capacity of the lungs, the

remaining in the lungs at the end of normal exmeasures approximately 2300 milliliters. Yet only 350 milliliters of new air is brought into the alveoli with each normal respiration, and this air

1

— 125

piration,

2 n

E

-=-

TO

CM

same amount of old alveolar air is expired. Therefore, the amount of alveolar air replaced by new at-

°-o

mospheric

>

only one seventh of the total, so that many breaths are required to exchange most of the alveolar air. Thus, at normal alveolar ventilation approximately half the gas is exchanged in 17 seconds. This slow replacement of alveolar air is of particular importance in preventing sudden changes in gaseous concentrations in the blood.

air

with each breath

is

SO 8°

75-

50-

vA

Normal mi

10

"'•-...

C0 2

alveolar

Pco 2

min

15

20

25

Alveolar ventilation (L min)

on alveolar Pco2 of alveolar ventilation at from the blood, 200 ml/min and 800 ml/min.

Figure

two

28-3

Effect

different rates of carbon dioxide excretion

28

Transport of

Oxygen and Carbon Dioxide Between the

Alveoli

and the Tissue

Cells

^

327

Terminal bronchiole

Atrium

Alveolar sacs

28-4 The respiratory lobule. (From W. The Lung. Springfield, 111., Charles Thomas, 1947.) Figure

S.

Miller:

C

two lungs, each alveolus having an average diameter of about 0.2 millimeter). The walls of the alveoli, alveolar ducts, and other parts of the respiratory unit are extremely thin, and within them is an almost solid network of interconnecting capillaries, illustrated in Figure 28-5. These membranes are collectively known as the respiratory membrane, also called the

continually being removed from the alveoli by ventilation. Figure 28-3 illustrates the effects on the alveolar Pco 2 of both alveolar ventilation and two rates of carbon dioxide excretion. The solid curve represents a normal rate of carbon dioxide excretion of 200 ml/min. At the normal rate of alveolar ventilation of 4.2 liters /min, the operating point for alveolar Pco 2 is at point in Figure 28-3 that is,

there are about 300 million in the

40

pulmonary membrane. The Respiratory Membrane. Figure 28-6

A

—

mm Hg.

Two 28-3:

other facts are also evident from Figure First, the alveolar

Pco 2

increases directly in pro-

portion to the rate of carbon dioxide excretion, as represented by the elevation of the dotted curve for 800 milliliters

alveolar

C0

Pco 2

2

excretion per minute. Second, the

decreases in inverse proportion to alveolar

concentrations and presand carbon dioxide in the alveoli are determined by the rates of absorption or excretion of the two gases, and also by the level of

ventilation. Therefore, the

illus-

trates to the left the ultrastructure of the respiratory

membrane shown

in cross-section

a red blood

also

cell. It

shows the

and to the right diffusion of oxy-

gen from the alveolus into the red blood

cell

and

diffusion of carbon dioxide in the opposite direction. Note especially the several different layers of

sures of both oxygen

the respiratory membranes. Despite the large number of layers, the overall thickness of the respiratory membrane in some ar-

alveolar ventilation.

eas

is

as

little

as 0.2 micrometer,

and

it

averages

about 0.6 micrometer.

THROUGH THE RESPIRATORY MEMBRANE

DIFFUSION OF GASES

The Respiratory Unit. Figure 28-4 illustrates the which is composed of a respiratory bronchiole, alveolar ducts, atria, and alveoli (of which

respiratory unit,

From histologic studies it has been estimated that the total surface area of the respiratory membrane is approximately 50 to 100 square meters in the normal adult. This is equivalent to the floor area of by 30 foot room. The total quantity of blood in the capillaries of the lung at any given instant is 60 a 25

to 140 milliliters.

Now

imagine

this small

amount

+

VII

Respiration

%

V

Figure

laries

Alveolus

in

the

alveolar

wall.

capil-

(From

Maloney and Castle: Resp. Physiol., 7:150, 1969. Reproduced by permission of ASP Biological and Medical

Perivascular interstitial

28-5 A, Surface view of

space

Press.

North-Holland

Division.)

B,

Cross-sectional view of alveolar walls and their vascular supply.

B

of blood spread over the entire surface of a 25 by 30 foot floor, and it is very easy to understand the rapidity of respiratory exchange of gases.

Factors That Affect the Rate of Diffusion Through the Respiratory

Gas

Membrane

Referring to the earlier discussion of diffusion

through water, one can apply the same principles

to diffusion of gases through the respiratory membrane. Thus, the factors that determine how rapidly a gas will pass through the membrane are (1) the thickness of the membrane; (2) the surface area of the membrane; (3) the diffusion rate of the specific gas in that is, in the wathe substance of the membrane ter of the membrane; and (4) the pressure difference between the two sides of the membrane. The thickness of the respiratory membrane occasionally increases, for instance as a result of edema

—

28

Transport of

Oxygen and Carbon Dioxide Between the

basement

solubility

membrane

^

Cells

329

in the

membrane and

inversely on the

square root of its molecular weight. The rate of diffusion in the respiratory membrane is almost exactly

Alveolar

epithelium

same

as that in water, for reasons explained Therefore, for a given pressure difference, carbon dioxide diffuses through the membrane about 20 times as rapidly as oxygen. Oxygen in turn diffuses about two times as rapidly as nitrogen. The pressure difference across the respiratory membrane is the difference between the pressure of the gas in the alveoli and the pressure of the gas in the blood. The alveolar pressure represents a measure of the total number of molecules of a particular gas striking a unit area of the alveolar surface of the membrane in unit time, and the pressure of the gas in the blood represents the number of molecules attempting to escape from the blood in the opposite direction. Therefore, the difference between these two pressures is a measure of the net tendency for the gas to move through the membrane. Obviously, when the pressure of a gas in the alveoli is greater than the pressure of the gas in the blood, as is true for oxygen, net diffusion from the alveoli into the blood occurs; but when the pressure of the gas in the blood is greater than the pressure in the alveoli, as is true for carbon dioxide, net diffusion from the

the

earlier.

and

surfactant layer

Figure

and the Tissue

The diffusion coefficient for the transfer of each gas through the respiratory membrane depends on its

Epithelial

Fluid

Alveoli

28-6 infrastructure of the respiratory membrane as shown

blood into the alveoli occurs.

in cross-section.

fluid in the interstitial space of the

in the alveoli, so that the respiratory gases

then diffuse not only through the also through this fluid. Also,

must

Respiratory

Membrane

membrane but

some pulmonary

dis-

eases cause fibrosis of the lungs, which can increase the thickness of some portions of the respiratory membrane. Because the rate of diffusion through the membrane is inversely proportional to the thickness of the membrane, any factor that increases the thickness to

Diffusing Capacity of the

membrane and

more than two

to three

The

ability of the respiratory

membrane

to ex-

change a gas between the alveoli and the pulmonary blood can be expressed in quantitative terms by its diffusing capacity, which is defined as the volume of a gas that diffuses through the membrane

mm

Hg. each minute for a pressure difference of 1 Obviously, all the factors previously discussed

mal respiratory exchange of gases. The surface area of the respiratory membrane can be greatly decreased by many different conditions. For instance, removal of an entire lung decreases the surface area to half normal. Also, in emphysema

that affect diffusion through the respiratory membrane can affect the diffusing capacity. The Diffusing Capacity for Oxygen. In the average young male adult the diffusing capacity for oxygen under resting conditions averages 21 ml/ mini mm Hg. In functional terms, what does this

many many

mean? The mean oxygen pressure difference the respiratory membrane during normal,

times normal can interfere significantly with nor-

area

of the alveoli coalesce, with dissolution of alveolar walls. Therefore, the total surface of

creased alveolar creased normal, is

respiratory membrane is often deas fivefold because of loss of the walls. When the total surface area is deto approximately one third to one fourth exchange of gases through the membrane the

as

impeded

much

to a significant

degree even under resting

During competitive sports and other strenuous exercise, even the slightest decrease in surface area of the lungs can be a serious detriment to respiratory exchange of gases.

conditions.

breathing

is

approximately

tion of this pressure

11

mm

across quiet

Hg. Multiplica-

by the diffusing capacity (11 X about 230 milliliters of oxygen

21) gives a total of diffusing through the respiratory

membrane each minute; this is equal to the rate at which the body uses oxygen. Change in Oxygen-Diffusing Capacity During Exercise. During strenuous exercise, or during other conditions that greatly increase pulmonary blood flow and alveolar ventilation, the diffusing capacity

VII

for

Respiration

oxygen increases

maximum

of about 65

young male adults to ml/min/mm Hg, which

in

>J»

diffusing capacity under resting conditions. This increase is caused mainly by opening up of many previously dormant pulmonary capillaries, thereby increasing the surface area of three times

Alveolus

Po 2 = 104

It Pulmonary

Capillary

l

a is

the

I

V

H

\

.yPo 2 = 40mm Hg Arterial

mm

Hg

IU

If

I

Po2 = 1 04

End

mm Hgy

Venous End

^*^^

&*"^

Alveolar oxygen partial pressure

which the oxygen can diffuse. Thereduring exercise, the oxygenation of the blood is increased not only by increased alveolar ventilation but also by a greater capacity of the respirathe blood into fore,

tory membrane for transmitting oxygen into the blood. Diffusing Capacity for Carbon Dioxide. The diffusing capacity for carbon dioxide has never been measured because of the following technical difficulty: Carbon dioxide diffuses through the respiratory membrane so rapidly that the average Pco 2 in the pulmonary blood is not far different from the Pco 2 in the alveoli the average difference is less than 1 Hg and with the available techniques, this difference is too small to be measured. Nevertheless, measurements of diffusion of other gases have shown that the diffusing capacity varies directly with the diffusion of the particular gas. Since the diffusion of carbon dioxide is 20 times that of oxygen, one would expect a diffusing capacity for carbon dioxide under resting conditions of

mm

—

—

Figure

28-8 Uptake

(The curve in

and

Pulley: Biophys.

at rest

and during

exer-

J.,

8:337, 1968.)

diffusing capacities of

all

these gases.

Uptake of Oxygen from the Alveoli

Figure 28-7 compares the measured or calculated diffusing capacities of oxygen, carbon diox-

and carbon monoxide

oxygen by the pulmonary capillary blood. was constructed from data in Milhorn

cise, showing the extreme diffusing capacity of carbon dioxide and also the effect of exercise on the

about 400 to 450 ml/min/mm Hg and during exercise of about 1200 to 1300 ml/min/mm Hg.

ide,

of

this figure

by the Pulmonary Blood

28-8 illustrates a puladjacent to a pulmonary capillary, showing diffusion of oxygen molecules between the alveolar air and the pulmonary blood. The Po 2 of the gaseous oxygen in the alveolus averages 104 Hg, whereas the Po2 of the venous blood Hg beentering the capillary averages only 40

The top part monary alveolus

mm

of Figure

mm

cause a large amount of oxygen has been removed from this blood as it has passed through the peripheral tissues. Therefore, the initial pressure difference that causes oxygen to diffuse into the pulmonary capillary is 104 - 40, or 64 Hg. The curve below the capillary shows the rapid rise in blood Po 2 as the blood passes through the capillary, showing that the Po 2 rises essentially to equal that of the alveolar air by the time the blood has moved

mm

a third of the distance through the capillary, be-

coming almost 104 mm Hg. Uptake of Oxygen by the Pulmonary Blood During Exercise. During strenuous exercise, a person's body may require as much as 20 times the normal amount of oxygen. Also, because of the increased cardiac output, the time that the blood remains in the capillary may be reduced to less than one half normal. Therefore, oxygenation of the blood could suffer for both these reasons. Yet because of the great safety factor for diffusion of oxyFigure 28 -7 Lung-diffusing capacities for carbon monoxide, oxygen, and carbon dioxide in the normal lungs.

gen through the pulmonary membrane, the blood is still almost completely saturated with oxygen when

28

it

pulmonary

leaves the

Transport of

capillaries.

Oxygen and Carbon Dioxide Between the

The reasons

that the rate of exercise;

numbers

earlier in the chapter

this

^

Cells

331

Venous end

end

of capillary

of capillary

Q

oxygen diffusion through the pul-

monary membrane ing

Arterial

was pointed out

it

and the Tissue

for

this are as follows: First,

Alveoli

40

mm

H

45

mm Hg

{')

increases almost threefold durresults mainly from increased

of capillaries participating in the diffu28-10 Uptake of carbon dioxide by the blood

sion.

Figure

Second, note in Figure 28-8 that during normal pulmonary blood flow the blood becomes almost saturated with oxygen by the time it has passed through one third of the pulmonary capillary, and little additional oxygen enters the blood during the latter two thirds of its transit. That is, the blood normally stays in the lung capillaries about three times as long as necessary to cause full oxygenation. Therefore, even with the shortened time of exposure in exercise, the blood still can become either fully oxygenated or nearly so.

laries.

In

summary,

determined by a baloxygen transport to the the blood and (2) the rate at which the utilized by the tissues.

ance between tissues in

oxygen

Po2

in the capil-

is

tissue

is

the rate of

(1)

Diffusion of

Oxygen from

the Capillaries

to the Tissue Cells

Oxygen

Diffusion of

Oxygen from

is always being used by the cells. Therethe intracellular Po, remains lower than the Po, in the capillaries. Also, in many instances, there is considerable distance between the capillaries

fore,

the Tissue

Capillaries into the Tissue Fluid

and the

When

the arterial blood reaches the peripheral tissues, its Po 7 on entering the capillaries is still 95 Hg. On the other hand, as shown in Figure 28-9, the Po, in the interstitial fluid averages only 40 Hg and only 23 Hg inside the cells. Thus, there is a tremendous initial pressure difference that causes oxygen to diffuse very rapidly from the blood into the tissues, so rapidly that the capillary Po, falls almost to equal the 40 Hg pressure in the interstitium. Therefore, the Po2 of the blood entering the veins from the tissue capil-

mm

mm

mm

mm

laries is also

olism on through

a

particular

If

oxygen are transported into the tissue in a given period of time, and the tissue Po, becomes correspondingly increased. However, the upper limit to which the Po, can rise, even

maximum

blood flow,

mm

Hg, because

this is the

is

normally about 95

oxygen pressure

in the

arterial blood.

Conversely, if the cells utilize more oxygen for metabolism than normally, this tends to reduce the interstitial fluid Po,.

Arterial

mm

Diffusion of Carbon Dioxide from the Tissue Cells into the Tissue Capillaries,

end

Venous end

of capillary

of capillary

P

p2

Pulmonary

= 40

mm

Hg {)

.

Thus, at each point in the gas transport chain, cardiffuses in a direction exactly opposite that of the diffusion of oxygen. Yet there is one major difference between the diffusion of carbon dioxide and that of oxygen: carbon dioxide can diffuse about 20 times as rapidly as oxygen. Therefore, the pressure differences that cause carbon dioxide diffusion are, in each instance, far less than the pressure differences required to cause oxygen diffusion.

bon dioxide

These pressures are the following: 1.

Figure

28-9 Diffusion of oxvgen from

Capillaries into the Alveoli

When oxygen is used by the cells, most of it becomes carbon dioxide, and this increases the intracellular Pco, Therefore, carbon dioxide diffuses from the cells into the tissue capillaries and is then carried by the blood to the lungs, where it diffuses from the pulmonary capillaries into the alveoli.

tial

cells.

and from the

increased,

greater quantities of

with

mm

vides a considerable safety factor.

the blood flow

becomes

tissue

mm

mm

mm

Interstitial Fluid Po,.

Therefore, the normal intracellular

mm

Hg. Blood Flow and Tissue Metab-

about 40

Effect of Rate of

cells.

Po, ranges from as low as 5 Hg to as high as 40 Hg, averaging (by direct measurement in lower animals) about 23 Hg. Because only 1 to 3 Hg of oxygen pressure is normally required for full support of the metabolic processes of the cell, one can see that even this low cellular Po of 2 23 Hg is more than adequate and actually pro-

a tissue capillary to the

mm

mm

Intracellular Pco,, about 46 Hg; interstiHg; thus, there is only a 1 Pco,, about 45

mm

Hg pressure differential, as illustrated in Figure 28-10.

332

Respiration

VII

Alveolus

Pco 2

40

mm

Hg

J

#

Pulmonary 45 mm Hg

Capillary

Pcog = 40 mm Hg Venous End

tissue

metabolism

affect the

Pco2

in a

way

exactly

opposite the way in which they affect tissue Po 2 Thus, it is easy to understand that increased tissue metabolism increases the C0 2 in the tissues, but increased blood flow carries more CO z away and therefore decreases the concentration. .

FUNCTION OF HEMOGLOBIN TO TRANSPORT

OXYGEN

pulmonary

capillary blood

Alveolar carbon dioxide partial pressure

28-11 Diffusion of carbon dioxide from the pulmonary blood into the alveolus. (This curve was constructed from data in Milhorn and Pulley: Biophys. J., 8:337, 1968.) Figure

IN

ARTERIAL BLOOD

Normally, about 97 per cent of the oxygen transported from the lungs to the tissues is carried in chemical combination with hemoglobin in the red blood cells, and the remaining 3 per cent is carried in the dissolved state in the water of the plasma and cells. Thus, under normal conditions oxygen is carried to the tissues almost entirely by hemoglobin.

Pco 2

of the arterial blood entering the tissues, Hg; Pco 2 of the venous blood leaving the Hg; thus, as also illustrated in tissues, about 45 Figure 28-10, the tissue capillary blood comes almost exactly to equilibrium with the interstitial Hg. Pco2 also 45 3. Pco of the venous blood entering the pul2 monary capillaries in the lungs, 45 Hg; Pco 2 of Hg; thus, only a 5 Hg the alveolar air, 40 2.

40

mm

mm

mm

,

mm

mm

mm

pressure difference causes all the required carbon dioxide diffusion out of the pulmonary capillaries into the alveoli. Furthermore, as illustrated in Figure 28-11, the Pco2 of the pulmonary capillary blood falls almost exactly to equal the alveolar Pco 2 of 40 Hg before it has passed more than about one third the distance through the capillaries. This is the same effect that was observed earlier for

Effect of Tissue

Pco 2

.

bound with oxygen as the blood Po 2 increases, which is called the per cent saturation of the hemoglo-

Metabolism and Blood Flow on Tissue capillary blood flow and

uration of the hemoglobin

diffusion.

Interstitial

which shows a progressive increase in the percentage of the hemoglobin that is dissociation curve,

Because the blood in the arteries usually has a Hg, one can see from the dissociation curve that the usual oxygen saturation of hemoglobin in arterial blood is about 97 per cent. On the other hand, in normal venous blood returning from Hg and the satthe tissues, the Po 2 is about 40

mm

oxygen

The chemistry of hemoglobin was presented in Chapter 24, where it was pointed out that the oxygen molecule combines loosely and reversibly with the heme portion of the hemoglobin. When the Po2 is high, as in the pulmonary capillaries, oxygen binds with the hemoglobin, but when the Po2 is low, as in the tissue capillaries, oxygen is released from the hemoglobin. This is the basis for almost all oxygen transport from the lungs to the tissues. The Oxygen-Hemoglobin Dissociation Curve. Figure 28-12 illustrates the oxygen-hemoglobin

20 30 40

50

60

Gaseous pressure

70 ou 80 90 yu 100 iuu 110 120 130 140 oxygen (mm Hg)

bin.

Po2

of about 95

mm

mm

is

about 75 per cent.

i

of

Figure

28-12 The oxygen-hemoglobin dissociation curve.

28

Maximum Amount

of

Transport of

Oxygen and Carbon Dioxide Between the

Alveoli

ADP = v2

Oxygen That Can Com-

bine with the Hemoglobin of the Blood. The blood of a normal person contains approximately 15 grams of hemoglobin in each 100 milliliters of blood, and each gram of hemoglobin can bind with a maximum of about 1.34 milliliters of oxygen. Therefore, on the average, the hemoglobin in 100 milliliters of blood can combine with a total of almost exactly 20 milliliters of oxygen when the hemoglobin is 100 per cent saturated. This is usually expressed as 20 volumes per cent. Amount of Oxygen Released from the Hemoglobin in the Tissues. The total quantity of oxygen bound with hemoglobin in normal arterial blood, which is 97 per cent saturated, is approximately 19.4 milliliters per 100 milliliters of blood. On passing through the tissue capillaries, this amount is reduced, on the average, to 14.4 milliliters. Thus, under normal conditions about 5 milliliters of oxygen are transported to the tissues by each 100 milliliters of blood.

Oxygen During Strenuous Exerheavy exercise the muscle cells utilize oxygen at a rapid rate, which causes the interstitial Hg. At this fluid Po 2 to fall to as low as 15 pressure only 4.4 milliliters of oxygen remains bound with the hemoglobin in each 100 milliliters Transport of

and the Tissue

1

ADP =

-i

'

2

resting level

normal

r-

1

2

1

Intracellular

333

normal

Normal

ADP=

^

Cells

3

Po 2 (mm Hg)

28-13 Effect of intracellular Po2 on rate of oxygen usage by the cells. Note that increasing the intracellular concentration of adenosine diphosphate (ADP) increases the rate of oxygen

Figure

usage.

cise. In

mm

shown in Figure 28-12. Thus, or 15 milliliters, is the quantity of oxygen then transported by each 100 milliliters of blood. Thus, under these conditions three times as much oxygen is transported as normally for each of blood, as also 19.4

-

4.4,

amount

of hemoglobin.

And when one remembers

that the cardiac output can increase to seven times in well-trained marathon runners, multiplying these two gives a 20-fold increase in oxygen transport to the tissues: this is about the limit that can be achieved.

normal

tion is altered, the rate of oxygen usage changes in proportion to the change in ADP concentration. It will be recalled from the discussion in Chapter 3 that when adenosine triphosphate (ATP) is utilized in the cells to provide energy, it is converted into ADP. The increasing concentration of ADP, in turn, increases the metabolic usage of both oxygen and the various nutrients that combine with the oxygen to release energy. This energy is used to reconvert the ADP to ATP. Therefore, under normal operating conditions the rate of oxygen utilization by the cells is controlled

ultimately by the rate of energy expen-

ADP states

is

—

that is, by the rate at which formed from ATP. Only in abnormal hypoxic

diture within the cells

does the availability of oxygen become a lim-

iting condition.

Metabolic Use of

Oxygen by the

Cells

Effect of Intracellular Po 2 on Rate of Oxygen Usage. Only a minute level of oxygen pressure is required in the cells for normal intracellular chemical reactions to take place. The reason for this is that the respiratory enzyme systems of the cell, which are discussed in Chapter 47, are geared so that when the cellular Po, is more than 1 to 3 Hg, oxygen availability is no longer a limiting factor in the rates of the chemical reactions. Instead, ] the main limiting factor then is the concentration of) adenosine diphosphate (ADP) in the cells. This effect is illustrated in Figure 28-13, which shows the re-

mm

between intracellular Po 2 and rate of oxygen usage at different concentrations of ADP. Note that whenever the intracellular Po 2 is above 1 to 3 Hg, the rate of oxygen usage becomes constant for any given concentration of ADP in the lationship

mm

cell.

On

the other hand,

when

the

ADP

concentra-

Transport of

Oxygen

in

the Dissolved State

mm

Hg, approxiAt the normal arterial Po2 of 95 mately 0.29 milliliter of oxygen is dissolved in every deciliter of water in the blood. Then when Hg in the tissue the Po 2 of the blood falls to 40 capillaries, only 0.12 milliliter of oxygen remains dissolved. In other words, 0.17 milliliter of oxygen is normally transported in the dissolved state to the tissues by each deciliter of blood water. This compares with almost 5.0 milliliters transported by the hemoglobin. Therefore, the amount of oxygen

mm

transported to the tissues in the dissolved state is normally slight, only about 3 per cent of the total, as compared with 97 per cent transported by the hemoglobin. Yet if a person breathes oxygen at very high alveolar Po 2 s, the amount then transported in the dissolved state can become much

334

VII

Respiration

sometimes so much so that serious excesses of oxygen occur in the tissues and "oxygen poisoning" ensues. This often leads to convulsions and even death, as will be discussed in detail in Chap-

Capillary

greater,

Red blood

Interstitial

cell

fluid

ter 30 in relation to high-pressure breathing as occurs in deep sea divers.

Combination of Hemoglobin with Carbon

Monoxide

—

Displacement of Oxygen H2

WfXf -

Carbon monoxide combines with hemoglobin at the same point on the hemoglobin molecule as does oxygen and therefore can displace oxygen from the hemoglobin. Furthermore, it binds with

C0 2 transported as: 7% C0 2 2. Hgb C0 2 = 23% 70% 3. HC0 3 1

•

about 250 times as much tenacity as oxygen. Therefore, a carbon monoxide level only about Viso that

normal oxygen in the alveoli will displace so the hemoglobin as to be lethal. A patient severely poisoned with carbon monoxide can be advantageously treated by administering pure oxygen, for oxygen at high alveolar pressures displaces carbon monoxide from its combination with hemoglobin far more rapidly than can oxygen at the low pressure of atmospheric oxygen.

.

of

Figure

28- 14 Transport of carbon dioxide in the blood.

much oxygen from

TRANSPORT OF CARBON DIOXIDE IN THE BLOOD Transport of carbon dioxide in the blood is not so great a problem as transport of oxygen, because even in the most abnormal conditions carbon dioxide usually can be transported in far greater quantities than can oxygen. However, the amount of carbon dioxide in the blood does have much to do with acid-base balance of the body fluids, which was discussed in Chapter 23. Under normal resting conditions an average of 4 milliliters of carbon dioxide is transported from the tissues to the lungs in each 100 milliliters of blood.

Chemical Forms

Carbon Dioxide

is

in

Which

Transported

To begin the process of carbon dioxide transport, carbon dioxide diffuses out of the tissue cells in the dissolved molecular C0 2 form. On entering the capillary, the carbon dioxide initiates a host of almost instantaneous physical and chemical reactions, illustrated in Figure 28-14, that are essential for

C0

2

transport.

Transport of Carbon Dioxide in the Dissolved State. A small portion of the carbon dioxide is transported in the dissolved state to the lungs. It will be recalled that the Pco of venous blood is 2 45 Hg and that of arterial blood is 40 Hg. The amount of carbon dioxide dissolved in the

mm

mm

fluid of the (2.7

40

blood

volumes per

mm Hg

is

at

45

cent).

about

mm

Hg is about 2.7 ml/dl The amount dissolved at

2.4 milliliters, or a difference of

only about 0.3 milliliter of carbon dioxide is transported in the form of dissolved carbon dioxide by each deciliter (100 milliliters) of blood. This is about 7 per cent of all the carbon dioxide normally transported. Transport of Carbon Dioxide in the Form of Bicarbonate Ion. Reaction of Carbon Dioxide with Water in the Red Blood Cells Effect of Carbonic Anhydrase. The dissolved carbon dioxide in the blood also reacts with water to form carbonic acid. However, this reaction would occur much too slowly to be of importance were it not for the fact that inside the red blood cells is an enzyme called 0.3 milliliter. Therefore,

—

which catalyzes the reaction between carbon dioxide and water, accelerating its

carbonic anhydrase,

about 5000-fold. Therefore, instead of requiring seconds or minutes to occur, as is true in the plasma, the reaction occurs so rapidly in the red blood cells that it reaches almost complete equilibrium within a small fraction of a second. This allows tremendous amounts of carbon dioxide to react with the red cell water even before the blood rate

many

leaves the tissue capillaries. Dissociation of the Carbonic Acid into Bicarbonate and Hydrogen Ions. In another small fraction of a second, the carbonic acid formed in the red cells dissociates into hydrogen and bicarbonate ions. Most of the hydrogen ions then combine with the hemoglobin in the red blood cells because hemoglobin is a powerful acid-base buffer. In turn, many of the bicarbonate ions diffuse from the red cells into the plasma while chloride ions diffuse into the red cells to take their place. Thus, the chloride content of venous red blood cells is greater than that of arterial cells, a phenomenon called the chloride shift.

28

Transport of

Oxygen and Carbon Dioxide Between the

The reversible combination of carbon dioxide with water in the red blood cells under the influence of carbonic anhydrase accounts for about 70 per cent of the carbon dioxide transported from the tissues to the lungs. Thus, this means of transporting carbon dioxide is by far the most important of all

the

methods

for transport.

Transport of Carbon Dioxide in Combination Carwith Hemoglobin and Plasma Proteins baminohemoglobin. In addition to reacting with directly water, carbon dioxide also reacts with amine radicals of the hemoglobin molecules to form the compound carbaminohemoglobin (CO,HHb). This combination of carbon dioxide with the hemoglobin is a reversible reaction that occurs with a very loose bond, so that the carbon dioxide is easily released into the alveoli where the Pco 2 is lower than in the tissue capillaries. A small amount of carbon dioxide also reacts in this same way with the plasma proteins, but this is much less significant because the quantity of these proteins is only one fourth as great as the quantity of hemo-

Alveoli

and the Tissue

^

Cells

335

released from the blood in the lungs, the pH rising to the arterial value once again. In exercise, or in other conditions of high metabolic activity, or when the blood flow through the tissues is sluggish, the decrease in pH in the tissue blood (and in the tissues themselves) can be as much as 0.50, thus causing severe tissue acidosis.

—

THE RESPIRATORY EXCHANGE RATIO

The discerning student will have noted that normal transport of oxygen from the lungs to the tissues by each deciliter of blood is about 5 milliliters, whereas normal transport of carbon dioxide from the tissues to the lungs is about under normal resting conditions cent as much carbon dioxide is lungs as there is oxygen uptake ratio of

carbamino reaction is much slower than the reaction of carbon dioxide with water inside the red blood cells. Therefore, it is doubtful that

this

R =

this

mechanism provides transport

of

more

carbon dioxide output to oxygen uptake

called the respiratory exchange ratio (R). That

globin.

However,

4 milliliters. Thus, only about 80 per expired from the by the lungs. The is

is,

Rate of carbon dioxide output Rate of oxygen uptake

The value

for

bolic conditions.

R changes under When a person is

than 15 to 25 per cent of the total quantity of car-

sively carbohydrates for

bon dioxide.

to 1.00.

On

different metautilizing exclu-

body metabolism, R

the other hand,

when

the person

rises

is uti-

lizing exclusively fats for metabolic energy, the

R

low as 0.7. The reason for this difference is that when oxygen is metabolized with carbohydrates, one molecule of carbon dioxide is formed for each molecule of oxygen consumed; whereas when oxygen reacts with fats, a large share of the oxygen combines with hydrogen atoms from the fats to form water instead of carbon dioxlevel falls to as

Change

in

Blood Acidity

During Carbon Dioxide Transport

The carbonic acid formed when carbon dioxide enters the blood in the tissues decreases the blood pH. Fortunately, though, the reaction of this acid

with the buffers of the blood prevents the hydrogen ion concentration from rising greatly (and the pH from falling greatly). Ordinarily, arterial blood has a pH of approximately 7.41, and, as the blood acquires carbon dioxide in the tissue capillaries, the pH falls to a venous value of approximately 7.37. In other words, a pH change of 0.04 unit takes place. The reverse occurs when carbon dioxide is

ide.

In other words, the respiratory quotient of the when fats are me-

chemical reactions in the tissues

tabolized is about 0.70 instead of 1.00. The tissue respiratory quotient will be discussed in Chapter 47.

For a person on a normal diet consuming average amounts of carbohydrates, fats, and proteins, the average value for R is considered to be 0.825.

REFERENCES I.: Hypoxia, Metabolic Acidosis and the Circulation. New York, Oxford University Press, 1992. George, R. B., et al.: Chest Medicine. Baltimore, Williams & Wilkins Co.,

Arieff, A.

1995.

Co., 1994.

Haldane,

J.

G.,

and

R.,

Hall, S. M.:

Cardiopulmonary Physiology

in

Anes-

W.

and Noninvasive AlternaSaunders Co., 1990. Murray, J. R, and Nadel, J. A.: Textbook of Respiratory Medicine. Philadelphia, W. B. Saunders Co., 1994. Nikinmaa, M.: Membrane transport and control of hemoglobin-oxygen Malley,

J.:

Clinical Blood Gases: Application

W.

B.

affinity in nucleated erythrocytes. Physiol. Rev., 72:301, 1992. S.,

and

Priestley,

J.

G:

Respiration.

New

Haven, Yale Univer-

sity Press, 1935.

A.

M.

thesiology. Hightstown, NJ, McGraw-Hill, 1994. tives. Philadelphia,

Gonzalez, N. C, and Fedde, M. R.: Oxygen Transfer from Atmosphere to Tissues. New York, Plenum Publishing Corp., 1988. Grippi, M. A.: Pulmonary Pathophysiology. Philadelphia, J. B. Lippincott

Leff,

Levitzky,

and Schumacker, P. T: Respiratory Physiology: Basics and ApW. B. Saunders Co., 1993.

plications. Philadelphia,

Pulmonary Pathophysiology: The Essentials. Baltimore, B.: J. Williams & Wilkins Co., 1992. West, J. B.: Respiratory Physiology The Essentials. Baltimore, Williams & Wilkins Co., 1994. West,

—

336

VII

Respiration

QUESTIONS 1.

2.

3.

Explain the concept of partial pressures of individual gases when they exist in a mixture. Explain why net diffusion of a gas always occurs in the direction from high pressure to low pressure regardless of whether the gas is in the gaseous state, is dissolved in tissues, or is dissolved in the blood. Explain why the vapor pressure of water in the alveoli remains very nearly constant under normal conditions at a level of 47

4.

5.

6.

How much

oli.

rise

At

normal oxygen

maximum

when

What

12.

the cells back to the alveoli. Draw the oxygen-hemoglobin dissociation curve, giving exact values for the scales on the abscissa and the

13.

What minimum

is

ordinate.

how high can this breathing normal air at sea

14.

15. is

the normal carbon dioxide concentration in

the alveoli,

and what are the

factors that can increase

or decrease this? 8. 9.

Describe the anatomy of the respiratory unit. List and discuss the factors that determine how rapidly a gas will pass through the respiratory membrane.

intracellular concentration of oxygen required to allow maximum rates of the oxygenrelated metabolic reactions in the cell? When the oxyis

partial pressure in the alve-

rate of breathing,

the person

Give approximate values for diffusion of oxygen and carbon dioxide at rest and during exercise. Give the approximate quantitative values for Po2 in the alveoli, in the systemic arterial blood, in the interstitial fluid, and in the cells. Give the approximate quantitative values for Pco 2 in reverse order, from

diffuse

level? 7.

11.

mm Hg.

more rapidly does carbon dioxide

through tissues than does oxygen? At normal respiration, approximately how long must a person breathe before half of the alveolar air is exchanged with atmospheric air? State the

10.

16.

gen Po 2 is above this minimum level, what determines the rate of oxygen utilization? Explain why minute quantities of carbon monoxide can prevent the transport of oxygen to the tissues. List the chemical forms in which carbon dioxide is transported from the cells to the lungs, and give the approximate proportions of the carbon dioxide transported in each form. Define the respiratory exchange ratio, and give its value when a person is metabolizing (1) carbohydrates and (2) fats.

Regulation of Respiration; and Respiratory Insufficiency

The nervous system normally adjusts the

rate of

alveolar ventilation almost exactly to the demands of the body so that the arterial blood oxygen pressure (Po 2 ) and carbon dioxide pressure (Pco 2 ) are

hardly altered even during moderate to strenuous exercise and most other types of stress. The present chapter describes the operation of this neurogenic system for regulation of respiration and also discusses the different causes of respiratory insufficiency

THE RESPIRATORY CENTER

The "respiratory center"

is

composed

of several

groups of neurons located bilaterally in the medulla oblongata and pons, as illustrated in Figure 29-1. It is divided into three major collections of neurons: (1) a dorsal respiratory group, located in the dorsal portion of the medulla, which mainly causes inspiration, (2) a ventral respirator]/ group, located in the ventrolateral part of the medulla, which can cause either expiration or inspiration, depending upon which neurons in the group are stimulated, and (3) the pneumotaxic center, located dorsally in the superior portion of the pons, which helps control both the rate and pattern of breathing. The dorsal respiratory group of neurons plays the fundamental role in the control of respiration. Therefore, let us discuss its function first.

The Dorsal Respiratory Group of Neurons Its

Inspiratory

and Rhythmical

—

Functions

The dorsal respiratory group of neurons extends most of the length of the medulla. Either all or most of its neurons are located within the nucleus of the tractus solitarius, though additional neurons in the adjacent reticular substance of the medulla probably also play important roles in respiratory control. The nucleus of the tractus solitarius is also the sensory termination of both the vagal and glossopharyngeal nerves, which transmit sensory sig-

from the peripheral chemoreceptors, the baroreceptors, and several difnals into the respiratory center

ferent types of receptors in the lung. All the signals

from these peripheral areas help in the control of respiration, as we discuss in subsequent sections of this chapter.

Rhythmical Inspiratory Discharges from the Dorsal Respiratory Group. The basic rhythm of respiration is generated mainly in the dorsal respi-

Even when all the periphnerves entering the medulla are sectioned and the brain stem is transected both above and below the medulla, this group of neurons still emits repetitive bursts of inspiratory action potentials. Unfortunately, though, the basic cause of these repetitive discharges is still unknown. In primitive animals, neural networks have been found in which activity of one set of neurons excites a second set, which in turn inhibits the first. Then after a period of time the mechanism repeats itself, continuing throughout the life of the animal. Therefore, most respiraratory group of neurons. eral

tory physiologists believe that

work

some

similar net-

neurons located entirely within the medulla, probably involving not only the dorsal respiratory group but adjacent areas of the medulla of

as well,

is

responsible for the basic rhythm of respi-

ration.

Inspiratory "Ramp" Signal. The nervous is transmitted to the primary inspiratory muscles such as the diaphragm is not an instantaneous burst of action potentials. Instead, in normal respiration, it begins very weakly at first and increases steadily in a ramp fashion for about 2 seconds. It abruptly ceases for approximately the next 3 seconds, which turns off the excitation of the diaphragm and allows the elastic recoil of the chest wall and lungs to cause expiration. Then the inspiratory signal begins again for still another cycle, and again and again. Thus, the inspiratory signal is

The

signal that

The obvious advantage of this is that causes a steady increase in the volume of the lungs during inspiration, rather than inspiratory

a ramp signal. it

gasps.

The Pneumotaxic Center Limits the Duration of Inspiration

and Increases

the Respiratory Rate

The pneumotaxic center, located dorsally in the upper pons, transmits signals to the inspiratory

337

338

Respiration

the ventral group causes inspiration, whereas stimulation of others causes expiration. Therefore, these neurons contribute to both inspiration and expiration. However, they are especially important in providing the powerful expiratory signals to the in

Pneumotaxic center

Fourth ventricle 9

Apneustic center

Dorsal

abdominal muscles during expiration. Thus, this area operates more or less as an overdrive mechanism when high levels of pulmonary ventilation are required.

respiratory

Ventral

group

respiratory

(Inspiration)

(Expiration

group and Inspiration)

Lung

Inflation Signals Limit Inspiration

—

The Hering-Breuer Inflation Reflex

Vagus and In addition to the neural

glossopharyngeal Respiratory

from the lungs also help control

pathways Figure

mechanisms operating

entirely within the brain stem, reflex nerve signals

29-1 Organization of the respiratory center.

The primary effect of these is to control the "switch-off" point of the inspiratory ramp, thus controlling the duration of the filling phase of the lung cycle. When the pneumotaxic signals are strong, inspiration might last for as little as 0.5 second, thus filling the lungs only slightly; but when the pneumotaxic signals are weak, inspiration might continue for as long as 5 or more seconds, thus filling the lungs with a great excess of air. Therefore, the function of the pneumotaxic center is primarily to limit inspiration. However, this has a secondary effect of increasing the rate of breathing because limitation of inspiration also shortens expiration and the entire period of respiration. Thus, a strong pneumotaxic signal can increase the rate of breathing up to 30 to 40 breaths per area.

minute.

CHEMICAL CONTROL OF RESPIRATION The ultimate goal of respiration is to maintain proper concentrations of oxygen, carbon dioxide, in the tissues.

therefore, that respiratory activity Both Inspiration and Expiration

Located about 5 millimeters anterior and lateral group of neurons is the ventral respiratory group of neurons. The function of this neuronal group differs from that of the dorsal respiratory group in several important ways: to the dorsal respiratory

The neurons

of the ventral respiratory

group

during normal quiet normal quiet breathing is caused only by repetitive inspiratory signals from the dorsal respiratory group transmitted mainly to the diaphragm, and expiration results from elastic recoil of the lungs and thoracic cage.

remain almost

totally inactive

Therefore,

respiration.

It

is

fortunate,

highly respon-

Excess carbon dioxide or hydrogen ions mainly stimulate the respiratory center itself, causing greatly increased strength of both the inspiratory and expiratory signals to the respiratory muscles. Oxygen, on the other hand, does not have a significant direct effect on the respiratory center of the brain in controlling respiration. Instead, it acts almost entirely on peripheral chemoreceptors located in the carotid and aortic bodies, and these in turn transmit appropriate nervous signals to the respiratory center for control of respiration. Let us discuss first the stimulation of the respiratory center itself by carbon dioxide and hydrogen ions.

When

the respiratory drive for increased pulmonary ventilation becomes greater than normal, respiratory signals then spill over into the ventral respiratory neurons from the basic oscillating 2.

is

sive to changes in each of these.

The Ventral Respiratory Group of Neurons Functions

1.

Most

center.

and hydrogen ions

in

respiration.

important, located in the walls of the bronchi and bronchioles throughout the lungs are stretch receptors that transmit signals through the vagi into the dorsal respiratory group of neurons when the lungs become overstretched. These signals affect inspiration in much the same way as signals from the pneumotaxic center; that is, when the lungs become overly inflated, the stretch receptors activate an appropriate feedback response that "switches off" the inspiratory ramp and thus stops further inspiration. This is called the Hering-Breuer inflation reflex. This reflex also increases the rate of respiration, the same as is true for signals from the pneumotaxic

Direct Chemical Control of Respiratory Center

Activity by Carbon Dioxide and

Hydrogen Ions

mechanism sequence, contribute 3.

of the dorsal respiratory area. As a conthe ventral respiratory area then does

share to the respiratory drive as well. Electrical stimulation of some of the neurons its

The Chemosensitive Area of the Respiratory Center. We have discussed mainly three different areas of the respiratory center: the dorsal respira-

—

i

29

^

Regulation of Respiration; and Respiratory Insufficiency

339

tory group of neurons, the ventral respiratory group, and the pneumotaxic center. However, it is believed that none of these are affected directly by changes in blood carbon dioxide concentration of hydrogen ion concentration. Instead, an additional neuronal area, a very sensitive chemosensitive area, illustrated in Figure 29-2, is located bilaterally and lies only one fifth millimeter beneath the ventral surface of the medulla. This area is highly sensitive to changes in either blood Pco 2 or hydrogen ion concentration, and it in turn excites the other portions of the respiratory center.

Response of the Chemosensitive Neurons to

Hydrogen Ions

—

The Primary Stimulus

The sensor neurons in the chemosensitive area are especially excited by hydrogen ions; in fact, it is believed that hydrogen ions are perhaps the only important direct stimulus for these neurons. Unfortunately, though, hydrogen ions do not easily cross the blood-brain barrier nor the blood -cerebrospinal fluid barrier. For this reason, changes in hydrogen ion concentration in the blood actually have considerably less effect in stimulating the chemosensitive neurons than do changes in carbon dioxide, even though carbon dioxide is believed to stimulate these neurons secondarily by changing the hydrogen ion concentration, as is explained next.

— —40

—-i

1

20

30

i

60

50

Pco 2 (mm

70 Hg)

80

90

7.1

7.0

6.9

100

i

7.6

7.5

7.4

7.3

7.2

pH Figure

rial

29 -3 Effects of increased arterial Pco, and decreased arte(increased hydrogen ion concentration) on the rate of

pH

alveolar ventilation. Effect

of Blood Carbon Dioxide on

Stimulating the Chemosensitive Area

Though carbon dioxide has very

little

direct ef-

neurons in the chemosensitive area, it does have a very potent indirect effect. It does this by reacting with the water of the tissues to form carbonic acid. This in turn dissociates fect in stimulating the

into hydrogen and bicarbonate ions; the hydrogen ions then have a potent direct stimulatory effect. These reactions are illustrated in Figure 29-2.

Why is it that blood carbon dioxide has a more potent effect in stimulating the chemosensitive neurons than do blood hydrogen ions? The answer is that the blood-brain barrier and the blood-cerebrospinal fluid barrier are both almost completely impermeable to hydrogen ions, whereas carbon dioxide passes through both these barriers almost as if they did not exist. Consequently, whenever the blood Pco 2 increases, so also does the Pco 2 of both

Inspiratory

-j*-,

+

HCCK

area

Figure

29-2 Stimulation of the inspiratory area by the chemosensi-

located bilaterally in the medulla, lying only a fraction of a millimeter beneath the ventral medullary surface. Note also that hydrogen ions stimulate the chemosensitive area, whereas it tive area

carbon dioxide drogen ions.

is

in the fluid that gives rise to

most of the hy-

the interstitial fluid of the medulla and of the cerebrospinal fluid. In both of these fluids the carbon dioxide immediately reacts with the water to form hydrogen ions. Thus, paradoxically, more hydrogen ions are released into the respiratory chemosensitive sensory area when the blood carbon dioxide concentration increases than when the blood hydrogen ion concentration increases. For this reason, respiratory center activity is affected considerably more by changes in blood carbon dioxide than by changes in blood hydrogen ions. This is illustrated in Figure 29-3, which shows quantitatively the ap-

proximate effects of blood Pco2 and blood pH (which is an inverse logarithmic measure of hydrogen ion concentration) on alveolar ventilation. Note the marked increase in ventilation caused by the in-

340

VII

Respiration

Pco 2 But note

crease in

.

fect of increased

also the

much

800-1

smaller ef-

hydrogen ion concentration

(that

decreased pH). note the very great change in alveolar ventilation in the normal blood Pco range between 2 35 and 60 Hg. This illustrates the tremendous effect that carbon dioxide changes have in controlis,

Finally,

mm

ling respiration.

i

THE PERIPHERAL CHEM0RECEPT0R SYSTEM

100

FOR CONTROL OF RESPIRATORY ACTIVITYROLE OF OXYGEN IN RESPIRATORY CONTROL In addition to control of respiratory activity by the respiratory center itself, still another mecha-

nism

is

1

300

Arterial Figure

29-5

body

of a cat. (Curve

r

1

200

400

500

Po 2 (mm Hg)

Po 2 on impulse rate from the carotid drawn from data from several sources, but

Effect of arterial

primarily from

Von

Euler.)

also available for controlling respiration.

This is the peripheral chemoreceptor system, illustrated in Figure 29-4. Special nervous chemical receptors, called chemoreceptors, are located in several areas outside the brain, and these are especially important for detecting changes in oxygen in the blood, although they respond to changes in carbon dioxide and hydrogen ion concentrations, too. The chemoreceptors in turn transmit nervous signals to the respiratory center in the brain to help regulate

supply through a minute artery directly from the adjacent arterial trunk. Furthermore, the blood flow through these bodies is extreme, 20 times the weight of the bodies themselves each minute. Therefore, the percentage removal of oxygen from the flowing blood is virtually zero. This means that the chemoreceptors are exposed at all times to arterial blood, not venous blood, and their Po s are arterial 2

respiratory activity. By far the largest

Stimulation of the Chemoreceptors by Decreased Arterial Oxygen. Changes in arterial oxygen concentration have no direct stimulatory effect on the respiratory center itself, but when the oxygen concentration in the arterial blood falls below normal, the chemoreceptors become strongly stimulated. This is illustrated in Figure 29-5, which

number

of chemoreceptors

is

located in the carotid bodies. However, a sizable number are in the aortic bodies, also illustrated in Figure 29-4. The carotid bodies are located bilaterally in the bifurcations of the

and

their afferent

common

carotid arteries,

nerve fibers pass through Her-

nerves to the glossopharyngeal nerves and thence to the dorsal respiratory area of the medulla. The aortic bodies are located along the arch of the aorta; their afferent nerve fibers pass through the vagi also to the dorsal respiratory area. Each of these chemoreceptor bodies receives a special blood ing's

Medulla

Glossopharyngeal nerve

Vagus nerve Carotid body

Po 2 s.

the effect of different levels of arterial Po 2 on the rate of nerve impulse transmission from a carotid body. Note that the impulse rate is particu-

shows

larly sensitive to changes in range between 60 and 30

Figure

29-4 Respiratory control by the carotid and aorHc bodies.

Po 2

in

Hg, the range

the in

which the arterial hemoglobin saturation with oxygen decreases rapidly. Effect of Carbon Dioxide and Hydrogen Ion Concentration on Chemoreceptor Activity. An increase in either carbon dioxide concentration or hydrogen ion concentration also excites the chemoreceptors and in this way indirectly increases respiratory activity.

However, the

direct effects of

both these factors in the respiratory center itself are so much more powerful than their effects mediated through the chemoreceptors (about seven times as powerful) that for most practical purposes these indirect effects through the chemoreceptors do not need to be considered.

Quantitative Effect of Aortic bodies

arterial

mm

Low

Arterial

Po 2

on Alveolar Ventilation

When a person breathes air that has too little oxygen, this obviously will decrease the blood Po 2 and excite the carotid and aortic chemoreceptors,

29

thereby increasing respiration. However, the effect usually is much less than one would expect, because the increased respiration will remove carbon dioxide from the lungs and thereby decrease both blood PCO ? and hydrogen ion concentration. These two changes then severely depress the respiratory center, as discussed earlier, so that the final effect of the chemoreceptors in increasing respiration in response to low Po 2 is mostly counteracted. Yet the effect of low arterial Po., on alveolar ventilation is far greater under some other conditions, two of which are (1) when arterial carbon dioxide and hydrogen ion concentrations remain normal despite increased respiration and (2) breathing of oxygen at low concentrations for many days, which allows time for adaptation of respiratory control

mechanisms.

REGULATION OF RESPIRATION

DURING EXERCISE In strenuous exercise, oxygen consumption and carbon dioxide formation can increase as much as 20-fold. Yet alveolar ventilation ordinarily increases

almost exactly in step with the increased level of metabolism, as illustrated by the relationship be-

tween oxygen consumption and ventilation ure 29-6. Therefore, the arterial all

remain almost

in Fig-

Po 2 Pco,, and pH ,

exactly normal.

In trying to analyze the factors that cause increased ventilation during exercise, one is tempted

immediately to ascribe ations in the

body

^

Regulation of Respiration; and Respiratory Insufficiency

341

This question has not been answered least

two

different effects

seem

to

fully, but at be predominantly

concerned: 1. The brain, on transmitting impulses to the contracting muscles, is believed to transmit collateral impulses into the brain stem to excite the respiratory center. This is analogous to the stimulatory effect of the higher centers of the brain on the vasomotor center of the brain stem during exercise, causing a rise in arterial pressure as well as an increase in ventilation. 2. During exercise, the body movements, especially of the limbs, are believed to increase pulmonary ventilation by exciting joint proprioceptors that then transmit excitatory impulses to the respiratory center. The reason for believing this is that even passive movements of the limbs often increase pulmonary ventilation severalfold. It is possible that still other factors are also important in increasing pulmonary ventilation during exercise. For instance, some experiments even suggest that hypoxia developing in the muscles during exercise elicits afferent nerve signals to the respiratory center to excite respiration. However, because a large share of the total increase in ventilation begins immediately upon the initiation of exercise before the blood chemicals have time to change, most of the increase in respiration probably results from the two neurogenic factors noted above, namely,

impulses from the higher centers of and proprioceptive stimulatory reflexes.

stimulator}]

brain

the

chemical alterduring exercise, including

this to the

fluids

OTHER FACTORS THAT

hydrogen and decrease of oxygen. However, this is not valid, for measurements of arterial Pco pH, and 2 Po2 show that none of these usually changes signifincrease of carbon dioxide, increase of ions,

AFFECT RESPIRATION

,

Anesthesia

icantly.

Therefore, the question must be asked: What is it during exercise that causes the intense ventilation?

120i

Perhaps the most prevalent cause of respiratory depression and respiratory arrest is overdosage with anesthetics or narcotics. For instance, sodium pentobarbital is a poor anesthetic because it depresses the respiratory center considerably more than many other anesthetics such as halothane. At one time, morphine was used as an anesthetic, but this drug is now used only as an adjunct to anesthetics because it greatly depresses the respiratory center while having much less ability to anesthetize the cerebral cortex.

Periodic Breathing

An

abnormality

of

breathing occurs in a 1.0

2.0 2

29-6

3.0

Consumption

4.0

(L min)

on oxygen consumption and venGray: Pulmonary Ventilation and Its Physiological Regulation. Springfield, 111., Charles C Thomas, Figure

Effect of exercise

tilatory rate.

1950.)

(From

J.

S.

conditions.

respiration

number

called

periodic

of different disease

The person breathes deeply for a short and then breathes slightly or not at

interval of time

an additional interval, the cycle repeating itover and over again. The most common type of periodic breathing, Cheyne-Stokes breathing, is characterized by slowly

all for

self

342

VII

Respiration

respiration, occurring over and over again approximately every 40 to 60 seconds. Basic Mechanism of Cheyne-Stokes Breathing. The basic cause of Cheyne-Stokes breathing is the following: When a person overbreathes, thus blowing off too much carbon dioxide from the pulmonary blood and also increasing the blood oxygen, it still takes several seconds before the changed pulmonary blood can be transported to the brain and inhibit the excess ventilation. By this time, the person has already overventilated for an

waxing and waning

extra

change in ventilation than normally. This type of Cheyne-Stokes breathing occurs mainly in patients with brain damage. The brain damage often turns

few seconds; then an increase in blood carbon dioxide turns it back on with great force. Cheyne-Stokes breathing of this type is frequently a prelude to death. off the respiratory drive entirely for a

PHYSIOLOGY OF SPECIFIC PULMONARY ABNORMALITIES

few seconds. Therefore, when the respiratory does eventually respond, it becomes de-

Chronic Pulmonary

center

pressed too

much because

and now the opposite cycle begins. That is, carbon dioxide builds up and oxygen decreases in the pulmonary blood. Then again it is a few seconds before the brain can respond to the new changes. However, when the brain does respond, the person breathes hard once again. The cycle repeats itself again and again. Thus, the basic cause of Cheyne-Stokes breathing is present in everyone. However, this mechanism is highly "damped." That is, the fluids of the blood and of the respiratory center control areas have large amounts of stored and chemically bound carbon dioxide and oxygen. Therefore, normally the lungs cannot build up enough extra carbon dioxide or depress the oxygen sufficiently in a few seconds to cause the next cycle of the periodic breathing. Yet under two separate conditions the damping factors are overridden, and Cheyne-Stokes breathing does occur:

The term pulmonary emphysema

chioles. 2.

tory

The

infection,

edema

excess mucus, and inflamma-

of the bronchiolar epithelium together

cause chronic obstruction of ways.

many

of the smaller air-

makes it espethus causing entrapment of air in the alveoli and overstretching them. This, combined with the lung infection, causes marked destruction of many of the alveolar walls. Therefore, 3.

The obstruction

of the airways

cially difficult to expire,

the final picture of the

emphysematous lung

The physiological

effects of chronic

emphysema

1. The bronchiolar obstruction greatly increases airway resistance and results in greatly increased work of breathing.

2.

The marked

loss of

lung parenchyma greatly

decreases the diffusing capacity of the lung,

Confluent alveoli

cells

Pneumonia Figure

29-7 Pulmonary changes

that

are the following:

Edema

Normal

is

illustrated to the far right in Figure 29-7.

second cause of Cheyne-Stokes breathing is increased negative feedback gain in the respiratory control areas. This means that a change in blood carbon dioxide or oxygen now causes far greater

and blood

means

1. Chronic infection caused by inhaling smoke or other substances that irritate the bronchi and bron-

A

Fluid

literally

excess air in the lungs. However, when one speaks of chronic pulmonary emphysema, a complex obstructive and destructive process of the lungs generally is meant, and in most instances it is a consequence of long-term smoking. It results from three major pathophysiological events in the lungs:

1. When there is a long delay in the transport of the blood from the lungs to the brain, as occurs in heart failure, the gas changes in the blood will continue for many more seconds than usual; then the periodic respiratory drive becomes extreme, and Cheyne-Stokes breathing begins.

2.

Emphysema

of the overventilation,

in

pneumonia and emphysema.

Emphysema

which

re-

'

29

duces the ability of the lungs to oxygenate the blood and to excrete carbon dioxide. 3. Loss of large portions of the lung parenchyma

number

pulmonary capillaries through which blood can pass. As a result, the pulmonary vascular resistance increases markedly causing pulmonary hypertension. This in turn overloads the right side of the heart and frequently also decreases the

of

causes right-heart failure.

Chronic emphysema usually progresses slowly over many years. The person develops hypoxia and hypercapnia because of hypoventilation of many alveoli and because of loss of lung parenchyma.

The net

result of all of these effects is severe, prolonged, devastating air hunger that can last for years until the hypoxia and hypercapnia cause death a very high penalty to pay for smoking.

in

two major pulmonary abnormalities:

The term pneumonia includes any inflammatory condition of the lung in which some or all of the with fluid and blood cells, as shown in the center panel of Figure 29-7. A common type of pneumonia is bacterial pneumonia, caused most frequently by pneumococci. This disease begins with infection in the alveoli; the pulmonary membrane becomes inflamed and highly porous so that fluid and even red and white blood cells pass out of the blood into the alveoli. Thus, alveoli

are filled

become progressively filled and the infection spreads by extension of bacteria from alveolus to alveolus. Eventually, large areas of the lungs, sometimes whole lobes or even a whole lung, become "consolidated," which means that they are filled with fluid and cellular debris. In pneumonia the pulmonary function of the the

infected

alveoli

with fluid and

cells,

lungs changes in different stages of the disease. In the early stages, the pneumonia process might well be localized to only one lung; alveolar ventilation is often seriously reduced even though blood flow through the lung continues normally This results

Pulmonary

60%

O?

membrane and (2) no aeration at all of all the blood flowing through the consolidated lung. Both these effects cause reduced lung diffusing ca-

ratory

which results in hypoxemia (low blood oxygen) and hypercapnia (high blood carbon dioxide). Figure 29-8 illustrates the effect of the decreased ventilation in pneumonia, showing that the blood passing through the aerated lung becomes 97 per cent saturated, whereas that passing through the unaerated lung remains only 60 per cent saturated, causing the mean saturation of the aortic blood to be about 78 per cent, which is far below normal. pacity,

Left

pulmonary

Right pulmonary

vein

97%

vein

60%

saturated

= 97% y2 = 60%

Aorta: Blood Vs

Mean Figure

tion.

29-8

Effect of

pneumonia on

Atelectasis

Atelectasis means collapse of the alveoli. It can occur in a localized area of a lung, in an entire lobe, or in an entire lung. Its most common causes are (1) obstruction of the airway or (2) lack of surfactant in the fluids lining the alveoli.

Airway Obstruction. The airway obstruction type of atelectasis usually results from (1) blockage of many small bronchi with mucus or (2) obstrucbronchus by either a large mucous plug or some solid object such as cancer. The air entrapped beyond the block is absorbed within minutes to hours by the blood flowing in the pulmonary capillaries. If the lung tissue is pliable enough, this will lead simply to collapse of the alveoli. However, if the lung tissue cannot collapse, absorption of air from the alveoli creates tremendously negative pressures within the alveoli and tion of a major

pulls fluid out of the

arterial

pulmonary

interstitium into

the alveoli, thus causing the alveoli to fill pletely with edema fluid. This almost always

comis

the

occurs when an entire lung becomes atelectatic, a condition called massive collapse of the effect that

lung.

Lack of Surfactant. The secretion and function of surfactant in the alveoli was discussed in Chapter 27. It was pointed out that the substance surfactant is secreted by special alveolar epithelial cells into

However, in a number of different conditions, such as in hyaline membrane disease (also called respiratory distress syndrome), which often occurs in newborn premature babies, the quantity of surfactant secreted by the alveoli is greatly depressed. As a result, the surface tension of the alveolar fluid is increased so much that it causes a serious tendency for the lungs of these babies to collapse or to become filled with fluid. Many of these infants die of suffocation as increasing portions of the lungs become atelectatic or filled with alveolar collapse.

Pneumonia

saturated

reduc-

the fluids that line the alveoli. This substance decreases the surface tension in the alveoli twofold to tenfold, which plays a major role in preventing

blood

arterial

saturated with

(1)

343

tion in the total available surface area of the respi-

—

Pneumonia

^

Regulation of Respiration; and Respiratory Insufficiency

=

78%

blood oxygen satura-

fluid.

344

VII

Respiration

in approximately 3 per cent of all persons contract tuberculosis, if untreated, the wallingoff process fails, and tubercle bacilli spread throughout the lungs, often causing extreme de-

ever,

Asthma

who Asthma

characterized by spastic contraction of in the bronchioles, which causes extremely difficult breathing. It occurs in 3 to 5 per cent of all persons at some time in life. The usual cause is hypersensitivity of the bronchioles to foreign substances in the air, such as plant pollens or the

is

smooth muscle

irritants in

The

smog.

allergic reaction against plant pollens is be-

lieved to occur in the following way:

The

typically

person has a tendency to form abnormally large amounts of IgE antibodies, and these antibodies cause allergic reactions when they react with their complementary antigens, as was explained in Chapter 25. In asthma, these antibodies mainly attach to mast cells that lie in the lung interstitium in close association with the bronchioles and small bronchi. When the person breathes in pollen to which he or she is sensitive (that is, to which the person has developed IgE antibodies), the pollen reacts with the mast cell-attached antibodies and allergic

subare histamine, sloiv-reacting substance of anaphylaxis (which is a mixture of leukotrienes), eosinophilic chemotactic factor, and

causes these stances.

cells to release several different

Among them

bradykinin.

The combined

effects of all these factors,

especially of the slow-reacting substance of ana-

(SRS-A), are to produce (1) localized edema in the walls of the small bronchioles as well as secretion of thick mucus into the bronchiolar lumens and (2) spasm of the bronchiolar smooth muscle. Obviously, therefore, the airway resistance increases greatly. In asthma, the bronchiolar diameter becomes more reduced during expiration than during inspiration because the increased intrapulmonary pressure during expiratory effort compresses the outsides of the bronchioles. Because the bronchioles are already partially occluded, further occlusion resulting from the external pressure creates especially severe obstruction during expiration. Therefore, the asthmatic person usually can inspire quite adequately but has great difficulty expiring, and clini-

phylaxis

measurements show

reduced maximal expiratory rate. Also, this results in dyspnea, or "air hunger," which is discussed later in the chapcal

struction of lung tissue with formation of large abscess cavities. Thus, tuberculosis in

capacity,

and (2) reduced and increased

surface area

total

respiratory

membrane

thickness of the respiratory

membrane, these causing progressively diminished

pulmonary diffusing

capacity.

Hypoxia and Oxygen Therapy Obviously, almost any of the conditions discussed in the past few sections of this chapter can cause serious degrees of cellular hypoxia. In some of these, oxygen therapy is of great value; in others it is of moderate value; in still others it is of almost no value. Therefore, it is important to classify the different types of hypoxia; then we can readily discuss the physiological principles of therapy. The following is a descriptive classification of different causes of hypoxia: 1.

Inadequate oxygenation of the lungs because of extrinsic reasons a. Deficiency of oxygen in atmosphere b. Hypoventilation (neuromuscular disorders)

2.

Pulmonary disease a.

Hypoventilation due to increased airway resistance or decreased pulmonary compliance

b.

Uneven

alveolar ventilation

Diminished respiratory membrane diffusion Inadequate oxygen transport by the blood to the c.

3.

tissues a.

Anemia

b.

General circulatory deficiency

c.

a greatly

ter.

late stages

its

causes many areas of fibrosis throughout the lungs and reduces the total amount of functional lung tissue. These effects cause (1) increased "work" on the part of the respiratory muscles to cause pulmonary ventilation and reduced vital capacity and breathing

or abnormal hemoglobin

Localized

circulatory

deficiency

(peripheral,

cerebral, coronary vessels) d. 4.

Tissue

edema

Inadequate tissue capability of using oxygen a. Poisoning of cellular enzymes b. Diminished cellular metabolic capacity because of toxicity, vitamin deficiency, or other factors.

Tuberculosis

In tuberculosis, the tubercle bacilli cause a peculiar tissue reaction in the lungs, including (1) invasion of the infected region by macrophages and (2)

walling off of the tubercular lesion by fibrous tissue to form the so-called "tubercle." This walling-off process helps limit further transmission of the tubercle bacilli in the lungs and therefore is part of the protective process against the infection. How-

This classification of the different types of hypoxia is mainly self-evident from the discussions earlier in the chapter. Only one of the types of hypoxia in the classification needs further elaboration; this is the hypoxia caused by inadequate capability of the cells to use oxygen. Inadequate Tissue Capability of Using Oxygen. The classic cause of inability of the tissues to use

oxygen

is

cyanide poisoning, in

which the action of

29

300 H

cytochrome oxidase is completely blocked by the cyanide to such an extent that the tissues simply cannot utilize the oxygen even though plenty is

—

I

some

system can special example oc-

of other elements in the tissue oxidative

A

Q


Figure

cles.

of

200

CD

lead to this type of hypoxia. curs in the disease beriberi, in which several important steps in the tissue utilization of oxygen and the formation of carbon dioxide are compromised because of vitamin B deficiency. Effects of Hypoxia on the Body. Hypoxia, if severe enough, can cause death of the cells, but in less severe degrees it results principally in (1) depressed mental activity, sometimes culminating in coma, and (2) reduced work capacity of the mus-

patient's

Alveolar Pc^ with "tent" therapy

E^

Q O _i

enzymes or

oxidative

345

E

available.

Also, deficiencies of

^

Regulation of Respiration; and Respiratory Insufficiency

valuable. For instance:

less

oxygen to the tissues are deficient. Even so, when one breathes pure oxygen, a small amount of extra oxygen, between 7 and 30 per cent, can be transported in the dissolved state in the blood even though the amount transported by the hemoglobin hardly altered. This small amount of extra oxy-

is

gen may be the difference between

life and death. In the different types of hypoxia caused by inadequate tissue use of oxygen, there is abnormality neither of oxygen pickup by the lungs nor of transport

metabolic enzyme simply incapable of utilizing the oxygen that is delivered. Therefore, it is doubtful that oxygen therapy is of any measurable benefit. to the tissues. Instead, the tissue

oxygen therapy can obviously completely correct the depressed oxygen In atmospheric hypoxia,

level in the inspired gases and, therefore, provide

system

is

100 per cent effective therapy. In hypoventilation hypoxia, a person breathing 100

per cent oxygen can

move

five times as

much

oxy-

gen into the alveoli with each breath as when breathing normal air. Therefore, here again oxygen therapy can be extremely beneficial. (However, this provides no benefit for the excess blood C0 2 also caused by the hypoventilation.) In hypoxia caused by impaired alveolar membrane diffusion, essentially the

same

result occurs as in hy-

poventilation hypoxia, for oxygen therapy can increase the Po 2 in the lungs from a normal value of about 100 Hg to as high as 600 Hg. This raises the oxygen diffusion gradient between the alveoli and the blood from a normal value of 60 Hg to as high as 560 Hg, or an increase of more than 800 per cent. This highly beneficial effect of oxygen therapy in diffusion hypoxia is illustrated in Figure 29-9, which shows that the pulmonary blood in this patient with pulmonary edema picks up oxygen four times as rapidly as it would with no therapy. In hypoxia caused by anemia, abnormal hemoglobin

mm

mm

mm

mm

Dyspnea E)yspnea means mental anguish associated with inability to ventilate

for

air.

enough

A common synonym

to satisfy the is "air

demand

hunger."

At least three different factors often enter into the development of the sensation of dyspnea. These are abnormality of the respiratory gases in the body blood C0 2 (which will be discussed later) and, to a much lesser extent, hypoxia, (2) the amount of work that must be performed by the respiratory muscles to provide adequate ventilation, and (3) state of mind. A person becomes very dyspneic especially from excess buildup of carbon dioxide in body fluids. At times, however, the levels of both carbon dioxide and oxygen in the body fluids are completely normal, but to attain this normality of the respiratory gases, the person has to breathe forcefully. In these (1)

fluids, especially excess

instances

the

forceful

activity

of

the

respiratory

346

Respiration

Positive pressure

Negative pressure

valve

valve

Leather

diaphragm

Figure

29-10 A, The

resuscitator. B,

Tank

respi-

rator.

muscles frequently gives the person a sensation of very severe dyspnea. Finally, the person's respiratory functions may be completely normal, and still dyspnea may be experienced because of an abnormal state of mind. This is called neurogenic dyspnea or, sometimes, emotional dyspnea. For instance, almost anyone momentarily thinking about the act of breathing may suddenly start taking breaths a little more deeply than ordinarily because of a feeling of mild dyspnea. This feeling is greatly enhanced in persons who have a psychological fear of not being able to receive a sufficient quantity of air, such as on entering small or crowded rooms.

ARTIFICIAL RESPIRATION

The

Resuscitator.

available,

Many

and each has

its

types of resuscitators are

own

characteristic prin-

ciples of operation. Basically, the resuscitator illus-

29-10A consists of a supply of mechanism for applying intermittent positive pressure and, with some machines, negative pressure as well; and a mask that fits over trated in Figure

oxygen or

air;

a

the face of the patient or a connector for connecting the equipment to an endotracheal tube. This appa-

ratus forces air through the mask into the lungs of the patient during the positive pressure cycle and

then usually allows the air to flow passively out of the lungs during the remainder of the cycle. To prevent damage to the lungs from overexpan-

have adjustable positive pressure set at 12 to 15 cm water pressure for normal lungs but sometimes much higher for very noncompliant lungs. The Tank Respirator. Figure 29-1 OB illustrates sion, resuscitators

limits that are

commonly

the tank respirator with a patient's body inside the tank and his head protruding through a flexible but airtight collar. At the end of the tank opposite the patient's head is a motor-driven leather diaphragm that moves back and forth with sufficient excursion to raise and lower the pressure inside the tank. As the leather diaphragm moves inward, positive pressure develops around the body and causes expiration; as the leather diaphragm moves outward, negative pressure causes inspiration. Check valves on the respirator control the positive and negative pressures. Ordinarily these pressures are adjusted so that the negative pressure that causes inspiration falls to - 10 to -20 cm water and the positive pressure rises to to +5 cm water. Effect of the Resuscitator and the Tank Respirator on Venous Return. When air is forced into the lungs under positive pressure, or when the pressure around the patient's body is greatly reduced but with the trachea exposed to atmospheric pressure through the nose, as in the case of the tank respirator, the pressure inside the chest cavity is greater than the pressure everywhere else in the body. Therefore, the flow of blood into the chest

from the peripheral veins becomes impeded. As

a

use of excessive pressures with either the resuscitator or the tank respirator can reduce the cardiac output sometimes to lethal levels. result,

—

?

29

Regulation of Respiration; and Respiratory Insufficiency

^

347

REFERENCES Regulation of Respiration

Respiratory Insufficiency

Coleridge, H. M., and Coleridge, J. C. G.: Pulmonary reflexes: Neural mechanisms of pulmonary defense. Annu. Rev. Physiol., 56:69, 1994.

I.: Hypoxia, Metabolic Acidosis and the Circulation. New York, Oxford University Press, 1992. Brewis, R. A. L., and Geddes, D. M.: Respiratory Medicine. Philadelphia, W. B. Saunders Co., 1990. George, R. B., et al.: Chest Medicine. Baltimore, Williams & Wilkins Co.,

Dempsev,

J.

and Pack, A.

A.,

York, Marcel Dekker,

I.:

Regulation of Breathing, 2nd ed.

New

Inc., 1994.

Gonzalez, C, et al.: Carotid body chemoreceptors: From natural stimuli to sensory discharges. Physiol. Rev., 74:829, 1994. Guyton, A. C, et al.: Basic oscillating mechanism of Cheyne-Stokes breathing. Lahiri, S., et

Am. al.:

J.

to

Hypoxia.

New

York, Oxford

M. G, and

Cardiopulmonary Physiology in AnesMcGraw-Hill, 1994. Von Euler, C, and Langercrantz, H. (eds.): Central Nervous Control Hall, S. M.:

thesiology. Hightstown, NJ,

Mechanisms

in Breathing.

M.

A.:

Pulmonarv Pathophysiology. Philadelphia,

J.

B.

Lippincott

Murray,

J.

E,

and Nadel,

J.

A.:

Textbook of Respiratory Medicine.

Philadelphia, W. B. Saunders Co., 1994.

University Press, 1991. Levitzky,

1995.

Grippi,

Co., 1994.

Physiol., 187:395, 1956.

Response and Adaptation

Arieff, A.

New

York,

Pergamon

Press, 1980.

Saldana, M.

J.:

Pathology of Pulmonary Disease. Philadelphia,

pincott Co., 1994.

West, J. B.: Pulmonary Pathophysiology Williams & Wilkins Co., 1992.

— The

Essentials.

J.

B.

Lip-

Baltimore,

Witek, T. J., Jr., and Schachter, E. N.: Pharmacology and Therapeutics in Respiratory Care. Philadelphia, W. B. Saunders Co., 1994.

QUESTIONS 1.

Describe the anatomical

loci of the

various portions

2.

What

part of the respiratory center

is

14.

15.

depression? Explain periodic breathing, especially of the Cheyne-

responsible for

rhythm of respiration? does the pneumotaxic center control

the basic oscillating 3.

How

13.

respira-

tion? 4.

What

is

the function of the Hering-Breuer inflation

reflex? 5.

What

6.

neurons in the respiratory center? How powerful is each of the following

the role of the ventral respiratory group of

is

Stokes type. 16.

in directly

oxygen insuffiexcess carbon dioxide, excess hydrogen ion

controlling respiratory center activity: ciency,

concentration? 7. What is the relationship of the chemosensitive area of the respiratory center to the dorsal and ventral groups of respiratory neurons? 8. Approximately how much can excess carbon dioxide in the blood increase alveolar ventilation? 9. How much can excess hydrogen ion concentration in the blood increase ventilation? 10. Describe the relationship of the peripheral chemoreceptors to the respiratory center. 11. What is the importance of the peripheral chemoreceptors in the control of respiration by oxygen lack?

Why

is oxygen regulation of respiration of minimal importance under normal conditions but very important in pneumonia and at high altitudes? What special mechanisms cause powerful excitation of respiration during exercise? What conditions frequently cause respiratory center

12.

of the so-called respiratory center.

17.

Describe the relationship of pulmonan/ emphysema to smoking, its pathological effects on the lungs, and its devastating effects on pulmonary function. Describe the mechanism of atelectasis when there is either airway obstruction or lack of surfactant.

18.

Why

is it

often

much

easier to inspire air than to ex-

asthma and in emphysema? Define dyspnea and state its causes. How valuable is oxygen therapy in each of the following types of hypoxia: atmospheric hypoxia, hypovenpire air in

19.

20.

tilation hypoxia,

soning,

oxygen

hypoxia caused by carbon monoxide poiinadequate tissue use of

and hypoxia caused by

Aviation, Space,

and

Deep Sea Diving Physiology 30

Aviation, Space,

and Deep Sea Diving Physiology

Aviation, Space,

and Deep Sea Diving

Physiology

3()| _

As people have ascended altitudes in aviation, in

to higher and higher mountain climbing, and in

space vehicles, it has become progressively more important to understand the effects of altitude and low oxygen pressures on the human body. And as divers have gone deeper in the sea, it has become necessary to understand the effects of high gas pressures as well. The present chapter deals with these problems.

EFFECTS OF

Barometric

LOW OXYGEN PRESSURE ON THE BODY

Pressures

at

Different

Altitudes.

Table 30-1 gives the approximate barometric and oxygen pressures at different altitudes, showing that at sea level the barometric pressure is 760 Hg; Hg; and at 50,000 feet, at 10,000 feet, only 523 87 Hg. This decrease in barometric pressure is the basic cause of all the hypoxia problems in high altitude physiology, because as the barometric pressure decreases, the oxygen partial pressure decreases proportionately, remaining at all times slightly less than 21 per cent of the total barometric pressure at sea level approximately 159 Hg but at 50,000 feet only 18 Hg.

mm

mm

mm

—

mm

mm

Alveolar Po 2 at Different Elevations

Carbon Dioxide and Water Vapor Decrease the Alveolar Oxygen. Even at high altitudes carbon dioxide is continually excreted from the pulmonary blood into the alveoli. Also, water vaporizes into the inspired air from the respiratory surfaces. Therefore, these two gases dilute the oxygen in the

thus reducing the oxygen concentration. Water vapor pressure remains 47 Hg in the alveoli as long as the body temperature is normal, regardless of altitude. In the case of carbon dioxide, during exposure to very high altitudes the alveolar Pco 2 falls from the sea level value of 40 Hg to lower values. In the acclimatized person, who increases his ventilation about fivefold, the decrease alveoli,

mm

mm

is

to

about 7

mm

Hg, because of increased

respira-

tion.

Now let us see how the pressures of these two gases affect the alveolar oxygen. For instance, assume that the barometric pressure falls to 253 Hg, which is the measured value at the top of 29,028 foot Mount Everest. Forty-seven millimeters of mercury of this must be water vapor, leaving Hg for all the other gases. In the aconly 206 climatized person, 7 rnm of the 206 Hg must Hg. If be carbon dioxide, leaving only 199 there were no use of oxygen by the body, one fifth of this 199 Hg would be oxygen and four fifths would be nitrogen; or the Po 2 in the alveoli would Hg. However, some of this remaining be 40 alveolar oxygen would be absorbed into the blood, leaving about 35 Hg oxygen pressure in the alveoli. Therefore, at the summit of Mount Everest, only the best of acclimatized persons can barely survive when breathing air. But the effect is very different when the person is breathing pure oxygen, as we see in the following discussions. Alveolar Po 2 at Different Altitudes. The fifth column of Table 30-1 shows the Po 2 s in the alveoli at different altitudes when one is breathing air, for both the unacclimatized and the acclimatized perHg; at son. At sea level, the alveolar Po 2 is 104 20,000 feet altitude it falls to approximately 40 Hg in the unacclimatized person but only to 53 Hg in the acclimatized. The difference between these two is that the alveolar ventilation increases about five times as much in the acclimatized per-

mm

mm

mm mm

mm

mm

mm

mm

mm

mm son.

Hemoglobin with Oxygen at DifAltitudes. Figure 30-1 illustrates arterial oxygen saturation at different altitudes while Saturation of

ferent

Up to an even when

breathing air and while breathing oxygen. altitude of approximately 10,000 feet,

oxygen saturation remains at least as high as 90 per cent. However, above 10,000 feet the arterial oxygen saturation falls progressively, as illustrated by the left-hand

air is breathed, the arterial

curve of the figure, until 20,000 feet and still very

it

is

only 70 per cent at less at higher alti-

much

tudes.

351

352

and Deep Sea Diving Physiology

Aviation, Space,

TABLE 30-1 EFFECTS OF ACUTE EXPOSURE TO LOW ATMOSPHERIC PRESSURES ON ALVEOLAR GAS CONCENTRATIONS AND ON ARTERIAL OXYGEN SATURATION'

Breathing Air

Breathing Pure

Oxygen

Arterial

Po 2

Barometric

Altitude (ft)

Oxygen

in

Arterial

Pco 2

Po 2

in

in

Oxygen

Pressure

Air

Alveoli

Alveoli

Saturation

Alveoli

Alveoli

Saturation

(mm Hg)

(mm Hg)

(mm Hg)

(%)

(mm Hg)

(mm Hg)

(%)

760 523 349 226

40 (40) 36 (23) 24 (10) 24(7)

104 (104) 67 (77) 40 (53)

141

159 110 73 47 29

673 436 262 139 58

100 100 100 99 84

87

18

40 40 40 40 36 24

16

15

20,000 30,000 40,000 50,000

Numbers

Po 2

in

(mm Hg)

10,000

*

Pco 2

in

97 90 73 24

18 (30)

(97)

(92) (85) (38)

in parentheses are acclimatized values.

Effect of Breathing Pure

Oxygen on

Alveolar Po 2 at Different Altitudes

When

a person breathes pure oxygen instead of most of the space in the alveoli formerly occupied by nitrogen now becomes occupied by oxygen air,

instead. Therefore, at 30,000 feet the aviator could

have an alveolar Po 2 as high as 139 of the 18

mm

Hg when

mm Hg instead

breathing air (see Table

30-1).

The second curve of Figure 30-1 illustrates the oxygen saturation at different altitudes when one is breathing pure oxygen. Note that the arterial

breathing oxygen can ascend to far higher altitudes than one not breathing oxygen. For instance, the arterial saturation at 47,000 feet when one is breathing oxygen is about 50 per cent and is equivalent to the arterial oxygen saturation at 23,000 feet when one is breathing air. In addition, because an unacclimatized person may remain conscious until the arterial oxygen saturation falls acutely to 50 per cent, the ceiling for an aviator in an unpressurized airplane when breathing air is approximately 23,000 feet and when breathing pure oxygen about 47,000 feet, provided the oxygen-supplying equipment operates perfectly.

saturation remains above 90 per cent until the avia-

approximately 39,000 feet; then it rapidly to approximately 50 per cent at about 47,000 feet. tor ascends to

Acute Effects of Hypoxia

falls

Some

of the important acute effects of hypoxia,

at an altitude of approximately 12,000 are drowsiness, lassitude, mental and muscle fatigue, sometimes headache, occasionally nausea,

beginning The "Ceiling"

When Breathing

Breathing Oxygen

Comparing curves in

in

two

Air

and When

an Unpressurized Airplane

oxygen saturation Figure 30-1, one notes that an aviator the

arterial

feet,

and sometimes euphoria. All these progress to a stage of twitchings or convulsions above 18,000 feet and end, above 23,000 feet in the unacclimatized person, in coma. One of the most important effects of hypoxia is decreased mental proficiency, which decreases judgment, memory, and the performance of discrete motor movements. For instance, if an unacclimatized aviator stays at 15,000 feet without supplemental oxygen for 1 hour, mental proficiency ordinarily will have fallen to approximately 50 per cent of normal and after 18 hours at this level to approximately 20 per cent of normal.

Acclimatization to 10

20

40

30

Altitude (thousands of feet) Figure

30-1 Effect of high altitude on

when one

is

breathing air and

when

arterial

oxygen saturation

breathing pure oxygen.

Low Po 2

A person remaining at high altitudes for days, weeks, or years becomes more and more acclimatized to the low Po 2 so that it causes fewer delete,

rious effects

on the body and

also so that

it

be-

30

for the person to work harder without hypoxic effects or to ascend to still higher altitudes. The five principal means by which acclimatization comes about are (1) increase in pulmonary ventilation, (2) increased blood concentration of red blood cells, (3) increased diffusing capacity of the lungs, (4) increased vascularity of the tissues, and (5) increased ability of the cells to utilize oxygen despite the low Po 2 All these effects result from the low oxygen in the tissue fluids, for reasons discussed in the previous chapters on respiration.

comes possible

28

^

and Deep Sea Diving Physiology

Aviation, Space,

353

Mountain dwellers i

^---

26-

/

24-

22-

(T5.000

ft)

(Arterial values)

20-

O O 18J3

16-

1*

C 14OB

x

/"'(Venous values)

/

12-

.

,

10-

O

8-

>>

6-

c

4-

o

2-

Natural Acclimatization of Natives

0-

Living at High Altitudes

40

20 Pressure

Many

Andes and in the Himalayas above 13,000 feet one group in the Peruvian Andes actually lives at an altitude of 17,500 feet and works a mine at an altitude of 19,000 feet. Many of these natives are born at these altitudes and live there all their lives. In all aspects of acclimatization the natives are superior to even the best-acclimatized lowlanders, even though the lowlanders might also have lived at high altitudes natives in the

—

live at altitudes

for 10 or

more

years. This process of acclimatiza-

of

60

oxygen

100

80 in

blood (P02)

120 (

140

mm

H 9)

30-2 Oxygen-dissociation curves for blood of high-altitude and sea-level residents (lower curve), showing the respective arterial and venous Po,s and oxygen contents as recorded in their native surroundings. (From Oxygen-dissociation curves for bloods of high-altitude and sea-level residents. PAHO Scientific Publication No. 140, Life at High Altitudes, Figure

residents (top curve)

1966.)

especially, is greatly increased,

flight. At the beginning of flight, simple linear acceleration occurs; at the end of flight, deceleration; and every time the vehicle turns, centrifugal

size

acceleration.

tion of the natives begins in infancy.

The chest

size,

whereas the body somewhat decreased, giving a high ratio of ventilatory capacity to body mass. In addition, is

during

their hearts, particularly the right side of the heart,

a high pulmonary arterial pressure blood through a greatly expanded pul-

which provides to

pump

Centrifugal Acceleratory Forces

monary

capillary system, are considerably larger than the hearts of lowlanders. The delivery of oxygen by the blood to the tissues is also highly facilitated in these natives. For instance, Figure 30-2 shows the hemoglobin-oxygen dissociation curves for natives who live at sea level and for their counterparts who live at 15,000 feet. Note that the arterial oxygen Po in the na2 tives at high altitude is only 40 Hg, but because of the greater quantity of hemoglobin the quantity of oxygen in the arterial blood is actually greater than in the blood of the natives at the lower altitude. Note also that the venous Po, in the high altitude natives is only 15 Hg less than the venous Po 2 for the lowlanders, despite the very low

mm

mm

Po 2

indicating that oxygen transport to the tissues is exceedingly effective in the naturally acclimatized high-altitude natives. arterial

makes is

a turn, the force of cen-

determined by the following

relationship:

mv

l

/

which f is the centrifugal acceleratory force, m is mass of the object, v is the velocity of travel, and r is the radius of curvature of the turn. From

in

the

this

formula

creases,

obvious that as the velocity

is

it

of

force

the

centrifugal

acceleration

in-

in-

creases in proportion to the square of the velocity. It is also obvious that the force of acceleration is directly proportional to the

sharpness of the turn (the

IN

AVIATION

ON THE

AND SPACE PHYSIOLOGY

less the radius).

Measurement

When

a

Because of rapid changes in velocity and direc-

motion in airplanes and spacecraft, several types of acceleratory forces often affect the bodv

person

is

of Acceleratory

simply

Force

sitting in his or

— "G."

her seat,

the force with which he or she is pressing against the seat results from the pull of gravity, and it is equal to body weight. The intensity of this force is said to be

+

1

G

because

it

is

equal to the pull of

which the person presses against the seat becomes five times the normal weight during pull-out from a dive, the force acting gravitv.

tion of

airplane

,

EFFECTS OF ACCELERATORY FORCES

BODY

When an

trifugal acceleration

upon

If

the force with

the seat

is

+5

G.

354 If

Aviation, Space,

and Deep Sea Diving Physiology

the airplane goes through an outside loop so person is held down by his or her seat belt,

that the

negative G is applied to the body; and if the force with which the body is thrown against the belt is equal to the weight of the body the negative force is -1 G. Effects of Centrifugal Acceleratory Force (Positive G) on the Body. Effects on the Circulatory System. The most important effect of centrifugal acceleration is on the circulatory system, because blood is mobile and can be translocated by centrifugal forces.

When

the aviator is subjected to positive G, the centrifuged toward the lower part of the body. Thus, if the total acceleratory force is +5 G and the person is in an immobilized standing position, the hydrostatic pressure in the veins of the feet is five times normal, or approximately 450 Hg; even in the sitting position this pressure is nearly 300 Hg. As the pressure in the vessels of the lower part of the body increases, the vessels passively dilate, and a major proportion of the

blood

is

mm

Figure

30-3 Acceleratory

forces during the takeoff of a spacecraft.

mm

blood from the upper body is translocated into these lower vessels. Because the heart cannot pump unless blood returns to it, the greater the quantity of blood "pooled" in the lower body, the less be-

comes the cardiac output. Acceleration greater than 4 to 6 G in the sitting position causes "black-out" of vision within a few seconds and unconsiousness shortly thereafter. If this greater degree of acceleration is continued, the

person will die. Effects on the Vertebrae. Extremely high acceleratory forces for even a fraction of a second can fracture the vertebrae. The degree of positive acceleration that the average person can withstand in the sitting position before vertebral fracture occurs is

approximately 20 G. Protection of the Body Against Centrifugal Acceleratory Forces. Specific procedures and apparatus have been developed to protect aviators against the circulatory collapse that occurs during positive G. First,

if

the aviator tightens the abdominal

muscles to an extreme degree and leans forward to compress the abdomen, some of the pooling of blood in the large vessels of the abdomen can be prevented, thereby delaying the onset of blackout. Also, special "anti-G" suits have been devised to prevent pooling of blood in the lower abdomen

and

The simplest of these applies positive pressure to the legs and abdomen by inflating comlegs.

pression bags as the

G

increases.

tance except when the spacecraft goes into abnormal gyrations. On the other hand, blast-off acceleration and landing deceleration can be tremendous; both of these are types of linear acceleration. Figure 30-3 illustrates a typical profile of the acceleration during blast-off in a three-stage spacecraft, showing that the first-stage booster causes acceleration as high as 9 G and the second-stage booster, as high as 8 G. In the standing position the human body could not withstand this much acceleration, but in a semi-reclining position transverse to the axis of acceleration, this amount of acceleration can be withstood with ease despite the fact that the acceleratory forces continue for as long as several minutes at a time. Therefore, we see the reason for the reclining seats used by the astronauts. Problems also occur during deceleration when the spacecraft re-enters the atmosphere. A person traveling at Mach 1 (the speed of sound and of fast airplanes) can be safely decelerated in a distance of

approximately 0.12 mile, whereas a person traveling at a speed of Mach 100 (a speed possible in interplanetary space travel) would require a distance of about 10,000 miles for safe deceleration. The principal reason for this difference is that the total amount of energy that must be dispelled during deceleration locity,

is

proportional to the square of the ve-

which alone increases the required distance

about 10,000-fold. But, in addition to this, a human being can withstand far less deceleration if the period of deceleration lasts for a long time than for a short time. Therefore, deceleration must be accomplished much more slowly from the very high velocities than is necessary at lower velocities.

Effects of Linear Acceleratory

Forces on the

Body "Artificial

Acceleratory Forces in Space Travel. Unlike an airplane, a spacecraft cannot make rapid turns; therefore, centrifugal acceleration

is

of

little

impor-

in

the Sealed Spacecraft

is no atmosphere in outer space, an atmosphere and climate must be provided.

Since there artificial

Climate"

30

Most important of all, the oxygen concentration must remain high enough and the carbon dioxide concentration low enough to prevent suffocation. In some of the earlier space missions a capsule atmosphere containing pure oxygen at about 260 mm Hg

was used, but in the space shuttle gases approximating those in normal air are used. The presence of nitrogen in the mixture greatly diminpressure

and explosion. It also development of local patches of

ishes the likelihood of fire

protects against the

that often occur when breathing pure oxygen, because oxygen is absorbed very rapidly when small bronchi are temporarily blocked by atelectasis

mucous

Aviation, Space,

and Deep Sea Diving Physiology

^

355

strength and work capacity, (4) decrease in maxicardiac output, and (5) loss of calcium and phosphate from the bones as well as loss of bone mass. Most of these same effects also occur in persons lying in bed for an extended period of time. For this reason extensive exercise programs are car-

mum

ried out during prolonged Space Laboratory missions, and most of the aforementioned effects are

greatly reduced except for some of the bone loss. Therefore, it appears that with an appropriate exercise program the physiological effects of weightlessness will not be a serious problem even during

prolonged space voyages.

plugs.

For space travel lasting more than several months, it will be impractical to carry along an adequate oxygen supply and enough carbon dioxide absorbent. For this reason, "recycling techniques" have been proposed for use of the same oxygen over and over again. Some recycling processes depend on purely physical procedures, such as electrolysis of water to release oxygen, and so forth. Others depend on biological methods, such as use of algae with their large store of chlorophyll to generate foodstuffs and at the same time release oxygen from carbon dioxide by the process of photosynthesis. Unfortunately, a completely practical system for recycling is yet to be achieved.

PHYSIOLOGY OF DEEP SEA DIVING AND OTHER HYPERBARIC CONDITIONS

When human

beings descend beneath the sea, them increases tremendously. To keep the lungs from collapsing, air must be supplied also under high pressure. Unfortunately, this exposes the blood in the lungs to extremely high alveolar gas pressure, a condition called hyperbar ism. Beyond certain limits these high pressures can cause tremendous alterations in the body physthe pressure around

iology.

Relationship of Sea Depth to Pressure. A colof sea water 33 feet deep exerts the same pressure at its bottom as all the atmosphere above the earth. Therefore, a person 33 feet beneath the ocean surface is exposed to a pressure of 2 atmospheres, 1 atmosphere of pressure caused by the air above the water and the second atmosphere by the weight of the water itself. At 66 feet the pressure is 3 atmospheres, and so forth, in accord with the table in Figure 30-4.

umn Weightlessness

in

Space

A person in an orbiting satellite or in any nonpropelled spacecraft experiences weightlessness. That is, the person is not drawn toward the bottom, sides, or top of the spacecraft but simply floats inside its chambers. The cause of this is not failure of gravity to pull on the body, because gravity from any nearby heavenly body

is still active.

However,

by the centrifugal on both the spacecraft and the person at the same time, so that both are pulled with exactly the same acceleratory forces and in the same direction. For this reason, the person simply is not attracted toward any wall the gravity

is

exactly balanced

force of the orbital trajectory acting

of the spacecraft.

Physiological Problems of Weightlessness. Forproblems of weightlessness have not proved to be severe. Most of the problems that do occur appear to be related to three effects of the weightlessness: (1) motion sickness during the first few days of travel, (2) translocation of fluids within the body because of no gravity to cause hydrostatic pressures, and (3) diminished physical activity because no strength of muscle contraction is required to oppose the force tunately, the physiological

—

Effect of Depth on the Volume of Gases Boyle's Law. Another important effect of depth is the compression of gases to smaller and smaller volumes. The lower part of Figure 30-4 illustrates a bell jar at sea level containing 1 liter of air. At 33 feet beneath the sea where the pressure is 2 atmospheres, the volume has been compressed to only V2 liter, and at 8 atmospheres (233 feet) to Vs liter. Thus, the volume to which a given quantity of gas is compressed is inversely proportional to the pressure. This is the physical principle called Boyle's law, which is extremely important in diving because increased pressures can collapse air chambers of the diver's body, including the lungs, and often cause serious damage.

Effect of High Partial Pressures

of gravity.

The observed

of

are the following: (1)

decrease in red

prolonged stay in space decrease in blood volume, (2) mass, (3) decreased muscle

Gases on the Body

effects of

cell

The

three gases to

which

a diver breathing air

is

normally exposed are nitrogen, oxygen, and carbon

356

Aviation, Space,

Depth

Sea

Atmosphere

(feet)

level

quired of him. Beyond 250 feet (8.5 atmospheres pressure), the diver usually becomes almost useless as a result of nitrogen narcosis if he remains at these depths too long. Nitrogen narcosis has characteristics very similar to those of alcohol intoxication, and for this reason it has frequently been called "raptures of the depths." The mechanism of the narcotic effect is believed to be the same as that of essentially all the gas anesthetics. That is, nitrogen dissolves freely in the fats of the body, and it is presumed that it, like most other anesthetic gases, dissolves in the membranes of the neurons and, because of its physical

(s)

1

33 66 100 133 166 200 300 400 500

1

and Deep Sea Diving Physiology

2 3

4 5

6

7 10 13 16

liter

on altering electrical conductance of the membranes, reduces their excitability. Oxygen Toxicity at High Pressures. Breathing oxygen under very high partial pressure can also be detrimental to the central nervous system, sometimes causing epileptic convulsions followed by effect

1/2

liter

coma. Indeed, exposure to 3 atmospheres pressure of oxygen (Po 2 = 2280 Hg) will cause convulsions and coma in most persons after about 1 hour. These convulsions often occur without any warning, and they obviously are likely to be lethal to a

mm

1/4

liter

1/8

liter

Figure 30-4 Effect of sea depth on pressure volumes (bottom).

(top chart)

and on gas

diver submerged in the sea. The cause or causes of oxygen toxicity are yet unclear, but experiments have shown that excess oxygen in the tissues causes increasing concentrations of oxidizing free radicals such as superoxide (0 2 ~~), which can cause oxidative destruction of many essential elements of the cells, thereby damaging the metabolic systems of the cells. Carbon Dioxide Toxicity at Great Depths. If the diving gear is properly designed and also functions properly, the diver has no problem due to carbon dioxide toxicity, for depth alone does not increase the carbon dioxide partial pressure in the alveoli. This is true because depth does not increase the rate of carbon dioxide production in the body; and as long as the diver continues to breathe a normal tidal volume, he continues to expire the carbon dioxide as it is formed, maintaining his alveolar carbon dioxide partial pressure at a normal value of almost exactly 40

dioxide, and each of these at times can cause serious physiological effects at high pressures.

Nitrogen Narcosis at High Nitrogen Pressures. Approximately four fifths of the air is nitrogen. At sea level pressure the nitrogen has no known effect on bodily function, but at high pressures it can cause varying degrees of narcosis. When the diver remains beneath the sea for an hour or more and is breathing compressed air, the depth at which the first symptoms of mild narcosis appear is approximately 120 feet, at which level the diver begins to exhibit joviality

and

to lose

of his cares.

At

becomes drowsy. At 200 wanes considerably, and he becomes too clumsy to perform the work re-

150 to 200

feet,

the diver

to 250 feet, his strength

often

many

mm Hg.

Unfortunately, though, in certain types of diving gear, such as the diving helmet and the different types of rebreathing apparatuses, carbon dioxide can frequently build up in the dead space air of the apparatus and be rebreathed by the diver. Up to an alveolar carbon dioxide pressure (Pco 2 ) of about 80 Hg, two times that of normal alveoli, the diver survives this buildup, his minute respiratory vol-

mm

ume

increasing

up

to a

maximum

of 8-fold to 11-

compensate for the increased carbon dioxHg level the ide. However, beyond the 80 situation begins to become intolerable, and eventufold to

mm

ally the respiratory center begins to

be depressed,

rather than excited; the diver's respiration then begins to fail, rather than to compensate. In addition,

30

^

and Deep Sea Diving Physiology

Aviation, Space,

357

Pressure Outside Body

the diver develops severe respiratory acidosis, and varying degrees of lethargy, narcosis, and finally

sudden decompression After

Before

decompression

anesthesia ensue.

O2

=1044 N2 =3956

Totai=

mm

5000

Hg

2

N2

mm

Hg

=159mmHg =601

Totai=

760

mm

Hg

I

Decompression of the Diver After Exposure to High Pressures

When

a

person breathes

air

under high pressure

amount of nitrogen dissolved in the body fluids becomes great. The reason for this is the following: The blood flowing through the pulmonary capillaries becomes saturated with nitrogen to the same high pressure as that in the breathing mixture. Over several hours, enough nitrogen is carried to all the tissues of the body to for a long time, the

saturate the tissues also with dissolved nitrogen. Because nitrogen is not metabolized by the body, it

remains dissolved in the tissue fluids until the nitrogen pressure in the lungs decreases, at which time the nitrogen is then removed by the reverse respiratory process, but this removal takes hours to occur, which is the source of multiple problems called "decompression sickness." Volume of Nitrogen Dissolved in the Body Fluids at Different Sea Depths. At sea level almost 1 is dissolved in the entire body. A than half of this is dissolved in the water of the body and a little more than half in the fat of the body This is true despite the fact that fat constitutes only 15 per cent of the normal body because nitrogen is five times as soluble in fat as in

liter

of nitrogen

little less

water.

After the diver has become totally saturated with nitrogen, the approximate sea level volume of nitrogen dissolved in the body at the different depths is:

4065

mm

Hg

Gaseous pressure in H

the body fluids

0=47 mm Hg

ICO2 2 =40

02=60 N? =3918

30-5 Gaseous pressure both inside and outside the body, showing at left, saturation of the body to high gas pressure when breathing air at a total pressure of 5000 mm Hg, and at

Figure

intrabody pressure that bubble formation in the tissues when the body Hg. the normal pressure of 760

right, the great excess of

is

for

is

responsible returned to

mm

nitrogen have dissolved in his body and then he suddenly comes back to the surface of the sea, significant quantities of nitrogen bubbles can develop in his

body and

fluids either intracellularly or extracel-

can cause damage in almost any This is "decompression sickness." underlying bubble formation are 30-5. To the left, the diver's tissues have become equilibrated to a very high nitroHg, dissolving about 6Vi gen pressure, 3918 times the normal amount of nitrogen in the tissues. However, as long as the diver remains deep beneath the sea, the pressure against the outside of Hg) compresses all the body his body (5000 tissues sufficiently to keep the gases still dissolved. But when the diver suddenly rises to sea level, the pressure on the outside of his body becomes only 1 Hg), whereas the pressure inatmosphere (760 side the body fluids is the sum of the pressures of water vapor, carbon dioxide, oxygen, and nitrogen, Hg, which is far greater than or a total of 4065 the pressure on the outside of the body. Therefore, the gases can escape from the dissolved state and form actual bubbles both in the tissues and especially in the blood, where they plug the small these area of the body. The principles shown in Figure lularly,

mm

mm

Feet

Liters

33 100 200 300

2 4 7 10

However, several hours are required for the gas pressures of nitrogen in all the body tissues to come nearly to equilibrium with the gas pressure of nitrogen in the alveoli. The reason for this is that the blood does not flow rapidly enough and the nitrogen does not diffuse rapidly enough to cause instantaneous equilibrium. For this reason, if a person remains at deep levels for only a few minutes, not much nitrogen dissolves in the body fluids and tissues; whereas if the person remains at a deep level for several hours, both the fluids and tissues become almost completely saturated with nitrogen.

Decompression Compressed Air

Sickness

(Synonyms: Bends,

Caisson Disease, Diver's Paralysis, Dysbarism). If a diver has been beneath the sea long enough that large amounts of Sickness,

mm

mm

blood vessels.

Symptoms of Decompression Sickness. Most of symptoms of decompression sickness are

the

caused by gas bubbles blocking blood vessels in the different tissues. At first, only the smallest vessels are blocked by very minute bubbles, but as the bubbles coalesce, progressively larger vessels are affected. Obviously, tissue ischemia and sometimes tissue death are the result. In most persons with decompression sickness, the symptoms are pain in the joints and muscles of

358

Aviation, Space,

and Deep Sea Diving Physiology

the legs or arms, affecting about 89 per cent of

those joint

who

develop decompression sickness. The pain accounts for the term "bends" that is of-

ten applied to this condition. In 5 to 10 per cent of persons with decompression sickness, nervous system symptoms occur, ranging from dizziness in about 5 per cent to paral-

and unconsciousness in as many The paralysis may be temporary, but

ysis or collapse

3 per cent.

as

in instances the damage is permanent. Finally, about 2 per cent of persons with decompression sickness develop "the chokes," caused by massive numbers of microbubbles plugging the

some

capillaries of the lungs; this

is

characterized by seri-

ous shortness of breath, often followed by severe

ing at a minimum, which is extremely important, because highly compressed nitrogen is so dense that airway resistance can become extreme, some-

times making the work of breathing beyond endurance. Finally, in very deep dives it is important to reduce the oxygen concentration in the gaseous mixture, for otherwise oxygen toxicity would result. For instance, at a depth of 700 feet (22 atmospheres of pressure) a 1 per cent oxygen mixture will provide all the oxygen required by the diver, while a 21 per cent mixture of oxygen (the percentage in air) delivers a Po to the lungs of over 4 atmos2 pheres, a level likely to cause convulsions in as little as 30 minutes.

pulmonary edema and occasionally death. Nitrogen Elimination from the Body; Decomif a diver is brought the surface slowly, the dissolved nitrogen is eliminated through the lungs rapidly enough to

pression Tables. Fortunately,

Scuba Diving (Self-Contained

to

decompression sickness. Approximately two thirds of the total nitrogen is liberated in 1 hour and about 90 per cent in 6 hours. Special decompression tables have been prepared by the U.S. Navy that detail procedures for safe de-

Underwater Breathing Apparatus)

prevent

compression. To give the student an idea of the decompression process, a diver who has been breathing air and has been on the sea bottom for 60 minutes at a depth of 190 feet is decompressed according to the following schedule: 10 17 19 50 84

minutes minutes minutes minutes minutes

50 40 at 30 at 20 at

feet

at

feet feet feet

at 10 feet

depth depth depth depth depth

Thus, for a work period on the bottom of only 1 hour, the total time for decompression is about 3 hours. "Saturation Diving" and Use of Helium-Oxygen

Prior to the 1940s, almost all diving was done using a diving helmet connected to a hose through which air was pumped to the diver from the surface.

Then, in 1943, Jacques Cousteau developed

and popularized the

self-contained underwater breath-

known simply as the scuba apparatus. The type of scuba apparatus used in over 99 per cent of all sports and commercial diving is the open circuit demand system illustrated in Figure 30-6. This system consists of the following components: (1) one or more tanks of compressed air or of some other breathing mixture, (2) a firststage "reducing" valve for reducing the pressure from the tanks to a constant low pressure level, (3) a combination inhalation "demand" valve and exhalation valve that allows air to be pulled into the lungs with very slight negative pressure of breathing apparatus, popularly

Mixtures in Deep Dives. When divers must work very deep levels between 250 feet and nearly 1000 feet they frequently live in a large compression tank for days or weeks at a time, remaining compressed at a pressure level near that at which they will be working. This keeps the tissues and fluids of the body saturated with the gases to which they will be exposed while diving. Then

at

—

—

Mask

Demand valve

First

stage

valve

when

they work and later return to the same tank working, there are not significant changes in pressure, and so decompression bubbles do not ocafter

cur.

In very deep dives, especially during saturation diving, helium is usually used in the gas mixture instead of nitrogen for three different reasons: (1) it

has only about one fifth the narcotic effect of nitrogen, (2) only about half as much volume of helium dissolves in the body tissues as nitrogen, and (3) the low density of helium (one seventh the density of nitrogen) keeps the airway resistance for breath-

Air

cylinders Figure

30-6 The open

circuit

demand

type of scuba apparatus.

30

ing and then to be exhausted into the sea at very slight positive pressure, and (4) a mask and tube svstem with small "dead space." Basically, the demand system operates as follows: The first-stage reducing valve reduces the pressure from the tanks usually to a pressure of about 140 pounds per square inch. However, the breathing mixture does not flow continually into the mask. Instead, with each inspiration, slight negative pressure in the mask pulls the diaphragm of the demand valve inward, and this automatically releases air from the hose into the mask and lungs. In this wav onlv the amount of air needed for inhalation

Aviation, Space,

and Deep Sea Diving Physiology

^

359

enters the system. Then, on expiration, the air cannot go back into the tank, but instead is expired

through the expiration valve. The most important problem in use of the selfcontained underwater breathing apparatus is the time limit that one can remain beneath the surface; for instance, only a few minutes are possible at a 200 foot depth. The reason for this is that tremendous airflow from the tanks is required to wash carbon dioxide out of the lungs. That is, the greater the depth, the greater the airflow in terms of quantity of air that is required, because the volume has been compressed to a small size.

REFERENCES Aviation

and Space Physiology

Diving Physiology

American Physiological Society: High Altitude and Man. Washington, D.C., American Physiological Society, 1984. Blomqvist, C. G., and Stone, H. L.: Cardiovascular adjustments to gravitational stress, in Shepard, J. T., and Abboud, F. M. (eds.): Handbook of Physiology. Sec. 2, Vol. ID, Bethesda, Md., American Physiological Soci-

Oxygen

transport in

mammals and

birds. Physiol. Rev., 71:1135,

1991.

climatization. J.

and

B.:

Elliott,

D.

H: The Physiology and Medicine

of Diving.

1993'.

Bove, A. A., and Davis, J. C: Diving Medicine. Philadelphia, W. B. Saunders Co., 1990. Crapo, J. D.: Morphologic changes in pulmonary oxygen toxicity. Annu.

M: Renal effects of head-out water immersion in humans: A 15year update. Physiol. Rev., 72:563, 1992. Halsev, M. J.: Effects of high pressure on the central nervous system. Epstein,

Physiol. Rev., 62:1341, 1982.

Jamieson, D., et

Nicogossian, A. E., et al.: Space Physiology and Medicine. Baltimore, Williams & Wilkins Co., 1994. Smith, E. E., and Crowell, J. W.: Role of the hematocrit in altitude acWest,

P. B.,

Philadelphia, W. B. Saunders Co.,

Rev. Physiol., 48:721, 1986.

ety, 1983, p. 1025.

DeHart, R. L. (ed.): Fundamentals of Aerospace Medicine. Philadelphia, Lea &Febiger, 1985. Monge, C, and Leon-Velarde, F: Physiological adaptation to high altitude:

Bennett,

Aerospace Med., 38:39, 1966. physiology at extreme altitude on Mount Everest. '

Human

Annu. Rev. Sloan, A. W.:

Thomas,

al.:

The

relation of free radical production to hyperoxia.

Physiol., 48:703, 1986.

Man

in

Extreme Environments. Springfield,

111.,

Charles

C

1979.

Sci-

ence, 223:784, 1984.

West,

J.

B.:

Man

in space.

News

Physiol.

Sci., 1:198,

1986.

QUESTIONS 1.

2.

Approximately how much is the atmospheric Po, decreased from normal at an altitude of 20,000 feet? Why does water vapor pressure remain approximately constant in the alveoli at 47 Hg regard-

mm

9.

10.

4.

5.

Why

does the Pco 2 not decrease nearly so the alveoli at high altitudes as does the Po,?

much

in

At what altitude does the saturation of arterial blood with hemoglobin fall below approximately 50 per cent, which is the approximate ceiling at which an unacclimatized person can survive? How does breathing pure oxygen change the

What

are the effects of hypoxia

Po 2

in

on the bodv, espe-

cially the brain? 7.

Discuss the different physiological changes that allow a person to become acclimatized to high altitudes.

8.

What

the relationship of centrifugal acceleratorv force to the velocity of movement and to the sharpis

ness of a turn?

meant by

G

force?

Discuss the problems of

artificial

climate

and weight-

lessness in space.

the alveoli at 20,000 feet and at 50,000 feet, and what is the approximate ceiling at which a person can survive when breathing pure oxygen? 6.

is

are linear acceleratorv forces important in space

travel? 11.

less of the altitude? 3.

What

Why

How

deep below sea level must one go for the pressure of gases in the lungs to reach 4 atmospheres? 13. Explain the phenomenon of nitrogen narcosis, which occurs at deep levels below the sea surface when breathing air. 14. What are the effects of oxygen toxicity at great depths below the sea surface? 15. Explain the cause and the effects of decompression 12.

sickness. 16.

why

the compressed air mixture used up far more rapidly at 200 feet than at 50 feet below the sea surface? What is the relationship of carbon dioxide to this differIn scuba diving,

is

that the diver breathes

ence?

The Nervous System: (A) Basic Organization;

and

Sensory Physiology 31

Organization of the Nervous System; Basic Functions of Synapses and Transmitter Substances

32

Sensory Receptors; Neuronal Position

Circuits for Processing Information; Tactile

and

Senses

33

Pain,

34

The Eye:

I.

35

The Eye:

II.

36

The Sense of Hearing; The Chemical Senses of Taste and Smell

Headache, and Thermal Sensations Optics of Vision; The Fluids of the Eye; Function of the Retina

Neurophysiology of Vision

Organization of the Nervous System; Basic Functions of Synapses

31

and

Transmitter Substances

The nervous system, along with the endocrine system, provides most of the control functions for the body. In general, the nervou s system controls the r apid activities of the body such as muscular contractions, rapidly changing visceral events, and even the rates of secretion of some endocrine glands. The endocrine system, by contrast, regulates principally th e metabolic functions of the

(2) the reticular substance of the medulla, pons, and mesencephalon, (3) the cerebellum, (4) the thalamus, and (5) the somesthetic areas of the cerebral cortex. But in addition to these primary sensory areas, signals are then relayed to essentially all other parts of the nervous system as well.

levels,

body

The Motor Division

The nervous system

is

can perform. It information from the different sensory organs and then integrates all these to determine the response to be made by the body. The purpose of this chapter is to present a general outline of the overall mechanisms by which the nervous system performs such functions and then to discuss the basic functions of synapses and neuronal circuits. Before beginning this discussion, however, the reader should refer to Chapters 5 and 7, which present the principles of membrane potentials and transmission of signals in nerves and through neuromuscular junctions. plexity of the control actions that

receives

literally

millions

of

of

The Sensory Division of the

— Sensory

The most im portant ultimate

it

bits

GENERAL DESIGN OF THE NERVOUS SYSTEM

Nervous System

— The

Effectors

unique in the vast com-

Receptors

Most activities of the nervous system are initiated by sensory experience emanating from sensory receptors, whether visual receptors, auditory receptors, tactile receptors on the surface of the body, or other kinds of receptors. This sensory experience can cause an immediate reaction, or its memory can be stored in the brain for minutes, weeks, or years and then can help determine the bodily reactions at some future date. Figure 31-1 illustrates a portion of the sensory system, the somatic portion, which transmits sensory information from the receptors of the entire surface of the body and some deep structures. This information enters the central nervous system through the peripheral nerves and is conducted to multiple sensory areas in (1) the spinal cord at all

role of the

nervous

system

is

This

achieved by controlling (1) contraction of muscles throughout the body, (2) contrac-

is

skeletal

tion of (3)

in

to control the various bodily activities.

smooth muscle in the internal organs, and by both exocrine and endocrine glands

secretion

many

parts of the body. These activities are col-

lectively called motor functions of the

nervous sys-

tem, and the muscles and glands are called effectors, because they perform the functions dictated by the

nerve signals. Figure 31-2 illustrates the motor axis of the nervous system for controlling skeletal muscle contraction. Operating parallel to this axis is another similar system, called the autonomic nervous system, for control of the smooth muscles, glands, and other internal bodily systems; this is presented in Chapter 41. Note in Figure 31-2 that the skeletal muscles can be controlled from many different levels of the central nervous system, including (1) the spinal cord, (2) the reticular substance of the medulla, pons, and mesencephalon, (3) the basal ganglia, (4) the cerebellum, and (5) the motor cortex. Each of these different areas plays its own specific role, the

lower regions being concerned primarily with automatic, instantaneous muscle responses of the body to sensory stimuli; and the higher regions, with deliberate movements controlled by the thought process of the cerebrum.

Processing of Information

—

"Integrative"

Function of the Nervous System

The major function of the nervous system is to process incoming information in such a way that

363

^

364

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

However,

it is important to point out here that the synapses determine the directions that the nervous signals spread in the nervous system. That is, the synapses perform a selective action, often blocking the weak signals while allowing the strong signals to pass, often selecting and amplifying certain weak signals, and often channeling the signals in many different directions, rather than simply in one

Somesthetic area r

direction.

Storage of Information

— Memory

Only a small fraction of the important sensory information causes an immediate motor response. Pain, cold,

warmth

(Free nerve ending)

Pressure Pacinian corpuscle)

(Expanded

tip

receptor)

Touch (Meissner's corpuscle)

Golgi tendon

apparatus

31-1

Figure

The somatic sensory

axis of the

nervous system.

Much

of the remainder is stored for future control of motor activities and for use in the thinking processes. Most of this information storage occurs all, for even the basal regions of the brain and perhaps even the spinal cord can store small amounts of information. The storage of information is the process we call memory, and this, too, is a function of the synapses. That is, each time certain types of sensory signals pass through sequences of synapses, these synapses become more capable of transmitting the same signals the next time, a process that is called facilitation. After the sensory signals have passed through the synapses a large number of times, the synapses become so facilitated that signals generated within the brain itself can also cause transmission of impulses through the same sequences of synapses

in the cerebral cortex, but not

Motor area

occur. More than 99 per sensory information is discarded by the brain as irrelevant and unimportant. For instance,

appropriate

cent of

motor responses

all

unaware of the parts of the contact with clothing and is also seat pressure when sitting. Likewise, attention is drawn only to an occasional object in one's field of vision, and even the perpetual noise of our surroundings is usually relegated to the background. After the important sensory information has been one

is

ordinarily totally

body that are in unaware of the

Caudate nucleus

Thalamus Putamen Globus

pallidus

Subthalamic nucleus

then channeled into proper motor regions of the brain to cause the desired responses. This channeling of information is called the integrative function of the nervous system. Thus, if a person places a hand on a hot stove, the desired response is to lift the hand. There are other associated responses, too, such as moving the entire body away from the stove and perhaps even shouting with pain. Yet even these responses represent activity by only a small fraction of the total motor sysselected,

tem

it is

of the

body

Role of Synapses in Processing Information. The synapse is the junction point from one neuron to th e next and, therefore., is an adva ntageous sit e for

control

chapter

we

transmission. Later in this discuss the details of synaptic function. of

Muscle spindle

signal

Figure

31-2 The motor axis of the nervous svstem.

31

Organization of the Nervous System; Basic Functions of Synapses and Transmitter Substances

many

even though the sensory input has not been excited. This gives the person a perception of experiencing the original sensations, although in effect

pothalamus; and

they are only memories of the sensations. Once memories have been stored in the nervous system, they become part of the processing mechanism. The thought processes of the brain compare new sensory experiences with the stored memories; the memories help to select the important new sensory information and to channel this into appropriate storage areas for future use or into motor areas to cause immediate bodily responses.

out a cerebral cortex.

^

365

emotional patterns, such as

anger, excitement, sexual activities, reaction to pain, or reaction of pleasure, can occur in animals with-

The Higher Brain or Cortical Level

the nervous system functions and lower brain levels, what is left for the cerebral cortex to do? The answer to this begins with the fact that the cerebra l cortex is an extremely large memory storehouse.

After recounting

all

that can occur at the cord

The cortex^never functions

alone, but always in association with the lower centers of the nervous sys-

MAJOR LEVELS OF CENTRAL NERVOUS SYSTEM FUNCTION

THE THREE

tem.

characteristics

Without the cerebral cortex, the functions of the lower brain centers are often very imprecise. The vast storehouse of cortical information usually converts these functions to very determinative and

velopment. From this heritage, three major levels of the central nervous system have specific functional

precision operations. Finally, the cerebral cortex

attributes: (1) the spinal cord level, (2) the lower brain

our thought processes, but the cortex cannot function alone in this. In fact, it is the lower centers that cause wakefulness in the cerebral cortex, thus open-

The human nervous system has inherited specific from each stage of evolutionary de-

level,

and

(3)

the higher brain, or cortical,

level.

The Spinal Cord Level

We often think of the spinal cord as being only a conduit for signals from the periphery of the body to the brain or in the opposite direction from the brain back to the body. However, this is far from the truth. Even after the spinal cord has been cut in the high neck region, many spinal cord functions still occur. For instance, neuronal circuits in the cord can cause (1) walking movements, (2) reflexes that withdraw portions of the body from painful objects, (3) reflexes that stiffen the legs to support the body against gravity, and (4) reflexes that control local

and so

blood vessels, gastrointestinal movements,

forth, in addition to

many

other functions.

upper levels of the nervous system often operate not by sending signals directly to the periphery of the body but instead by sending sigIn fact, the

nals

to

the

control

"commanding"

centers

of

the

cord,

simply

the cord centers to perform their

The Lower Brain Level if

essential for

most of

ing its bank of memories to the thinking machinery of the brain. Thus, each portion of the nervous system performs specific functions. But it is the cortex that opens the world up for one's mind.

THE CENTRAL NERVOUS SYSTEM SYNAPSES Every student is aware that information is transmitted in the central nervous system mainly in the form of nerve impulses through a succession of neurons, one after another. However, it is not immediately apparent that each impulse (a) may be blocked in its transmission from one neuron to the

may

be changed from a single impulse (c) may be integrated with impulses from other neurons to cause highly intricate patterns of impulses in successive neurons. next, (b)

into repetitive impulses, or

All these functions are called the synaptic functions of neurons.

functions.

Many

is

not most of what

activities of the

body

—

we

call

subconscious

are controlled in the lower ar-

in the medulla, pons, mesencephalon, hypothalamus, thalamus, cerebellum, and basal ganglia. Subconscious control of arterial pressure and respiration is achieved mainly in the medulla and pons. Control of equilibrium is a combined function of the older portions of the cerebellum and neuronal centers in the medulla, pons,

eas of the brain

and mesencephalon. Feeding

reflexes,

such as

sali-

vation in response to the taste of food and the licking of the lips, are controlled by areas in the medulla, pons, mesencephalon, amygdala, and hy-

Almost all the synapses utilized for signal transmission in the central nervous system of the human being are chemical synapses. In these, the first neuron secretes a chemical substance called a neurotransmitter at the synapse, and this transmitter in turn acts on receptor proteins in the membrane of the next neuron to excite the neuron, to inhibit it, or to modify its sensitivity in some other way. Over 40 different transmitter substances have been discovered thus far. Some of the best known are acetylcholine, norepinephrine, histamine, gamma-aminobutyric acid

(GABA), and glutamate.

One-Way Conduction

at the Synapses. Synapses have one exceedingly important characteristic that makes them highly desirable as the form of transmission of nervous system signals: they always

366

^

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

—

that is, from transmit the signals in one direction the neuron that secretes the transmitter, called the presynaptic neuron, to the neuron on which the transmitter acts, called the postsynaptic neuron. This is the principle of one-way conduction through synapses.

Think for a moment about the extreme importance of the one-way conduction mechanism. It allows signals to be directed toward specific goals. Indeed, it is this specific transmission of signals to discrete and highly focused- areas in the nervous system that allows the nervous system to perform its myriad functions of sensation, motor control,

memory, and many

others.

Physiological

Anatomy

of the

numbers

that extend as

of branching projections of the

much

as

1

mm into

As many drites

Presynaptic Terminal

Synaptic cleft (200-300 angstroms)

Figure

soma

the surrounding

31-4 Physiological anatomy of the synapse.

mately 80 to 95 per cent of them on the dendrites and only 5 to 20 per cent on the soma. These presynaptic terminals are the ends of nerve fibrils that originate from many other neurons. Later it will bethat many of these presynaptic terminals are excitatory that is, they secrete a substance that excites the postsynaptic neuron, but many oth-

come evident

ers are inhibitory

— — they secrete a substance that

in-

hibits the postsynaptic neuron.

areas of the cord.

more small knobs called on the surfaces of the denand soma of the motor neuron, approxias 10,000 or

presynaptic terminals

Mitochondria

Synapse

Figure 31-3 illustrates a typical anterior motor neuron in the anterior horn of the spinal cord. It is composed of three major parts: the soma, which is the main body of the neuron; a single axon, which extends from the soma into a peripheral nerve that leaves the spinal cord; and the dendrites, which are great

Transmitter vesicles

lie

Neurons in other parts of the cord and brain difmarkedly from the anterior motor neuron in (1) the size of the cell body; (2) the length, size, and number of dendrites; ranging in length from almost none at all up to as long as many centimeters; (3) the length and size of the axon, with a few axons in the peripheral nerves having lengths over 1 meter; and (4) the number of presynaptic terminals, which may range from only a few to as many as fer

200,000. These differences

make neurons

in differ-

ent parts of the nervous system react differently to incoming signals and therefore perform different functions. The Presynaptic Terminals. Electron microscopic studies of the presynaptic terminals show that these have varied anatomical forms, but most resemble small round or oval knobs and therefore are frequently called terminal knobs, boutons, end-feet, or synaptic knobs.

Figure

nals

31-3 A typical motor neuron, showing presynaptic termion the neuronal soma and dendrites. Note also the single

Figure 31-4 illustrates the basic structure of the presynaptic terminal. It is separated from the postsynaptic neuronal soma by a synaptic cleft having a width usually of 200 to 300 angstroms. The terminal has two internal structures important to the excitatory or inhibitory functions of the synapse: the transmitter vesicles and the mitochondria. The transmitter vesicles contain a transmitter substance that, when released into the synaptic cleft, either excites or inhibits the postsynaptic neuron. The mitochondria provide adenosine triphosphate (ATP), which supplies the energy to synthesize new transmitter substance. When an action potential spreads over a presynaptic terminal, the membrane depolarization

31

causes a small number of vesicles to empty into the cleft; and the released transmitter in turn causes an immediate change in the permeability characteristics of the postsynaptic neuronal membrane, which leads to excitation or inhibition of the postsynaptic neuron, depending on its receptor characteristics.

Potentials Cause Transmitter

Release at the Presynaptic Terminals

The

—

The Ion Channels. The ion channels in the postmembrane are usually of two

that most often allow but sometimes potassium or calcium ions, and (2) anion channels that allow mainly chloride ions to pass but also minute quan-

types: (1)

Role of Calcium Ions

the presynaptic terminals, which is called the presynaptic membrane, contains large numbers of voltage-gated calcium channels. This is quite different from the other areas

which contain very few of these an action potential depolarizes the terminal, these calcium channels open and allow of the nerve fiber,

channels.

When

numbers of calcium ions to flow into the terminal. The quantity of transmitter substance that is released into the synaptic cleft is directly related to the number of calcium ions that enter the terminal. The precise mechanism by which the calcium ions cause this release is not known but is believed to be the following: When the calcium ions enter the presynaptic terminal, it is believed that they bind with protein molecules on the inner surfaces of the presynaptic membrane, called release sites. This in turn causes the transmitter vesicles in the local vicinity to bind with the membrane and actually to fuse with it, and finally to open to the exterior by the process called exocytosis. Usually, a few vesicles release their transmitter into the cleft following each single action potential. For those vesicles that store the neurotransmitter acetylcholine, between 2000 and 10,000 molecules of acetylcholine are present in each vesicle, and there are enough vesicles in the presynaptic terminal to transmit from a few hundred to more than 10,000 action potentials. large

Action of the Transmitter Substance on the Postsynaptic

Neuron

—

The Function of Receptor Proteins

At the synapse, the membrane of the postsynapneuron contains large numbers of receptor proteins, also illustrated in Figure 31-4. These receptors have^two. important components: (1) a binding component that protrudes outward from the membrane into the synaptic cleft it binds with the neurotransmitter from the presynaptic terminal and (2) an ionophore component that passes all the way t hrough the membrane to the interior of the postsynaptic neuron. The ionophore in turn is one of two types: (1) an ion channel that allows passage of specified types of ions through the channel, or (2) a "second messenger" activator that is not an ion channel but instead protrudes into the cell cytoplasm and activates one or more substances inside the postsynaptic neuron. These substances, in turn, serve as "second messengers" to change specific tic

—

cellular functions.

cation

sodium ions

channels

to pass

of other anions.

The cation channels

that conduct

sodium ions

are

lined with negative charges. These charges attract

membrane covering

cell

367

synaptic neuronal

tities

Mechanism by Which Action

^

Organization of the Nervous System; Basic Functions of Synapses and Transmitter Substances

—

,

the positively charged sodium ions into the channel the channel diameter becomes increased to a

when

size larger than the

hydrated sodium

same negative charges other anions and prevent

repel

ion.

chloride

But the

ions

and

their passage.

For the anion channels, when their diameters belarge enough, chloride ions pass into the channels and on through to the opposite side, while the sodium, potassium and calcium cations

come

are blocked.

We

will

learn

later

that

opening the sodium

channels excites the postsynaptic neuron. Therefore, a transmitter substance that opens sodium channels is called an excitatory transmitter. On the other hand, opening chloride channels inhibits the neuron, and transmitter substances that open these are called inhibitory transmitters.

When a transmitter substance activates an ion channel, the channel usually opens within a fraction of a millisecond, and when the transmitter substance is no longer present the channel closes equally rapidly. Therefore, opening and closing of ion channels provides a means for rapid activation or rapid inhibition of postsynaptic neurons. The "Second Messenger" System in the Postsynaptic Neuron. Many functions of the nervous system for instance, the process of memory require prolonged changes in neurons for seconds to months after the initial transmitter substance is gone. Obviously, the ion channels are not suitable prolonged postsynaptic neuronal for causing changes because these channels close within milliseconds after the transmitter substance is no longer present. In many instances, prolonged neuronal action is achieved by activating a "second messenger" chemical system inside the postsynaptic neuronal cell itself, and then the second messenger causes the prolonged effect. There are several different types of second messenger systems. One of the most prevailing types in neurons employs a group of proteins called G-proteins. Figure 31-5 illustrates in the upper left corner a membrane receptor protein that has been activated by a transmitter substance. A G-protein is attached to the portion of the receptor protein that protrudes to the interior of the cell. The G-protein in turn is composed of three different components: an alpha (a) component that is the activator portion of the G-protein and beta (j8) and gamma (y) components that attach the G-protein to the inside of the cell membrane adjacent to the receptor protein. Upon activation by a nerve impulse, the alpha

—

—

—

^

368

A

The Nervous System: (A) Basic Organization; and Sensory Physiology

IX

Transmitter substance

Opens

G-protein

—

4

channel

/

-

i

^1 /

-40

J

-60

373

membrane

+20-

£

^

Organization of the Nervous System; Basic Functions of Synapses and Transmitter Substances

31

/

\

Excitatory postsynaptic

\

potential

\

®

\.

from second sources.

//

//'"®~^~^^r~^~~^--_// """

—

Resting

membrane

potential

-*

1-

Special Functions of Dendrites

-80

6

8

10

12

in Exciting

16

14

Neurons

Milliseconds

31-8 Excitatory postsynaptic potentials, showing that simultaneous firing of only a few synapses will not cause sufficient summated potential to elicit an action potential, but the simultaneous firing of many synapses will raise the summated potential to the threshold for excitation and cause a superim-

Figure

posed action potential.

comes great enough, the threshold for firing will be reached, and an action potential will develop spontaneously in the initial segment of the axon. This effect is illustrated in Figure 31-8, which shows several excitatory postsynaptic potentials. The bottom postsynaptic potential in the figure was caused by simultaneous stimulation of four synapses; the next higher potential was caused by stimulation of two times as many synapses; finally, a still higher excitatory postsynaptic potential was caused by stimulation of four times as many synapses. This time an action potential was generated in the initial

axon segment. potentials

summing simultaneous postsynap-

by

on

activating multiple terminals

widely spaced areas of the membrane tial

by way

of the dendrites.

Many

Dendrites Cannot Transmit Action PotenThey Can Transmit Signals by Electronic Conduction. Many dendrites fail to transmit action potentials because their membranes have reltials

— But

atively

few voltage-gated sodium channels, so

their thresholds for excitation are too

This effect of tic

The Large Spatial Field of Excitation of the Dendrites. The dendrites of the anterior motor neurons extend for 500 to 1000 micrometers in all directions from the neuronal soma. Therefore, these dendrites can receive signals from a large spatial area around the motor neuron. This provides vast opportunity for summation of signals from many separate presynaptic nerve fibers. It is also important that between 80 and 90 per cent of all the presynaptic terminals terminate on the dendrites of the anterior motor neuron, in contrast to only 10 to 20 per cent terminating on the neuronal soma. Therefore, the preponderant share of the excitation is provided by signals transmitted

is

called spa-

summation.

tion potentials to occur. Yet they

Each time a terminal fires, the released transmitsubstance opens the membrane channels for

ter

only a millisecond or so, but the postsynaptic potential lasts up to 15 milliseconds. Then a second opening of the same channels can increase the post-

synaptic potential to a still greater level; therefore, the more rapid the rate of terminal stimulation, the greater the effective postsynaptic potential. Thus, successive postsynaptic potentials, if they occur rapidly enough, can summate in the same way that postsynaptic potentials can summate from widely distributed terminals over the surface of the neuron. This summation is called temporal summation.

do transmit

electro-

down

the dendrites to the soma. Transmission of electrotonic current means the direct spread of current by electrical conduction in the fluids of the dendrites with no generation of action tonic current

potentials. Stimulation of the

Temporal Summation

that

high for ac-

neuron by

this cur-

rent has special characteristics, as follows: Decrement of Electrotonic Conduction

— Greater

in

the

Excitatory (or Inhibitory) Effect by Synapses Near the Soma. In Figure 31-9, a

Dendrites

number of excitatory and inhibitory synapses are shown stimulating the dendrites of a neuron. On the two dendrites to the left in the figure are shown excitatory effects near the tip ends of the dendrites; note the high levels of the excitatory that is, the postsynaptic potentials at these ends less negative membrane potentials at these points.

—

However, tic

a large share of the excitatory postsynap-

potential

is lost

before

it

reaches the soma. The

and and their membranes are also thin and excessively permeable to potassium and chloride ions, making them "leaky" to electrical current. There-

reason for this

is

that the dendrites are long

thin, Facilitation

of Neurons

Often the summated postsynaptic potential citatory in nature but has not risen high

is

ex-

enough

to

reach the threshold for excitation. When this happens the neuron is said to be facilitated. That is, its

fore,

before the excitatory potentials can reach the

soma, a large share of the potential is lost by leakage through the membrane. This decrease in membrane potential as it spreads electrotonically along

^

374

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

maximum frequency of discharge, whereas neuron 3 has the highest maximum frequency. Some neurons in the central nervous system fire continuously because even the normal excitatory state is above the threshold level. Their frequency of firing can usually be increased still more by lowest

-40

increasing

further

their

excitatory

Or

state.

the

frequency may be decreased, or firing even be stopped, by superimposing an inhibitory state on the neuron. Thus, different neurons respond differently, have different thresholds for excitation, and have widely differing

maximal frequencies

of discharge.

With

a

imagination one can readily understand the importance of having neurons with many different types of response characteristics to perform the widely varying functions of the nervous system. little

Figure 31-9 Stimulation of a neuron by presynaptic terminals located on dendrites, showing, especially, decremental conduction of excitatory electrotonic potentials in the two dendrites to the left and inhibition of dendritic excitation in the dendrite that is uppermost. A powerful effect of inhibitor)' synapses at the initial

segment of the axon

is

also

dendrites toward the is

soma

is

called decremental con-

also obvious that the nearer the excitatory

synapse is to the soma of the neuron, the less will be the decrement of conduction. Therefore, those synapses that he near the soma have far more excitatory effect than those that he far away from the soma.

Relation of the Rate of Firing of a

Neuron to

The Excitatory

State.

Its

Excitatory State

The "excitatory

state" of a

defined as the summated degree of excitatory drive to the neuron. If there is a higher degree of excitation than inhibition of the neuron at any given instant, then it is said that there is an excitatory state. On the other hand, if there is more inhibition than excitation, then it is said that there is

neuron

an

OF SYNAPTIC TRANSMISSION

shown.

duction. It

SOME SPECIAL CHARACTERISTICS

is

Fatigue of Synaptic Transmission. When excitatory synapses are repetitively stimulated at a rapid rate, the number of discharges by the postsynaptic

neuron

is

very great, but

at first

it

becomes pro-

gressively less in succeeding milliseconds or seconds. This is called fatigue of synaptic transmission.

Fatigue

is

an exceedingly important characteristic when areas of the nervous

of synaptic function, for

system become overexcited, fatigue causes them to lose this excess excitability after a while. For example, fatigue is probably the most important means by which the excess excitability of the brain during an epileptic convulsion is finally subdued so that the convulsion ceases. Thus, the development of fatigue is a protective mechanism against excess neuronal activity.

The mechanism

of fatigue

is

mainly exhaustion

of the stores of transmitter substance in the synaptic

terminals, particularly because the excitatory ter-

inhibitory state.

When

the excitatory state of a neuron rises above

the threshold for excitation, then the neuron will fire repetitively as long as the excitatory state re-

mains

at this level. However, the rate at which it will determined by how much the excitatory state is above threshold. Response Characteristics of Different Neurons to Increasing Levels of Excitatory State. As would be expected, the ability to respond to stimulation by the synapses varies from one type of neuron to another. Figure 31-10 illustrates theoretical responses of three different types of neurons to varying levels of the excitatory state. Note that neuron 1 has a low threshold for excitation, whereas neuron 3 has a high threshold. But note also that neuron 2 has the

fire is

10

15

20

25

30

35

Excitatory state (arbitrary units) Figure

31-10 Response characteristics of different types of neurons

to progressively increasing levels of excitatory state.

31

minals on

many

if

not most neurons can store

enough

excitatory transmitter for only about 10,000 normal synaptic transmissions, so that the transmitter can be exhausted in only a few seconds to a few

minutes of rapid stimulation. Effect of Drugs on Synaptic Transmission. Many different drugs are known to increase the exsynapses, and others are known to decrease the excitability. For instance, caffeine, theophylline, and theobromine, which are found in citability of

and cocoa, respectively, all increase expresumably by reducing the threshold for excitation of the neurons. Also, strychnine is one of coffee, tea, citability,

the best

known

of

all

excitability of neurons.

375

Organization of the Nervous System; Basic Functions of Synapses and Transmitter Substances

the agents that increase the

However,

it

does not reduce

the threshold for excitation of the neurons at instead,

inhibits

it

the action

of

on the neurons,

tory transmitters

all;

some

of the inhibiespecially the in-

hibitory effect of glycine in the spinal cord. In con-

sequence, the effects of the excitatory transmitters the neurons become so excited that they go into rapidly repetitive discharge, resulting in severe tonic muscle spasms.

become overwhelming, and

Most anesthetics increase the membrane threshold for excitation and thereby decrease synaptic transmission at many points in the nervous system. Because most of the anesthetics are lipid-soluble, it has been reasoned that they might change the physical characteristics of the neuronal membranes, making them less responsive to excitatory agents.

REFERENCES Catterall,

W.

A.: Cellular

and molecular biology of voltage-gated sodium

channels. Physiol. Rev., 72:(Suppl.)S15, 1992. Elbert, T., et cell

al.:

Chaos and physiology: Deterministic chaos

in excitable

Origins of Neuroscience: A History of Explorations into Brain New York, Oxford University Press, 1994. Hendelman, W. J.: Student's Atlas of Neuroanatomy. Philadelphia, W. B. S.:

Function.

Saunders Co., 1994. Huguenard, J., and McCormick,

Companion

to

Neuroanatomy. Baltimore, Williams

&

Wilkins Co.,

1995.

assemblies. Physiol. Rev., 74:1, 1994.

Finger,

Human

Parent, A.:

D.: Electrophysiology of the Neuron: A Shepherd's Neurobiology: An Interactive Tutorial. New

York, Oxford University Press, 1994.

L. P.: Merritt's Textbook of Neurology. Baltimore, Williams & Wilkins Co., 1995. Sealfon, S. C: Receptor Molecular Biology. San Diego, CA, Academic

Rowland,

Press, 1995.

Shepherd, G. M.: Neurobiology. New York, Oxford University Press, 1994. Siegel, G. J., et al.: Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Vincent,

demic

Kuno, M.: Synapse: Function, Plasticity, and Neurotrophism. Oxford University Press, 1995.

New

York,

New

S. R.:

York, Raven Press, 1994.

Nitric

Oxide

Nervous System. San Diego, CA, Aca-

in the

Press, 1995.

Walton, J.: Brain's Diseases of the Nervous System. University Press, 1994.

New

York, Oxford

Marcus, E. M., et al.: An Introduction to the Neurosciences. Baltimore, Williams & Wilkins Co., 1994.

QUESTIONS 1.

2.

Discuss in general the sensory and motor divisions and the integrative function of the nervous system. What are the general functions at the three major levels of the central nervous system: the spinal cord, the

and the higher brain, or cortical, levels? Describe the structure of the typical synapse. What is the role of calcium ions in the release of transmitter substance at a synapse? How is transmitter substance synthesized in the presynaptic terminals? Explain the action of the transmitter substance on the postsynaptic neuron membrane. What determines whether a transmitter substance will be excitatory or inhibitory? Name the specific characteristics of several of the more important neu-

what the mechanism

membrane 10.

lower brain,

3.

4.

5.

6.

7.

rotransmitter substances. 8.

Give the concentrations of the important ions for

11.

membrane. Explain what is meant by the Nernst

9.

and

developing the resting

membrane.

Why

is

released.

neuron segment of the axon? 13 What are the differences between presynaptic and

do action

potentials in the postsynaptic

originate in the initial

14

postsynaptic inhibition? Explain spatial and temporal summation of postsynaptic potentials; also explain the phenomenon of facilitation.

What

are the special functions of dendrites in synaptic transmission? 16. What is the relationship between the excitatory state 15.

of a neuron 17.

potential,

for

Explain the sequence of events and changes in membrane potential that occur when an excitatory transmitter is released at a synapse. Explain also the events that occur when an inhibitory transmitter

12.

neuronal function on the two sides of the neuronal cell

is

potential of the neuronal cell

What

is

the

and its rate mechanism

of firing? of synaptic fatigue?

—

Sensory Receptors; Neuronal

Circuits

for Processing Information; Tactile

and

Position Senses

Input to the nervous system is provided by the sensory receptors that detect such sensory stimuli as touch, sound, light, pain, cold, warmth, and so forth. The purpose of this chapter is to discuss the basic

mechanisms by which these receptors change

sensory stimuli into nerve signals and how the information conveyed in the signals is processed in the nervous system. Also, we will see how these basic principles apply to the tactile and position

the other types of sensory stimuli. Thus, the rods and cones of the eye are highly responsive to light but are almost completely nonresponsive to heat, cold, pressure on the eyeballs, or chemical changes in the blood. And pain receptors in the skin are almost never stimulated by usual touch or pressure stimuli but do become highly active the moment tactile stimuli become severe enough to damage the tissues.

senses.

TYPES OF SENSORY RECEPTORS

AND THE

TRANSDUCTION OF SENSORY STIMULI INTO NERVE IMPULSES

SENSORY STIMULI THEY DETECT Local Currents at

There are basically five different types of sensory mechanoreceptors, which detect mechanical deformation of the receptor or of tissues adjacent to the receptor; (2) thermoreceptors, which detect changes in temperature, some receptors detecting cold and others warmth; (3) nociceptors (pain receptors), which detect damage occurring in the tissues, whether physical damage or chemical damage; (4) electromagnetic receptors, which detect light on the retina of the eye; and (5) chemoreceptors, which detect taste in the mouth, smell in the nose, oxygen level in the arterial blood, osmolality of the body fluids, carbon dioxide concentration, and some other factors that make up the chemistry of the body. Figure 32-1 illustrates some of the different types of mechanoreceptors found in the skin or in the deep structures of the body. These are the receptors that are most important for the tactile and position senses, which we will discuss specifically later in the chapter.

Nerve Endings

Receptor Potentials

receptors: (1)

All sensory receptors have one feature in common. Whatever the type of stimulus that excites the receptor, its immediate effect is to change the membrane potential of the receptor. This change in potential is called a receptor potential.

Mechanisms of Receptor Potentials. Different receptors can be excited in one of several different ways to cause receptor potentials: (1) by mechanical deformation of the receptor, which stretches the receptor membrane and opens ion channels; (2) by application of a chemical to the membrane, which also opens ion channels; (3) by change of the temperature of the membrane, which alters the permeability of the membrane; and (4) by the effects of electromagnetic radiation such as light on the receptor, which either directly or indirectly changes the membrane characteristics and allows ions to flow through membrane channels. It will be recognized that these four different means of exciting receptors correspond in general with the different types of

Differential Sensitivity of Receptors

The first question that must be answered is, how do different types of sensory receptors detect different types of sensory stimuli? The answer is that each type of receptor is very highly sensitive to the one type of stimulus for which it is designed, and yet is almost nonresponsive to normal intensities of

376

known

sensory receptors. In

all

instances,

the basic cause of the change in membrane potential is a change in receptor membrane permeability, which allows ions to diffuse more or less readily through the membrane and thereby change the

transmembrane

potential.

Relationship of the Receptor Potential to Action

When the receptor potential rises above the threshold for eliciting action potentials in the Potentials.

\ 32

Sensory Receptors; Neuronal

Circuits; Tactile

^

and Position Senses

377

Action potentials

o+30

§

Oh

.55

Expanded

Free nerve endings

Tactile

tip

receptor

I

-30

o

hair

Q.

I CO

Receptor potential -60

S3

— Resting membrane potential

I -90 10

20

30

40

60

100

80

120

140

Milliseconds

Meissner's

Pacinian corpuscle

corpuscle

Krause's corpuscle

32-2 Typical relationship between receptor potential and when the receptor potential rises above the threshold level. Figure

action potentials

have opened in the membrane, allowing positively charged sodium ions to diffuse to the interior of This creates increased positivity inside the is the receptor potential. The receptor potential in turn induces a local circuit of current flow, illustrated by the red arrows, that spreads along the nerve fiber. At the first node of Ranvier, which itself lies inside the capsule of the pacinian corpuscle, the local current flow depolarizes the fiber membrane at the node, and this then sets off typical action potentials that are transmitted along the nerve fiber toward the central nervous system. Relationship Between Stimulus Intensity and the Receptor Potential. Figure 32-4 illustrates the changing amplitude of the receptor potential caused by progressively stronger mechanical compression applied experimentally to the central core of a pacinian corpuscle. Note that the amplitude increases rapidly at first but then progressively less rapidly at high stimulus strength. This decreasing sensitivity at higher levels of stimulus is an exceedingly important principle, employed by almost all sensory receptors. It allows the receptor to be very sensitive to weak sensory experience and yet not reach a maximum firing the

Figure

Ruffini's

Golgi tendon

Muscle

end-organ

apparatus

spindle

32-1 Several types of somatic sensory nerve endings.

nerve fiber attached to the receptor, then action potentials begin to appear, as was discussed in the previous chapter. This is illustrated in Figure 32-2.

Note also that the more the receptor potential rises above the threshold level, the greater becomes the action potential frequency. Thus, the receptor potential stimulates the sensory nerve fiber in the

same way

that the excitatory postsynaptic potential

in the central

nervous system neuron stimulates the

neuron's axon.

The Receptor Potential of the Pacinian Corpuscle

— An

Illustrative

Example of Receptor Function

The student should at this point restudy the anatomical structure of the pacinian corpuscle illustrated in Figure 32-1. Note that the corpuscle has a central nerve fiber extending through its core. Surrounding this are multiple concentric capsule layers, so that compression anywhere on the outside of the corpuscle will elongate, indent, or otherwise deform the central

Now

fiber.

study Figure 32-3, which

illustrates

fiber.

fiber,

only

which

Action

//

_

,

Deformed

f

Receptor potential X.

\Ppotential

^

—

the central fiber of the pacinian corpuscle after all but one capsule layers have been removed by microdissection. The very tip of the central fiber inside the capsule is unmyelinated, but the fiber does

become myelinated

shortly before leaving the corpuscle to enter the peripheral sensory nerve.

The figure also illustrates the mechanism by which a receptor potential is produced in the pacinian corpuscle. Observe the small area of the terminal fiber that has been deformed by compression of the corpuscle, and note that ion channels

32-3 Excitation of a sensory nerve fiber by a receptor poproduced in a pacinian corpuscle. (Modified from Loewenstein: Ann. N.Y. Acad. Sri., 94:510, 1961.) Figure

tential

378

^

The Nervous System: (A) Basic Organization; and Sensory Physiology

IX

100

within the corpuscle redistributes, so that the pressure becomes essentially equal all through the corpuscle; this now applies an even pressure on all sides of the central nerve fiber, so that the receptor potential is no longer elicited. Thus, the receptor potential appears at the onset of compression but then disappears within a small fraction of a second

even though the compression continues. The Rapidly Adapting Receptors Detect Change in Stimulus Strength The "Rate Receptors" or

—

"Movement

40

20

60

80

100

Stimulus strength (per cent) Figure 32-4 Relationship of amplitude of receptor potential to strength of a stimulus applied to a pacinian corpuscle. (From

Loewenstein: Ann. N.Y. Acad.

Sci.,

94:510, 1961.)

rate until the sensory experience is extreme. ously, this allows the receptor to

Obvihave an extreme

range of response, from very weak to very intense.

Adaptation of Receptors

Receptors." Obviously, receptors that adapt rapidly cannot be used to transmit a continuous signal because these receptors are stimulated only when the stimulus strength changes. Yet they react strongly while a change is actually taking place. Furthermore, the number of impulses transmitted is directly related to the rate at which the change takes place. Therefore, these receptors are called rate receptors or movement receptors. Thus, in the case of the pacinian corpuscle, sudden pressure applied to the tissue excites this receptor for a few milliseconds, and then its excitation is over even though the pressure continues. But later it transmits a signal again when the pressure is released. In other words, the pacinian corpuscle is exceedingly important in apprising the nervous system of rapid tissue deformations, but it is useless for transmitting information about constant conditions in the

body

A

special characteristic of all sensory receptors is that they adapt either partially or completely to their stimuli after a period of time. That is, when a

continuous sensory stimulus is applied, the receptors respond at a very high impulse rate at first, then at a progressively slower rate until finally many of them no longer respond at all. Figure 32-5 illustrates typical adaptation of certain types of receptors. Note that the pacinian corpuscle adapts extremely rapidly and hair receptors adapt within a second or so, whereas some joint capsule and muscle spindle receptors adapt very

—

Importance of the Rate Receptors Their Predictive Function. If one knows the rate at which some change in bodily status is taking place, one can predict the state of the body a few seconds or even a few minutes later. For instance, the receptors of the semicircular canals in the vestibular apparatus of the ear detect the rate at which the head begins to turn when one runs around a curve. Using this information, a person can predict how much he or she will turn within the next 2 seconds and can adjust the motion of the limbs ahead of time to keep from losing balance.

slowly.

Mechanisms by Which Receptors Adapt. Adaptation of receptors

is

an individual property of each

much

the same way that develreceptor potential is an individual property. For instance, in the eye, the rods and cones adapt by changing the concentrations of their light-sensitive chemicals (which is discussed in

type of receptor, in

opment

Chapter

of a

-o200

-

34).

In the case of the mechanoreceptors, the receptor that has been studied for adaptation in greatest de-

again the pacinian corpuscle. Adaptation occurs in this receptor mainly in the following way: The pacinian corpuscle is a viscoelastic structure so tail is

when a distorting force is suddenly applied to one side of the corpuscle, this force is instantly transmitted by the viscous component of the corpuscle directly to the same side of the central nerve fiber, thus eliciting the receptor potential. However, within a few hundredths of a second the fluid that

3

4

5

Seconds Figure 32-5 Adaptation of different types of receptors, showing rapid adaptation of some receptors and slow adaptation of

others.

32

Myelinated

Unmyelinated

Diameter (micrometers) 10 12.0 5 I

I

20

Sensory Receptors; Neuronal

15

0.5

+4Conduction velocity (m/sec)

60

90

120

30

62.0

0.5

-HGeneral classification

Circuits; Tactile

and

Position Senses

^

379

eludes both sensory and motor fibers, including the autonomic nerve fibers as well. The other is a classification of sensory nerve fibers that is used primarily by sensory neurophysiologists. In the general classification, the fibers are divided into types A and C, and the type A fibers are further subdivided into a, (3, y, and 8 fibers. Type A fibers are the typical myelinated fibers of spinal nerves. Type C fibers are the very small, un-

myelinated nerve fibers that conduct impulses at low velocities. The C fibers constitute more than half the sensory fibers in most peripheral nerves Sensory nerve

and also all of the postganglionic autonomic fibers. The sizes, velocities of conduction, and functions

classification

-=x-

of the different nerve fiber types are also given

IV

Note that a few very large fibers can transmit impulses at velocities as great as 120 m/sec, a distance in 1 second that is longer than a football field. On the other hand, the smallest fibers transmit impulses as slowly as 0.5 m/sec, requiring about 2 seconds to go from the big toe to in the figure.

IA IB,

Sensory functions Muscle spindle

Musde sondle

(primary ending)

(secondary ending)

Muscle tendon (Golgi tendon organ)

Hair receptors

the spinal cord. vocation

Crude touch and pressure

High discrimination touch IMeissner's. expanded tips)

c

Deep pressure and

TRANSMISSION OF SIGNALS OF DIFFERENT

Tickle

touch

INTENSITY IN NERVE

Pricking pain

TRACTS— SPATIAL AND

Aching pain

TEMPORAL SUMMATION Cold

Warmth

One

Motor function Skeletal (t

musde

ype

I

(tYPe A-y

Sympathetic

J

i

i

20 Figure

Muscle spindle

Aa)

15

10

1

i

2.0

0.5

32-6 Physiological classifications and functions of nerve

fibers.

of the characteristics of each signal that al-

ways must be conveyed is its intensity, for instance, the intensity of pain. The different gradations of intensity can be transmitted either by utilizing increasing numbers of parallel fibers or by sending more impulses along a single fiber. These two mechanisms are called, respectively, spatial summaand temporal summation. Summation. Figure 32-7 illustrates the phenomenon of spatial summation, whereby increasing signal strength is transmitted by using progressively greater numbers of fibers. This figure shows a section of skin innervated by a large number of tion

Spatial

THE NERVE FIBERS THAT TRANSMIT DIFFERENT TYPES OF SIGNALS

AND

THEIR

PHYSIOLOGICAL CLASSIFICATION

Some signals need to be transmitted to or from the central nervous system extremely rapidly; otherwise the information would be useless. An example of this is the sensory signals that apprise the brain of the momentary positions of the limbs at each fraction of a second during running. At the other extreme, some types of sensory information, such as that depicting prolonged, aching pain, do not need to be transmitted rapidly at all, so that very slowly conducting fibers will suffice. Fortu-

nerve fibers come in all sizes between 0.2 in diameter the larger the diameter, the greater the conducting velocity. The range of conducting velocities is between 0.5 and 120 m/sec. The upper half of Figure 32-6 gives two different classifications of nerve fibers that are in general nately,

and 20 micrometers

use.

One

of these

is

—

a general classification that in-

Weak

Moderate

Strong

stimulus

stimulus

stimulus

Figure 32-7 Pattern of stimulation of pain fibers in a nerve trunk leading from an area of skin pricked by a pin. This is an example of spatial summation.

380

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

parallel pain nerve fibers.

spread for hundreds to thousands of micrometers

into

in the pool.

Each of these arborizes hundreds of minute free nerve endings that serve as pain receptors. The entire cluster of fibers from one pain fiber frequently covers an area of skin as large as 5 centimeters in diameter, and this area is called the receptor field of that fiber. The

number of endings is large in the center of the field but diminishes toward the periphery. One can also see from the figure that the arborizing nerve fibrils overlap those from other pain fibers. Therefore, a pinprick of the skin usually stimulates endings from many different pain fibers simultaneously. When the pinprick is in the center of the receptive field of a particular pain fiber, however, the degree of stimulation of that fiber is far greater than when it is in the periphery of the field. Thus, in the lower part of Figure 32-7 are shown three separate views of the cross-section of the nerve bundle leading from the skin area. To the left is shown the effect of a weak stimulus, and the other two views show the effect, respectively, of a moderate stimulus and a strong stimulus, with progressively more fibers being stimulated. This is the phenomenon of spatial summation. Temporal Summation.

A

second obvious means

for transmitting signals of increasing strength is

by

increasing the frequency of nerve impulses in each fiber, which is called temporal summation.

TRANSMISSION AND PROCESSING OF SIGNALS IN NEURONAL POOLS The

central nervous system is composed of literthousands of separate neuronal pools, some of which contain very few neurons while others have vast numbers. For instance, the entire cerebral cortex could be considered to be a single large neuronal pool. Other neuronal pools include the differ-

Note

of the terminals

in the figure that large

from each input

numbers on the

fiber lie

nearest neuron in its area, but progressively fewer terminals lie on the neurons farther away. Excitation or Facilitation of Neurons in a Pool. From the discussion of synaptic function in the previous chapter, it will be recalled that discharge of a single excitatory presynaptic terminal almost never causes an action potential in the postsynaptic neuron. Instead, large numbers of input terminals must discharge on the same neuron either simultaneously or in rapid succession to cause excitation. For instance, in Figure 32-8, let us assume that six separate terminals must discharge simultaneously to excite any one of the neurons. If the student will count the number of terminals on each one of the neurons from each input fiber, he or she will see that input fiber 1 has more than enough terminals to cause neuron a to discharge. Therefore, the stimulus from input fiber 1 to this neuron is said to be

an

excitatory stimulus.

Input fiber 1 also contributes terminals to neurons b and c, but not enough to cause excitation. Nevertheless, discharge of these terminals makes both these neurons more likely to be excited by signals arriving through other incoming nerve fibers. Therefore, the neurons are said to be facilitated. It must be recognized that Figure 32-8 represents a highly condensed version of a neuronal pool, for each input nerve fiber usually provides massive numbers of branching terminals to hundreds or thousands of separate neurons in its distri-

bution

"field."

ally

ent

basal

ganglia,

the

specific

nuclei

in

the

thalamus, and in the cerebellum, mesencephalon, pons, and medulla. Each pool has its own special characteristics of organization that cause it to process signals in its own special way, thus allowing the total consortium of pools to achieve the multitude of functions of the nervous system.

Relaying of Signals Through Neuronal Pools

Organization of Neurons for Relaying Signals. Figure 32-8 is a diagram of several neurons in a neuronal pool, showing "input" fibers to the left and "output" fibers to the right. Each input fiber divides hundreds to thousands of times, providing an average of a thousand or more terminal fibrils that spread over a large area in the pool to synapse with the dendrites or cell bodies of the neurons in the pool. The dendrites usually also arborize and

Figure

32-8 Basic organization of a neuronal pool.

32

Sensory Receptors; Neuronal

Circuits; Tactile

^

and Position Senses

381

the corticospinal pathway in its control of skeletal muscles, with a single large pyramidal cell in the motor cortex capable, under highly facilitated conditions, of exciting as many as 10,000 muscle fibers.

The second type ure 32-9B

is

of divergence illustrated in Fig-

divergence into multiple tracts. In this

is transmitted in two separate direcfrom the pool. For instance, in the thalamus almost all sensory information is relayed both into deep structures of the thalamus and to discrete re-

case, the signal

tions

gions of the cerebral cortex. Divergence

in

same

tract

Divergence

in

multiple tracts

B

A

Convergence of Signals

Figure 32-9 "Divergence" in neuronal pathways. A, Divergence within a pathway to cause "amplification" of the signal. B, Divergence into multiple tracts to transmit the signal to separate

Inhibition of a Neuronal Pool.

member

that

some incoming

rather than exciting them. This site

of facilitation,

hibitory branches

and the is

We must

also re-

fibers inhibit neurons, is

exactly the oppo-

entire field of the in-

called the inhibitory zone.

The

degree of inhibition in the center of this zone obviously is very great because of large numbers of endings in the center; it becomes progressively less

toward

its

"Convergence" means signals from multiple inputs converging to excite a single neuron. Figure 32-10A shows convergence from a single source, and Figure 32-10B shows convergence (excitatory or inhibitory) from multiple sources. Convergence allows summation of weak signals to achieve a positive output response. Obviously, therefore, convergence is one of the important means by which the central nervous system correlates, summates, and sorts different types of information.

Neuronal

edges.

Excitatory

Divergence of Signals Passing Through Neuronal Pools

Often it is important for signals entering a neuronal pool to excite far greater numbers of nerve fibers leaving the pool. This phenomenon is called divergence. Two major types of divergence are illustrated in Figure 32-9.

An amplifying type of divergence is illustrated in Figure 321-9 A. This means simply that an input signal spreads to an increasing number of neurons as it passes through successive orders of neurons in its path. This type of divergence is characteristic of

and

Causing Both

Circuit

Inhibitory Output Signals

Sometimes an incoming signal to a neuronal pool causes an output excitatory signal going in one direction and at the same time an inhibitory signal going elsewhere. For instance, at the same time that an excitatory signal is transmitted by one set of neurons in the spinal cord to cause forward movement of a leg, an inhibitory signal is transmitted simultaneously through a separate set of neurons to inhibit the muscles on the back of the leg so that they will not oppose the forward movement. This type of circuit is characteristic for controlling all antagonistic pairs of muscles, and it is called the reciprocal inhibition circuit.

Figure 32-11 illustrates the means by which the is achieved. The input fiber directly excites the excitatory output pathway, but it stimulates an intermediate inhibitory neuron (neuron 2) which then secretes a different type of transmitter substance to inhibit the second output pathway

Source

inhibition

from the pool.

synapses

Excitatory Input fiber

Convergence from single source

A

Convergence from multiple sources

M^—

-> Excitation

£#2 #3

B

-> Inhibition 4

32-10 "Convergence" of multiple input fibers on a single neuron. A, Multiple input fibers from a single source. B, Input fibers from multiple sources. Figure

Inhibitory Figure

32-1

1

Inhibitory circuit.

synapse

Neuron

2

is

an inhibitory neuron.

^

382

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

Prolongation of a Signal By a

Neuronal Pool

—

If)

CD

"Afterdischarge"

s CO

Thus

ops in the neuron that

lasts for

many

milliseconds,

when some of the long-acting synaptransmitter substances are involved. As long as this potential lasts, it can continue to excite the neuron, causing it to transmit a continuous train of especially so tic

output impulses. Thus, as a result of "afterdischarge"

mechanism

alone,

this synaptic

it is

possible for

a single instantaneous input to cause a sustained signal output (a series of repetitive discharges) last-

ing for

many

milliseconds.

The Reverberatory

(Oscillatory)

Cause of Signal Prolongation. One

Circuit of the

as

a

most im-

portant of all circuits in the entire nervous system is the reverberatory, or oscillatory, circuit. Such cir-

Input

Output

xy Input

3

we have

considered signals that are merely relayed through neuronal pools. However, in many instances, a signal entering a pool causes a prolonged output discharge, called after discharge, lasting even after the incoming signal is over for a few milliseconds to as long as many minutes. The two most important mechanisms by which afterdischarge occurs are the following: Synaptic Afterdischarge. When excitatory synapses discharge on the surfaces of dendrites or the soma of a neuron, a postsynaptic potential develfar,

Q.

3

3

/^^^r~^r^?!i

ecy

E T5

3 a. _c

n 3

^ o

/

^^V^C^N

ill

\

/

\

\

\

/

/

\

1

Time 32-13 Typical pattern of the output signal from a reverberatory circuit following a single input stimulus, showing the effects of facilitation

and

inhibition.

caused by positive feedback within the neuronal network. That is, the output of a neuronal circuit feeds back to re-excite the input of the same circuit. Consequently, once stimulated, the circuit discharges repetitively for a long time. cuits are

Several different possible varieties of reverberatory circuits are illustrated in Figure 32-12, the

32-12A, involving only a single neuron. In this case, the output neuron simply sends a collateral nerve fiber back to its own dendrites or soma to restimulate itself; therefore, once the neuron has discharged, the feedback stimuli could keep the neuron discharging for a time theresimplest, in Figure

after.

Figure 32-12B illustrates a few additional neurons in the feedback circuit, which would give a longer period of time between the initial discharge and the feedback signal. Figure 32-12C illustrates a

more complex system in which both facilitaand inhibitory fibers impinge on the reverberating circuit. Figure 32-1 2D illustrates that most reverberating pathways are constituted of many parallel fibers, and at each cell station the terminal still

tory

Output

IP Facilitation

Inhibition

D

diffuse widely. Characteristics of Signal Prolongation from a Reverberatory Circuit. Figure 32-13 illustrates output signals from a typical reverberatory circuit. The input stimulus need last only 1 millisecond or so, and yet the output can last for many milliseconds or even minutes. The figure demonstrates that the intensity of the output signal usually increases to a high value early in the reverberation, then decreases to a critical point, at which it suddenly ceases entirely. The cause of this sudden cessation of reverberation is fatigue of synaptic junctions in the circuit, for fatigue beyond a certain critical level lowers the stimulation of the next neuron in the circuit below threshold level so that the circuit feedback is suddenly broken. Obviously, the duration of the signal before cessation can also be controlled by signals from other parts of the brain that inhibit or facilitate the circuit. fibrils

Continuous Signal Output from Neuronal Circuits

Figure

32-12 Reverberatory circuits of increasing complexity.

Some neuronal circuits emit output signals continuously even without excitatory input signals. At

32

Sensory Receptors; Neuronal

body

^

and Position Senses

Circuits; Tactile

383

stimulated by arterial oxygen defiand amplitude of the rhythmic signal pattern increase progressively. carotid

is

ciency, the frequency

DETECTION

AND TRANSMISSION

OF TACTILE SENSATIONS

The Time

tors are 32-14 Continuous output from either a reverberating circuit or a pool of intrinsically discharging neurons. This figure also shows the effect of excitatory or inhibitory input signals. Figure

known. Some

trated in Figure 32-1, tics

some

everywhere

two

different mechanisms can cause this efcontinuous intrinsic neuronal discharge and (2) continuous reverberatory signals. Figure 32-14 illustrates a continual output signal from a pool of neurons, whether a pool emitting impulses because of intrinsic neuronal excitability or as a result of reverberation. Note that an excitatory input signal to the pool greatly increases the output signal, whereas an inhibitory input signal greatly decreases the output. Those students who are familiar with radio transmitters will recognize this to be a carrier wave type of information transmission. That is, the excitatory and inhibitory control signals are not the cause of the output signal, but they do control it. Note that this carrier wave system allows decrease in signal intensity as well as increase, whereas, up to this point, the types of information transmission that we have discussed have been only positive information. This type of information transmission is used by the autonomic nervous system to control such functions as vascular tone, gut tone, degree of constriction of the iris, fect: (1)

heart rate,

and

sensations"

"tactile

of these receptors

and

were

illus-

their special characteris-

are the following:

First,

least

The

Tactile Receptors.

are those that detect touch, pressure, and vibration. At least six entirely different types of tactile recep-

free nerve endings,

in the skin

and

in

which are found

many

other tissues,

can detect touch and pressure. For instance, even light contact with the cornea of the eye, which contains no other type of nerve ending besides free nerve endings, can nevertheless elicit touch and pressure sensations. Second, a touch receptor of special sensitivity is Meissner's corpuscle, an elongated encapsulated nerve ending that excites a large (type A/3) myelinated sensory nerve fiber. Inside the capsulation are many branching whorls of terminal nerve filaments. These receptors are present in the nonhairy parts of the skin (called glabrous skin)

abundant in the fingertips, areas of the skin where one's ability ticularly

and are parand other

lips,

to discern spa-

characteristics of touch sensations

is highly developed. Meissner's corpuscles adapt in a fraction of a second after they are stimulated, which means that they are particularly sensitive to movement of very light objects over the surface of the skin and also to low frequency vibration. Third, the fingertips and some other areas also contain large numbers of expanded tip tactile receptors, one type of which is Merkel's discs, illustrated

tial

others.

Rhythmic Signal Output

Many nals

neuronal circuits emit rhythmic output siginstance, the rhythmic respiratory signal

— for

originating in the respiratory centers of the medulla and pons. This respiratory rhythmic signal contin-

I C

ues throughout life, whereas other rhythmic signals, such as those that cause scratching movements by the hind leg of a dog or the walking movements in an animal, require input stimuli into the respective circuits to initiate the rhythmic sig-

C 2?

!

I

I

i

a.

a

nals.

Either all or almost all rhythmic signals that have been studied experimentally have been found to result from reverberating circuits or a succession of

sequential reverberating circuits that feed excitatory or inhibitory signals from one to the next.

Figure 32-15 illustrates the rhythmic respirator}' in the phrenic nerve. However, when the

signal

Increasing carotid

body stimulation

The rhythmical output of summated nerve impulses center, showing that progressively increasing stimulation of the carotid body increases both the intensitv and frequency of the phrenic nerve signal to the diaphragm to Figure

32-1 5

from the respiratory

increase respiration.

— 384

^

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

32-16 The Iggo dome recepNote the multiple numbers of Merkel's discs innervated by a single large myelinated fiber and abutting Figure tor.

tightly the undersurface of the epithe-

lium. (From Iggo

and Muir:

J.

Phvs-

iol, 200:763, 1969.)

These receptors differ from Meissner's corpuscles in that they transmit an initially-

in Figure 32-16.

strong but partially adapting signal and then a continuing weaker signal that adapts only slowly. Therefore, they are responsible for giving steady state signals that allow one to determine continuous touch of objects against the skin. Merkel's discs are often grouped together in a single receptor organ called the Iggo dome receptor, illustrated in Figure 32-16. The epithelium at this point protrudes outward, thus creating a dome and constituting an extremely sensitive receptor. Also note that the entire group of Merkel's discs is innervated by a single large type of myelinated nerve fiber (type A/3). These receptors, along with Meissner's corpuscles, play extremely important roles in localizing touch sensations to the specific surface areas of the body and also in determining the texture of what is felt. Fourth, slight movement of any hair on the body stimulates the nerve fiber entwining its base. Thus, each hair and its basal nerve fiber, called the hair end-organ, is also a touch receptor. This receptor adapts readily and, therefore, like Meissner's corpuscles, detects mainly movement of objects on the surface of the body or initial contact with the body. Fifth, located in the deeper layers of the skin and also in deeper tissues are many Ruffini's end-organs, which are multibranched, encapsulated endings, as illustrated in Figure 32-1. These endings adapt very little and, therefore, are important for signaling continuous states of deformation of the skin

ment

of the tissues because they adapt in a few hundredths of a second. Therefore, they are particularly important for detecting tissue vibration or other rapid changes in the mechanical state of the tissues.

Transmission of Tactile Sensations in Peripheral

Nerve

Fibers.

Almost

all

the specialized tactile sen-

sory receptors, such as Meissner's corpuscles, Iggo dome receptors, hair receptors, pacinian corpuscles, and Ruffini's endings, transmit their signals in type A/3 nerve fibers that have transmission velocities of 30 to 70 m/sec. On the other hand, free nerve ending tactile receptors transmit signals mainly via the small type AS myelinated fibers that conduct at velocities of 5 to 30 m/sec. Some tactile free nerve endings transmit via type C unmyelinated fibers at velocities of from a fraction of a meter up to 2 m/sec; these send signals into the spinal cord and lower brain stem, probably subserving mainly the sensation of tickle. Thus, the more critical types of sensory signals those that help determine precise localization on the skin, minute gradations of intensity, or rapid changes in sensory signal intensity are all transmitted in more rapidly conducting types of sensory nerve fibers. On the other hand, the cruder types of signals, such as crude pressure, poorly localized touch, and especially tickle, are transmitted via much slower nerve fibers that require much less space in the nerve bundle than the faster fibers.

—

and deeper

tissues, such as heavy and continuous touch signals and pressure signals. They are also found in joint capsules and help signal the degree

of joint rotation. Sixth, pacinian corpuscles, earlier in the chapter, lie

which were discussed

both immediately beneath

the skin and also deep in the fascial tissues of the body. These are stimulated only by rapid move-

Detection of Vibration

All the different tactile receptors are involved in detection of vibration, though different receptors detect different frequencies of vibration. Pacinian corpuscles can signal vibrations of from 30 to 800 cycles per second, because they respond extremely

32

Sensory Receptors; Neuronal

rapidly to minute and rapid deformations of the tissues, and they also transmit their signals over type A/3 nerve fibers, which can transmit more than 1000 impulses per second. Low frequency vibrations of up to 80 cycles per second, on the other hand, stimulate other tactile especially Meissner's corpuscles, which receptors are less rapidly adapting than pacinian corpuscles.

—

Circuits; Tactile

and

^

Position Senses

With this differentiation in mind we can the types of sensations transmitted in the tems:

385 now two

list

sys-

The Dorsal Column -Medial Lemniscal System

1.

Touch sensations requiring a high degree of

localization of the stimulus. 2.

Touch sensations requiring transmission

of

fine gradations of intensity.

THE TWO SENSORY PATHWAYS FOR TRANSMISSION OF SOMATIC SIGNALS INTO THE CENTRAL NERVOUS SYSTEM

3.

Phasic

such as vibratory sensa-

sensations,

tions. 4.

Sensations that signal

movement

against the

skin.

Position sensations. Pressure sensations having to do with fine degrees of judgment of pressure intensity. 5.

Almost segments

sensory information from the somatic of the body enters the spinal cord

all

through the dorsal roots of the spinal nerves. However, from the entry point of the cord and then to the brain the sensory signals are carried through one of two alternate sensory pathways: (1) the dorsal column -medial lemniscal system and (2) the anterolateral system. These two systems again come together partially at the level of the thalamus. The dorsal column -medial lemniscal system, as its name implies, carries signals mainly in the dorsal columns of the cord and then, after synapsing and crossing to the opposite side in the medulla, upward through the brain stem to the thalamus by way of the medial lemniscus. On the other hand, signals of the anterolateral system, after originating in the dorsal horns of the spinal gray matter, cross to the opposite side of the cord and ascend through the anterior and lateral white columns of the cord to terminate at all levels of the brain stem and also in the thalamus. The dorsal column -medial lemniscal system is

composed

of large, myelinated

nerve fibers that

transmit signals to the brain at velocities of 30 to 110 m/sec, whereas the anterolateral system is composed of much smaller myelinated fibers (averaging 4 micrometers in diameter) that transmit signals at velocities ranging from a few meters per second up to 40 m/sec. Another difference between the two systems is that the dorsal column -medial lemniscal system has a very high degree of spatial orientation of the nerve fibers with respect to their origin, whereas the anterolateral system has a much smaller degree of spatial orientation.

Thus, sensory information that must be transmitted rapidly and with temporal and spatial fidelity is transmitted in the dorsal column -medial lemniscal system, whereas that which does not need to be transmitted rapidly nor with great spatial fidelity is transmitted mainly in the anterolateral system. The anterolateral system has a special capability that the dorsal system does not have: the ability to transmit a broad spectrum of sensory modalities pain, warmth, cold, and crude tactile sensations; most of these will be discussed in detail in the following chapter.

6.

Jifie

Anterolateral System

1.

Pain.

2.

Thermal sensations, including both

warm and

cold sensations. 3.

Crude touch and pressure sensations capable on the surface of the

of only crude localizing ability

body.

and

itch sensations.

4.

Tickle

5.

Sexual sensations.

DORSAL COLUMN-MEDIAL LEMNISCAL SYSTEM TRANSMISSION

Anatomy

IN THE

of the Dorsal

Column-Medial Lemniscal System

On entering the spinal cord from the spinal nerve dorsal roots, the large myelinated fibers from specialized mechanoreceptors pass immediately -Spinal nerve

Dorsal column Tract of Lissauer

^Lamina marginalis •substantia gelatinosa

Spinocervical tract

Anterolateral

Dorsal spino-

--

spinothalamic

pathway

cerebellar tract

Ventral-' spinocerebellar tract

— Figure

32-17

Cross-section

of

the

spinal

cord,

showing the

anatomical laminae I through IX of the cord gray matter and the ascending sensory tracts (in red) in the white columns of the spinal cord.

^

386

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

into the lateral margin of the dorsal white column. However, each fiber then divides to form a medial branch and a lateral branch, as illustrated by the right-hand spinal root fiber in Figure 32-17. The medial branch turns upward in the dorsal column and proceeds by way of the dorsal column path-

way

POSTCENTRAL GYRUS

to the brain.

The

lateral branch enters the dorsal horn of the cord gray matter and then divides many times, synapsing with neurons in almost all parts of the intermediate and anterior portions of the cord gray

matter.

Many

of these neurons elicit local spinal

cord reflexes, which will be discussed in Chapter 37. Others give rise to the spinocerebellar tracts, which we will discuss in Chapter 38 in relation to the function of the cerebellum. The Dorsal Column -Medial Lemniscal Pathway. Note in Figure 32-18 that the nerve fibers entering the dorsal columns pass uninterrupted up to the medulla, where they synapse in the dorsal col-

umn

nuclei

(the

cuneate

and

gracile

nuclei).

From

here, second-order neurons cross immediately to the

opposite side and then continue

upward

to

the

Ventrobasal complex thalamus

of

MESENCEPHALON Spinothalamic

tract

Medial lemniscus Figure

32-19 Projection of the dorsal column-medial lemniscal

system from the thalamus to the somatic sensory cortex. (Modified from Brodal: Neurological Anatomy in Relation to Clinical Medicine. New York, Oxford University Press, 1969.)

thalamus through

bilateral

brain stem pathways

called the medial lemnisci.

Cortex

In the thalamus, the medial lemniscal fibers

the dorsal

columns terminate

From here, third-order nerve fibers shown in Figure 32-19, mainly to the

plex.

gyrus of the cerebral cortex, which sensory area

Ventrobasal complex of

from

in the ventrobasal com-

is

project, as

postcentral

called somatic

I.

Spatial Orientation of the Nerve Fibers in the

thalamus

Dorsal Column -Medial Lemniscal System

One

of the distinguishing features of the dorsal

column -medial lemniscal system

is a distinct spaorientation of nerve fibers from the individual parts of the body that is maintained throughout.

tial

Medulla oblongata

For instance, in the dorsal columns, the fibers from the lower parts of the body lie toward the center, while those that enter the spinal cord at progressively higher segmental levels form successive layers laterally.

In the thalamus, the distinct spatial orientation

is

maintained, with the tail end of the body represented by the most lateral portions of the venstill

Ascending branches

of

dorsal root fibers

trobasal

Spinocervical tract

Dorsal root and

complex and the head and face repre-

sented in the medial component of the complex. However, because of the crossing of the medial lemnisci in the medulla, the left side of the body is represented in the right side of the thalamus, and the right side of the body is represented in the left side of the thalamus.

spinal ganglion

32-18 The dorsal column and spinocervical pathways for transmitting critical types of tactile signals. (Modified from Ranson, S. W. and Clark, S. L.: Anatomy of the Nervous System.

fa

Figure

Philadelphia,

W.

B.

Saunders Company, 1959.)

The Somatic Sensory Cortex

Figure 32-20 illustrates the cerebrum of the hubrain, but with the temporal lobe pulled

man

32

Sensory Receptors; Neuronal

Somatic sensory area I

Somatic sensory

Vea

II

Circuits; Tactile

^

and Position Senses

387

sented by relatively small areas. The sizes of these areas are directly proportional to the number of specialized sensory receptors in each respective peripheral area of the body. For instance, a great

number of specialized nerve endings are found in the lips and thumb, whereas only a few are present in the skin of the trunk. Note also that the head is represented in the most lateral portion of somatic sensory area I, whereas the lower part of the body is represented medially.

The Layers of the Somatic Sensory Cortex Figure

32-20 The two somatic sensory cortical areas, somatic sen-

sory areas

I

and

downward. fifths of

a

deep

the

II.

On

the top of the brain, about two the front and the back, is

way between

fissure called the central fissure that extends

horizontally across the brain. In general, sensory signals from all modalities of sensation terminate in the cerebral cortex posterior to the central fissure. Most importantly, the somatic sensory cortex lies im-

mediately behind the central fissure, as shown in the figure. This is the portion of the cortex called lobe. In addition, visual signals terminate in the occipital lobe, the most posterior part of the cortex; and auditory signals terminate in the temporal lobe, the part that is pulled downward in the figure. The portion of the cortex anterior to the central fissure is devoted to motor control of the body and to some aspects of analytical thought. Two distinct and separate areas are known to receive direct afferent nerve fibers from the somesthetic relay nuclei in the ventrobasal complex of the thalamus; these, called somatic sensory area I and somatic sensory area II, are illustrated in Figure 32-20. However, somatic sensory area I is so much more important to the sensory functions of the body than is somatic sensory area II that in popular usage the term "somatic sensory cortex" most often is used to mean area I. Projection of the Body in Somatic Sensory Area I. Somatic sensory area I lies in the postcentral gyrus of the human cerebral cortex (the gyrus immediately behind the central fissure). A distinct spatial orientation exists in this area for reception of nerve signals from the different areas of the body. Figure 32-21 illustrates a cross-section through the brain at the level of the postcentral gyrus, showing the representations of the different parts of the body in separate regions of somatic sensory area I. Note, however, that each side of the cortex receives sensory information almost exclusively from the opposite side of the body. Some parts of the body are represented by large areas in the somatic cortex the lips the greatest of all, followed by the face and thumb whereas the entire trunk and lower part of the body are repre-

the parietal

—

—

and

Their Function

The cerebral cortex contains six separate layers of neurons, beginning with layer I next to the surface and extending progressively deeper to layer VI, as illustrated in Figure 32-22. As would be expected, the neurons in each layer perform functions different from those in other layers. Some of these functions are as follows: 1.

The incoming sensory

layer IV

first;

signal excites neuronal then the signal spreads both toward

the surface of the cortex and also toward the deeper layers. 2. Layers I and II receive a diffuse, nonspecific input from lower brain centers that can facilitate a specific region of the cortex; this system will be described in Chapter 40. This input mainly controls

the overall level of excitability of the region stimulated. 3.

The neurons

in layers

II

and

III

send axons

to

other related portions of the cerebral cortex. 4.

The neurons

in layers

V

and VI send axons

to

the deeper parts of the nervous system. Those in layer V are generally larger and project to more

Lower

lip

SI— Teeth, gums, and jaw m\

—

Tongue

' ^fc--" Pharynx ^^^Intra-abdominal

Figure

32-21 Representation of the different areas of the

body

in

(From Penfield and Rasmussen: Cerebral Cortex of Man: A Clinical Study of Localization of Function. New York, Macmillan Company, 1968.) the somatic sensory area

I

of the cortex.

^

388

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

Many

of the signals from these in turn spread di-

motor cortex located immediately anand help control muscle function. As one proceeds more posteriorly in somatic sensory cortex I, more and more of the vertical columns respond to the slowly adapting cutaneous receptors, and then still farther posteriorly greater numbers of the columns are sensitive to deep pressure. rectly to the

terior to the central fissure

it

i\

1

'

1

Vl

V




1

/

Heat-pain

45

50

In general, thermal signals are transmitted in al55

60

most

parallel,

but not exactly the same, pathways

as pain signals.

33-8 Frequencies of discharge of (1) a cold-pain fiber, (2) a cold fiber, (3) a warmth fiber, and (4) a heat-pain fiber. (The responses of these fibers are drawn from original data collected in separate experiments by Zotterman, Hensel, and Kenshalo.) Figure

person determines the different gradations of thermal sensations by the relative degrees of stimulation of the different types of endings. One can understand also from this figure why extreme degrees of cold or heat can be painful. Mechanism of Stimulation of the Thermal Receptors. It is believed that the cold and warmth receptors are stimulated by changes in their meta-

On

entering the spinal cord, the

few segments upward or downward and then terminate mainly in laminae I, II, and III of the dorsal horns the same as for pain. After a small amount of processing by one or more signals travel for a

—

cord neurons, the signals enter long, ascending thermal fibers that cross to the opposite anterolateral sensory tract and terminate in both (1) the reticular areas of the brain stem and (2) the ventrobasal complex of the thalamus. A few thermal signals are also relayed to the somatic sensory cortex from the ventrobasal complex. Removal of the postcentral gyrus in the human being reduces the ability to distinguish gradations of temperature but does not abolish the perception of cold or warmth.

REFERENCES Aubin,

P.:

J.

A Viability ApCambridge University Press, 1994. Multisensory Control of Movement. New York, Oxford UniNeural Networks and Qualitative Physics:

New

proach.

Berthoz, A.:

York,

versity Press, 1993. Crinella,

M: Brain Mechanisms. New York Academy of Sciences, 1994. Human neuronal control of automatic functional movements: between central programs and

Interaction

afferent input. Phvsiol. Rev.,

MIT

D.:

The Neurobiology

of Neural Networks.

Cambridge,

MA, The

Press, 1993. Artificial Intelligence

and Neural Networks. San

Diego, CA, Academic Press, 1994. Kendall, D. A., and Hill, S. J.: Signal Transduction Protocols. Totowa, NJ,

Humana

New

J.:

Press,

Scott,

S.

New

A.:

Sensory Neurons: Diversity, Development, and

Plasticity.

York, Oxford University Press, 1992.

Tollison, C. D.:

Handbook

of Pain

Management. Baltimore, Williams

&

Valiant, L. G.: Circuits of the

Mind.

New

York, Oxford University Press,

1994.

Honavar, V, and Uhr, L:

Olesen,

MIT

Wilkins Co., 1994.

72:33, 1992.

Gardner,

From Neu-

1994.

F.

Dietz, V:

et al.: Brain Mechanisms of Perception and Memory: ron to Behavior. New York, Oxford University Press, 1993. Schacter, D. L.: Memory Systems 1994. Cambridge, MA, The

Ono, T,

Press, Inc., 1995.

Wiener, S. L.: Differential diagnosis of acute pain: By body region. Hightstown, NJ, McGraw-Hill, 1993. Ziv, I., et al.: Simulator for neural networks and action potentials: Description and application. J. Neurophysiol., 71:294, 1994.

Migraine and Other Headaches: The Vascular Mechanisms.

York,

Raven

Press, 1991.

QUESTIONS 1.

2.

Discuss the differences between acute pain and slow

6.

pain.

7.

What

are the different types of pain receptor endings,

and what and pain? 3.

is

the relationship

between

tissue

damage

Describe the two separate pathways for transmission of pain signals into the central nervous system and

8.

9.

their functional differences. 4.

Describe the functions of the reticular formation, the thalamus, and the cerebral cortex in the appreciation of pain.

5.

Describe the pain-control (analgesic) system of the brain and spinal cord.

What

is meant by the brain's opiate system? Explain the mechanism of referred pain. Why is referred pain from the viscera often localized far from the organ causing the pain? What pain receptor regions within the head are responsible for headache?

What

is

the

theoretical

mechanism

for

migraine

headache? 10.

Explain the mechanism by which a person determines the temperature of objects touched by the skin.

The Eye:

I.

Optics of Vision; The Fluids

of the Eye; Function of the Retina

age on a sheet of paper, the lens system of the eye can focus an image on the retina. The image is inverted and reversed with respect to the object.

THE OPTICS OF THE EYE The Eye as a Camera

The

eye, illustrated in Figure 34-1, is optically

equivalent to the usual photographic camera. It has a lens system, a variable aperture system (the pupil), and a retina that corresponds to the film. The lens system of the eye is composed of four refractive interfaces: (1) the interface

between

air

and

the anterior surface of the cornea, (2) the interface between the posterior surface of the cornea and the

aqueous humor, (3) the interface between the aqueous humor and the anterior surface of the crystalline lens of the eye, and (4) the interface between the posterior surface of the lens and the vitreous humor. The Reduced Eye. If all the refractive surfaces of the eye are algebraically added together and then considered to be one single lens, the optics of the normal eye may be simplified and represented schematically as a "reduced eye." This is useful in simple calculations. In the reduced eye, a single refractive surface is considered to exist tral

a

point 17

total

diopters

mm

refractive

when

power

the lens

is

(Remember

of

with

its

and

to

cen-

have approximately 59

in front of the retina

accommodated

for dis-

diopter

is the strength of a lens that focuses parallel light rays at a distance of 1 meter.) Most of the refractive power of the eye is provided not by the crystalline lens but instead by the anterior surface of the cornea. The principal reason for this is that the refractive index of the cornea is markedly different from that of air, as illustrated in Figure 34-1. On the other hand, the total refractive power of the crystalline lens of the eye, as it normally lies in the eye surrounded by fluid on each side, is only 20 diopters, about one third the total refractive power of the eye's lens system. Yet, the importance of the crystalline lens is that its curvature can be increased markedly to provide "accommodation,"

tant

vision.

that

1

which will be discussed later in the chapter. Formation of an Image on the Retina. In exactly the same manner that a glass lens can focus an im-

400

However, the mind perceives objects in the upright position despite the upside-down orientation on the retina because the brain is trained to consider an inverted image as the normal.

The Mechanism of Accommodation

The

refractive

power

of the crystalline lens of the

eye can be voluntarily increased from 20 diopters to approximately 34 diopters in young children;

"accommodation" of 14 diopters. To the shape of the lens is changed from that of a moderately convex lens to that of a very convex lens. The mechanism is the following: this is a total

do

this,

In the young person, the lens is composed of a strong elastic capsule filled with viscous, proteinaceous, but transparent fibers. When the lens is in a relaxed state, with no tension on its capsule, it assumes an almost spherical shape, owing mainly to the elasticity of the lens capsule. However, as illustrated in Figure 34-2, approximately 70 ligaments (called zonules) attach radially around the lens, pulling the lens edges toward the outer circle of the eyeball. These ligaments are constantly tensed by their attachments to the ciliary body at the anterior border of the choroid and retina. The tension on the ligaments causes the lens to remain relatively flat under normal resting conditions of the eye. At the insertions of the ligaments in the ciliary body is a muscle called the ciliary muscle. This muscle has two sets of smooth muscle fibers, the meridional fibers and the circular fibers. The meridional fibers extend to the corneoscleral junction. When these muscle fibers contract, the peripheral insertions of the lens ligaments are pulled forward, thereby releasing a certain amount of tension on the lens. The circular fibers are arranged circularly all the way around the eye so that when they contract, a sphincter-like action occurs, decreasing the diameter of the circle of ligament attachments; this also allows the ligaments to pull less on the lens capsule.

34

Total refractive

The Eye:

I.

power =59 diopters

^

Optics of Vision; Fluids; Retina

401

The Pupillary Diameter

A

major function of the

amount of light that enters and to decrease the light

Image*

iris

is

to increase the

the eye during darkness in bright light. The re-

mechanism will be considered in the discussion of the neurology of the eye in the next chapter. The amount of light that enters the eye through the pupil is proportional to the area of the pupil or to the square of the diameter of the pupil. The pupil of the human eye can beand as come as small as approximately 1.5 in diameter. Therefore, the quantity large as 8 of light entering the eye can change 30 times as a result of changes in pupillary aperture. flexes for controlling this

Vitreous

Lens

humor

1.40

Aqueous humor 1.33

1.34 Figure

34-1 The eye as a camera. The numbers are the refractive

indices.

mm

mm

Thus, contraction of either set of smooth muscle muscle relaxes the ligaments to

fibers in the ciliary

the lens capsule, and the lens assumes a more spherical shape, like that of a balloon, because of the natural elasticity of its capsule. Therefore, when the ciliary muscle is completely relaxed, the dioptric strength of the lens is as weak as it can be-

On

when the ciliary muscle strongly as possible, the dioptric strength of the lens becomes maximal. Accommodation Is Controlled by the Parasympathetic Nerves. The ciliary muscle is controlled alcome.

contracts

most

the other hand, as

entirely

by parasympathetic nerve

signals

from the third cranial nerve transmitted to the eve J nucleus in the brain stem, as explained in the next chapter. Stimulation of the parasympathetic nerves contracts the ciliary muscle, which relaxes the lens ligaments and increases the refractive power. With an increased refractive power, the eye is capable of focusing on objects nearer at hand than when the eye has less refractive power. Consequently, as a distant object moves toward the eye, the number of parasympathetic impulses impinging on the ciliary muscle must be progressively increased for the eye to keep the object constantly in focus. Presbyopia. As a person grows older, the lens

and

becomes

grows larger and

thicker,

less elastic, partly

because of progressive denatura-

it

also

Errors of Refraction

Emmetropia. As shown in Figure 34-3, the eye considered to be normal, or "emmetropic," if light rays from distant objects are in sharp focus on the retina when the ciliary muscle is completely relaxed. This means that the emmetropic eye can see all distant objects clearly, with its ciliary muscle relaxed. However, to focus objects at close range the eye must contract its ciliary muscle and thereby provide appropriate degrees of accommodation. Hyperopia. Hyperopia, also known as "far-sightedness," is usually due either to an eyeball that is too short or occasionally to a lens system that is too weak. In this condition, as seen in the middle panel is

of Figure 34-3, parallel light rays are not bent sufficiently by the lens system to come to a focus by

the time they reach the retina. To overcome this abnormality, the ciliary muscle must contract to increase the strength of the lens. Therefore, the farsighted person is capable, by using the mechanism of accommodation, of focusing distant objects on the retina. If the person has used only a small

far

tion of the lens proteins. Therefore, the ability of

the lens to change shape progressively decreases with age. The power of accommodation decreases from approximately 14 diopters in the child to less

than 2 diopters at the age of 45 to 50 years and to about zero at age 70 years. Thereafter, the lens is almost totally nonaccommodating, a condition known as "presbyopia." Once a person has reached the state of presbyopia, each eye remains focused permanently at an almost constant distance; this distance depends on the physical characteristics of each individual's eyes. Obviously, the eyes can no longer accommodate for both near and far vision. Therefore, to see clearly both in the distance and nearby, an older person must wear bifocal glasses with the upper segment normally focused for far-seeing and the lower segment focused for near-seeing that is, for

Cornea

Sclerocorneal junction

Choroid

Suspensory,

Circular^

ligaments

fibers

Meridional fibers

Ciliary

muscle

Suspensory ligaments Lens

—

reading.

Figure

34-2 Mechanism of accommodation

(focusing).

^

402

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

concave spherical lens, as illusby the top diagram in Figure 34-4, which

front of the eye a

trated

will diverge rays.

On

the other hand, in a person who has hyperis, someone who has too weak a lens abnormal vision can be corrected by

— that system — the

opia

adding refractive power with

a convex lens in front of the eye, illustrated in the lower diagram in Fig-

ure 34-4. One usually determines the strength of the concave or convex lens needed for clear vision by "trial and error" that is, by trying first a strong lens and then a stronger or weaker lens until the one that gives the best visual acuity is found.

—

Astigmatism

Myopia Figure 34-3 Parallel light rays focus exactly on the retina in emmetropia, behind the retina in hyperopia, and in front of the

retina in

myopia.

Astigmatism is a refractive error of the eye that causes the visual image in one plane to focus at a different distance from that of the plane at right angles. This most often results from too great a curvature of the cornea in one of its planes. A lens surface like the side of an egg lying sidewise to the

incoming

amount modate has

of strength in the ciliary muscle to accomfor the distant objects, then

much accommodative power

he or she

left,

and

still

objects

and closer to the eye can also be focused sharply until the ciliary muscle has contracted to its closer limit.

In old age, when the lens becomes presbyopic, the far-sighted person often is not able to accom-

modate

even

his or her lens sufficiently to focus

distant objects,

Myopia.

much

less to focus

near objects.

In myopia, or "near-sightedness,"

the ciliary muscle

when

completely relaxed the light rays coming from distant objects are focused in front of the retina, as shown in the lowest panel of Figure 34-3. This is usually due to too long an eyeball, but it can occasionally result from too much refractive power of the lens system of the eye. No mechanism exists by which the eye can decrease the strength of its lens to less than that which exists when the ciliary muscle is completely relaxed. Therefore, the myopic person has no mechanism by which he or she can ever focus distant objects sharply on the retina. However, as an object comes nearer to the eye, it finally comes near enough that its image can be focused. Then, when the object comes still closer to the eye, the person can use the mechanism of accommodation to keep the image focused clearly Therefore, a myopic person has a definite limiting "far point" for clear is

light

would be an example

of

an

astig-

matic lens. The degree of curvature in the plane through the long axis of the egg is not nearly so great as the degree of curvature in the plane through the short axis. Because the curvature of the astigmatic lens along one plane is less than the curvature along the other plane, light rays striking the peripheral portions of the lens in one plane are not bent nearly so much as are rays striking the peripheral portions of the other plane. This is illustrated in Figure 34-5, which shows rays of light emanating from a point source and passing through an oblong, astigmatic lens. The light rays in the vertical plane, indicated by plane BD, are refracted greatly by the astigmatic

lens because of the greater curvature in the vertical

direction than in the horizontal direction.

However,

the light rays in the horizontal plane, indicated by

vision.

Correction of Myopia and Hyperopia by Use of Lenses. It will be recalled that light rays passing

through a concave lens diverge. Therefore, if the refractive surfaces of the eye have too much refractive power, as in myopia, some of this excessive refractive power can be neutralized by placing in

Figure

34-4 Correction of myopia with a concave convex lens.

rection of hyperopia with a

lens,

and

cor-

34

Point source of light

The Eye:

I.

Optics of Vision; Fluids; Retina

^

403

principles of optics that the axis of the out-of-focus component of the optical system is par-

cylindrical

the bars that are fuzzy. Once this axis is found, the examiner tries progressively stronger and weaker positive or negative cylindrical lenses, the axes of which are placed parallel to the out-offocus bars, until the patient sees all the crossed bars with equal clarity. When this has been accomplished, the examiner directs the optician to grind a special lens having the spherical correction as well as the cylindrical correction at the appropriate axis. allel to

Focal line plane BD

for

Plane

AC

Plane

(less refractive

BD more

refractive

power)

power

-Focal line for plane AC

Correction of Optical Abnormalities

Figure

focal

34-5 Astigmatism, illustrating distance in one focal plane and

that light rays focus at at

one

another focal distance in

the plane at right angles.

In recent years,

plane.

The accommodative power of the eye can never compensate for astigmatism because, during accommodation, the curvature of the eye lens changes equally in both planes. In other words, each of the two planes requires a different degree of accommodation to be corrected, so that the two planes are never corrected at the same time. Thus, vision never occurs with a sharp focus without the help of glasses. of Astigmatism with a Cylindrical consider an astigmatic eye as having a lens system made up of two cylindrical lenses of different strengths and placed at right angles to each other. Therefore, to correct for astigmatism the usual procedure is to find a spherical lens by "trial and error" that corrects the focus in one of the two planes of the astigmatic lens. Then an additional cylindrical lens is used to correct the error in the remaining plane. To do this, both the axis and the strength of the required cylindrical lens must be determined. There are several methods for determining the axis of the abnormal cylindrical component of the lens system of an eye. One of these methods is based on the use of parallel black bars of the type shown in Figure 34-6. Some of these parallel bars are vertical, some horizontal, and some at various angles to the vertical and horizontal axes. After placing various spherical lenses in front of the astigmatic eye by trial and error, a strength of lens will usually be found that will cause sharp focus of one set of these parallel bars but will not correct the fuzziness of the set of bars at right angles to the sharp bars. It can be shown from the physical

Correction

Lens.

One may

either glass

or plastic contact

snugly against the anterior surface of the cornea. These lenses are held in place by a thin layer of tears that fills the space between the contact lens and the anterior eye surface. lenses

A plane AC, are bent not nearly so much as the light rays in the vertical plane. It is obvious, therefore, that the light rays passing through an astigmatic lens do not all come to a common focal point, because the light rays passing through one plane focus far in front of those passing through the other

have been

by Use of Contact Lenses

lifies

fitted

special feature of the contact lens

is

that

it

nul-

almost entirely the refraction that normally

occurs at the anterior surface of the cornea. The reason for this is that the tears between the contact lens and the cornea have a refractive index almost equal to that of the cornea so that no longer does the anterior surface of the cornea play a significant role in the eye's optical system. Instead, the anterior surface of the contact lens now plays the major role. Thus, the refraction of this contact lens substitutes for the cornea's usual refraction. The contact lens has several other advantages as well, including (1) the lens turns with the eye and gives a broader field of clear vision than do usual glasses, and (2) the contact lens has little effect on the size of the object that the person sees through the lens; on the other hand, lenses placed several

centimeters in front of the eye do affect the size of the image in addition to correcting the focus.

12

Figure 34-6 Chart composed of parallel black bars at different angular orientations for determining the axis of astigmatism.

^

404

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

Cataracts

Cataracts are an especially common eye abnormality that occurs mainly in older people. A cataract is a cloudy or opaque area or areas in the lens. In the early stage of cataract formation the proteins in some of the lens fibers become denatured. Later, these same proteins coagulate to form opaque areas in place of the normal transparent protein fibers. When a cataract has obscured light transmission so greatly that it seriously impairs vision, the condition can be corrected by surgical removal of the lens. When this is done, however, the eye loses a large portion of its refractive power, which must be replaced by a powerful convex lens in front of the eye; or an artificial lens may be implanted inside the eye in place of the removed lens.

Visual Acuity

from a distant point source, focused on the retina, should be infinitely small. However, since the lens system of the eye is not perfect, such a retinal spot ordinarily has a total diameter of about 11 micrometers even with maximal resolution of the optical system. However, it is brightest in its very center and shades off gradually toward the edges, as illustrated by the two-point images in Figure 34-7. The average diameter of cones in the fovea of the Theoretically, light

when

where vision is most highly developed, is approximately 1.5 micrometers, which is one seventh the diameter of the retina, the central part of the retina

spot of light. Nevertheless, since the spot of light has a bright center point and shaded edges, a person can normally distinguish two separate points if their centers he as much as 2 micrometers apart on the retina, which is slightly greater than the width of a foveal cone. This discrimination between points is also illustrated in Figure 34-7. The normal visual acuity of the human eye for discriminating between point sources of light is

about 25 seconds of arc. This means that a person with normal acuity looking at two bright pinpoint spots of light 10 meters away can barely distinguish the spots as separate entities when they are 1.5 to 2 millimeters apart.

The fovea is less than one half a millimeter (less than 500 micrometers) in diameter, which means that maximal visual acuity occurs in less than 2 degrees of the visual field (about 20 centimeters wide at 10 meters distance). Outside this foveal area the visual acuity is reduced five- to tenfold, and it becomes progressively poorer as the periphery is approached. This is caused by the connection of many rods and cones to the same optic nerve fiber in the nonfoveal parts of the retina. Clinical Method for Stating Visual Acuity. Usually the test chart for testing eyes is placed 20 feet away from the tested person, and if the person can see the letters of the size that he should be able to see at 20 feet, he is said to have 20/20 vision: that is, normal vision. If he can see only letters that he should be able to see at 200 feet, he is said to have 20/200 vision. In other words, the clinical method for expressing visual acuity is to use a mathematical fraction that expresses the ratio of two distances,

which

to that of the

is

also the ratio of one's visual acuity

normal person.

Determination of Distance of an Object from the Eye

— Depth

Perception

The visual apparatus normally perceives distance by several different means. This phenomenon is known as depth perception. Two of these means are (1) the size of the image of known objects on the retina, and (2) the phenomenon of stereopsis. Determination of Distance by Sizes of Retinal Images of Known Objects. If one knows that a

man whom he is viewing is 6 feet tall, he can termine how far away the man is simply by size of the man's image on his retina. He does

dethe not consciously think about the size, but his brain has learned to calculate automatically from image sizes the distances of objects when the dimensions are

known.

—

Determination of Distance by Stereopsis Binocular Vision. Another method by which one

perceives distance is that of binocular vision. Because one eye is a little more than 2 inches to one side of the other eye, the images on the two retinas that is, an object are different one from the other that is 1 inch in front of the bridge of the nose forms an image on the left side of the retina in the left eye but on the right side of the retina in the right eye, whereas a small object 20 feet in front of

—

Figure

34-7 Maximal visual acuity

for two-point sources of light.

the nose has its image at closely corresponding points in the middle of each retina. This effect is illustrated in Figure 34-8, which shows the images of a black spot and a square actually reversed on

34

Object of known distance and size

Unknown object

2.

Figure

Stereopsis

34-8 Perception and (2) as a

the retina

the

two

of distance (1)

by the

size of the

image on

result of stereopsis.

retinas because they are at different dis-

tances in front of the eyes. This gives a type of vision that is present all the time when both eyes are being used. It is almost entirely this visual phenomenon (or stereopsis), that gives a person with

two eyes far greater ability to judge relative distances when objects are nearby than a person who has only one eye. However, stereopsis is virtually useless for depth perception at distances beyond 200

I.

^

and the correction

for

abnormal refractive power of be made by selecting a lens

either or both eyes can

of appropriate strength.

THE FLUID SYSTEM OF THE

EYE— THE

The eye is filled with intraocular fluid, which maintains sufficient pressure in the eyeball to keep it distended. Figure 34-10 illustrates that this fluid can be divided into two portions, the aqueous hu-

INSTRUMENT— THE

The ophthalmoscope is an important instrument used by all doctors to look into another person's eye and see the retina with clarity. Though the ophthalmoscope appears to be a relatively complicated its

components are

principles

are

The basic 34-9 and may

simple.

illustrated in Figure

be explained as follows.

on the retina of an emrays from this spot diverge to-

a bright spot of light is

metropic eye, light

ward

the lens system of the eye, and, after passing through the lens system, they are parallel with each other because the retina is located exactly one focal length distance behind the lens. Then, when these parallel rays pass into an emmetropic eye of another person, they focus back again to a point focus on the retina of the second person because his retina is also one focal length distance behind the lens. Therefore,

any spot of

light

on the

mor, which lies in front and to the sides of the lens, and the fluid of the vitreous humor, which lies between the lens and the retina. The aqueous humor is a freely flowing fluid, whereas the vitreous humor, sometimes called the vitreous body, is a gelatinous mass held together by a fine fibrillar network composed primarily of greatly elongated proteogly-

can molecules. Substances can diffuse slowly in the vitreous humor, but there is little flow of fluid. Aqueous humor is continually being formed and reabsorbed. The balance between formation and reabsorption of aqueous humor regulates the total volume and pressure of the intraocular fluid.

Observed eye

Observer's eye

y

/

retina of

the observed eye projects to a focal spot on the retina of the observing eye. Thus, if the retina of is made to emit light, the image of his be focused on the retina of the observer provided the two eyes are simply looking into each other. These principles, of course, apply only to completely emmetropic eyes. To make an ophthalmoscope, one need only devise a means for illuminating the retina to be examined. Then, the reflected light from that retina can

one person retina will

405

INTRAOCULAR FLUID

OPHTHALMOSCOPE

instrument,

Optics of Vision; Fluids; Retino

be seen by the observer simply by putting the two eyes close to each other. To illuminate the retina of the observed eye, an angulated mirror or a segment of a prism is placed in front of the observed eye in such a manner, as illustrated in Figure 34-9, that light from a bulb is reflected into the observed eye. Thus, the retina is illuminated through the pupil, and the observer sees into the subject's pupil by looking over the edge of the mirror or prism, or through an appropriately designed prism. It was noted above that these principles apply only to persons with completely emmetropic eyes. If the refractive power of either eye is abnormal, it is necessary to correct this refractive power in order for the observer to see a sharp image of the observed retina. Therefore, the usual ophthalmoscope has a series of lenses mounted on a turret so that the turret can be rotated from one lens to another,

feet.

OPTICAL

If

The Eye:

Illuminated retina with

Corrective lens

blood vessel

turret (4 diopters for

in

normal eyes)

Collimating lens

Figure

34-9 The

optical

system of the ophthalmoscope.

406

IX

The .Nervous System: (A) Basic Organization; and Sensory Physiology

carbonate ions along with them to maintain electrical neutrality. Then all these ions together cause osmosis of water from the sublying tissue into the

Aqueous humor Spaces Flow

of

Fontana

of

fluid

Canal

of

Schlemm

Ciliary

body

Diffusion of fluid

same

epithelial intercellular spaces, and the resulting solution washes from the spaces onto the surfaces of the ciliary processes. In addition, several nutrients are transported across the epithelium by active transport or facilitated diffusion; these include amino acids, ascorbic acid, and glucose.

and

other constituents

Outflow of Aqueous Humor from the Eye Filtration

and

diffusion

at retinal

vessels

After aqueous humor is formed by the ciliary processes, it flows, as shown in Figure 34-10, belens, then through the pupil chamber of the eye. Here, the fluid flows into the angle between the cornea and the iris and thence through a meshwork of trabeculae, finally entering the canal of Schlemm, which empties into extraocular veins. Figure 34-12 illustrates the anatomical structures at the iridocorneal angle, showing that the spaces between the trabeculae extend all the way from the anterior chamber to the canal of Schlemm. The canal of Schlemm in turn is a thin-walled vein that extends circumferentially all

tween the ligaments of the into the anterior

Optic nerve Figure

34-10 Formation and flow of

fluid in the eye.

Formation of Aqueous Humor

by the

Ciliary

Body

Aqueous humor is formed in the eye at an average rate of 2 to 3 microliters each minute. Essentially all of this is secreted by the ciliary processes, which are linear folds projecting from the ciliary body into the space behind the

where the

lens ligaments the eyeball. cross-section of these ciliary processes is illustrated

and

ciliary

iris

muscle also attach

in Figure 34-11.

The surfaces

A

to

The sodium ions

in turn pull chloride

Ciliary

Intraocular Pressure

of these processes are

covered by highly secretory epithelial cells, and immediately beneath these is a highly vascular area. Aqueous humor is formed almost entirely as an active secretion of the epithelium lining the ciliary processes. Secretion begins with active transport of sodium ions into the spaces between the epithelial cells.

way around the eye. Its endothelial membrane so porous that even large protein molecules, as well as small particulate matter up to the size of red blood cells, can pass from the anterior chamber into the canal of Schlemm. the

is

and

bi-

The average normal intraocular pressure is approximately 15 Hg, with a range from 12 to 20. This pressure remains very constant in the normal eye, normally within about ± 2 Hg. The level of this pressure is determined mainly by the resistance to outflow of aqueous humor from the anterior chamber into the canal of Schlemm. This outflow resistance results from the meshwork of

mm

mm

processes

Cornea

Vascular layer

Ciliary

muscle Figure

Figure

34-11 Anatomy of the

ciliary processes.

tem

34-12 Anatomy of the iridocorneal angle, showing the sysoutflow of aqueous humor into the conjunctival veins.

for

34

trabeculae through which the fluid must percolate on its way from the lateral angles of the anterior chamber to the wall of the canal of Schlemm. These trabeculae have minute openings of only 2 to 3 micrometers. Fortunately though, as the pressure rises Hg, it enlarges these spaces and lets above 15 off the excess pressure. Glaucoma, Principal Cause of Blindness. Glaucoma is one of the most common causes of blindness. It is a disease of the eye in which the intraocular pressure becomes pathologically high, sometimes rising acutely to as high as 60 to 70 Hg. Pressures rising above as little as 20 to 30 Hg can cause loss of vision when maintained for long periods of time. And extremely high pressures can cause blindness within days or even hours. As the pressure rises, the axons of the optic nerve are compressed where they leave the eyeball at the optic disc. This compression is believed to block axonal flow of cytoplasm from the neuronal cell bodies in the retina to the extended optic nerve fibers entering the brain. The result is lack of appropriate nutrition of the fibers, which eventually causes death of the involved neurons. In most cases of glaucoma the abnormally high pressure results from increased resistance to fluid outflow through the trabecular spaces into the canal of Schlemm at the iridocorneal junction. For instance, in acute eye inflammation, white blood cells and tissue debris can block these trabecular spaces and cause acute increase in intraocular pressure. In chronic conditions, especially in older age,

mm

A

The Eye:

I.

^

Optics of Vision; Fluids; Retina

407

fibrous occlusion of the trabecular spaces appears be the likely culprit.

to

Glaucoma can sometimes be treated by placing drops in the eye containing a drug that diffuses into the eyeball and causes reduced secretion or increased absorption of aqueous humor. However, when drug therapy fails, operative techniques to open the spaces of the trabeculae or to make channels directly between the fluid space of the eyeball and the subconjunctival space outside the eyeball can often effectively reduce the pressure.

mm mm

OUTSIDE .--Pigmented layer

Layer

of rods

and cones

Outer

limiting

membrane

I

.J-

| Outer nuclear layer Outer plexiform layer Horizontal cell

Inner nuclear layer Fiber of MLiller

-J-Amacrine

cell

nner plexiform layer

\{f

lj~~}

t

t

Ganglion

cells

Figure

served.)

the light-sensitive portion of the which are responsible for color vision, and the rods, which are mainly responsible for vision in the dark. When the rods and cones are excited, signals are transmitted through successive neurons in the retina itself and finally into the optic nerve fibers and cerebral cortex. The purpose of the present chapter is to explain specifically the mechanisms by which the rods and cones detect both white and colored light and convert the visual image into electrical signals. retina

is

Anatomy and

Function of the

Structural Elements of the Retina

The Layers of the Retina. Figure 34-13 shows the functional components of the retina arranged in layers from the outside to the inside as follows: (1) pigment layer, (2) layer of rods and cones projecting into the pigment, (3) outer limiting membrane, (4) outer nuclear layer containing the cell bodies of the rods and cones, (5) outer plexiform layer, (6) inner nuclear layer, (7) inner plexiform layer, (8) ganglionic layer, (9) layer of optic nerve fibers, and (10) inner limiting membrane. After light passes through the lens system of the eye and then through the vitreous humor, it enters the retina from the inside (Figure 34-13); that is, it passes first through the ganglion cells, then through the plexiform layers, the nuclear layer, and the limiting membranes before it finally reaches the layer of rods and cones located all the way on the outer side of the retina. This distance is a thickness of several hundred micrometers; visual acuity is obviously decreased by this passage through such

nonhomogeneous

Stratum opticum

region of the retina, as will be discussed below, the inside layers are pulled aside for prevention of this

Inner limiting

membrane

34-13 Plan of the retinal neurons. (Modified from Polyak: © 1941 by the University of Chicago. All rights re-

Retina.

The

eye, containing the cones,

Ganglionic layer

DIRECTION OF LIGHT The

THE RETINA

tissue.

However,

in

the central

loss of acuity.

The Foveal Region of the Retina and Its Importance in Acute Vision. A minute area in the center of the retina, illustrated in Figure 34-14, called the macula and occupying a total area of less than 1 square millimeter, is especially capable of acute and detailed vision. The central portion of the macula,

408

^

The Nervous System: (A) Basic Organization; and Sensory Physiology

IX

Figure

34-14 Photomicrograph of the macula and of the fovea

in its center.

ers of the retina are pulled to the side to decrease the interference

A

only 0.4 millimeter in diameter,

is called the fovea; area is composed entirely of cones, and its cones also have a special structure that aids their detection of detail in the visual image, especially a

this

long slender body, in contrast to

much

fatter

cones

located further peripherally in the retina. Also, in this region the blood vessels, the ganglion cells, the inner nuclear layer of cells, and the plexiform layers are all pulled to one side rather than resting directly on top of the cones. This allows light to pass unimpeded to the cones. The Rods and Cones. Figure 34-15 is a diagram-

matic representation of a photoreceptor (either a rod or a cone). As illustrated in Figure 34-16, the

Membrane shelves lined with

rhodopsin

Note

that the inner lay-

\

Outer

segment

or color

pigment

(From Saunders

light transmission.

Textbook of Histology. 11th ed. Philadelphia, W. 1986; courtesy of H. Mizoguchi.)

Fawcett, D. W.:

Company

Bloom and Fawcett:

with

B.

outer segment of the cones is conical in shape. In general, the rods are narrower and longer than the cones, except in the fovea where the cones have a diameter of only 1.5 micrometers. To the right in Figure 34-15 are labeled the four major functional segments of either a rod or a cone: (1) the outer segment, (2) the inner segment, (3) the nucleus, and (4) the synaptic body. In the outer segment the light-sensitive photochemical is found. In the case of the rods, this is rhodopsin, and in the cones it is one of three "color" photochemicals, usually called simply color pigments, that function almost exactly the same as rhodopsin except for differences in color sensitivity.

Note in Figures 34-15 and 34-16 the large numbers of discs in both the rods and the cones. In the cones, each of the discs is actually an infolded shelf of cell membrane; in the rods this is also true near the base of the rod. However, toward the tip of the rod the discs separate from the membrane and are flat sacs lying totally inside the cell. There are as many as 1000 discs in each rod or cone. Both rhodopsin and the color pigments are conjugated proteins. These are incorporated into the membranes of the discs in the form of transmembrane proteins. The concentrations of these photosensitive pigments in the discs are so great that the pigments themselves constitute approximately 40

Synaptic

body Figure

34-15 The functional parts of the rods and cones.

per cent of the entire mass of the outer segment. The inner segment contains the usual cytoplasm of the cell with the usual cytoplasmic organelles. Particularly important are the mitochondria; the mitochondria in this segment play the important role in providing the energy for function of the photoreceptors. The synaptic body is the portion of the rod or cone that connects with the subsequent neuronal cells, the horizontal and bipolar cells, that represent the next stages in the vision chain. The Pigment Layer of the Retina. The black pig-

34

The Eye:

I.

409

Optics of Vision; Fluids; Retina

Figure 34-16 Membranous structures of the outer segments of a rod (left) and a cone (right). (Cour-

tesy of Dr. Richard Young.)

ment melanin

in the

pigment layer prevents

light

throughout the globe of the eyeball; this is extremely important for clear vision. This pigment performs the same function in the eye as the black coloring inside the bellows of a camera. Without it, light rays would be reflected in all directions within the eyeball and would cause diffuse lighting of the retina rather than the contrast between dark and light spots required for formation of precise reflection

images.

The chemical in the rods is called rhodopsin, and the light-sensitive chemicals in the cones, called the cone pigments, have compositions only slightly different from that of rhodopsin. eye.

In the present section

we

discuss principally the

photochemistry of rhodopsin, but

we

most exactly the same principles ments of the cones.

to the

can apply alcone pig-

—

The Blood Supply of the Retina The Central Artery, and the Choroid. The nutrient

The Rhodopsin-Retinal Visual Cycle,

Retinal

blood supply for the internal layers of the retina is derived from the central retinal artery, which enters the eyeball along with the optic nerve and then divides to supply the entire inside retinal surface. Thus, to a great extent, the retina has its own blood supply independent of the other structures of the eye.

However, the outside surface of the retina is adherent to the choroid, which is a highly vascular tissue between the retina and the sclera. The outer layers of the retina, including the outer segments of the rods and cones, depend mainly on diffusion from the choroid vessels for their nutrition, espe-

and Excitation of the Rods

Rhodopsin and Its Decomposition by Light EnThe outer segment of the rod that projects

ergy.

into the

pigment layer of the retina has a concenabout 40 per cent of the light-sensitive

tration of

pigment called rhodopsin, or visual purple. This substance is a combination of the protein scotopsin and the carotenoid pigment retinal. Furthermore, the retinal is a particular type called 11-cz's retinal. The cis form of the retinal is important because only this form can bind with scotopsin to synthesize rhodopsin.

PHOTOCHEMISTRY OF VISION

When light energy is absorbed by rhodopsin, the rhodopsin begins within trillionths of a second to decompose, as shown at the top of Figure 34-17. The cause of this is photoactivation of electrons in

Both the rods and cones contain chemicals that decompose on exposure to light and, in the process, excite the nerve fibers leading from the

the retinal portion of the rhodopsin, which leads to an instantaneous change of the cis form of retinal into an a\\-trans form, which still has the same chemical structure as the cis form but has a differ-

cially for their

oxygen.

^

410

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

Light

energy

Rhodopsin

Bathorhodopsin (n sec)

(p sec) It

I Lumirhodopsin (ij.

sec)

ducing the amount of light-sensitive pigment

I Metarhodopsin (m sec)

(minutes)

I

II

(sec)

Opsin

Isomerase all-trans-Retinal

H

it

Isomerase

We

in the

shall see later that this intercon version

retinal

and vitamin

A

is

especially impor-

tant in long-term adaptation of the retina to differ-

Metarhodopsin

all-trans-Retinol

l-cis-Retinol

retina.

between

I

ll-cis-Retinal

Vitamin A is present both in the cytoplasm of the rods and in the pigment layer of the retina as well. Therefore, vitamin A is normally always available to form new retinal when needed. On the other hand, when there is excess retinal in the retina, the excess is converted back into vitamin A, thus re-

(Vitamin A) Figure 34-17 The rhodopsin-retinal visual cycle in the rod, showing decomposition of rhodopsin during exposure to light and subsequent slow reformation of rhodopsin by the chemical

ent light intensities. Night Blindness. Night blindness occurs in se-

vere vitamin A deficiency. The simple reason for this is that not enough vitamin A is then available to form adequate quantities of retinal. Therefore, the amount of rhodopsin that can be formed becomes severely depressed. This condition is called "night blindness" because the amount of light available at night is then too little to permit adequate vision, though in daylight the cones can still be excited despite some reduction of their color

pigments as well.

processes. Excitation of the

—

ent physical structure a straight molecule rather than an angulated molecule. Because the threedimensional orientation of the reactive sites of the all-frarcs retinal no longer fits with the orientation of the reactive sites on the protein scotopsin, it begins to pull away from the scotopsin. The immediate product

unstable

is

bathorhodopsin,

compound

which

that decays in

lumirhodopsin. This then decays in

is an extremely nanoseconds to microseconds to

metarhodopsin I, then in about a millisecond to metarhodopsin II, and, finally, much more slowly (in seconds) into the completely split products: scotopsin and fl//-trans retinal. It is the metarhodopsin II, also called activated rhodopsin, that excites electrical changes in the rods that then transmit the visual image into the central nervous system, as we discuss later.

Rhodopsin Is Reformed Each Time It Is Used. The first stage in reformation of rhodopsin, as

shown

in Figure

34-17,

is

to reconvert the a\\-trans

retinal into 11 -as retinal. This process is catalyzed

by the enzyme

retinal isomerase.

Once

the 11-cis

reti-

nal is formed, it automatically recombines with the scotopsin to reform rhodopsin, which then remains stable until its decomposition is again triggered by

absorption of light energy. The Role of Vitamin A in the Formation of Rhodopsin. Note in Figure 34-17 that there is a second chemical route by which all-trans retinal can be converted into 11-cis retinal. This is by conversion of the all-trans retinal first into a//-trans retinal, which is one form of vitamin A. Then, the all-trans

converted into 11-cis retinol under the inenzyme isomerase. And, finally, the 11-cis retinol is converted into 11-cis retinal that combines with scotopsin to form rhodopsin. retinol

is

fluence of the

Rod When Rhodopsin

Is

Activated

The Rod Receptor Potential Is Hyperpolarizing, Not Depolarizing. When the rod is exposed to light,

the resulting receptor potential

is

different

from the receptor potentials in almost all other sensory receptors. That is, excitation of the rod causes increased negativity of the

which

is

rod

membrane

potential,

a state of hyperpolarization. This is exactly

opposite to the decreased negativity (the process of "depolarization") that occurs in almost all other sensory receptors. But how does activation of rhodopsin cause hyperpolarization? The answer is that when rhodopsin decomposes, it decreases the membrane conductance for sodium ions in the outer segment of the rod. And this causes hyperpolarization of the entire rod membrane in the following way: Figure 34-18 illustrates movement of sodium ions in a complete electrical circuit through the in-

ner and outer segments of the rod. The inner segment continually pumps sodium from inside the rod to the outside, thereby creating a negative potential on the inside of the entire cell. However, the outer segment of the rod, where the photoreceptor discs are located, is entirely different: here the rod membrane, in the dark state, is very leaky to sodium ions. Therefore, sodium ions continually leak back to the inside of the rod and thereby neutralize much of the negativity on the inside of the entire cell. Thus, under normal dark conditions when the rod is not excited, there is a reduced amount of electronegativity inside the membrane of the rod, normally measuring about — 40 millivolts rather than the more usual - 70 to - 80 millivolts found in most sensory receptors. When the rhodopsin in the outer segment of the rod is exposed to light and begins to decompose, this decreases the membrane conductance of sodium

34

Leakage

N

decreased by decomposing rhodopsin

i

Optics of Vision; Fluids; Retina

I.

^

411

quantal unit of light energy, can cause a receptor potential in a rod of about 1 millivolt. And only 30 photons of light will cause half saturation of the rod. How can such a small amount of light cause such great excitation? The answer is that the photoreceptors have an extremely sensitive chemical cascade that amplifies the stimulatory effects about

current

Na


i

3

5

1

55

—

^36^ 31,

>i

i

25

Q.

i\

roi

o/

1,

500

Wave Violet

|

|

\

Blue

|

Red-Green Color Blindness. When a single group of color receptive cones is missing from the

\ \

\

\

\

i

400

600

[

Yellow

|prangej

is unable to distinguish some colors from others. For instance, one can see in Figure 34-20 that green, yellow, orange and red colors, which are the colors between the wavelengths of 525 and 675 nanometers, are normally distinguished one from the other by the red and the

eye, the person

X. 700

length (nanometers)

Green

413

Color Blindness

\

\42

CI

n

^

|

/\

!

Optics of Vision; Fluids; Retina

approximately equally.

a. fa \ /

'

m

5

-

83) ^83|\

a> 9>

75

I.

lengths of the spectrum. Furthermore, the sensation of white can be achieved by stimulating the retina with a proper combination of only three chosen colors that stimulate the respective types of cones

/\"

/\

r

The Eye:

Red

34-20 Demonstration of the degree of stimulation of the by monochromatic lights of four separate colors: blue, green, yellow, and orange. Figure

different color-sensitive cones

green cones.

If

two cones mechanism

either of these

one no longer can use

this

is

missing,

for distin-

guishing these four colors; the person is especially unable to distinguish red from green and therefore said to have red-green color blindness. Red-green color blindness is a genetic disease that occurs almost exclusively in males but is transmitted through the female. That is, genes in the female X chromosome code for the respective cones. Yet color blindness almost never occurs in the female because at least one of her two X chromosomes will almost always have a normal gene for each type of cone. But the male has only one X chromosome, so that a missing gene will lead to is

peak stimulation

at

optimum wavelength). And

it

stimulates the green cones to a stimulus value of approximately 42 but the blue cones not at all. Thus, the ratios of stimulation of the three different types of cones in this instance are 99:42:0. The nervous system interprets this set of ratios as the sensation of orange. On the other hand, a monochromatic blue light with a wavelength of 450

nanometers stimulates the red cones to

a stimulus value of 0, the green cones to a value of 0, and the blue cones to a value of 97. This set of ratios

0:0:97

—

interpreted

is

by the nervous system

as

blue. Likewise, ratios of 83:83:0 are interpreted as

and 31:67:36 as green. Perception of White Light. Approximately equal stimulation of all the red, green, and blue cones gives one the sensation of seeing white. Yet there is no wavelength of light corresponding to white; instead, white is a combination of all the waveyellow,

color blindness in him.

Since the X chromosome in the male is always inherited from the mother, never from the father, color blindness is passed from mother to son, and the mother is said to be a color bli?tdness carrier; this is the case for about 8 per cent of all women. Blue Weakness. Only rarely are blue cones miss-

though sometimes they are underrepresented, which is a state also genetically inherited, giving ing,

rise to the

phenomenon

called blue weakness.

REFERENCES Eye Lens System and Eye Fluids

Tifie

D.: Duke-Elder's Practice of Refraction, 10th ed. New York, Churchill Livingstone, 1993. Albert, D. M., and Jakobiec, F. A.: Principles and Practice of Ophthalmology. Philadelphia, W. B. Saunders Co., 1994. Bennett, E. S., and Henrv, V. A.: Clinical Manual of Contact Lenses. Philadelphia, J. B. Lippincott Co., 1994.

Abrams,

Catalano, R. A., and Nelson, L. B.: Pediatric Ophthalmology: las. N'orwalk, CT, Appleton and Lange, 1994.

Davson, H.:

Phvsiology

of

the

Eve

Hightstown,

NJ,

A

Text/At-

S. A.:

rabbit retina.

Raven

J.

Press, 1993.

and Rowland,

R.:

Ophthalmic Pathology.

New

York, Churchill

Livingstone, 1994.

Smiddv, W.

1990.

Guvton, D.

L.:

Sights and

Binocular Vision.

Kaufman, H.

St.

E., et al.:

Sounds

Louis, C. V.

in

Ophthalmology: Ocular Motilitv and

Mosby

D., et

al.:

J.

B.

General Ophthalmology, 14th ed. Norwalk, CT, Ap-

pleton and Lange, 1995.

J.

B.

Spom,

Co., 1989.

Corneal and Refractive Surgery. Philadelphia,

Lippincott Co., 1991.

Vaughan,

Orientation-sensitive amacrine and ganglion cells in the Neurophysiol., 71:1672, 1994. Bovino, J. A.: Macular Surgery. Norwalk, CT, Appleton and Lange, 1994. Freeman, W. R.: Practical Atlas of Retinal Disease and Therapy. New York, Raven Press, 1993. Friedlaender, M. H.: Allergy and Immunology of the Eye. New York,

Bloomfield,

Iyer, P. V.,

McGraw-Hill,

Retina

E., et al.: Retinal Surgery and Ocular Trauma. Philadelphia, Lippincott Co., 1994. M. B., et al.: The Retinoids: Biology, Chemistrv, and Medicine.

New York, Raven Press, 1994. Wassle, H., and Boycott, B. B Functional Architecture of the :

Mammalian

Retina. Physiol. Rev, 71:447, 1991.

Wu,

S.

M.: Svnaptic transmission in the outer retina.

56:141, 1994.

Annu. Rev.

Physiol.,

^

414

The Nervous System: (A) Basic Organization; and Sensory Physiology

IX

QUESTIONS 1.

Why

is

the anterior surface of the cornea the major

13.

refractive surface of the eye's lens system? 2.

3.

When

the ciliary muscle of the eye

laxed,

what happens

to the tension

is

completely

re-

ments of the lens? What happens to lens and its focusing strength? What happens to the range of accommodation of the lens as a person becomes older? What is meant by

What

List the

15.

What

6.

7.

and

is

how the visual system determines distance an object from the eyes by the mechanism of stere-

Explain of

opsis. 9.

Describe the formation, flow, and absorption of fluid in the eyeball.

10.

Explain the factors that control the intraocular pressure.

11.

What fects

12.

is

glaucoma? Describe

on the

Describe the physical and chemical events that take place after rhodopsin is exposed to an instantaneous bright light.

necessary to correct each of the aforementioned abnormalities of vision? How far apart on the retina must two separate points of light be separated in order for a person to distinguish that there are two points rather than a single point? If a person is said to have 20/50 vision, what is of lens

17.

its

usual cause and

its ef-

eye.

Give the structure of fer from the rods?

a typical rod.

How

do

cones dif-

Describe the reformation of rhodopsin after

been decomposed 18.

What

is

19.

it

has

in bright light.

the relationship between vitamin

visual pigments of the rods

meant? 8.

the relationship of the pigment layer of the and cones, and what is the importance of this relationship? is

retina to the rods 16.

are the causes of hypermetropia, myopia,

What type

function in high acuity vi-

rhodopsin or iodopsin.

astigmatism? 5.

its

major functional segments of a rod or cone. Also describe the discs and their relationship to

14.

on the radial ligathe shape of the

presbyopia? 4.

Describe the fovea and sion.

A

and the

and cones?

How

does generation of the receptor potential in the rods differ from the generation of a receptor potential in most sensory receptors of the body? Explain the mechanism for generating this potential.

What

are the respective wavelengths for peak absorption by the different color types of cones? 21. Why are light and dark adaptation very important in vision? 22. Explain how the brain interprets color from the visual signals received from the retina. 23. What is the cause of color blindness? What type of color blindness is common? 20.

The Eye:

II.

Neurophysiology of Vision

35 laterally in the outer plexiform layer,

THE NEURAL FUNCTION OF THE RETINA

cells

form layer. To the left

The Neural Circuitry of the Retina Figure 34-13 of the previous chapter illustrated the tremendous complexity of neural organization in the retina. To simplify this, Figure 35-1 presents the basic essentials of the retina's neural connections, showing to the left the circuit in the peripheral retina retina. 1.

The

and

to the right the circuit in the foveal

different neuronal cell types are:

The photoreceptors themselves: the

rods

and

cones. 2.

The

izontally

horizontal cells, which transmit signals horfrom the rods and cones to the bipolar cell

dendrites. 3.

The bipolar cells, which transmit signals difrom the rods and cones and also from the

rectly

horizontal cells to either amacrine cells or ganglion cells. 4.

two

The amacrine

which transmit signals in from bipolar cells to or horizontally between the axons of cells,

directions, either directly

ganglion

cells

the bipolar cells, the dendrites of the ganglion cells,

and /or other amacrine cells. 5. The ganglion cells, which transmit output nals from the retina through the optic nerve

sig-

into

the brain.

The Visual Pathway from the Cones to the Ganglion Cells Is Different from the Rod Pathway. As is true for many of our other sensory systems, the retina has both a very old type of vision based on rod vision and a new type of vision based on cone vision.

The neurons and nerve

fibers that

conduct

the visual signals for cone vision are considerably larger than those for rod vision, and the signals are to the brain two to five times as rapidly. Also, the circuitries for the two systems are slightly

conducted

visual

far right in Figure

pathway from

retina, representing the

in Figure 35-1 are illustrated the neural connections for the peripheral retina where both rods and cones are present. Three bipolar cells are shown; the middle of these connects only to rods, representing the old visual system. In this case, the output from the bipolar cell passes only to amacrine cells, and these in turn relay the signals to the ganglion cells. Thus, for pure rod vision there are four neurons in the direct visual pathway: (1) rods, (2) bipolar cells, (3) amacrine cells, and (4) ganglion cells. Also, both horizontal and amacrine cells provide lateral connectivity. The other two bipolar cells illustrated in the peripheral retinal circuitry of Figure 35-1 connect with both rods and cones; the outputs of these bipolar cells pass both directly to ganglion cells

also by way of amacrine cells. Neurotransmitters Released by Retinal Neurons. The neurotransmitters employed for synaptic transmission in the retina still have not all been entirely delineated. However, both the rods and the cones release glutamate, an excitatory transmitter, at their synapses with the bipolar cells. And histological and pharmacological studies have shown there to be many different types of amacrine cells secreting at least eight different types of transmitter substances, including gamma-aminobutyric acid (GABA),

and

and indolamine, all of which normally function as inhibitory transmitters. The transmitters of the bipolar and horizontal cells

glycine, dopamine, acetylcholine,

are

still

unclear.

Transmission of Most Signals Occurs in the Retinal Neurons by Electrotonic Conduction, Not by Action Potentials. The only retinal neurons that always transmit visual signals by means of action potentials are the ganglion cells; these send their signals all the

different, as follows:

To the

the

new,

35-1

is

illustrated the

portion of the cone system. This

foveal fast,

and amacrine

transmit signals laterally in the inner plexi-

shows three neurons in the direct pathway: (1) cones, (2) bipolar cells, and (3) ganglion cells. In addition, horizontal cells transmit inhibitory signals

way

neurons conduct

by

to the brain. All other retinal

their visual signals

electrotonic conduction,

almost entirely

which can be explained

as

follows:

Electrotonic conduction

is the direct flow of elecnot action potentials, in the neuronal cytoplasm from the point of excitation all the way

trical current,

415

^

416

IX

The Nervous System: (A) Basic Organization; and Sensory Physiology

It is probable that some of the amacrine cells provide additional lateral inhibition and further enhancement of visual contrast as

ders in the visual image.

well.

Excitation of

Some

Bipolar Cells

and

of Others

Inhibition

The Depolarizing and Hyperpolarizing Bipolar

—

Cells

Two different types of bipolar cells provide opposing excitatory and inhibitory signals in the visual pathway, the depolarizing bipolar cell and the hyperpolarizing bipolar cell. That is, some bipolar cells depolarize when the rods and cones are excited, and others hyperpolarize. The importance of this reciprocal

between depolarizing and

relationship

hyperpolarizing bipolar

second mechanism for ...Ganglion -~„

©V

_y Figure

the

y

J

35-1 Neural organization of the

left,

cells is that

provides a

it

lateral inhibition in addition

mechanism. Since depolarizing and hyperpolarizing bipolar cells lie immediately along side each other, this gives a mechanism for separating contrast borders in the visual image even when the border lies exactly between two adjacent photoreceptors. to the horizontal cell

cells

retina: peripheral area to

foveal area to the right.

to the output synapses. Even in the rods and cones, conduction from their outer segments where the visual signals are generated to the synaptic bodies is by elecrrotonic conduction. That is, when hyperpolarization occurs in response to light in the outer segment, approximately the same degree of hyperpolarization is conducted by direct electrical current flow to the synaptic body, and no action potential at all occurs. Then, when the transmitter from a rod or cone stimulates a bipolar cell or horizontal cell, once again the signal is transmitted from the input to the output of either of these cells by direct electrical current flow, not by action potentials.

The importance

of electrotonic conduction is that allows graded conduction of signal strength. Thus, for the rods and cones, the strength of the hyperpolarizing output signal is directly related to the intensity of illumination; the signal is not all-or-none, as would be the case for action potential conduc-

The Amacrine

and

Their Functions

About 30 different types of amacrine cells have been identified by morphological or histochemical means. The functions of a half dozen different types of amacrine cells have been characterized, and all of these are different from each other. One type of amacrine cell is part of the direct pathway for rod vision that is, from rod to bipolar cells to amacrine cells to ganglion cells. Another type of amacrine cell responds very

—

strongly at the onset of a visual signal, but the response dies out rapidly. Other amacrine cells respond very strongly at the offset of visual signals, but again the response dies quickly.

it

tion.

Cells

Still

another type of amacrine

cell

responds to

movement

of a spot across the retina in a specific direction; therefore, these amacrine cells are said to

be

directionalhj sensitive.

In a sense, then, amacrine cells are types of interneurons that help in the beginning analysis of

visual signals before they ever leave the retina. Lateral Inhibition to Enhance Visual Contrast

—

Function of the Horizontal Cells

Excitation of the Ganglion Cells

The horizontal cells, illustrated in Figure 35-1, connect laterally between the synaptic bodies of the rods and cones and also with the dendrites of the bipolar cells. The outputs of the horizontal cells are always

inhibitory. Therefore, this lateral connection provides the same phenomenon of lateral inhibition that is important in all other sensory systems, that is, helping ensure transmission of visual patterns with proper visual contrast into the central nervous system. This is an essential mechanism to allow high visual accuracy in transmitting contrast bor-

Connectivity of the Ganglion Cells with Cones Fovea and with Rods and Cones in the Peripheral Retina. Each retina contains about 100,000,000 rods and 3,000,000 cones; yet the number of ganglion cells is only about 1,600,000. Thus, an average of 60 rods and 2 cones converge on each optic nerve fiber. However, major differences exist between the pein the

ripheral retina

and the

central retina.

As one ap-

proaches the fovea, fewer rods and cones converge

— 35

and the rods and cones both beThese two effects progressively increase the acuity of vision toward the central retina. And in the very center, in the fovea itself, there are only slender cones, about 35,000 of them, and no rods at all. Also, the number of optic nerve fibers leading from this part of the retina is almost equal on each optic

come

to the

fiber,

slenderer.

number

of cones, as illustrated to the right in

Figure 35-1. This mainly explains the high degree of visual acuity in the central retina in comparison with much poorer acuity peripherally. Another difference between the peripheral and central portions of the retina is a much greater sensitivity of the peripheral retina to weak light. This results partly from the fact that rods are 30 to 300 times more sensitive to light than are cones, but it is further magnified by the fact that as many as 200 rods converge on the same optic nerve fiber in the more peripheral portions of the retina, so that the signals from the rods summate to give even more intense stimulation of the peripheral ganglion cells.

Three Different Types of Retinal Ganglion Cells

and

Their Respective Fields

There are three distinct groups of ganglion cells designated as W, X, and Y cells. Each of these serves a different function: Transmission of Rod Vision by the Cells. The cells, constituting about 40 per cent of all the ganglion cells, are small, having a cell body diameter of less than 10 micrometers and transmitting signals in their optic nerve fibers at the slow velocity of only 8 m/sec. These ganglion cells receive most of their excitation from rods, transmitted by way of small bipolar cells and amacrine cells. They have very broad fields in the retina because their dendrites spread widely in the retina. On the basis of histology as well as physiological experiments, it appears that the cells are especially sensitive for detecting directional movement anywhere in the field of vision, and they probably also are important for much of our crude rod vision under dark conditions. Transmission of the Visual Image and Color by the X Cells. The most numerous of the ganglion cells are the X cells, representing 55 per cent of the total. They are of medium cell body diameter, between 10 and 15 micrometers, and transmit signals in their optic nerve fibers at about 14 m/sec. The X cells have very small fields because their dendrites do not spread widely in the retina. Because of this, the signals represent rather discrete retinal locations. Therefore, it is through the X cells that the visual image itself is mainly transmitted. Also, because every X cell receives input from at least one cone, X cell transmission is believed to be responsible for all color vision. Function of the Y Cells in Transmitting Instantaneous Changes in the Visual Image. The Y cells

W

W

W

The Eye:

II.

Neurophysiology of Vision

^

417

all, up to 35 micrometers in diamand they transmit their signals to the brain faster than 50 m/sec. However, they are the fewest

are the largest of eter,

of all the ganglion cells, representing only 5 per

cent of the

total.

Also, they

have very broad denpicked up by these

dritic fields, so that signals are

from widespread retinal areas. The Y ganglion cells respond like many

cells

of the

rapid changes in the visual image, either rapid movement or rapid change in light intensity, sending bursts of signals for only a fraction of a second. Therefore, these ganglion cells undoubtedly apprise the central nervous system almost instantaneously when an abnormal visual event occurs anywhere in the visual field, but without specifying with great accuracy the location of the event other than to give appropriate clues for moving the eyes toward the exciting vision.

amacrine

cells to

Excitation of the Ganglion Ceils

Spontaneous, Continuous Action Potentials in the Ganglion Cells. It is from the ganglion cells that the long fibers of the optic nerve lead into the brain. Because of the distance involved, the electrotonic method of conduction is no longer appropriate; therefore, ganglion cells transmit their signals by means of action potentials instead. Furthermore, even when unstimulated they still transmit continuous impulses at rates varying between 5 and 40 per second, with the nerve fibers from the large ganglion cells firing more rapidly. The visual signals, in turn, are superimposed onto this back-

ground ganglion cell firing. Transmission of Changes in Light Intensity The On-Off Response. Many ganglion cells are especially excited by changes in light intensity. This is illustrated by the records of nerve impulses in Figure 35-2, showing in the upper panel rapid impulses for a fraction of a second when a light was first turned on; but the rapidity decreased in a fraction of a second. The lower tracing is from a ganglion cell located lateral to the spot of light; this

on

off

Excitation

Lateral inhibition

35-2 Responses of ganglion cells to light in (1) an area exby a spot of light and (2) an area immediately adjacent to the excited spot; the ganglion cells in this area are inhibited by the mechanism of lateral inhibition. (Modified from Granit: Receptors and Sensory Perception: A Discussion of Aims, Means, and Results of Electrophysiological Research into the Process of Reception. New Haven, Conn., Yale University Press, 1955.) Figure

cited

—

1 1

418 cell

^

The Nervous System: (A) Basic Organization; and Sensory Physiology

IX

was markedly

inhibited

when

the light

was

turned on because of lateral inhibition. Then, when the light was turned off, exactly the opposite effects occurred. Thus, these records are called "on-off"

and "off-on" responses. This capability of the eyes to detect change in developed in the peripheral retina as in the central retina. For instance, a minute gnat flying across the peripheral field of vision is instantaneously detected. On the other hand, the same gnat sitting quietly remains entirely below the threshold of visual detection. light intensity is as equally

The reason for this is that the signals transmitted from the photoreceptors through the depolarizing bipolar cells are excitatory, whereas the sig-

directly

nals transmitted laterally through the hyperpolarizing bipolar cells as well as through the horizontal

Thus, the direct excitatory signal through one pathway is likely to be completely neutralized by the inhibitory signals through the cells are inhibitory.

lateral

One

pathways.

in Figure 35-3,

circuit for this is illustrated

which shows three photoreceptors;

the central one of these receptors excites a depolarizing bipolar

However, the two receptors on

cell.

either side are connected to the Transmission of Signals Depicting Contrasts in the Visual

Scene

—

The Role of Lateral Inhibition

Many of the ganglion cells do not respond to the actual level of illumination of the scene; instead they respond mainly to contrast borders in the scene. Since it seems that this is the major means by which the form of the scene is transmitted to the brain, let us explain how this process occurs. When flat light is applied to the entire retina that is, when all the photoreceptors are stimulated equally by the incident light the contrast type of ganglion cell is neither stimulated nor inhibited.

—

through inhibitory horizontal

let us examine what happens when a conborder occurs in the visual scene. Referring again to Figure 35-3, let us assume that the central photoreceptor is stimulated by a bright spot of light while one of the two lateral receptors is in the

Now,

The bright spot of light pathway through the bipolar dark.

C=3

s

s

Mr

«0

Then, in addi-

is

in

be inhibited. In turn,

on the bipolar

this cell loses its inhibitory ef-

cell,

and

m

this

cell.

—

1=

°J

Excitation

w ,o.»

cell.

one of the lateral photoreceptors the dark causes one of the horizontal cells to

tion, the fact that

In summary, the mechanism of lateral inhibition functions in the eye in the same way that it functions in most other sensory systems as well that is, to provide contrast detection and enhancement.

c=>

1

9>y

will excite the direct

allows still more Thus, where visual contrasts occur, the signals through the direct and lateral pathways actually accentuate each other.

t

l

two recep-

trast

excitation of the bipolar

— —

cell

that neutralize

the direct excitatory signal if the lateral tors are also stimulated by light.

fect

CZD

same bipolar

cells

.

Transmission of Color Signals

by

the Ganglion Cells

Many of the ganglion cells are excited by only one color type of cone but inhibited by a second type. For instance, this frequently occurs for the red

excitation and green causing inhibition or vice versa, with green causing excitation and red, inhibition. The same type of reciprocal effect also occurs between blue cones on the one hand and a combination of red and green cones on the other hand, giving a reciprocal excitation-inhibition relationship between the blue and yellow colors.

and green cones, red causing

—

The mechanism is

the following:

of this opposing effect of colors color-type cone excites the

One

through while the other colortype cone inhibits the ganglion cell by the indirect inhibitory route through a hvperpolarizing bipolar ganglion

cell

by the

direct excitatory route

a depolarizing bipolar

cell,

cell.

The importance 35-3 Typical arrangement of rods, horizontal cells (H), a bipolar cell (B), and a ganglion cell (G) in the retina, showing excitation at the synapses between the rods and the horizontal cells but inhibition between the horizontal cells and the bipolar Figure

cells.

nisms

is

of these color-contrast

mecha-

mechanism by which differentiate colors. Thus

that they represent a

the retina itself begins to each color-contrast type of ganglion cell is excited by one color but inhibited by the "opponent color."

35

Therefore, the process of color analysis begins in the retina and is not entirely a function of the

The Eye:

II.

Neurophysiology of Vision

^

419

superior colliculus in the same manner that the visual cortex is used in mammals.

brain. Function of the Dorsal Lateral Geniculate Nucleus

The Visual Pathways into the Brain

The

optic nerve fibers of the

new

visual system

terminate in the dorsal lateral geniculate nucleus, located at the dorsal end of the thalamus and frequently called simply the lateral geniculate body, as illustrated in Figure 35-4. The dorsal lateral geniculate nucleus serves two principal functions: First, it serves as a station to transmit visual information from the optic tract to the visual cortex by way of all

Figure 35-4 illustrates the ways from the two retinas to

principal visual paththe visual cortex. After

nerve impulses leave the retinas they pass backward through the optic nerves. At the optic chiasm all the fibers from the nasal halves of the retinas cross to the opposite side, where they join the fibers from the opposite temporal retinas to form the optic tracts. The fibers of each optic tract synapse in the dorsal lateral geniculate nucleus, and from here the geniculocalcarine fibers pass by way of the optic radiation (or geniculocalcarine tract) to the primary visual cortex in the calcarine area of the occipital lobe.

In addition, visual fibers also pass to older areas of the brain: especially important are fiber path-

ways

(1)

from the optic

tracts into the pretectal nu-

movements

of the eyes to focus on objects of importance and also for activating the pupillary light reflex, and (2) into the superior colliculus, for control of rapid directional movements of the two eyes. Thus, the visual pathways can be divided roughly into an old system to the midbrain and a neiv system for direct transmission into the visual cortex. The new system is responsible in human beings for the perception of virtually all aspects of visual form, colors, and other conscious vision. On the other hand, in many primitive animals, even visual form is detected by the older system, using the

clei,

for eliciting reflex

Lateral geniculate

body

Optic tract i

Optic radiation

Optic chiasm '

Optic nerve

Visual cortex

35-4 The principal visual pathways from the eyes to the visual cortex. (Modified from Polyak: The Retina. ©1941 by The Figure

University of Chicago. All rights reserved.)

the optic radiation (also called the geniculocalcarine tract). This relay function is very accurate, so much

so that there

is

exact point-to-point transmission

with a high degree of spatial fidelity all the way from the retina to the visual cortex. It will be recalled that half the fibers in each optic tract, after passing the optic chiasm, are derived from one eye and half from the other eye, representing corresponding points on the two retinas. However, the signals from the two eyes are kept apart in the dorsal lateral geniculate nucleus. This is composed of six nuclear layers. Layers II, III, and V (from ventral to dorsal) receive signals from the temporal portion of the same side eye, whereas layers I, IV, and VI receive signals from the nasal half of the opposite eye. The second major function of the dorsal lateral geniculate nucleus is to "gate" the transmission of signals to the visual cortex, that is, to control how much of the signal is allowed to pass to the cortex. The nucleus receives gating control signals from two major sources: (1) from corticofugal fibers returning in a backward direction from the primary visual cortex to the lateral geniculate nucleus and (2) the reticular areas of the mesencephalon. Both of these are inhibitory and, when stimulated, can either turn off or suppress transmission through selected portions of the dorsal lateral geniculate nucleus. Finally, the dorsal lateral geniculate nucleus is divided in another way: (1) Layers I and II are called magnocellular layers because they contain very large neurons. These receive their usual input almost entirely from the large type Y retinal ganglion cells. This magnocellular system provides a very rapidly conducting pathway to the visual cortex. On the other hand, it is "color blind," transmitting only black-and-white information. Also, its point-topoint transmission is poor, for there are not so many Y ganglion cells, and their dendrites spread widely in the retina. (2) Layers III through VI are called parvocellular layers because they contain large numbers of small to medium-sized neurons. These receive their input almost entirely from the type X retinal ganglion cells that (a) transmit color and (b) also convey accurate point-to-point spatial information, but at only a moderate velocity of conduction rather than high velocity.

nucleus

^

420

The Nervous System: (A) Bask Organization; and Sensory Physiology

IX

Motor cortex

ORGANIZATION AND FUNCTION OF THE VISUAL CORTEX

Somatic sensory area I

I

Figures 35-5 and 35-6 show that the visual cortex is located primarily in the occipital lobes. Like the cortical representations of the other sensory systems, the visual cortex is divided into a primary visual cortex and secondary visual areas. The Primary Visual Cortex. The primary visual cortex (see Fig. 35-5) lies in the calcarine fissure area and extends to the occipital pole on the medial aspect of each occipital cortex. This area is the terminus of direct visual signals from the eyes. Signals from the macular area of the retina terminate near the occipital pole, as shown in the figure, whereas signals from the more peripheral retina terminate in concentric circles anterior to the pole and along the calcarine fissure. Note in the figure the especially large area that represents the macula. The fovea transmits its signals to this region. The fovea is responsible for the highest degree of visual acuity. Based on retinal area, the fovea has several hundred times as much representation in the primary visual cortex as do the peripheral portions of the retina. Another name for the primary visual cortex is the striate cortex, because this area has a grossly striated appearance. The Secondary Visual Areas of the Cortex. The

secondary visual areas, also called

visual association

and inferior to the priSecondary signals are transmit-

areas, lie anterior, superior,

mary

visual cortex.

ted to these areas for analysis of visual meanings. The importance of these areas is that various aspects of the visual image are progressively dissected and analyzed.

The Layered Structure of the Primary Visual Cortex

Like almost tex, the

all

other portions of the cerebral cor-

primary visual cortex has

six distinct lay-

Secondary Visual

Areas

Primary Visual


bmc-te-v Intense Antral Peristaltic Contractions During

Stomach Emptying. Most of the time the rhythmic stomach peristaltic contractions are weak and function mainly to cause mixing of the food and gastric secretions. However, about 20 per cent of the time while food is in the stomach, the contractions become very intense in midstomach and spread through the antrum no longer as weak mixing contractions but instead as strong, peristaltic, very tight ringlike constrictions. As the stomach becomes progressively more and more empty, these constrictions begin farther and farther up the body

of the stomach, gradually pinching off the lowermost portions of the stored food and adding this

food to the chyme in the antrum. These intense much as 50 to 70 centimeters of water pressure, which is about six times as powerful as the usual mixing type of peristaltic waves. Thus, the intensity of this antral peristalsis is the principal factor that determines the rate of stomach emptying. Role of the Pylorus in Controlling Stomach peristaltic contractions often create as

Emptying. The distal opening of the stomach is the Here the thickness of the circular muscle becomes 50 to 100 per cent greater than in the earlier portions of the stomach antrum, and it also remains slightly tonically contracted almost all the time. Therefore, the pyloric circular muscle is frepylorus.

quently called the pyloric sphincter. Despite the tonic contraction of the pyloric sphincter, the pylorus usually will open enough for water and other fluids to empty from the stomach with ease. On the other hand, the constriction usually prevents passage of most food particles until they have become mixed in the chyme to an almost fluid consistency.

However, the degree of constriction of the pylorus can be increased or decreased under the influence of nervous and humoral signals from both

contractions,

the stomach

the stomach

shortly.

has been empty for several hours or more. These are rhythmical peristaltic contractions in the body of the stomach that are usually most intense in young, healthy persons with high degrees of gastrointestinal tonus; and they are greatly increased by a low level of blood sugar.

is

peristaltic contractions of the

and the duodenum, as

is

discussed

Regulation of Stomach Emptying

The lated

rate at which the stomach empties is reguby signals both from the stomach and from

^

518 the

The Gastrointestinal Tract

XI

duodenum, each

of

which functions

for a dif-

ferent purpose.

The

Weak

Gastric Factors That

Promote Emptying

Food Volume on Rate of Empvery easy to see how increased food volume in the stomach could promote increased emptying from the stomach. However, it is not increased pressure in the stomach that causes the increased emptying, because in the usual normal range of volume, increasing the volume does not increase the pressure significantly. On the other hand, stretching of the stomach wall does elicit vagal and local myenteric reflexes that both excite the activity of the pyloric pump. Thus, these stretch reflexes play an important roll in emptying. Effect of the Hormone Gastrin on Stomach Emptying. In the following chapter we shall see that stretch, as well as the presence of certain types of foods in the stomach particularly meat also Effect of Gastric

tying.

It is

—

—

elicits

release of a

hormone

called gastrin

from the

antral mucosa. This has potent effects to cause secretion of highly acidic gastric juice by the stomach

fundic glands. Gastrin also has moderate stimulatory effects on motor functions of the stomach. Most important, it enhances the activity of the pyloric pump. Thus, it, too, has an important influence in promoting stomach emptying.

upper intestine do so as well. The stimulus for producing the hormones is mainly^fats entering the duodenum, though other types of foods can increase the hormones to a lesser degree. On entering the duodenum, the fats extract several different hormones from the duodenal and jejunal epithelium, either by binding with "recep-

some other way. In hormones are carried by way of the blood the stomach, where they (1) inhibit the activity the pyloric pump and at the same time (2) in-

tors" in the epithelial cells or in

turn, the to

of

crease slightly the strength of contraction of the pyloric sphincter. These effects are important because fats are digested much more slowly than most other foods.

what the precise hormones are hormonal feedback inhibition of the stomach is not fully clear. The most potent appears to be cholecystokinin (CCK), which is released from the mucosa of the jejunum in response to fatty substances in the chyme. This hormone acts as a competitive inhibitor to block the increased stomach motility caused by gastrin. In summary, several different hormones are known that could serve as hormonal mechanisms for inhibiting gastric emptying when excess quantities of chyme, especially acidic or fatty chyme, enter the duodenum from the stomach. CCK is probably the most important. Unfortunately,

that cause the

The Powerful Duodenal Factors That Inhibit Emptying

Summary

The Inhibitory Effect of Enterogastric Nervous Reflexes from the Duodenum. When food enters the duodenum, multiple nervous reflexes are iniated from the duodenum wall that pass back to the stomach and slow or even stop stomach emptying as the volume of chyme in the duodenum becomes too much. These reflexes are mediated mainly by way of the enteric nervous system in the gut wall. They have two

effects on stomach emptying: first, they strongly inhibit the antral propulsive contractions; and second, they increase slightly to moderately the tone of the pyloric sphincter. The types of factors that are continually monitored in the duodenum and that can excite the enterogastric reflexes include 1.

2.

The degree of distension of the duodenum. The presence of any degree of irritation of

of the Control of Stomach Emptying

Emptying of the stomach is controlled only to a moderate degree by stomach factors, such as the degree of filling in the stomach and the excitatory effect of gastrin on antral peristalsis. However, probably more important control of stomach emptying resides in feedback signals from the duodenum, including both the enterogastric nervous feedback reflexes and hormonal feedback. These two feedback inhibitory mechanisms work together to slow the rate of emptying when (1) too much

chyme chyme

already in the small intestine or (2) the excessively acid, contains too much unprocessed protein or fat, is hypotonic or hypertonic, or

is

is is

irritating.

emptying

is

In this

way

limited to that

the rate of stomach of chyme that

amount

the small intestine can process. the

duodenal mucosa.

The degree of acidity of the duodenal chyme. The degree of osmolality of the chyme. 5. The presence of certain breakdown products in the chyme, especially breakdown products of proteins and perhaps to a lesser extent of fats. 3.

MOVEMENTS OF THE SMALL

4.

Hormonal Feedback from hibits Gastric

Hormone

the

Emptying— Role

Duodenum of Fats

In-

and the

Cholecystokinin. Not only do nervous

from the duodenum to the stomach inhibit stomach emptying, but hormones released from the reflexes

INTESTINE

The movements of the small intestine, as elsewhere in the gastrointestinal tract, can be divided into mixing contractions and propulsive contractions. However, to a great extent this separation is artificial

because essentially

intestine cause at least

all movements of the small some degree of both mixing

and propulsion. Yet the usual processes follows.

classification of these

42

The Gastrointestinal

Tract:

Nervous Control, Movement of Pood Through the

Tract,

^

and Blood Flow

519

Mixing Contractions (Segmentation Contractions)

When a portion of the small intestine becomes distended with chyme, the stretch of the intestinal wall elicits localized concentric contractions spaced at intervals along the intestine. The longitudinal length of each one of the contractions is only about 1 centimeter, so that each set of contractions causes "segmentation" of the small intestine, as illustrated in Figure 42-8, dividing the intestine into spaced segments that have the appearance of a chain of sausages. As one set of segmentation contractions relaxes, a new set begins, but the new contractions occur at points between the previous contractions. These segmentation contractions "chop" the chyme usually about two to three times a minute, in this way promoting progressive mixing of the solid food particles with the secretions of the small intes-

Pressure and chemical irritation

peristalsis Fluidity of

contents

promotes emptying

,

Pressure or chemical inhibits peristalsis of

irritation—t/

ileum and

excites sphincter

tine.

Figure

Propulsive

relax sphincter

and excite

42-9 Emptying

at the ileocecal valve.

Movements

Small Intestine. Chyme is prothrough the small intestine by peristaltic waves. These can occur in any part of the small intestine, and they move analward at a velocity of 0.5 to 2 cm/sec, much faster in the proximal intestine and much slower in the terminal intestine. However, they are normally very weak and usually die out after traveling only 3 to 5 centimeters, very rarely farther than 10 centimeters, so that movement of the chyme is also very poor; so poor in fact that the net movement of the chyme along the small intestine averages only 1 cm/min. This means that normally 3 to 5 hours are required for passage of chyme from the pylorus to the ileocecal Peristalsis in the

pelled

valve.

of Peristalsis by Nervous and HorSignals. Peristaltic activity of the small intestine is greatly increased after a meal. This is

Control

monal

caused partly by the beginning entry of chyme into the duodenum but also by a so-called gastroenteric

Regularly spaced

reflex that is initiated by distension of the stomach and conducted principally through the myenteric plexus from the stomach down along the wall of

the small intestine. In addition to the

monal

nervous signals, several horThese include

factors also affect peristalsis.

gastrin, cholecystokinin , insulin,

which enhance

and

intestinal motality

serotonin, all of

and are secreted

during various phases of food processing. On the other hand, secretin and glucagon inhibit small intestinal motility. Unfortunately, the quantitative importance of each of these hormonal factors for controlling motility is

The

still

questionable.

Rush. Though peristalsis in the small intestine is normally very weak, intense irritation of the intestinal mucosa, as occurs in some severe cases of infectious diarrhea, can cause very Peristaltic

powerful, rapid peristalsis called the peristaltic rush. This is initiated partly by extrinsic nervous reflexes to the autonomic nervous system ganglia and to the brain stem and back again to the gut, and partly by direct enhancement of the myenteric plexus reflexes. The powerful peristaltic contractions then travel long distances in the small intestine within minutes, sweeping the contents of the intestine into the colon and thereby relieving the small intestine of either irritative chyme or excessive distension.

a Isolated

Function of the Ileocecal Valve

Weak, Figure

regularly

spaced

42-8 Segmentation movements

of the small intestine.

A principal function of the ileocecal valve is to prevent backflow of fecal contents from the colon into the small intestine. As illustrated in Figure 42-9, the lips of the ileocecal valve protrude into the lumen of the cecum and therefore are forcefully closed when any excess pressure builds up in the

.

s£L(u\~

520

The Gastrointestinal Tract

XI

cecum and tries ward against the

push the

cecal contents backUsually the valve can resist reverse pressure of as much as 50 to 60 centimeters to

lips.

of water. In addition, the wall of the ileum for several centimeters immediately preceding the ileocecal valve has a thickened muscular coat called the ileocecal sphincter. This normally remains mildly constricted and slows the emptying of ileal contents into the

cecum except immediately gastroileal

reflex

after a meal,

intensifies

when

Semi-fluid

the peristalsis in the

Ileocecal

ileum.

The

Solid

Fluid

a

valve

resistance to

emptying

chyme

at the ileocecal

valve

ileum and, therefore, facilitates absorption. Only about 1500 milliliters of chyme empty into the cecum each day. Feedback Control of the Ileocecal Sphincter by Reflexes from the Cecum. The degree of contracprolongs the stay of

Excess motility causes less absorption and diarrhea or loose feces

in the

Figure

42-10 Absorptive and storage functions of the large

intes-

tine.

tion of the ileocecal sphincter, as well as the intensity of peristalsis in the

terminal ileum,

is

also con-

by reflexes from the cecum. Whenever the cecum is distended, the contraction of the ileocecal sphincter is intensified and ileal peristalsis inhibited, which greatly delays emptying of additional chyme from the ileum. Also, any irritant in the cecum delays emptying. For instance, significantly

trolled

when

a

person has an inflamed appendix, the

tation of this vestigial

irri-

remnant of the cecum can

cause such intense spasm of the ileocecal sphincter and paralysis of the ileum that this completely blocks emptying of the ileum. These reflexes from the cecum to the ileocecal sphincter and ileum are mediated both by way of the myenteric plexus in the gut wall itself and through extrinsic nerves, especially reflexes of the prevertebral sympathetic

contractions, once initiated, usually reach

peak

in-

about 30 seconds and then disappear during the next 60 seconds. They also at times move slowly analward during their period of contraction and therefore provide a minor amount of forward propulsion of the colonic contents. After another few minutes, new haustral contractions occur in other areas nearby. Therefore, the fecal material in the large intestine is slowly dug into and rolled over in much the same manner that one spades the earth. In this way, all the fecal material is gradually exposed to the surface of the large intensity in

testine,

and

fluid

and dissolved substances are pro-

gressively absorbed until only 80 to 200 milliliters of the daily load of chyme is lost in the feces.

Propulsive

Movements

waves

— "Mass

Movements."

of the type seen in the small intes-

ganglia.

Peristaltic

The principal functions of the colon are (1) absorption of water and electrolytes from the chyme and (2) storage of fecal matter until it can be expelled. The proximal half of the colon, illustrated in Figure 42-10, is concerned principally with absorption, and the distal half with storage. Because intense movements are not required for these func-

most parts of the colon. most propulsion occurs by (1) the slow analward movement of the haustral contractions just discussed and (2) mass movements. In the transverse colon and sigmoid, mass movements mainly take over the propulsive role. These movements usually occur only one to three times each day, most abundantly for about 15 minutes during the first hour after eating breakfast. A mass movement is a modified type of peristalsis characterized by the following sequence of tine only rarely occur in

Instead,

MOVEMENTS OF THE COLON

the movements of the colon are normally sluggish. Yet in a sluggish manner, the movements

events:

have characteristics similar to those of the small intestine and can be divided once again into mixing movements and propulsive movements. Mixing Movements Haustrations. In the same manner that segmentation movements occur in the small intestine, large circular constrictions also occur in the large intestine. At the same time, the longitudinal muscle of the colon, which is aggregated into three longitudinal strips called the teniae coli,

transverse colon. Then rapidly thereafter 20 or more centimeters of colon distal to the constriction contract as a unit, forcing its fecal material en masse down the colon. The contraction develops progressively more force for about 30 seconds, and relaxation then occurs during the next 2 to 3 minutes before another mass movement occurs, this time perhaps farther along the colon. But the whole series of mass movements will usually persist for only 10 minutes to half an hour. If defecation does not occur during this time, a new set of mass movements might not recur for another half day or day.

tions,

still

—

These combined contractions of the circuand longitudinal strips of muscle cause the un-

contract. lar

stimulated portion of the large intestine to bulge into baglike sacs called haustrations. These

outward

First,

tended or

a

constrictive ring occurs at a dis-

irritated point in the colon, usually in the

42

The Gastrointestinal

Tract:

Mass Movements by the Gastroand Duodenocolic Reflexes. The appearance of mass movements after meals is facilitated by gastrocolic and duodenocolic reflexes. These reflexes result from distension of the stomach and duodenum. It is probable that these reflexes are conducted mainly through the extrinsic nerves of the autonomic nervous system. Initiation of

in the colon

can also

initiate

521

Afferent

colic

Irritation

^

Nervous Control, Movement of Food Through the Trad, and Blood Flow

nerve ii

I

fibers

)

Descending colon

intense

mass movements. For instance, a person who has an ulcerated condition of the colon (ulcerative colitis) frequently has mass movements that persist almost all the time. Also, mass movements can be initiated by in-

Sigmoid

/Rectum

tense stimulation of the parasympathetic nervous

Skeletal

motor nerve

system.

External anal sphincter Internal anal sphincter

Defecation

Figure

42-11 The afferent and efferent pathways of the parasymmechanism for enhancing the defecation reflex.

pathetic

Most

of the time, the rectum

is

empty

of feces.

This results partly from the fact that a weak functional sphincter exists approximately 20 centimeters from the anus at the juncture between the sigmoid and the rectum. However, when a mass movement forces feces into the rectum, the desire for defecation is normally initiated, including reflex contraction of the rectum and relaxation of the anal sphincters.

Continual dribble of fecal matter through the anus is prevented by tonic constriction of (1) the anal sphincter, a several centimeters long thickening of the intestinal circular smooth muscle that lies immediately inside the anus, and (2) the external anal sphincter, composed of striated voluntary muscle that both surrounds the internal sphincter and also extends distal to it. The external sphincter is controlled by nerve fibers in the pudendal nerve, which is part of the somatic nervous system and therefore is under voluntary, conscious internal

control.

The Defecation is

initiated

by

Reflexes. Ordinarily, defecation reflexes. One of these re-

defecation

an intrinsic reflex mediated by the local ennervous system. That is, when feces enter the

flexes is teric

rectum, distension of the rectal wall initiates afferent signals that spread through the myenteric plexus to initiate peristaltic

waves

in the

descending colon,

sigmoid, and rectum, forcing feces toward the anus. As the peristaltic wave approaches the anus, the internal anal sphincter is relaxed by inhibitory signals from the myenteric plexus; and if the external anal sphincter is voluntarily relaxed at the same time, defecation will occur. However, the intrinsic defecation reflex itself is weak; and to be effective in causing defecation it usually must be fortified by a parasympathetic defecation reflex that involves the sacral segments of the spinal cord, as illustrated in Figure 42-11. When the nerve endings in the rectum are stimulated, signals are transmitted into the spinal cord and thence, reflexly, back to the descending colon, sig-

moid, rectum, and anus by way of parasympathetic nerve fibers in the pelvic nerves. These parasympathetic signals greatly intensify the peristaltic waves, relax the internal anal sphincter,

and thus convert

the intrinsic defecation reflex from a weak movement into a powerful process of defecation. This is sometimes effective in emptying the large bowel in one movement all the way from the splenic flexure of the colon to the anus. Also, the afferent signals entering the spinal cord initiate other effects, such as taking a deep breath, closing the glottis, contracting the abdominal wall muscles to force the fecal contents of the colon downward, and at the same time causing the pelvic floor to extend downward and pull outward on the anal ring to evaginate the feces. However, despite the defecation reflexes, other effects are also necessary before actual defecation occurs. In the toilet-trained human being, relaxation of the internal sphincter and forward movement of feces toward the anus normally initiate an instantaneous contraction of the external sphincter, which still temporarily prevents defecation. Except in babies and mentally inept persons, the conscious mind then takes over voluntary control of the external sphincter and either relaxes it to allow defecation to occur or further contracts it if the moment is not socially acceptable for defecation.

GASTROINTESTINAL BLOOD FLOW

The blood

vessels of the gastrointestinal system

are part of a more extensive system called the splanchnic circulation, illustrated in Figure 42-12. It

includes the blood flow through the gut itself plus the blood flow through the spleen, the pancreas, and the liver. The design of this system is such that all of the blood that courses through the gut, spleen, and pancreas then flows immediately into the liver by way of the portal vein. In the liver, the

522

^

The Gostrointestinol Tract

XI

tion of nutrients, blood flow in the villi and adjacent regions of the submucosa is increased, sometimes as much as eightfold. Likewise, blood flow in the muscle layers of the intestinal wall increases with increased motor activity in the gut. For instance, after a meal the motor activity, secretory ac-

Vena cava Hepatic artery to connective tissue

Hepatic vein Hepatic sinuses

tivity,

//

\

^rPor\a\^y

,

v

Splenic

—\^

vein

/

\




2

CH

3

— C— S— Co-A

+ 2C0 2 + 4H

(Acetyl Co-A)

From this reaction it can be seen that two carbon dioxide molecules and four hydrogen atoms are released, while the remaining portions of the two pyruvic acid molecules combine with coenzyme A, a derivative of the vitamin pantothenic acid, to form two molecules of acetyl Co-A. In this conversion, no ATP is formed, but six molecules of ATP are produced when the four released hydrogen atoms are later oxidized, as is discussed in a later section.

Glucose

ATP

-

ADP

Glucose 6-phosphate

The

Citric

Acid Cycle

Fructose 6-phosphate

»St

ATP

Fructose

1

ADP ,

The next stage

6-phosphate

molecule

is

in the degradation of the glucose

called the citric acid cycle (also called

the tricarboxylic acid cycle, or the Krebs cycle). This Dihydroxyacetone phosphate

a sequence of chemical reactions, illustrated in Figure 45-4, in which the acetyl portion of acetyl Co-A is degraded to carbon dioxide and hydrogen atoms. These reactions all occur in the matrix of the is

2 (Glyceraldehyde 3-phosphate)

4H 2 (1,3-D ipJiosphoglycericacid)

2ADP

^ +

2ATP

mitochondrion.

2 (3-PhpsDhoglyceric acid) 2 (2-Phpsphoglyceric acid) 2 (Phosphoenolpyruvic asphc acid)

*~ 2ATP

2ADP 2 (Pyruvic acid)

NET REACTION PER MOLECULE OF GLUCOSE: **2 Pyruvic acid + 2ATP 2ADP + 2P04 """

Glucose + Figure

45-3 The sequence

glycolysis.

—

+

4H

of chemical reactions responsible for

The released hydrogen atoms

are

subsequently oxidized, as discussed later, releasing tremendous amounts of energy to form ATP. The substances to the left in Figure 45-4 are added during the chemical reactions, and the products of the chemical reactions are shown to the right. Note at the top of the column that the cycle begins with oxaloacetic acid, and then at the bottom of the chain of reactions oxaloacetic acid is formed once again. Thus, the cycle can continue indefinitely.

In the initial stage of the citric acid cycle, acetyl

CH3— CO— CoA Acetyl

0=C-COOH

coenzyme A

I

* HiC— COOH (Oxaloacetic acid)

CoA

H2O

HjC-COOH

Co-A combines with oxaloacetic acid to form citric The coenzyme A portion of the acetyl Co-A is released and can be used again and again for the formation of still more quantities of acetyl Co-A from pyruvic acid. The acetyl portion, however, becomes an integral part of the citric acid molecule. acid cycle,

and carbon

and hydrogen atoms are released at various shown on the right in the

dioxide

stages in the cycle, as

(Citric acid)

*" H,0

I

figure.

The net

HjC-COOH

shown

C-COOH

results of the entire citric acid cycle are

at the

bottom of Figure 45-4,

illustrating

metab-

that for each molecule of glucose originally

II

two

Co-A molecules

enter into the citric acid cycle along with six molecules of water. These molecules are then degraded into four carolized,

HC-COOH (cis-

citric

several molecules of water are added,

HjC-COOH

555

acid.

During the successive stages of the

HOC- COOH

H 2 0-

^

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

45

Aconitic acid)

*~\

H2C-COOH

acetyl

bon dioxide molecules, 16 hydrogen atoms, and molecules of coenzyme A.

HC-COOH

2

Formation of ATP in the Citric Acid Cycle. Figure 45-4 also shows that for each molecule of glucose metabolized in the citric acid cycle, two molecules of ATP are formed.

HOC- COOH H (Isocitric acid)

2H

HjC-COOH

HC-COOH

Formation of Large Quantities of ATP

by Oxidative Phosphorylation of

0=C-COOH (Oxalosuccinic acid)

the Hydrogen

^CO,

Atoms

H^-COOH Despite

all

the complexities of glycolysis

acid cycle, pitifully small formed during these processes

HjC

citric

0=C-COOH H2

+

ADP

HjC-COOH

cules in the glycolysis

amounts

— only 2

and the

ATP are ATP moleof

scheme and another 2

in the

(a-Ketoglutaric acid)

CO, 2H

ATP

the hydrogen atoms that have been released during these earlier stages of glucose degradation. Indeed,

2H

the principal function of

H^-COOH (Succinic acid)

make

II

HOOC-CH

*

(Fumaric acid)

ries

HjC-COOH (Malic acid)

-2H

I

0=C-COOH

to

process 45-4 The chemical reactions of the citric acid cycle, showing the release of carbon dioxide and an especially large number of hydrogen atoms during the cycle. reaction per molecule of glucose:

— 4CO, + 16H + 2CoA + 2ATP

(b) use the electrons eventually to

is

called oxidative phosphorylation.

entirely in the mitochondria

(Oxaloacetic acid) Figure

and

change the dissolved oxygen of the fluids into hydroxyl ions. Then the hydrogen and hydroxyl ions combine to form water. During this sequence of oxidative reactions, tremendous quantities of energy are released to form ATP Formation of ATP in this

manner HjC-COOH

2

is

of enzymatically catalyzed reactions that (a)

electrons

HO- C-COOH

Acetvl-CoA + 6H,0 - 2ADP

these earlier stages

the

change the hydrogen atoms into hydrogen ions and

H

Net

all

hydrogen of the glucose molecule available in a form that can be utilized for oxidation. Oxidation of hydrogen is accomplished by a se-

HC-COOH

H2

acid cycle. Instead, almost 90 per cent of the final ATP is formed during subsequent oxidation of citric

by

It

occurs

a highly specialized

called the chemiosmotic trated in Figure 45-5.

mechanism,

illus-

The Chemiosmotic Mechanism for Forming ATP

Ionization of Hydrogen, the Electron Transport Chain, and Formation of Water. The first step in

556

Metabolism and Temperature Regulation

XII

Food Substrate

of water molecules. During the transport of these electrons through the electron transport chain, en-

ergy is released that ATP, as follows:

used

is

to cause synthesis of

Pumping of Hydrogen Ions into the Outer Chamber of the Mitochondrion, Caused by the

3ADP-JI ._

Diffusion

3 ATP-*t

Outside

Inside

membrane

Membrane

CYTOPLASM figure 45-5 The chemiosmotic mechanism of oxidative phosphorylation for forming great quantities of ATP.

oxidative phosphorylation is to ionize the hydrogen atoms that are removed from the food substrates. These hydrogen atoms are removed in pairs during glycolysis and during the citric acid cycle; one immediately becomes a hydrogen ion, H + and the other combines with NAD + to form NADH. The upper portion of Figure 45-5 shows in color the subsequent disposition of the NADH and H + in the mitochondrion. The initial effect is to release the other hydrogen atom bound with NAD to form another hydrogen ion, H + this process also + reconstitutes NAD which will be reused again and again. During these changes, the electrons that are removed from the hydrogen atoms to cause their ionization immediately enter an electron transport chain of electron acceptors that are an integral part of the ,

Electron Transport Chain. The energy released as the electrons pass through the electron transport chain is used to pump hydrogen ions from the inner matrix of the mitochondrion (to the right side in Figure 45-5) into the space between the inner and outer mitochondrial membranes. This creates a high concentration of positive charged hydrogen ions in this space, and it also creates a strong negative electrical potential in the inner matrix. Formation of ATP. The final step in oxidative phosphorylation is to convert ADP into ATP. This conversion occurs in conjunction with a large protein molecule with a knoblike head that protrudes all the way through the inner mitochondrial membrane and into the inner matrix. This molecule is an ATPase, the physical nature of which is illustrated in Figure 45-5. It is called ATP synthetase. The high concentration of hydrogen ions in the space between the two mitochondrial membranes and the large electrical potential difference across the inner membrane cause the hydrogen ions to flow into the mitochondrial matrix through the substance of the ATPase molecule. In doing so, energy derived from this hydrogen ion flow is utilized by the ATPase to convert ADP into ATP by combining

an ADP with a free ionic phosphate radical, thus adding an additional high energy phosphate bond to the molecule.

For each two hydrogen atoms ionized by the up to three ATP molecules are thus synthesized. electron transport chain,

;

,

inner membrane (the shelf membrane) of the mitochondrion. The electron acceptors can be reversibly reduced or oxidized by accepting or giving up elec-

The important members of this electron transport chain include flavoprotein, several iron sulfide proteins, ubiquinone, and cytochromes B, C v C, A, and A y Each electron is shuttled from one of these acceptors to the next until it finally reaches cytochrome A 3 which is called cytochrome oxidase because it is capable, by giving up two electrons, of trons.

,

causing elemental oxygen to combine with hydro-

gen ions

to

form water.

Thus, Figure 45-5 illustrates transport of electrons through the electron chain and their ultimate use by cytochrome oxidase to cause the formation

Summary

of

ATP Formation

During the Breakdown of Glucose

We can now determine the total number of ATP molecules formed by the energy from one molecule of glucose. 1.

2. 3.

The number

Two during Two during

is

glycolysis,

the citric acid cycle, and Thirty-four during oxidative phosphorylation.

Thus, a total of 38 ATP molecules is formed for each molecule of glucose degraded to carbon dioxide and water. Therefore, 456,000 calories of energy are stored in the form of ATP, while 686,000 calories are released during the complete oxidation of each mole of glucose. This represents an overall efficiency of energy transfer of 66 per cent. The remaining 34 per cent of the energy becomes heat and therefore cannot be used by the cells to per-

form

specific functions.

45

Adenosine Diphosphate (ADP)

CH

3

— C— COOH

Concentration

Continuous release of energy from glucose when is not needed by the cells would be an

extremely wasteful process. Fortunately glycolysis and the subsequent oxidation of hydrogen atoms is continuously controlled in accordance with the needs of the cells for ATP. This is accomplished mainly in the following manner: Referring back to the various chemical reactions, we see that at different stages ADP is converted into ATP. If ADP is not available, the reactions cannot occur, and the degradation of the glucose molecule is stopped. Therefore, once all the ADP in the cells has been converted to ATP, the entire glycolytic and oxidative process stops. Then, when more ATP is the

perform different physiological functions in new ADP is formed. This automatically glycolysis and oxidation once more. In this

to

cell,

starts

+

CH,— C— COOH

+ NAD"

NADH

+

]

(Pyruvic Acid)

way, essentially a full store of ATP is automatically maintained all the time, except when the activity of the cell becomes so great that ATP is used more rapidly than it can be formed.

OH

lactic

the energy

used

557

O

Control of Glycolysis and Glucose Oxidation by Intracellular

^

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

dehydrogenase

±

H (Lactic acid)

Thus, under anaerobic conditions, by far the larger portion of the pyruvic acid is converted into lactic acid, which diffuses readily out of the cells into the extracellular fluids

and even

into the intracellular

fluids of other less active cells. Therefore, lactic acid

represents a type of "sinkhole" into which the glycolytic end-products can disappear, allowing glycolysis to proceed far longer than would be possible if the pyruvic acid and hydrogen were not removed from the reacting medium. Indeed, glycolysis could proceed for only a few seconds without this conversion. Instead, it can proceed for several minutes, supplying the body with considerable quantities of ATP even in the absence of respiratory

oxygen.

When Release of Energy of

Oxygen

—

in the

Absence

"Anaerobic" Glycolysis

NADH

by glycolysis, for the chemical reactions during the glycolytic breakdown of glucose to pyruvic acid do not require oxygen. Unfortunately, this process is extremely wasteful of glucose because only 24,000 calories of energy are used to form ATP for each mole of glucose utilized, which represents only a little over 3 per cent of the total energy in the glucose molecule. Nevertheless, this release of glycolytic energy to the cells can be a lifesaving measure for a few minutes when oxygen the cells

becomes unavailable. Formation of Lactic Acid During Anaerobic Glycosis Allows Release of Extra Anaerobic Energy. The law of mass action states that as the endproducts of a chemical reaction build up in a reacting medium, the rate of the reaction approaches zero. The two end-products of the glycolytic reactions (see Figure 45-3) are (1) pyruvic acid and (2) hydrogen atoms in the forms and FT. The buildup of excessive amounts of these would stop the glycolytic process and prevent further formation of ATP. Fortunately, when their quantities begin to be excessive, these end-products react with each other to form lactic acid, in accordance with the following equation.

NADH

and

H+

up in the body fluids the tissues of the body, thereby undergoing great reduction in their concentrations. As a result, the chemical reaction for formation of lactic acid immediately reverses itself, the lactic acid once again becoming pyruvic acid, which is oxidized to supply additional cellular energy. and

Occasionally, oxygen becomes either unavailable or insufficient, so that cellular oxidation of glucose cannot take place. Yet, even under these conditions, a small amount of energy can still be released to

oxygen again metabolism, the extra as well as the extra pyruvic acid

the person begins to breathe

after a period of anaerobic lactic acid that

have

are rapidly oxidized in

built

all

RELEASE OF ENERGY

FROM GLUCOSE BY THE PENTOSE PHOSPHATE PATHWAY Though essentially all the carbohydrates utilized by the muscles are degraded to pyruvic acid by glycolysis and then converted to carbon dioxide and hydrogen atoms by the citric acid cycle, this glycolytic, citric acid schema is not the only means by which glucose can be degraded to provide energy. A second important schema for glucose break-

down

the

pentose phosphate pathway. not discussed here, it is responsible for as much as 30 per cent of the glucose breakdown in the liver and for even more than that in fat cells. It is especially important in providing energy and some of the substrates required for conversion of carbohydrates into fat, as will be discussed in the following chapter.

Though

is

called

this process is

^

558

XII

Metabolism and Temperature Regulation

FORMATION OF CARBOHYDRATES FROM PROTEINS AND FATS— "GLUCONEOGENESIS"

When

body's stores of carbohydrates de-

the

below normal, moderate quantities of glucose can be formed from amino acids and from the crease

glycerol portion of fat. This process is called gluco-

Approximately 60 per cent of the amino body proteins can easily be converted into carbohydrates, while the remaining 40 per cent have chemical configurations that make this difficult. Each amino acid is converted into glucose by neogenesis.

acids in the

a slightly different chemical process. For instance, alanine can be converted directly into pyruvic acid

simply by deamination; the pyruvic acid then is converted into glucose by the liver. Regulation of Gluconeogenesis. Diminished carbohydrates in the cells and decreased blood sugar are the basic stimuli that set off an increase in the rate of gluconeogenesis. The diminished carbohydrates can directly cause reversal of many of the glycolytic reactions, thus allowing conversion of deaminated amino acids and glycerol into carbohy-

However, in addition, several of the hormones secreted by the endocrine glands are espedrates. cially

important in

this regulation, as follows:

and Glucocorticoids on normal quantities of carbo-

Effect of Corticotropin

Gluconeogenesis. When hydrates are not available to the

cells,

the anterior

pituitary gland, for reasons not yet completely understood, begins to secrete increased quantities of corticotropin. This stimulates the adrenal cortex to produce large quantities of glucocorticoid hormones, especially Cortisol. In turn, Cortisol mobilizes proteins from essentially all cells of the body, making them available in the form of amino acids in the body fluids. A high proportion of the amino acids immediately become deaminated in the liver and therefore provide ideal substrates for conversion into glucose. Thus, one of the most important

means by which gluconeogenesis

is

promoted

is

through the release of glucocorticoids from the adrenal cortex.

BLOOD GLUCOSE The normal blood glucose concentration in a person who has not eaten a meal within the past 3 to 4 hours is approximately 90 mg per 100 ml of blood, and even after a meal containing large

amounts of carbohydrates, this concentration rarely rises above 140 mg per 100 ml of blood unless the person has diabetes mellitus. The regulation of blood glucose concentration intimately related to insulin ject will

and glucagon;

is

this sub-

be discussed fully in relation to the functwo hormones in Chapter 52.

tions of these

REFERENCES Friedmann, H. C.

&

(ed.):

Enzymes. Stroudsburg, PA, Dowden, Hutchinson

Ross, 1980.

M, et al.: Sugars in Nutrition. New York, Raven Press, 1991. Hediger, M. A., and Rhoads, D. B.: Molecular physiology of sodium-glucose cotransporters. Physiol. Rev., 74:993, 1994. Jackson, R. L., et al.: Glycosaminoglycans: Molecular properties, protein Gracey,

interactions,

and

role in physiological processes. Physiol. Rev., 71:481,

1991.

Jungas, R. L., et al.: Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans. Physiol. Rev., 72:419, 1992.

Kraus-Friedmann, N.: Hormonal regulation of hepatic gluconeogenesis. Physiol. Rev, 64:170, 1984.

H. A.: The tricarboxylic acid cycle. Harvey Lectures, 44:165, 1948-1949. Lemasters, J. J., et al. (eds.): Integration of Mitochondrial Function. New York, Plenum Publishing Corp., 1988. Murad, F: Cyclic GMP: Synthesis, Metabolism, and Function. San Diego, Krebs,

CA, Academic Press, 1994. Rombeau, J. L., and Caldwell, M. D.: Clinical Nutrition: Parenteral Nutrition. Philadelphia, W. B. Saunders Co., 1993. Ruderman, N., et al.: Hyperglycemia, Diabetes, and Vascular Disease.

New

York, Oxford University Press, 1992.

Senior, A.

E.:

ATP

synthesis by oxidative phosphorylation. Physiol. Rev.,

68:177, 1988

QUESTIONS 1.

Describe the special features of the ATP molecule that allow it to function as an energy currency. At body temperature and at the concentrations of ATP found in the body cells, how much energy is present in each high-energy phosphate bond per mole of

ATP?

How

5.

6.

7.

2.

glucose transported through the cell membrane, and what is the effect of insulin on this transport?

3.

does phosphorylation of glucose cause the capture of glucose in the cell?

4.

What

is

the composition of glycogen,

role in cells, especially in the liver

and what is and in muscle?

its

A and the role of the citric acid cycle in converting the acetyl portion of the acetyl coenzyme A into carbon dioxide and hydrogen atoms. Explain the chemiosmotic mechanism for formation of ATP in the mitochondria. What percentage of the ATP normally used by the cell is formed by oxidative phosphorylation? zyme

is

How

Explain glycogenolysis and the release of glucose from the liver when glucose is needed elsewhere in the body. Explain, in general, the glycolytic pathway for dissolution of the glucose molecule. Describe the conversion of pyruvic acid to acetyl coen-

8.

9.

45

10.

How

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

does the concentration of adenosine diphosphate determine the rate of glycolysis? Explain the mechanism and importance of anaerobic glycolysis; also explain the formation of lactic acid and tell why this is important to anaerobic glycolysis.

12.

in the cells

11.

559

is meant by gluconeogenesis, how it is and its importance. What is the normal resting blood glucose concentration, and how high does this rise after meals in the normal person?

Explain what controlled,

13.

^

Lipid

and Protein Metabolism

THE BODY LIPIDS

TRANSPORT OF

Several different chemical compounds in the food and in the body are classified as lipids. These include (1) neutral fat, known also as triglycerides, (2) phospholipids, (3) cholesterol,

and

(4)

of less importance. These substances similar cially,

few others have certain a

—

physical and chemical properties espethey are miscible with each other. Chemi-

cally the basic lipid moiety of both the triglycerides and the phospholipids is fatty acids, which are simply long-chain hydrocarbon organic acids. Though

cholesterol does not contain fatty acid,

nucleus is synthesized from degradation products of fatty acid molecules, thus giving it many of the physical and chemical properties of other lipid subits

sterol

stances.

The

Transport

used in the body mainly

triglycerides are

to

form the membranes of

all cells

of the

body and

to

provide other intracellular functions. Basic Chemical Structure of Triglycerides (NeuSince most of this chapter deals with utilization of triglycerides for energy, the following tral Fat).

basic structure of the triglyceride molecule

— (CH — COO — CH CH — (CH — COO— CH CH — (CH — COO— CH )

3

2 16

3

2 16

3

and subclavian

Removal

veins.

from the Blood. The chylomicrons are removed from the plasma within an hour or so. Most are removed as the of the Chylomicrons

blood passes through the capillaries of the also the fat tissue.

The membranes

)

contain large quantities of an enzyme called lipase. This enzyme hydrolyzes the triglycerides of the chylomicrons into fatty acids and glycerol. Then, the fatty acids, being highly miscible with the membranes of the cells, immediately diffuse into the fat cells. Once within these cells, the fatty acids are resynthesized into triglycerides, new glycerol being supplied by the metabolic processes of the fat cells, as will be discussed later in the chapter. cells

lipoprotein

Combination with Albumin

—

in

the Blood

in

"Free Fatty Acid"

2

When

the fat that has been stored in the fat cells be used elsewhere in the body, usually for providing energy, it must first be transported to the other tissues. It is transported almost entirely in the form of free fatty acid, which is achieved by hydrolysis of the triglycerides stored in the fat cells once is

2

Tristearin

that three long-chain fatty acid molecules are of glycerol.

bound with one molecule

liver

of the fat

must be

)

2 16

Gastrointestinal

Chylomicrons

Transport of Fatty Acids

CH

560

— The

BLOOD

It will be recalled from Chapter 44 that almost all the fats of the diet are absorbed into the intestinal lymph in the form of chylomicrons, which have a size averaging 0.4 micron. The chylomicrons are then transported up the thoracic duct and emptied into the venous blood at the juncture of the jugular

understood:

Note

Lymph from the

Tract

and

provide energy for the different metabolic processes; this function they share almost equally with the carbohydrates. However, some lipids, especially cholesterol, the phospholipids, and small amounts of triglycerides, are used throughout the body to

in

LIPIDS IN THE

to

again into fatty acids and glycerol. Part of the stimulus for initiating this hydrolysis is the following:

46

When to

glucose

form new

is

not present in sufficient amounts

glycerol, the glycerol concentration in

the cell falls so

low

that the triglycerides dissociate

and glycerol, and these are released into the blood. In addition, a cellular lipase called hormone-sensitive triglyceride lipase becomes activated by one of several different means, and this activated lipase promotes even more rapid hy-

back into

fatty acids

drolysis of the triglycerides.

On leaving the fat cells, the fatty acids ionize strongly in the plasma and immediately combine loosely with albumin of the plasma proteins. The fatty acid bound with proteins in this manner is called free fatty acid or nonesterified fatty acid (or simply FFA). The concentration of free fatty acid in the plasma under resting conditions is about 15 mg per 100 ml of plasma, which is a total of only 0.45 gram of fatty acids in the entire circulatory system. Yet, strangely enough, even this small amount accounts for almost all of the transport of lipids from one part of the body to another, for the following reasons: (1) Despite the minute amount of free fatty acid in the blood, its rate of turnover is extremely rapid, half the plasma fatty acid being replaced by new fatty acid every 2 to 3 minutes. One can calculate that at this rate over half of all the energy required by the body can be provided by the free fatty acid transported even without increasing the free fatty acid concentration. (2) All conditions that increase the rate of utilization of fat for cellular energy also increase the free fatty acid concentration in the blood; this concentration sometimes increases as much as five- to eightfold. This occurs especially in starvation and in diabetes when a person is not using or cannot use carbohydrates for energy. The Lipoproteins

—

Lipid

and Protein Metabolism

^

561

Types of Lipoproteins. Chylomicrons sometimes are also classified as lipoproteins because they contain both lipids and protein. In addition to the chylomicrons, however, there are three other major classes of lipoprotein: (1) very low density lipoproteins, which contain high concentrations of triglycerides and moderate concentrations of both phospholipids and cholesterol; (2) low density lipoproteins, which contain relatively few triglycerides but a very high percentage of cholesterol; and (3) high density lipoproteins, which contain about 50 per cent protein with smaller concentrations of the lipids. Formation of the Lipoproteins. The lipoproteins are formed almost entirely in the liver, which is in keeping with the fact that most plasma phospholipids, cholesterol, and triglycerides (except those in the chylomicrons) are synthesized in the liver. Function of the Lipoproteins. The principal function of the lipoproteins in the plasma is to transport their special types of lipids throughout the body. The turnover of triglycerides in the lipoproteins is as much as several grams per hour and perhaps half this much turnover of cholesterol and phospholipids. Triglycerides are synthesized mainly from carbohydrates in the liver and are transported to the adipose tissue and other peripheral tissues in the very low density lipoproteins. The low density lipoproteins are the residuals of the very low density lipoproteins after they have delivered most of their triglycerides to the adipose tissue, leaving large concentrations of phospholipids and moderate concentrations of protein. On the other hand, the high density lipoproteins transport cholesterol away from the peripheral tissues and to the liver; therefore, this type of lipoprotein plays a very important role in preventing the development of atherosclerosis, which we shall discuss later in the chapter.

Their Special Function in

Transporting Cholesterol and Phospholipids

THE FAT DEPOSITS

— that when no — over 95 per cent of

In the postabsorptive state chylomicrons are in the blood

is,

the lipids in the plasma (in terms of mass, but form of lipoproteins, which are particles much smaller than chylomicrons but similar in composition, contain-

all

not in terms of rate of transport) are in the

ing mixtures of triglycerides, phospholipids, cholesterol, and protein. The total concentration of lipoproteins in the plasma averages about 700 mg per 100 ml of plasma and can be broken down into the following average concentrations of the individual constituents:

mg/100 ml of plasma

Cholesterol

Phospholipids Triglycerides

Lipoprotein protein

180 160 160 200

Adipose Tissue

Large quantities of

fat are

two major and the liver.

stored in

tissues of the body, the adipose tissue

The adipose

tissue is usually called the fat deposits, or simply the fat depots. The major function of adipose tissue is storage of

triglycerides until these are needed to provide energy elsewhere in the body. However, a subsidiary function is to provide heat insulation for the body, as discussed in Chapter 47. The Fat Cells. The fat cells of adipose tissue are modified fibroblasts that are capable of storing almost pure triglycerides in quantities equal to 80 to 95 per cent of their volume. Fat cells can also synthesize very, very small

quantities of fatty acids

and

triglycerides

from

car-

bohydrates, this function supplementing the very

^

562 large

Metabolism and Temperature Regulation

XII

amount

of synthesis of fat in the liver, dis-

Exchange of Fat Between the Adipose Tissue and the Blood Tissue Lipases. As noted earlier,

—

large quantities of lipases are present in adipose

Some

tis-

enzymes catalyze the deposition of triglycerides derived from the chylomicrons and other lipoproteins. Others, when activated by horsue.

of these

mones, cause

splitting of the triglycerides of the fat

cells to release free fatty acids into

the blood. Be-

cause of rapid exchange of the fatty acids, the triglycerides in the fat cells are renewed approximately once every 2 to 3 weeks, which means that the fat stored in the tissues today is not the same fat that was stored last month, thus emphasizing the

dynamic

state of the storage fat.

The Liver

The principal functions

Lipids

of the liver in lipid

me-

degrade fatty acids into small compounds that can be used for energy; (2) to synthesize triglycerides mainly from carbohydrates and, to a lesser extent, from proteins; and (3) to synthesize other lipids from fatty acids, especially cholesterol and phospholipids. tabolism are

The erides,

(1)

to

liver cells, in addition to containing triglyc-

contain large quantities of phospholipids

and cholesterol, which are continually synthesized by the liver. Also, the liver cells are much more capable than other tissues of desaturating fatty acids, so that the liver triglycerides normally are much more unsaturated than the triglycerides of the adipose tissue. This capability of the liver to desaturate fatty acids is functionally important to all the tissues of the body, because many of the structural members of all cells contain reasonable quantities of desaturated fats, and their principal source is the liver. This desaturation is accomplished by a dehydrogenase in the liver

utilization of the fatty acids

is

their transport into

mitochondria. This is an enzyme-catalyzed process that employs carnitine as a carrier substance. Once inside the mitochondria, the fatty acid splits away from the carnitine and is then oxidized. Degradation of Fatty Acid to Acetyl Coenzyme A by Beta Oxidation. The fatty acid molecule is degraded in the mitochondria by progressive release of 2-carbon segments to form acetyl coenzyme A (acetyl Co-A). This process is illustrated in Figure 46-1; it is called the beta oxidation mechanism for degradation of fatty acids. Each time the reactions of this schema go through a complete cycle, beginning at the top left-hand corner of the figure and proceeding to the bottom right-hand corner, a new acetyl Co-A molecule is formed, and the fatty acid chain becomes two carbon atoms shorter. The process is repeated again and again until the entire fatty acid molecule is split into acetyl Co-A. For instance, from each molecule of stearic acid, nine molecules of acetyl Co-A are formed. Oxidation of Acetyl Co-A. The acetyl Co-A molecules formed by this beta oxidation of fatty acids enter the citric acid cycle, as explained in the preceding chapter for the acetyl Co-A derived from glucose, and are degraded into carbon dioxide and hydrogen atoms. The hydrogen is subsequently oxidized by the oxidative enzymes of the mitochondria to form ATP. the

cussed later in the chapter.

Tremendous Amounts of ATP Are Formed by Oxidation of Fatty Acid. In Figure 46-1 note that four hydrogen atoms are released each time a molecule of acetyl Co-A is formed from the fatty acid chain. Then additional hydrogen is released in the citric acid cycle. The oxidation of all these hydrogen atoms gives rise to the formation of 139 molecules of ATP for each stearic acid molecule oxidized. Also, another 7 molecules of ATP are formed in other ways during this entire process, making a total

of 146 molecules of ATP.

cells.

Formation of Acetoacetic Acid in

USE OF TRIGLYCERIDES FOR ENERGY:

— An

Accessory Method

for Transporting Lipids in the Blood

FORMATION OF ADENOSINE TRIPHOSPHATE (ATP)

the Liver

A

large share of the degradation of fatty acids

Co-A occurs in the liver. However, the uses only a small proportion of the acetyl Co-A for its own intrinsic metabolic processes. Instead, pairs of acetyl Co-A condense to form moleinto acetyl

Approximately 40 per cent of the calories in the normal American diet are derived from fats, which amount is about equal to the calories derived from carbohydrates. Therefore, the use of fats by the body for energy is just as important as the use of

liver

cules of acetoacetic acid, as follows:

carbohydrates. In addition, much of the carbohydrates ingested with each meal is converted into triglycerides, then stored, and later utilized as fatty acids released from the triglycerides for energy. Entry of Fatty Acids into the Mitochondria. The

degradation and oxidation of fatty acids occur only in the mitochondria. Therefore, the first step in the

2CH 3 COCo-A + H Acetyl

2

Co-A liver cells

other cells

CH COCH COOH 3

2

Acetoacetic acid

+ 2HCo-A

46

Lipid

and Protein Metabolism

^

563

Thiokinase (1)

RCH 2 CH 2 CH 2 COOH

CoA

+

+

»

ATP

n

RCH 2 CH 2 CH 2 COCoA

(Fatty acid)

(2)

RCH 2 CH 2 CH 2 COCoA (Fatty acyl

+

AMP

(Fatty acyl

Acyl dehydrogenase

FAD

+

+ Pyrophosphate

CoA)

+ RCH 2 CH=CHCOCoA + FADH 2

-

CoA) Enoyl hydrase

RCH 2 CH=CHCOCoA

(4)

RCH 2 CHOHCH 2 COCoA

+

RCH 2 CHOHCH 2 COCoA

H 2Q

(3)

fi

+

NAD +

-Hydroxyacyl

RCH 2 COCH 2 COCoA

-«

+

NADH

+ H+

Dehydrogenase Thiolase (5)

RCH 2 COCH 2 COCoA

+

RCH 2 COCoA

CoA

+

CH3COC0A

(Fatty acyl CoA)(Acetyl

Figure

Then part

of the acetoacetic acid

is

fatty acids to yield

converted into

and minute quantities

[3-hydroxybutyric acid, tone, in

46-1 Beta oxidation of

to ace-

accordance with the following reactions:

O

O

CH,—C— CH — C— OH :

Acetoacetic acid

+ 2H

CO.

OH

O

CH —CH—CH —C— OH

ojX^U

;

Xvv leH R'— CH— COOH-

R— CH— CO XH + H,0 I

R'— CH— COOH

tide

chain.

Some complicated

protein

molecules

and Protein Metabolism

^

567

for each of the 20 amino acids, though some are present in far greater concentrations than others. Since the amino acids are relatively strong acids, they exist in the blood principally in the ionized state and account for 2 to 3 milliequivalents of the negative ions in the blood. Fate of Amino Acids Absorbed from the Gas-

ml

trointestinal Tract. It will be recalled from Chapter 44 that the end-products of protein digestion in the gastrointestinal tract are almost entirely amino acids and that polypeptide or protein molecules are only rarely absorbed from the digestive tract into the blood. Immediately after a meal, the amino acid concentration in the blood rises, but the rise is usually only a few milligrams per 100 ml because, after entering the blood, the excess amino acids are absorbed within 5 to 10 minutes by cells throughout the entire body, especially by the liver. Therefore, almost never do large concentrations of amino acids accumulate in the blood. Nevertheless, the turnover rate of the amino acids is so rapid that

many grams Note that in this reaction the amino radical of one amino acid combines with the carboxyl radical of the other amino acid. A hydrogen ion is released from the amino radical, a hydroxyl is released from the carboxyl radical, and these two combine to form a molecule of water. Note that after the peptide linkage has been formed, an amino radical and a carboxyl radical are still at opposite ends of the new molecule, both of which are capable of combining with additional amino acids to form a pep-

Lipid

of proteins in the

form of amino acids

can be carried from one part of the body to another each hour. Active Transport of Amino Acids into the Cells. The molecules of essentially all the amino acids are much too large to diffuse through the pores of

membranes. Instead, the amino acids are transported through the membrane only by active transport or facilitated diffusion, utilizing carrier mechanisms. The nature of some of the carrier mechanisms is still poorly understood, but some are discussed in Chapter 4. the cell

have many thousand amino acids joined by peptide linkages, and even the smallest protein usually has more than 20 amino acids joined by peptide

Storage of Amino Acids as Proteins

in

the Cells

linkages.

Fibrous Proteins

Many and

of the highly

complex proteins are

are called fibrous proteins. In these,

fibrillar

many

sep-

Almost immediately after entry into the cells, amino acids are conjugated under the influence of intracellular enzymes into cellular proteins, so that the concentration of free amino acids inside the cells almost always remains low. Instead, the amino acids are mainly stored in the form of actual pro-

many

arate chains are held together in parallel bundles

teins.

by

decomposed again

Major types of fibrous proteins are (1) collagens, which are the basic structural proteins of connective tissue, tendons, cartilage, and bone; (2) elastins, which are the elastic fibers of tendons, arteries, and connective tissue; (3) keratins, which are the structural proteins of hair and nails; and (4) actin and myosin, the contractile proteins of cross-linkages.

muscle.

Yet

into

be rapidly

amino acids under the

in-

lysosomal digestive enzymes, and these amino acids in turn can be transported again from the cell into the blood. However, most of the structural proteins, such as collagen and muscle contractile proteins, do not participate fluence

of

significantly

intracellular

in

this

reversible

storage

of

amino

acids.

Some TRANSPORT AND STORAGE OF AMINO ACIDS The Blood Amino Acids

is

an average of about 2

tissues of the

body

participate in the stor-

age of amino acids to a greater extent than others. For instance, the liver, which is a large organ and also has special systems for processing amino acids, stores large quantities of labile proteins.

The normal concentration of amino acids in the blood is between 35 and 65 mg per 100 ml of plasma. This

intracellular proteins can

mg

per 100

Release of Amino Acids from the Cells, and Regulation of Plasma Amino Acid Concentration. Whenever the plasma amino acid concentration falls below its normal level, amino acids are trans-

568

Metabolism and Temperature Regulation

ported out of the cells to replenish the supply in the plasma. Simultaneously, intracellular proteins are degraded back into amino acids. In this way, the plasma concentration of each type of amino acid is maintained at a reasonably constant value. Later it will be noted that various

hormones secreted by the endocrine glands are able to alter the balance between tissue proteins and circulating amino acids; growth hormone and insulin increase the formation of tissue proteins, while adrenocortical glucocorticoid hormones increase the concentration of circulating amino acids.

protein storage medium and represent a rapidly available source of amino acids whenever a particular tissue requires them.

bile

CHEMISTRY OF PROTEIN SYNTHESIS Proteins are synthesized in

all cells

of the body,

and the functional characteristics of each cell are dependent upon the types of protein that it can

can be extremely high, as

plasma protein formation by the liver much as 30 grams per

form. Basically, the genes of the cells control the protein types and thereby control the functions of the cell. This regulation of cellular function by the genes was discussed in detail in Chapter 3. Chemically, two basic processes must be accomplished for the synthesis of proteins; these are (1) synthesis of the amino acids and (2) appropriate linkage of the amino acids to form the respective types of whole proteins in each individual cell. Essential and Nonessential Amino Acids. Ten of the twenty amino acids normally present in animal proteins can be synthesized in the cells, while the other ten either cannot be synthesized at all or are synthesized in quantities too small to supply the body's needs. The first group of amino acids is called nonessential, while the second group is called essential amino acids because these must be present in the diet if protein formation is to take place in the body. Use of the word essential does not mean that the other 10 amino acids are not equally essential in the formation of the proteins, but only that these others are not essential in the diet. Synthesis of the nonessential amino acids depends on the formation, first, of appropriate a-keto acids, which are the precursors or the respective amino acids. For instance, pyruvic acid, which is formed in large quantities during the glycolytic breakdown of glucose, is the keto acid precursor of the amino acid alanine. Then, by the simple process

day Certain

disease conditions often cause rapid

of transamination, an

Functional Roles of the Plasma Proteins

The three major types of protein in the plasma are albumin, globulin, and fibrinogen. The principal function of albumin is to provide colloid osmotic pressure in the plasma, which in turn prevents loss of plasma fluid from the capillaries, as discussed in Chapter 13. The globulins perform a number of enzymatic functions in the plasma itself, but more important than this, they are mainly responsible for immunity against invading organisms, a subject discussed in Chapter 20. The fibrinogen polymerizes into long, branching fibrin threads during blood coagulation, thereby forming blood clots that help repair leaks in the circulator}' system, discussed in Chapter 25.

Formation of the Plasma Proteins. Essentially all the albumin and fibrinogen in the plasma proteins, as well as about one half of the globulins, are formed in the liver. The remainder of the globulins are formed principally in the lymphoid tissues and bone marrow. These are mainly the gamma globulins that

constitute

the

antibodies

of

the

immune

system.

The

rate of

plasma proteins; severe burns that denude large surface areas can cause loss of many liters of plasma through the denuded areas each day. The rapid production of plasma proteins by the liver is obviously valuable in preventing death in such states. Furthermore, occasionally, a person with severe renal disease may lose as much as 20 grams of plasma protein in the urine each day for months, and this plasma protein is continuously replaced. Use of Plasma Proteins as a Source of Amino Acids for the Tissues. When the tissues become depleted of proteins, the plasma proteins can act as loss of

a source for rapid replacement of these proteins. Indeed, whole plasma proteins can be imbibed in toto by the liver cells and macrophages; then they are

amino acids that are transported back and utilized throughout the body to build cellular proteins wherever needed. In this way, therefore, the plasma proteins function as a lasplit

into

into the blood

amino radical is transferred to the a-keto acid to form the alanine molecule while the keto oxygen is transferred to the donor of the

amino radical. Formation of Proteins from Amino Acids. Once the appropriate amino acids are present in a cell, whole proteins are synthesized rapidly. However, each peptide linkage requires many thousand calories of energy, and this must be supplied from ATP and GTP (guanosine triphosphate) in the cell. Protein formation proceeds through two steps: (1) "activation" of each amino acid, during which the amino acid is "energized" by energy derived from ATP and GTP; and (2) alignment of the amino acids into the peptide chains, a function that is under control of the DNA-RNA system of each individual cell. Both of these processes were discussed in Chapter 3. Indeed, the formation of cellular proteins is the basis of life itself and is so important that the reader would do well to review Chapter 3.

46

and Protein Metabolism

569

in the formation of urea are essenfollowing:

tially the

an upper limit to the amount of protein accumulate in each particular type of cell. Once the cells are filled to their limits, the feedback controls of the DNA-RNA system block further protein synthesis, as explained in Chapter 3, and any additional amino acids in the body fluids are degraded and used for energy or stored mainly as fat. This degradation occurs almost entirely in the liver, and it begins with the process known as is

Ornithine

that can

+ C0 2 + NH 3 Citrulline

Urea

deamination.

Deamination. Deamination means removal of the amino groups from the amino acids. This can occur by several different means, two of which are especially important: (1) transamination, which means transfer of the amino group to some acceptor substance (as explained earlier in relation to the synthesis of amino acids) and (2) oxidative deamination.

The greatest amount of deamination occurs the following transamination schema: a-Ketoglutaric acid

+ Amino

by

acid

NADH

+ H + + NH,

Note from this schema that the amino group from the amino acid is transferred to a-ketoglutaric acid, which then becomes glutamic acid. The glutamic acid can then transfer the amino group to still other substances or can release it in the form of ammonia. In the process of losing the amino group, the glutamic acid once again becomes a-ketoglutaric acid, so that the cycle can be repeated again and again.

Urea Formation by the Liver. The ammonia released during deamination is removed from the blood almost entirely by conversion into urea, two

The

amino acid derivative which combines with one molecule of carbon dioxide and one molecule of ammonia to form a second substance, citrulline. This in turn combines with still another molecule of ammonia to form arginine, which then splits into ornithine and urea. The urea diffuses from the liver cells into the body fluids and is excreted by the kidneys, while the ornithine is reused in the cycle again and again. Oxidation of Deaminated Amino Acids. Once the amino acids have been deaminated, the resulting keto acid products can in most instances be oxireaction begins with the

ornithine,

dized to release energy for metabolic purposes. This usually involves two processes: (1) The keto acid is changed into an appropriate chemical substance that can enter the citric acid cycle, and (2) this substance is then degraded by this cycle in the same manner that acetyl Co-A derived from carbohydrate and fat metabolism is degraded. In general, the amount of adenosine triphosphate formed for each gram of protein that is oxidized is slightly less than that formed for each gram of glucose oxidized. Gluconeogenesis and Ketogenesis. Certain deaminated amino acids are similar to the breakdown products that result from glucose and fatty acid metabolism. For instance, deaminated alanine is pyruvic acid. Obviously, this can be converted into glucose or glycogen; or it can be converted into acetyl Co-A, which can then be polymerized into fatty acids. Also, two molecules of acetyl Co-A can to form acetoacetic acid, which is one of the so-called keto acids, as explained earlier in the chapter. The conversion of amino acids into glucose or

condense

molecules of ammonia and one molecule of carbon dioxide combining in accordance with the follow-

glycogen

ing net reaction:

sion of

2NH, + CO,

H 2 N— C— NH 2 + H

2

O urea formed in the human body is synthesized in the liver. In the absence of the liver or in serious liver disease, ammonia accumulates in the blood. This in turn is extremely toxic, especially to the brain, often leading to a state called hepatic Essentially

coma.

^

The stages

USE OF PROTEINS FOR ENERGY There

Lipid

is

called gluconeogenesis,

amino acids

and the conver-

into keto acids or fatty acids

is

called ketogenesis. Eighteen of twenty of the deaminated amino acids have chemical structures that al-

low them

to

be converted into glucose, and nine-

teen can be converted into

fats.

all

"Obligatory" Degradation of Proteins

When

a

person eats no proteins, a certain pro-

portion of his or her

own body

proteins continues

^

570 to

Metabolism and Temperature Regulation

XII

be degraded into amino acids, deaminated, and

oxidized. This process requires 20 to 30 grams of protein each day, which is called the obligatory loss of proteins. Therefore, to prevent a net loss of protein from the body, one must ingest at least 20 to 30 grams of protein each day, and to be on the safe

minimum

side a

of 60 to 75

grams

usually rec-

is

ommended. Effect of Starvation

weeks of

ter several

on Protein Degradation. Af-

starvation,

when

the quantity

is completely gone and the stored fats are also beginning to run out, the amino acids of the blood begin to be rapidly deaminated and oxidized for energy. From this point on, the as much proteins of the tissues degrade rapidly

of stored carbohydrates

grams daily

as 125

— and

—

the cellular functions de-

teriorate precipitously.

Because use of carbohydrate and fat for energy occurs in preference to protein utilization, carbohydrates and fats are called protein sparers.

REFERENCES Protein Metabolism

Lipid Metabolism Bjorntorp,

P.,

and Brodoff,

B. N.: Obesity.

Philadelphia,

J.

B.

Lippincott

Co., 1994.

and Deckelbaum, R. J.: Polyunsaturated Fatty Acids in Human New York, Raven Press, 1992. Brownell, K. D., et al.: Eating, Body Weight and Performance in Athletes: Bracco, U.,

Nutrition.

Disorders of Modern Society. Baltimore, Williams & Wilkins Co., 1992. Catapano, A. L., et al.: High-Densitv Lipoproteins: Physiopathology and Clinical Relevance.

New

Disalvo, E. A., and Simon,

York, Raven Press, 1993. S. A.:

Permeability and Stability of Lipid Bilav-

Physiol. Rev., 74:761, 1994. Balti-

more, Williams & Wilkins Co., 1992. Stunkard, A. J., and Wadden, T. A.: Obesity: Theory and Therapy.

New

al.:

Principles

C, and

P.

Factors,

Leaf, A.: Atherosclerosis: Cellular Interactions,

and Lipids.

New

and

Glycosaminoglycans: Molecular properties, protein

role in physiological processes. Phvsiol. Rev., 71:481,

1991.

Jungas, R.

Kimball,

L., et al.:

Quantitative analysis of amino acid oxidation and re-

R., et al.:

S.

Growth

humans. Physiol.

Rev., 72:419, 1992.

Regulation of protein synthesis by insulin. Annu.

Rev. Physiol., 56:321, 1994.

Mumby, M. C, and

Walter, G.: Protein serine /threonine phosphatases:

and functions

in cell

growth. Phvsiol. Rev., 73:673,

1993.

Rombeau,

York, Raven Press, 1993.

Weber,

L., et al.:

interactions,

Structure, regulation,

and Management of Lipid Disorders.

A., et

1994.

Jackson, R.

lated gluconeogenesis in

ers. Boca Raton, FL, CRC Press, Inc., 1994.' Kissebah, A. H., and Krakower, G. R.: Regional adiposity and morbidity

Oberman,

S. H., and Corbin, J. D.: Structure and function of cyclic nucleotide-dependent protein kinases. Annu. Rev. Physiol., 56:237,

Francis,

J.

L.,

and Caldwell, M. D.: Clinical Nutrition: Parenteral NutriW. B. Saunders Co., 1993.

tion. Philadelphia,

White, S. H.: Membrane Protein Structure: Experimental Approaches. Vol. 1. Bethesda, MD, American Physiology Society, 1994.

York, Raven Press, 1994.

QUESTIONS 1.

Explain to

2.

3.

4.

5.

6.

7.

form

how

fatty acid molecules

combine with

glycerol

Describe the transport of fats from the digestive tract to the blood and their ultimate storage in the fat tissues of the body. Explain how tremendous quantities of fatty acids can be transported in the "free" fatty acid form by the plasma protein albumin even though the plasma concentration of these fatty acids is very slight. Explain what is meant by a lipoprotein, and also explain in general the function of lipoproteins in the blood. Describe the storage and release of fats from adipose tissue, including the function of hormone-sensitive li-

are the functions of phospholipids

in the

body?

and

cholesterol

Describe the development of atherosclerosis and arteriosclerosis in the arteries of older persons, and explain the effects of heredity and diet on these processes.

12

Explain the peptide linkage mechanism for the formation of peptide chains.

13

How how

14

are

amino

acids transported in the blood,

and

are they stored in cells?

Explain

how amino

teins in cells

acids stored in the form of pro-

can be released for use elsewhere in the

also explain how the plasma proteins can be used to provide amino acids for the body's

body and cells.

Explain the general schema for beta oxidation of the fatty acid molecule.

What

What

tion as one of the initial steps in the utilization of proteins for energy. What is meant by gluconeogenesis and ketogenesis in

is

is meant by an essential amino acid? Explain the processes of deamination and urea forma-

the role of acetoacetic acid in the transport of

degradation products from the liver to peripheral 17

cells?

How

are carbohydrates converted into triglycerides,

and what controls 9.

11.

What

pase.

fat

8.

10.

triglycerides,

Explain tion.

how

this process?

the different

hormones

relation to the utilization of 18.

affect fat utiliza-

What

How

is

meant bv the

great protein loss

is

amino acids?

"obligatory"

this loss normally,

become

in starvation?

loss

of proteins?

and how great can

and

Energetics, Metabolic Rate,

Regu ation of Body Temperature

ADENOSINE TRIPHOSPHATE (ATP) FUNCTIONS AS AN "ENERGY CURRENCY" IN METABOLISM In the last

few chapters

that carbohydrates,

used by the

fats,

it has been pointed out and proteins can all be

synthesize large quantities of ATP and that the ATP in turn can be used as an energy source for almost all other cellular functions. The attribute of ATP that makes it highly valuable as a means of "energy currency" is the large quantity of free energy (7300 calories per mole under standard conditions, and 12,000 calories per mole under physiological conditions) vested in each of its two high energy phosphate bonds. The amount cells to

bonds in the cells. On the contrary, phosphocreatine, which also contains high energy phosphate bonds, is several times as abundant, at least in muscle. The high energy bond (~) of phosphocreatine contains about 13,000 calories per mole under conditions in the body (37° C and low concentrations of the reactants). This is not greatly different from the 12,000 calories per mole in each of the

two high energy phosphate bonds of ATP. The mula for phosphocreatine is the following:

CH NH H 3

HOOC— CH

2

almost any step of any chemical reaction in the to take place if appropriate transfer of the energy is achieved. Some chemical reactions that require ATP energy use only a few hundred of the available 12,000 calories,

and the remainder

of this

then lost in the form of heat. Yet even this inefficiency in the utilization of energy is better than lack of the ability to energize the necessary chemical reactions at all.

energy

is

Throughout this book we have listed many funcSo we will review here only its principal functions, which are 1. To energize the synthesis of important cellular tions of ATP.

chemicals 2. To energize muscle contraction 3. To energize active transport across membranes for (a) absorption from the intestinal tract, (b) absorption from the renal tubules, (c) formation of glandular secretions, and (d) establishment of ionic concentration gradients in nerves, which in turn provide the energy required for nerve impulse transmission.

O

— N— C— N ~ PO—

of energy in each bond, when liberated by decomposition of one molecule of ATP, is enough to cause

body

for-

O H Phosphocreatine, unlike ATP, cannot act as a dicoupling agent for transfer of energy between the foods and the functional cellular systems. But it can transfer energy interchangeably with ATP. rect

When cell,

extra

much

amounts of

its

of

energy

ATP is

are available in the

utilized to synthesize

up

this storehouse begins to be used up, the energy in the phosphocreatine is transferred rapidly back to ATP and then from the ATP to the functional systems of the cells. The higher energy level of the high energy phosphate bond in phosphocreatine, 13,000 in comparison with 12,000 calories per mole, causes the reaction between phosphocreatine and ATP to proceed very much in favor of ATP. Therefore, the slightest utilization of ATP by the cells calls forth the energy from the phosphocreatine to synthesize new ATP This effect keeps the concentration of ATP at almost peak level as long as any phosphocreatine remains in the cell. Therefore, one can also call phosphocreatine an ATP "buffer" compound.

phosphocreatine, thus building of energy.

Then when

the

ATP

Phosphocreatine Serves as an Accessory

Storage Depot for Energy

Despite the paramount importance of ATP as a coupling agent for energy transfer, ATP is not the most abundant store of high energy phosphate

Summary

of Energy Utilization by the Cells

With the background of the past few chapters and the preceding discussion, we can now synthesize a

composite picture of overall energy

utiliza-

571

572

^

XII

Metabolism and Temperature Regulation

by the cells, as illustrated in Figure 47-1. This shows formation of ATP during the initial breakdown of glycogen and glucose, which is called "anaerobic" metabolism because this initial stage does not require oxygen; the figure also shows subsequent aerobic utilization of compounds derived from carbohydrates, fats, proteins, and tion

figure

other substances for the formation of additional ATP. In turn, ATP is in reversible equilibrium with phosphocreatine in the cells, and since large quantities of phosphocreatine are present in the cell, much of the energy of the cell is stockpiled in this energy storehouse. Conversion of Food Energy to Body Heat. Now let us consider the energy used for muscle activity. Much of this energy simply overcomes the viscosity of the muscles themselves or of the surrounding tissues so that the limbs can move. The viscous movement in turn causes friction within the tissues, which generates heat. We might also consider the energy expended by the heart in pumping blood. The blood distends the arterial system, the distention in itself representing a reservoir of potential energy. However, as the blood flows through the peripheral vessels, the friction of the different layers of blood flowing over each other and the friction of the blood against the walls of the vessels turns this energy into heat. Therefore, we can say that essentially all the energy expended by the body is eventually converted into heat. The only real exception to this occurs when the muscles are used to perform some form of work outside the body. For instance, when the muscles elevate an object to a height or carry the person's body up steps, a type of potential energy outside the body is thus created by raising a mass against gravity. But, on the whole, this normally averages no more than 1 per cent of the energy me-

tabolism of the body. Therefore, measuring the body's heat production is an excellent means for studying the body's overall metabolism.

METABOLIC RATE

The

Calorie. To discuss the rate of energy usage

which is called the "metabolic rate," it necessary to use some unit for expressing the quantity of energy released from the different foods or expended by the different functional processes of the body. Most often, the Calorie is the unit used for this purpose. It will be recalled that 1 calorie, spelled with a lower case c, is the quantity of heat required to raise the temperature of 1 gram of water 1° C. The calorie is much too small a unit for ease of expression in speaking of energy in the body. Consequently the kilocalorie, or in common parlance the large Calorie (with a capital C), which is equivalent to 1000 calories, is the unit ordinarily used. in the body,

is

Measurement Rate

Indirect Calorimetry

more than 95 per expended in the body is derived oxygen with the different foods,

Indirect Calorimetry. Since cent of the energy

from reaction of the whole body metabolic rate can be calculated with a high degree of accuracy from the rate of oxygen utilization. For the average diet, the quantity of energy liberated per liter of oxygen utilized in the body averages approximately 4.825 Calories, and this rarely varies from the average more than plus or minus 3 per cent. Therefore, using this energy equiv-

alent of

Glycogen

oxygen, one can calculate approximately

_jr-

Energy 1

Glucose

ATP Lactic acid

^t: Pyruvic acid

Whole Body Metabolic

of the

—

-- ^^

2 3 4

for

Synthesis and growth Muscular contraction Glandular secretion Nerve conduction Active absorption

5 6 Etc.

Acetyl-CoA Phosphocreatine

Deaminated amino acids

>

f

AMP

Other substrates Creatine +

P0 4

COs+hfeO 47-1 Overall scheme of energy transfer from foods to the adenylic acid system and then to cells. (Modified from Saskin and Levine: Carbohydrate Metabolism. Chicago, University of Chicago Press. © 1946, 1952 by The University of Chicago. All rights re-

Figure

the functional elements of the served.)

47

Energetics, Metabolic Rate,

^

and Regulation of Body Temperature

573

Oxygen

Recording on drum

v

Figure

Counterbalancing weight

47-2 The metabolator.

the rate of heat liberation in the body from the quantity of oxygen utilized in a given period of time. This procedure is called indirect calorimetry. Tlie Metabolator. Figure 47-2 illustrates the metabolator, a device that measures oxygen utilization by the body and is therefore used for indirect calorimetry. This apparatus contains a floating drum, under which is an oxygen chamber connected to a mouthpiece through two flexible tubes. Valves in these tubes allow air to pass from the oxygen chamber into the mouth through one tube, while the expired air is directed through the second tube. Before this expired air re-enters the oxygen chamber, it flows through a container filled with pellets of soda lime, which combines chemically with the carbon dioxide in the expired air. Therefore, as oxygen is used by the person's body and the carbon dioxide is absorbed by the soda lime, the floating oxygen chamber, which is precisely balanced by a weight, gradually sinks in the water, owing to the oxygen loss. This chamber is coupled to a pen that records on a moving paper drum the rate at which the chamber sinks in the water and thereby records the rate at which the body utilizes oxygen.

trained athlete,

which

is

an increase in metabolic

rate to 2000 per cent of normal.

Energy Requirements for Daily Activities. When an average man weighing 70 kilograms lies in bed all day, he utilizes approximately 1650 Calories of energy in the total 24-hour period. The process of eating and digesting the food increases the amount of energy utilized an additional 200 or more Calories, so that the same man lying in bed and also eating a reasonable diet requires a dietary intake of approximately 1850 Calories per day. Table 47-1 illustrates the rates of energy utiliza-

one performs different types of activities. walking up stairs requires approximately 17 times as much energy as lying in bed asleep. In general, over a 24-hour period a laborer can tion while

Note

that

TABLE 47-1

ENERGY EXPENDITURE PER HOUR DURING DIFFERENT TYPES OF ACTIVITY FOR A 70-KILOGRAM

MAN Calories per

Form of

Hour

Activity

Sleeping

Awake

lying

65 77 100 105 118 135 140 170

still

Sitting at rest

Factors That Affect the

Whole Body

Metabolic Rate

Standing relaxed Dressing and undressing Tailoring

Typewriting rapidly

Factors that increase the chemical activity in the cells also increase the metabolic rate. Some of these are the following: Exercise. The factor that causes by far the most

dramatic effect on metabolic rate is strenuous exercise. Short bursts of maximal muscle contraction in

any single muscle liberate as much as a hundred times its normal resting amount of heat for a few seconds at a time. In the entire body, however, maximal muscle exercise can increase the overall heat production of the body for a few seconds to about 50 times normal or can sustain it for several minutes to about 20 times normal in the well-

"Light" exercise

Walking slowly

(2.6 miles per hour) Carpentry, metal working, industrial painting "Active" exercise "Severe" exercise

200 240 290 450 480 500 570 600 650

Sawing wood

Swimming Running

(5.3 miles per hour) "Very severe" exercise Walking very fast (5.3 miles per hour)

Walking up

1100

stairs

Extracted from data compiled by Professor M.

S.

Rose.

574

Metabolism and Temperature Regulation

achieve a maximal rate of energy utilization as in other words as great as 6000 to 7000 Calories much as three and a half times the basal rate of metabolism. Thyroid Hormone. When the thyroid gland secretes maximal quantities of thyroxine, the metabolic rate sometimes rises to as much as 50 to 100 per cent above normal. On the other hand, total loss of thyroid secretion decreases the metabolic rate to as low as 40 to 60 per cent of normal. These effects can readily be explained by the basic function of thyroxine, which is to increase the rates of activity of almost all the chemical reactions in all cells of the body. This relationship between thyroxine and metabolic rate will be discussed in greater detail in Chapter 50 in relation to thyroid function, because one of the useful methods for diagnosing abnormal rates of thyroid secretion is to determine the basal metabolic rate of the patient. Sympathetic Stimulation. Stimulation of the sympathetic nervous system with liberation of norepinephrine and epinephrine increases the metabolic rates of most tissues of the body. These hormones directly affect cells to cause glycogenolysis, and this, along with other intracellular effects of these hormones, increases cellular activity. Maximal stimulation of the sympathetic nervous system can increase the whole body metabolic rate in some lower animals as much as several hundred per cent, but the magnitude of this effect in human beings is in question. It is probably 15 per cent or less in the adult but as much as 100 per cent in the

—

newborn

child.

The Basal Metabolic Rate

The Basal Metabolic Rate as a Method for Comparing Metabolic Rates Between Individuals. It is often important to measure the inherent metabolic rate of the tissues independently of exercise and other extraneous factors that would make it impossible to compare one person's metabolic rate with another's. To do so the metabolic rate is measured under so-called

measured in a wide variety of different persons and comparisons are made within single age, weight, and sex groups, 85 per cent of normal persons have been found to have basal metabolic rates within 10 per cent of the mean. Thus, it is obvious that measurements of metabolic rates performed under basal conditions offer an excellent means for comparing the rates of metabolism from one person to another.

BODY TEMPERATURE The temperature is,

body

— remains

body

— that

almost ex-

± 1° F (±0.6° C), day in and day out except when a person develops a febrile illness. Indeed, a person can be exposed while nude to temperatures as low as 55° F or as high as 130° F in dry, still air and still maintain an almost constant internal body temperature. Therefore, it is obvious that the mechanisms for control of body actly constant, within

temperature represent a beautifully designed control

system.

The Normal Body Temperature. No

single temperature level can be considered normal, for measurements in many normal persons have shown a range of normal temperatures, as illustrated in Figure 47-3, from approximately 97° F to over 99° F when measured orally When measured by rectum, the values are approximately 1° F greater than the oral temperatures. The average normal oral temperature is generally considered to be 98.6° F. However, when excessive heat is produced in the body by strenuous exercise, the temperature can rise to as high as 101° to 104° F for short periods of time.

BALANCE BETWEEN HEAT PRODUCTION AND HEAT LOSS Heat

is

continuously being produced in the body and body heat is

as a byproduct of metabolism,

basal conditions; this rate is called

Oral

For the normal adult, the average basal metabolic rate is about 70 Calories per the basal metabolic

of the inside of the

in the "core" of the

°F

rate.

Rectal

°C

104- -40

hour.

The following basal conditions are necessary measuring the basal metabolic rate: 1.

No

for

food for at least 12 hours

2.

A night

3.

No

of restful sleep before determination strenuous exercise after the night of restful sleep, and complete rest in a reclining position for at least 30 minutes prior to actual determination 4. Elimination of all psychic and physical factors that cause excitement 5. Air temperature comfortable and somewhere

between the limits of 20° and 27° C (68° and 80° F). Constancy of the Basal Metabolic Rate from Person to Person. When the basal metabolic rate is

>

102- -39

Hard work, emotion r A few normal adults I

Many

active children

Hard exercise

Emotion or moderate exercise

A few normal adults Many active children

-38 100-

J>

-

-37

Usual range of normal Early morning Cold weather,

Figure

sons. 1948.)

Usual range normal

98-

of

-36 1

etc.

96-

47-3 Estimated range (From DuBois: Fever.

Early morning

y Cold weather, etc. of

body temperature

Springfield,

111.,

in

Charles

normal perC Thomas,

47

Energetics, Metabolic Rate,

^

and Regulation of Body Temperature

whereas reduction

575 of blood

also continuously being lost to the surroundings.

ficiency,

When

the rate of heat production is exactly equal to the rate of loss, the person is said to be in heat balance. But when the two rates are out of equilib-

flow to

rium, body heat, and body temperature as well, will obviously either increase or decrease.

Obviously, therefore, the skin is an effective con"heat radiator" system, and the flow of blood to the skin is a most effective mechanism of heat transfer from the body core to the skin. Control of Heat Conduction to the Skin by the Sympathetic Nervous System. Heat conduction to the skin by the blood is controlled by the degree of vasoconstriction of the arterioles and arteriovenous

Tifie

The

skin,

Insulator System of the

the subcutaneous

Body

tissues,

and espe-

subcutaneous tissues are a heat insulator for the body The fat is important because it conducts heat only one third as readily as other tissues. When no blood is flowing from the heated internal organs to the skin, the insulating properties of the normal male body are approximately cially the fat of the

equal to three quarters the insulating properties of a usual suit of clothes. In

even

women

this insulation is

better.

The means

is an effective normal internal core temper-

insulation beneath the skin of maintaining

its

minimum

from the core much. tion

in

the

rate

level decreases heat

to

as

little

conduc-

as one eighth as

trolled

that supply blood to the venous plexus of the skin. This vasoconstriction in turn is controlled almost entirely by the sympathetic nervous system in response to changes in the body core temperature and changes in the environmental temperature. This will be discussed later in the chapter in connection with control of body temper-

anastomoses

ature

by the hypothalamus.

even though it allows the temperature of the skin to approach the temperature of the surroundature,

Heat Loss

ings.

The various methods by which heat Blood Flow

to the Skin

from the Body Core

Provides Heat Transfer

Blood vessels penetrate the insulator tissues

fatty

subcutaneous

and are distributed profusely im-

mediately beneath the skin. Especially important is a continuous venous plexus that is supplied by inflow of blood from the skin capillaries, illustrated in Figure 47-4. In the most exposed areas of the body the hands, feet, and ears blood is also supplied to the plexus directly from the small arteries through highly muscular arteriovenous anasto-

—

—

person in a room maintained at normal temperature loses about 60 per cent of the total heat loss by radiation.

Loss of heat by radiation means loss in the form

waves that any surroundings that are

of infrared heat rays, electromagnetic

moses.

The

from

is lost

skin are shown pictorially in Figure 47-5. These include radiation, conduction, and evaporation. Also, convection of the air plays a major role in heat loss by both conduction and evaporation. The amount of heat lost by each of these different mechanisms obviously varies with atmospheric conditions. Radiation. As illustrated in Figure 47-5, a nude the

blood flow into the venous plexus can vary tremendously from barely above zero to rate of

—

as great as 30 per cent of the total cardiac output.

A

high rate of blood flow causes heat to be conducted from the core of the body to the skin with great ef-

radiate from the skin to

colder than the skin itself. This loss increases as the temperature of the surroundings decreases. Conduction. Usually, only minute quantities of heat perhaps about 3 per cent of the total are

—

—

Epidermis

Capillaries

Dermis Artery

Veins

—

± 1

Venous plexus Subcutaneous tissue -

Arteriovenous

anastomosis Figure

47-4 The skin

circulation.

Artery

576

XII

Metabolism and Temperature Regulation

as long as the

Evaporation (22%)

Walls

body temperature

is

greater than that

of the surroundings, heat is lost by radiation and conduction; but when the temperature of the surConduction

to

objects (3%)

roundings

is

greater than that of the skin, instead body gains heat by radiation and from the surroundings. Under these

of losing heat, the

conduction

conditions, the only means by which the body can rid itself of heat is evaporation. Therefore, anything that

Figure

47-5 Mechanisms of heat

loss

from the body.

from the body by direct conduction from the to other objects, such as a chair or a bed. However, loss of heat by conduction to air does replost

body

resent a sizeable proportion of the body's heat loss even under normal conditions. It will be recalled that heat is actually the kinetic energy of molecular motion, and the molecules that compose the skin of the body are continuously undergoing vibratory motion. Thus, the vibratory motion of the skin molecules can cause increased velocity of motion of the air molecules that come into direct contact with the skin. But once the temperature of the air immediately adjacent to the skin approaches the temperature of the skin, additional exchange of heat from the body to the air is self-limited unless the heated air moves away from the skin so that new, unheated air is continuously brought in contact with

the skin, a

phenomenon called convection. Movement of air is known

and the removal

convection air currents loss

by convection.

conducted to the air

of heat is

away from

called

must

heat

first

be

and then carried away by the

the

body

When

water evaporates from the is lost for each of water that evaporates. Water evaporates insensibly from the skin and lungs at a rate of about 450 to 600 ml per day. This causes continuous heat loss at a rate of 12 to 16 Calories per hour. Unfortunately, this insensible evaporation of water directly through the skin and lungs cannot be controlled for purposes of temperature regulation because it results from continuous diffusion of water molecules Evaporation.

body gram

surface, 0.58 Calorie of heat

body temperature. However, additional evaporative loss of heat by evaporation of sweat can be controlled by regulating the rate of sweating, which is discussed later. Evaporation Is a Necessary Cooling Mechanism regardless

When

of

at High Air Temperatures. In the preceding discussions of radiation and conduction, it was noted that

the

body becomes overheated,

large quan-

of sweat are secreted onto the surface of the skin by the sweat glands to provide rapid evaporative cooling of

the body. Stimulation of the preoptic

area in the anterior part of the hypothalamus excites sweating. The impulses from this area that cause sweating are transmitted in the autonomic paththetic

commonly

Regulation by the Autonomic

tities

ways

Actually, the heat

Its

Nervous System

as con-

convection currents. A small amount of convection almost always occurs around the body because of the tendency for the air adjacent to the skin to rise as it becomes heated. Therefore, a nude person seated in a comfortable room loses about 12 per cent of his or her heat by conduction to the air and then by convection

Sweating and

from the body by

Convection. vection,

prevents adequate evaporation when the surrounding temperatures are higher than body temperature causes the body temperature to rise to abnormally high levels. This circumstance occurs occasionally in human beings who are born with congenital absence of sweat glands. These persons can withstand cold temperatures as well as a normal person can, but they are likely to die of heat stroke in tropical zones, for without the evaporative refrigeration system, the body temperatures will remain at levels greater than those of the surroundings.

and thence through the sympaoutflow to the sweat glands in the skin everywhere in the body. Rate of Sweating. In cold weather the rate of sweat production is essentially zero, but in very hot weather the maximum rate of sweat production is from 1.0 liter per hour in an unacclimatized person to 2 to 3 liters per hour in a person maximally acclimatized to heat. Thus, during maximal sweating, a person can lose as much as 2 to 6 pounds of body weight per hour. Evaporation of this much sweat can remove body heat at a rate as great as ten times the normal basal rate of heat production. Mechanism of Sweat Secretion. The sweat gland, illustrated in Figure 47-6, is a tubular structo the cord

ture consisting of

two

parts: (1) a

sweat and

deep

coiled portion

duct portion passing outward to the surface of the skin. As is true of the salivary glands, the secretory portion of the sweat gland emits a fluid called the precursor secretion; then the constituents of this fluid are altered that secretes the

as

it

(2) a

flows through the duct.

The precursor

secretion is an active secretory product of the epithelial cells lining the coiled portion of the sweat gland. Cholinergic sympathetic nerve fibers (fibers that secrete acetylcholine) ending on or near the glandular cells elicit the secretion.

in

Since large the sweat,

of sodium chloride are lost especially important to know

amounts it

is

47

Energetics, Metabolic Rate,

^

and Regulation of Body Temperature

577

- O—

/>— CH,— CHNH,

1 Calcium-

Calcium-

Alkaline

binding

stimulated

phosphatase

protein

ATPase

I i

Inhibition

I

Intestinal absorption of

calcium

I

Plasma calcium

ion concentration

/

Calcium 53-1 Activation of vitamin D 3 to form 1 ,25-dihydroxycholecalciferol; and the role of vitamin D in controlling the plasma cal-

in

Plasma and

Interstitial Fluid

Figure

cium concentration.

calciferol is

converted in the kidneys to 1,25-dihy-

droxycholecalciferol. This latter substance

is

the ac-

form of vitamin D; none of the previous products in the schema of Figure 53-1 have very much tive

D effect. Therefore in the absence of the kidneys, vitamin D is almost totally ineffective. Note also in Figure 53-1 that the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol requires parathyroid hormone. In the absence of this hormone, either none or almost none of the 1,25-dihydroxy cholecalciferol is formed. Therefore, parathyroid hormone exerts a potent effect in determining the functional effects of vitamin D in the body. Hormonal Effect of 1,25-Dihydroxycholecalciferol on the Intestinal Epithelium in Promoting Calcium Absorption. 1,25-Dihydroxycholecalciferol has several effects on the intestinal epithelium in promoting intestinal absorption of calcium. Probably the most important of these effects is that it causes formation of a calcium-binding protein in the intestinal epithelial cells. The rate of calcium absorption seems to be directly proportional to the quantity of this calcium-binding protein. Furthermore, this protein remains in the cells for several weeks after the 1,25-dihydroxycholecalciferol has been removed from the body, thus causing a prolonged effect on calcium absorption. Other effects of 1,25-dihydroxycholecalciferol that might play a role in promoting calcium absorption are (1) the formation of a calcium-stimulated ATPase in the brush border of the epithelial cells and (2) the formation of an alkaline phosphatase in vitamin

The concentration of calcium in plasma is approximately 9.4 mg/dl, normally varying between 9.0 and 10.0 mg/dl; this is equivalent to approximately 2.4 millimoles of calcium per liter. It is apparent that the calcium level in the plasma is regulated within narrow limits and mainly by parathyroid hormone, as discussed later in the

—

chapter.

The calcium

in the

plasma

shown

is

present in three dif-

in Figure 53-2. (1)

Approximately 40 per cent of the calcium is combined with the plasma proteins and consequently is not different forms, as

++ Figure 53-2 Distribution of ionic calcium (Ca ), diffusible but un-ionized calcium (Ca X), and nondiffusible calcium proteinate (Ca Prot) in blood plasma.

^

636

Endocrinology and Reproduction

XIII

through the capillary membrane. (2) Approximately 10 per cent of the calcium (0.2 mmol per liter) is diffusible through the capillary membrane but is combined with other substances of the plasma and interstitial fluids (citrate and phosphate, for instance) in such a manner that it is not ionized. (3) The remaining 50 per cent of the calcium in the plasma is both diffusible through the capillary membrane and ionized. Thus, the plasma fusible

and

interstitial fluids

centration

have a normal calcium

ionic calcium

is

the

ion con-

mmol per liter. This calcium form that is important

of approximately

1.2

most functions of calcium in the body, including its effect on the heart, on the nervous system, and on bone formation. for

53-3 Hypocalcemic tetany in the hand, called "carpopedal spasm." (Courtesy of Dr. Herbert Langford.)

Figure

Inorganic Phosphate in Extracellular Fluids

increased cell membrane permeability in other cells besides nerve cells, and impaired blood tivities,

Inorganic phosphate in the plasma

two forms: HPO^" and liter.

Because

it is

is mainly in PO~. The concentration 2

approximately 1.3 mmol difficult to determine chemi-

of both of these together

per

H

cally the exact ratio of

is

HPO""

to

H

2

PC>- in the

blood, ordinarily the total quantity of phosphate is expressed in terms of milligrams of phosphorus per deciliter of blood. The average total quantity of inorganic phosphorus represented by both phosphate ions is about 4 mg per dl.

Non-bone Physiological

Effects of

clotting.

Hypercalcemia. When the level of calcium in the fluids rises above normal, the nervous system

body

depressed, and reflex activities of the central nervous system can become sluggish. Also, increased calcium ion concentration causes constipation and lack of appetite, probably because of depressed contractility of the muscular walls of the gastroinis

testinal

tract.

above 17

Abnormal

rapidly lethal.

Tetany Resulting from Hypocalcemia. When the fluid concentration of calcium ions falls below normal, the nervous system becomes progressively more excitable because of increased neuronal membrane permeability. Especially, the peripheral nerve fibers become so excitable that they begin to discharge spontaneously, initiating nerve impulses that pass to the peripheral skeletal

BONE AND ITS RELATIONSHIPS TO EXTRACELLULAR CALCIUM AND PHOSPHATES

extracellular

elicit tetanic

contraction.

Con-

sequently, hypocalcemia causes tetany.

Figure 53-3 illustrates tetany in the hand, which usually occurs before generalized tetany all over the body develops. This is called carpopedal spasm. Acute hypocalcemia in the human being ordinarily causes essentially no other significant effects besides tetany, because tetany kills the patient before other effects can develop. Tetany ordinarily occurs when the blood concentration of calcium falls from

normal level of 9.4 mg to approximately 6 mg per dl, which is only 35 per cent below the normal calcium concentration, and it is usually lethal at about 4 mg per dl. In experimental animals, in which the level of calcium can be reduced beyond the normal lethal stage, extreme hypocalcemia can cause marked dilatation of the heart, changes in cellular enzyme acits

If ever the level of calcium rises per dl in the blood, calcium phos-

phate crystals are likely to precipitate throughout the blood and soft tissues, an effect that can be

Calcium Concentration in the Body Fluids

muscles, where they

mg

Bone is

is

composed

of a tough organic matrix that

greatly strengthened

by deposits

of calcium

salts.

Average compact bone contains by weight approximately 30 per cent matrix and 70 per cent salts. However, newly formed bone may have a considerably higher percentage of matrix in relation to salts. The Organic Matrix of Bone. The organic matrix of bone is 90 to 95 per cent collagen fibers, and the remainder is a homogeneous gelatinous medium called ground substance. The collagen fibers extend primarily along the lines of tensional force. These fibers give bone its powerful tensile strength. The ground substance is composed of extracellular fluid plus proteoglycans, especially chondroitin sulfate and hyaluronic acid. The precise functions of these are not known, though they do help control the deposition of calcium

The Bone

Salts.

The

the organic matrix of pally of calcium

and

major crystalline

salts.

crystalline salts deposited in

bone are composed The formula

phosphate.

salt,

known

princifor the

as hydroxyapatite,

is

53

Ca 10 (PO 4 6 (OH) 2

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

Each crystal— about 400 ang) stroms long, 10 to 30 angstroms thick, and 100 angstroms wide is shaped like a long, flat plate. The relative ratio of calcium to phosphorus can vary markedly under different nutritional conditions, the Ca/P ratio on a weight basis varying be.

—

tween 1.3 and 2.0. Magnesium, sodium, potassium, and carbonate ions are also present among the bone salts. They are believed to be adsorbed to the surfaces of the hydroxyapatite crystals

rather

distinct crystals of their

than

own. This

organized into ability of

different types of ions to adsorb to

bone

many

crystals

extends to many ions normally foreign to bone, such as strontium, uranium, plutonium and the other transurank elements, lead, gold, other heavy metals, and at least 9 of 14 of the major radioactive products released by explosion of the hydrogen bomb. Deposition of radioactive substances in bone can cause prolonged irradiation of the bone tissues, and if a sufficient amount is deposited, an osteogenic cancer almost invariably eventually develops. Tensile and Compressional Strength of Bone. Each collagen fiber of bone is composed of repeating periodic segments every 640 angstroms along its length; hydroxyapatite crystals he adjacent to each segment of the fiber bound tightly to it. This intimate bonding prevents the crystals and collagen fibers from slipping out of place, which is essential in providing strength to the bone. In addition, the segments of adjacent collagen fibers overlap each other, also causing the hydroxyapatite crystals to be overlapped like bricks keyed to each other in a brick wall. The collagen fibers of bone, like those of tendons, have great tensile strength, while the calcium salts, which are similar in physical properties to marble,

have great compressional strength. These combined bondage between the collagen fibers and the crystals, provide a bony structure that has both extreme tensile strength and extreme compressional strength. Thus, bones are

properties, plus the degree of

constructed in exactly the same way that reinforced concrete is constructed. The steel of reinforced concrete provides the tensile strength, while the cement, sand, and rock provide the compressional strength. Indeed, the compressional strength of bone is greater than, and the tensile strength approaches, that of reinforced concrete.

AND ABSORPTION OF CALCIUM AND PHOSPHATE

PRECIPITATION

IN

BONE— EQUILIBRIUM

WITH

THE EXTRACELLULAR FLUIDS Supersaturated State of Calcium and Phosphate Ions in Extracellular Fluids with Respect to Hydroxyapatite. The concentrations of calcium and

phosphate ions

in extracellular fluid are consider-

^

637

ably greater than those required to cause precipitation of hydroxyapatite. However, inhibitors are present in almost all tissues of the body, as well as in plasma, to prevent such precipitation; one such inhibitor is pyrophosphate. Therefore, hydroxyapatite crystals fail to precipitate in tissues other than bone, despite the state of supersaturation of the ions.

Mechanism

of Bone Calcification. The initial bone production is the secretion of collagen and ground substance by the osteoblasts. The collagen polymerizes rapidly to form collagen fibers, and the resultant tissue becomes osteoid, a cartilage-like material but differing from cartilage in that calcium salts will soon precipitate in it. As the osteoid is formed, some osteoblasts become entrapped in it, and these are called osteocytes. Within a few days after the osteoid is formed, calcium salts begin to precipitate on the surfaces of the collagen fibers. The precipitates appear at peristage of

odic intervals along each collagen fiber, forming minute nidi that gradually, over a period of days and weeks, grow into the finished product, hydroxyapatite crystals.

The initial calcium salts to be deposited are not hydroxyapatite crystals but amorphous compounds (noncrystalline), probably a mixture of such salts as CaHP04 2H 2 0, Ca 3 (P04 ) 2 3H 2 0, and others. Then by a process of substitution and addition of atoms, these salts are reshaped into the hydroxyap•

•

atite crystals. It is still not known what causes calcium salts to be deposited in osteoid. One theory holds that at the time of formation the collagen fibers are specially constituted in advance for causing precipitation of calcium salts. The osteoblasts supposedly also secrete a substance into the osteoid to neutralize the inhibitor pyrophosphate that normally prevents hydroxyapatite crystallization. Once the inhibitor has been neutralized, the natural affinity of the collagen fibers for calcium salts supposedly

causes the precipitation.

Exchangeable Calcium If soluble calcium salts are injected intravenously, the calcium ion concentration can be made to increase immediately to very high levels. However,

within 30 minutes to an hour or so, the calcium ion concentration returns to normal. Likewise, if large quantities of calcium ions are removed from the circulating body fluids, the calcium ion concentration again returns to normal within 30 minutes to

an hour or so. These effects result in great part from the fact that the bone and other body tissues contain a type of exchangeable calcium that is always in equilibrium with the calcium ions in the extracellular fluids. Most of this exchangeable calcium is in the bone, and it normally amounts to about 0.4 to 1.0 per cent of the total bone calcium.

—

^

638 Most

XIII

Endocrinology and Reproduction

of this calcium

such as

CaHP0 4

is

readily mobilizable salts

and other amorphous calcium

salts.

The importance of exchangeable calcium is that it provides a rapid buffering mechanism to keep the calcium ion concentration in the extracellular fluids from rising to excessive levels or falling to very low levels under transient conditions of excess or diminished availability of calcium.

Magnified section

Osteon

Deposition and Absorption of Bone

Remodeling of Bone

Deposition of Bone by the Osteoblasts. Bone is continually being deposited by osteoblasts, and it is continually being absorbed where osteoclasts are active. Osteoblasts are found on the outer surfaces of the bones and in the bone cavities, as illustrated in Figure 53-4. A small amount of osteoblastic activity occurs continually in all living bones (on about 4 per cent of all surfaces in adult bone), so that at

some new bone is being formed constantly. Absorption of Bone Function of the Osteoclasts. Bone is also being continually absorbed in the presence of osteoclasts, which are normally active at any one time on about 1 per cent of the bone surfaces. Later in this chapter we will see that parathyroid hormone controls the bone absorptive least

analiculi

—

bone absorption occurs immedi-

ately adjacent to the osteoclasts, as illustrated in

Figure 53-4. The mechanism of this absorption is believed to be the following: The osteoclasts send

Osteoblasts Fibrous periosteum

53-5 The structure of bone.

out villus-like projections toward the bone and from these "villi" secrete two types of substances

—

(1)

activity of osteoclasts.

Histologically,

Figure

proteolytic

somes

enzymes, released from the lyso-

of the osteoclasts,

and

(2)

several acids, in-

The enzymes presumably digest or dissolute the organic matrix cluding

citric

acid

and

lactic

acid.

of the bone, while the acids cause solution of the

bone salts. Equilibrium Between Bone Deposition and Absorption. Normally, except in growing bones, the rates of bone deposition and absorption are equal to each other, so that the total mass of bone remains constant. Usually, osteoclasts exist in small masses, and once a mass of osteoclasts begins to develop, it usually eats away at the bone for about 3 weeks, eating out a tunnel that ranges in diameter from 0.2 to 1 millimeter, and several millimeters

At the end of this time, the osteoclasts and the tunnel is invaded by osteoblasts instead. Bone deposition then occurs for several months, the new bone being laid down in successive layers on the inner surfaces of the cavity until the tunnel is filled. Deposition of new bone ceases when the bone begins to encroach on the blood vessels supplying the area. The canal through which these vessels run, called the haversian canal, in length.

disappear,

Vein

Bone

is all that remains of the original cavity. Each new area of bone deposited in this way is called an osteon, shown in Figure 53-5. Value of Continual Remodeling of Bone. The continual deposition and absorption of bone have a

therefore,

number

Osteoclasts Figure

bone.

53-4 Osteoblastic and

osteoclastic activity

in

the

same

First,

tion

of

physiologically

bone ordinarily adjusts to the degree of bone

important its

functions. strength in propor-

stress.

Consequently,

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

53

bones thicken when subjected to heavy loads. Second, even the shape of the bone can be rearranged for proper support of mechanical forces by deposition and absorption of bone in accordance with stress patterns. Third, since old bone becomes brittle and weak, new organic matrix is needed as the old organic matrix degenerates. In this

Bone

deposited in proportion to the compressional load that the bone must carry. For instance, the bones of athletes become considerably heavier than those of nonathletes. Also, if a person has one leg in a cast but continues to walk on the opposite leg, the bone of the leg in the cast becomes thin and decalcified, while the opposite bone remains thick and normally calcified. Therefore, continual physical stress stimulates osteoblastic deposition of new bone. The deposition of bone at points of compressional stress has been suggested to be caused by a Stress.

cell

Oxyphil

cell

Red blood

Figure

cell

53-6 Histological structure of a parathyroid gland.

is

piezo-electric effect, as follows:

Compression of bone potential at the com-

causes a negative electrical pressed site and a positive potential elsewhere in the bone. It has been shown that minute quantities of current flowing in bone cause osteoblastic activity at the negative end of the current flow, which could explain the increased bone deposition at

compression sites. Repair of a Fracture. A fracture of a bone in some way maximally activates all the periosteal and intraosseous osteoblasts involved in the break.

Immense numbers

Chief

639

manner

the normal toughness of bone is maintained. Indeed, the bones of children, in whom the rate of deposition and absorption is rapid, show little brittleness in comparison with the bones of old age, at which time the rates of deposition and absorption are slow. Control of the Rate of Bone Deposition by

Bone

9/

^

of

new

osteoblasts are

almost immediately from osteoprogenitor

formed which

cells,

are bone stem cells that line the surfaces of bone. Therefore, within a short time a large bulge of osteoblastic tissue and new organic bone matrix, fol-

lowed shortly by the deposition of calcium salts, develops between the two broken ends of the bone. This is called a callus. It is reshaped into an appropriate structural bone during the ensuing months.

glands in the

human

being; these are located

diately behind the thyroid gland

imme-

— one behind each

upper and each lower pole of the thyroid. Each parathyroid gland is 3 wide, and 2

mm

approximately 6 long, thick and has a macroscopic appearance of dark brown fat; for this reason the parathyroid glands are difficult to locate. Removal of half the parathyroid glands usually

mm

mm

little physiological abnormality. However, removal of three of the four normal glands usually causes transient hypoparathyroidism. But even a small quantity of remaining parathyroid tissue is usually capable of enough hypertrophy to perform

causes

the function of

the glands. of the adult human being, illustrated in Figure 53-6, contains mainly chief cells and oxyphil cells, but oxyphil cells are absent in all

The parathyroid gland

many

animals and in young humans. The chief most of the parathyroid hormone. The function of the oxyphil cells is not certain; they are believed to be aged chief cells that no longer secells secrete

hormone. Chemistry of Parathyroid Hormone. Parathyroid hormone has been isolated in a pure form. It is a small protein with a molecular weight of approximately 9500 and is composed of a polypeptide crete

chain of 84 amino acids.

Effect of Parathyroid

Hormone on Calcium and

Phosphate Concentrations

in Extracellular Fluid

PARATHYROID HORMONE years it has been known that increased activity of the parathyroid gland causes rapid absorption of calcium salts from the bones with resultant hypercalcemia in the extracellular fluid; conversely, hypofunction of the parathyroid glands causes hypocalcemia, often with resultant tetany, as described earlier in the chapter. Also, parathyroid

For

many

hormone

is

important

in

phosphate metabolism as

well as in calcium metabolism. Physiological Anatomy of Glands. Normally there are

the four

Parathyroid parathyroid

Figure 53-7 illustrates the effects on blood calcium and phosphate concentrations caused by sud-

denly beginning to infuse parathyroid hormone an animal and continuing the infusion for an indefinite period of time. Note that at the onset of infusion the calcium ion concentration begins to rise and reaches a plateau level in about 4 hours. On the other hand, the phosphate concentration falls and reaches a depressed plateau level within an hour or two. The rise in calcium concentration is caused principally by (1) a direct effect of parathyroid hormone in causing calcium and phosphate into

^

640

XIII

Endocrinology and Reproduction

from osteocyte

to osteocyte throughout the bone and these processes also connect with the surface osteocytes and osteoblasts. This extensive system is called the osteocytic membrane system, and

Calcium

structure,

5~2.40

E2.35

E "2.30 3

.2

15

the

Begin

(0

O

bone and

its

internal

When

parathyroid

tracellular fluid.

hormone

cessively activated, the

0.8

53-7 Approximate changes

in calcium

and phosphate conhormone in-

centrations during the first 5 hours of parathyroid fusion at a moderate rate.

absorption from the bone and (2) an effect on the kidneys to decrease the excretion of calcium in the urine. The decline in phosphate concentration, on the other hand, is caused by a very strong effect of parathyroid hormone on the kidney, resulting in excessive renal phosphate excretion that is usually great enough to override the increased phosphate absorption from the bone.

Calcium and Phosphate Absorption from Bone Caused by Parathyroid

Hormone

Parathyroid hormone seems to have two separate on bone in causing absorption of calcium and phosphate. One effect, very rapid, begins in minutes and probably results from activation of the already existing bone cells to promote calcium and effects

phosphate absorption. The second phase is a much slower one, requiring several days or even weeks to become fully developed; it results from the proof osteoclasts, followed by greatly increased osteoclastic reabsorption of the bone itself, not merely absorption of calcium phosphate salts from the bone. The Rapid Phase of Calcium and Phosphate Absorption Osteolysis. When large quantities of parathyroid hormone are injected, the calcium ion concentration in the blood begins to rise within minutes, long before any new bone cells can be developed. Histological studies have shown that the parathyroid hormone causes removal of bone salts from two areas in the bone: (1) from the bone matrix in the vicinity of the osteocytes lying within the bone, and (2) in the vicinity of the osteoblasts along the bone surface. Yet, strangely enough, one does not usually think of either osteoblasts or osteocytes functioning to cause bone salt absorption, because both these types of cells are osteoblastic in nature and are normally associated with bone deposition and its calcification. However, recent studies have shown that the osteoblasts and osteocytes form a system of interconnected cells that spreads all through the bone and also over all the bone surfaces except the small surface areas adjacent to the osteoclasts. In fact, long filmy processes extend

—

that separates

the osteocytes

bone

become

ex-

fluid calcium concen-

and calcium phosphate salts are then absorbed from the bone. This effect is called osteolysis, and it occurs without absorption of the

3

Hours

liferation

membrane

"bone fluid" from the ex-

tration falls lower,

I

1

Figure

believed to provide a

it is

bone matrix. When the pump is inactivated, the bone fluid calcium concentration rises to a higher level, and calcium phosphate salts are then redeposited in the matrix. But where does parathyroid hormone fit into this picture? It seems that parathyroid hormone can strongly activate the osteocyte calcium pump, thereby causing rapid removal of calcium phosphate salts from the amorphous bone crystals that lie near the osteocytes. The Slow Phase of Bone Absorption and Calcium Phosphate Release Activation of the Osteoclasts. much better-known effect of parathyroid hormone is activation of the osteoclasts. These in turn set about their usual task of gobbling up the bone over a period of weeks or months. Activation of the osteoclastic system occurs in two stages: (1) immediate activation of the osteoclasts that are already formed and (2) formation of new osteoclasts. Usually, several days of excess parathyroid hormone cause the osteoclastic system to become well developed, but it can continue to grow for literally months under the influence of very strong parathyroid hormone stimulation. Bone contains such great amounts of calcium in comparison with the total amount in all the extracellular fluids (about 1000 times as much) that even when parathyroid hormone causes a great rise in calcium concentration in the fluids, it is impossible to discern any immediate effect at all on the bones. Yet prolonged administration or secretion of parathyroid hormone finally results in very evident absorption in all the bones and even development of large cavities filled with very large, multinucleated osteoclasts.

—

A

Effect

of Parathyroid Hormone on Phosphate and Calcium Excretion

by the Kidneys

Administration of parathyroid hormone causes

immediate and rapid loss of phosphate in the urine. This effect is caused by parathyroid diminishment of renal tubular reabsorption of phosphate ions.

Parathyroid hormone also causes renal tubular same time that it diminishes phosphate reabsorption. Were it not for this effect of parathyroid hormone on the kidneys to increase calcium reabsorption, the continual loss of calcium into the urine would eventually deplete reabsorption of calcium at the

53

both the extracellular fluid and the bones of

Parathyroid

this

Acute

mineral.

effect

3Effect

of Vitamin

^

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

D on Bone and

Its

Relation

to Parathyroid Activity

Calcitonin

M

effect

;

)

) /•

\

0)

C

Vitamin D plays important roles in both bone absorption and bone deposition. Administration of extreme quantities of vitamin D causes absorption of bone in much the same way that administration of parathyroid hormone does. Also, in the absence of vitamin D, the effect of parathyroid hormone in causing bone absorption is greatly reduced or even prevented. It is possible, if not likely, that parathyroid hormone functions in bone the same way that it functions in the kidneys that is, by causing the conversion of vitamin D to 1,25-dihydroxycholecalciferol, which in turn acts to cause the bone absorp-

hormone Chronic

_

-1000

'

\

i

-800

OLUJOL)

CM

641

1

f Q.

"D

\

'

i

-600

\i

/

pa ma

CL

Normal

levels

400 S

V — V

CO

1o 'o

TO

E

'

(/>

-200

—

£

n C)

2

4

8 10 12 Plasma calcium (mg/dl) 6

14

16

tion.

D

much smaller amounts promotes bone calcification. One of the ways in which it does Vitamin

in

is to increase calcium and phosphate absorption from the intestines. However, even in the absence of such increase, it still enhances the mineralization of bone. Here again, the mechanism of the effect is unknown, but it probably results from the ability of

so

1,25-dihydroxycholecalciferol, a derivative of vitamin D, to cause transport of calcium ions through cell membranes perhaps through the osteoblastic

—membranes of bone.

or osteocytic cell

Figure 53-8 Approximate effect of plasma calcium concentration on the plasma concentrations of parathyroid hormone and calcitonin. Note especially that long-term, chronic changes of only a

small percentage in calcium concentration can cause as much as 100 per cent change in parathyroid hormone concentration.

changed over a period of a few hours. This shows that even small decreases in calcium concentration from the normal value can double or triple the plasma parathyroid hormone. On the other hand, the approximate chronic relationship that one finds

when Control of Parathyroid Secretion

by Calcium Ion Concentration

Even the slightest decrease in calcium ion concentration in the extracellular fluid causes the parathyroid glands to increase their rate of secretion of parathyroid hormone and also to hypertrophy. For instance, the parathyroid glands become greatly enlarged in rickets, in which the level of calcium is usually depressed only a few per cent; they also become greatly enlarged in pregnancy, even though the decrease in calcium ion concentration in the mother's extracellular fluid is hardly measurable; and they are greatly enlarged during lactation because calcium is used for milk formation. On the other hand, any condition that increases the calcium ion concentration above normal causes decreased activity and reduced size of the parathyroid glands. Such conditions include (1) excess quantities of calcium in the diet, (2) increased vitamin D in the diet, and (3) bone absorption caused by factors other than parathyroid hormone (for example, bone absorption caused by disuse of the bones).

Figure

proximate

53-8

illustrates

quantitatively

the

ap-

between plasma calcium plasma parathyroid hormone

relationship

concentration and concentration. The solid curve shows the acute relationshiship when the calcium concentration is

the calcium ion concentration changes over a period of many weeks, thus allowing time for the glands to hypertrophy greatly, is illustrated by the dashed line; this illustrates that chronically, a very slight, almost unmeasurable, decrease in calcium can give as much as a 100 per cent increase in parathyroid hormone. Obviously, this is the basis of the body's extremely potent feedback system for control of plasma calcium ion concentration.

CALCITONIN

About 35 years ago, a new hormone that has weak effects on blood calcium, but opposite to those of parathyroid hormone, was discovered. This hormone is named calcitonin; it reduces the blood calcium ion concentration. In the human being, it is secreted not by the parathyroid glands but instead by the thyroid gland, by parafollicular cells, or C cells, in the interstitium between the thyroid follicles. is a large polypeptide with a molecuweight of approximately 3400; it consists of a

Calcitonin lar

chain of 32 amino acids. Effect of Calcitonin in Decreasing Plasma Calcium Concentration. In young animals, calcitonin decreases blood calcium ion concentration very rapidly, beginning within minutes after injection of the calcitonin.

Thus the

effect of calcitonin

calcium ion concentration

is

on blood

exactly opposite that

^

642

Endocrinology ond Reproduction

XIII

of parathyroid hormone, and it occurs several times as rapidly. Calcitonin reduces plasma calcium concentration in at least

two separate ways:

1. The immediate effect is to decrease the absorptive activities of the bone osteoclasts, also thus shifting the balance in favor of deposition of calcium in the bone.

2.

The second and more prolonged

prevent formation of

new

effect is to

osteoclasts. ."-

'

Calcitonin has only a weak effect on plasma calcium concentration in the adult human being. The reason for this is simply that the daily rates of bone absorption and deposition of calcium are small, and the stimulatory effect of calcitonin cannot alter the rates enough to make much difference.

Effect

of Plasma Calcium Concentration

on the Secretion of Calcitonin

An increase in plasma calcium concentration of about 10 per cent causes an immediate twofold or more increase in the rate of secretion of calcitonin, which is illustrated by the dot-dash line of Figure 53-8. This provides a second hormonal feedback mechanism for controlling the plasma calcium ion concentration, but one that works exactly opposite to the parathyroid hormone system. That is, an increase in calcium concentration causes increased calcitonin secretion, and the increased calcitonin in

turn reduces the plasma calcium concentration back toward normal. However, there are two major differences between the calcitonin and the parathyroid feedback systems.

more

First,

the calcitonin

rapidly, reaching

peak

bone become almost totally inactive. As a result, bone reabsorption is so depressed that the level of calcium in the body fluids decreases. If the parathyroid glands are suddenly removed, the calcium level in the blood falls from the normal

mg/dl within 2 to 3 days. reached, the usual signs of tetany develop. Among the muscles of the body

of 9.4

When

an

—

system. As was pointed out above, the calcimechanism is a very weak one in the normal

system that

anyway. Therefore, over a prolonged it is almost entirely the parathyroid

sets the

long-term level of calcium ions

in the extracellular fluid.

PHYSIOLOGY OF PARATHYROID AND BONE DISEASES Hypoparathyroidism

The cause

of hyperparathyroidism

parathyroid-secreting parathyroid glands.

ficient

the parathyroid glands

do not

secrete suf-

parathyroid hormone, the osteoclasts of the

tumor

in

most often one of the

is

In hyperparathyroidism, extreme osteoclastic ac-

occurs in the bones, and this elevates the cal-

cium ion concentration

in

the extracellular fluid

while usually (but not always) depressing the concentration of phosphate ions because of increased renal excretion of phosphate. In severe hyperparathyroidism, the osteoclastic absorption of bone soon far outstrips osteoblastic deposition, and the bone may be eaten away almost entirely. Indeed, often the reason a hyperparathyroid person comes to the doctor is a broken bone caused by the mildest of trauma. X-ray films of the bones show extensive decalcification, and occasionally large

punched-out cystic areas of the with osteoclasts in the form of

bones that are

filled

so-called giant

cell

tumors.

of hyperparathyroidism is surgical removal of the parathyroid tumor, but this is a difficult procedure because these tumors are of-

The obvious treatment

When

are the

Hyperparathyroidism

tivity

adult,

spasm

mechanism operates

activity in less than

The second difference is that the calcitonin mechanism acts mainly as a short-term regulator and has little long-term effect, month in and month out, on calcium ion concentration contrary to the powerful long-term effect of the parathyroid hor-

period of time

is

Treatment of Hypoparathyroidism Parathyroid Hormone (Parathormone). Parathyroid hormone is occasionally used for treating hypoparathyroidism. However, because of the expense of this hormone, because its effect lasts only a few hours, and because the tendency of the body to develop immune bodies against it makes it progressively less active in the body, treatment of hypoparathyroidism with parathyroid hormone is rare in present-day therapy. Vitamin D and Calcium Titerapy. In most patients administration of extremely large quantities of vitamin D, as high as 100,000 units per day, along with 1 to 2 grams of calcium, will suffice to keep the calcium ion concentration in a normal range. At times it may be necessary to administer 1,25-dihydroxycholecalciferol instead of the nonactivated form of vitamin D because of its much more potent and rapid action, but this can also cause unwanted effects, because it is sometimes difficult to prevent overactivity by this activated form of vitamin D.

a

human

to 6 to 7

level

that are especially sensitive to tetanic

parathyroid secretion.

tonin

this

laryngeal muscles. Laryngeal spasm obstructs respiration, which is a usual cause of death in tetany unless appropriate treatment is applied.

hour, in contrast with the 3 to 4 hours required for peak activity to be attained following the onset of

mone

mg/dl

53

ten only a few millimeters in size to find at operation.

and are

difficult

Rickets

Rickets occurs mainly in children as a result of calcium or phosphate deficiency in the extracellular fluid. Ordinarily rickets is not due to lack of calcium or phosphate in the diet but instead to a deficiency of vitamin D. However, if the child is prop-

exposed to sunlight, the ultraviolet rays will form enough vitamin D 3 in the skin to prevent rickets by promoting calcium and phosphate absorption from the intestines, as discussed earlier in the erly

chapter.

Children generally

amin

D

who remain

indoors through the winter

do not receive adequate quantities of vitwithout some supplementary vitamin D

therapy in the diet. Rickets tends to occur especially in the spring months because a supply of vitamin D formed during the preceding summer can remain stored through the fall months in the liver, and also, calcium and phosphorus absorption from the bones

must take place

fore clinical signs of rickets

increased parathyroid hormone secretion protects the body against blood hypocalcemia by causing osteoc/asf/c absorption of the bone; this in turn causes the bone to become decalcified, a condition called osteomalacia. The bone becomes progressively weaker, resulting also in rapid osteoids,

activity.

The

quantities of organic

osteoblasts

lay

bone matrix,

down

large

which because the calcium and osteoid,

does not become calcified phosphate concentrations are insufficient to cause calcification. Consequently, the newly formed, uncalcified osteoid gradually takes the place of other bone that is being reabsorbed. Obviously, hyperplasia of the parathyroid glands is marked in rickets because of the decreased blood calcium level. Tetany in Rickets. In the early stages of rickets, tetany almost never occurs, because the parathyroid glands continually stimulate osteoclastic absorption of bone and therefore maintain an almost normal level of calcium in the body fluids. However, when the bones become exhausted of calcium, the level of calcium may fall rapidly As the plasma level of calcium falls below 7 mg/dl, the usual

and the child may die of spasm unless intravenous calcium administered, which relieves the tetany within

signs of tetany develop, tetanic laryngeal is

seconds.

Treatment of Rickets. The treatment of rickets depends on supplying adequate calcium and phosphate in the diet and also on administering vitamin D.

Osteoporosis

Osteoporosis is the most common of all bone diseases in adults, especially in old age. It is a different disease from osteomalacia and rickets, for it results from diminished organic bone matrix rather than abnormal bone calcification. Usually, in osteoporosis the osteoblastic activity in the bone is less

than normal, and consequently the rate of bone osteoid deposition is depressed. But occasionally, as in hyperparathyroidism, the cause of the diminished bone is excess osteoclastic activity. Among common causes of osteoporosis are (1) lack of physical stress on the bones because of inactivity; (2) malnutrition to the extent that sufficient protein matrix cannot be formed; (3) postmenopausal lack of estrogen secretion, for estrogens have an osteoblast-stimulating activity; and (4) old age, in which growth hormone and other growth factors diminish greatly, plus the fact that many of the protein anabolic functions are poor anyway, so that bone matrix cannot be deposited satisfactorily.

for several months bebecome apparent.

Effects of Rickets on Bone. During prolonged deficiency of calcium and phosphate in the body flu-

blastic

643

Parathyroid Hormone, Calcitonin, Calcium and Phosphate Metabolism, Vitamin D, Bone, and Teeth

PHYSIOLOGY OF THE TEETH The teeth cut, grind, and mix the food. To perform these functions, the jaws have powerful muscles capable of providing an occlusive force of as much as 50 to 100 pounds between the front teeth and as much as 150 to 200 pounds for the jaw teeth. Also, the upper and lower teeth are provided with projections and facets that interdigitate, so that the upper set of teeth fits with the lower. This fitting is called occlusion, and it allows even small particles of food to be caught and ground between the tooth surfaces.

Functions of the Different Ports of the Teeth

Figure 53-9 illustrates a

showing

sagittal

section

of a

major functional parts: the enamel, dentine, cementum, and pulp. The tooth can also be divided into the crown, which is the portion that protrudes from the gum into the mouth, and the root, which is the portion that protrudes into tooth,

its

bony socket of the jaw. The collar between the crown and the root where the tooth is surrounded by gum is called the neck. Dentine. The main body of the tooth is composed of dentine, which has a strong, bony structure. Dentine is made up principally of hydroxyapatite crystals similar to those in bone but much the

embedded

in a strong meshwork other words, the principal constituents of dentine are very much the same as those of bone. The major difference is its histologi-

denser. These are

of collagen fibers.

In

^

644

Endocrinology ond Reproduction

XIII

Enamel

Crown
J

in the ovaries, illustrating, first,

follicle

LH

cause accelerated growth of the theca and granulosa cells in about 20 of the ovarian follicles each month. These cells in turn secrete a follicular fluid that contains a h^h_ concentration of estrog en, one of the important female sex hormones discussed later. The accumulation of this fluid in the follicle causes a fluid-filled cavity called the antrum to appear within the mass of theca and granulosa cells, as illustrated at the third stage in Figure 55-3. After the antrum is formed, the theca and granulosa cells continue to proliferate, the rate of secretion accelerates, and each of the growing follicles is

now

FSH

Function of

Figure 55-2 Approximate plasma concentrations of the gonadotropins and ovarian hormones during the normal female

follicle

o ^yjl) bes ecreted in large quantities, the entire ovarie s erams j b if nursing does not continue, j ; mately 100 grams of lactose, which must be dethe breasts lose their ability to produce milk within rived from the mother's glucose. Also, some 2 to 3 a few days. However, milk production can continue grams of calcium phosphate may be lost each day, for several vears if the child continues to suckle, and unless the mother is drinking large quantities but the rate of milk formation normally decreases of milk and has an adequate intake of vitamin D, considerably after 7 to 9 months. the output of calcium and phosphate by the lactatHypothalamic Control of Prolactin Secretion. ing mammae will often be much greater than the Though secretion of most of the anterior pituitary intake of these substances. To supply the excess calhormones is enhanced by neurosecretory releasing cium and phosphate, the parathyroid glands enfactors transmitted from the hypothalamus to the large greatly, and the bones become progressively anterior pituitary gland through the hypothalamicdecalcified. The problem of decalcification is usuhypophysial portal system, the secretion of proally not very great during pregnancy, but it can be lactin is normally controlled by an exactly opposite a distinct problem during lactation. effect. That is, the hypothalamus synthesizes a prolactin inhibitory hormone (PIH) that almost certainly is the small catecholamine dopamine. This, between j pregnancies, prevents the formation of excess proGROWTH AND FUNCTIONAL lactin. Then, during the months of lactation, the seDEVELOPMENT OF THE FETUS cretion of dopamine itself is suppressed, the prolactin mechanism is activated, and milk production During the first 2 to 3 weeks of gestation, the fe-

sent,

if it is

.,_

.

damage, or

.

occurs.

,

,

,

.

tus remains almost microscopic in size, but thereafter its

The Ejection (or "Let-Down") Process in

Milk Secretion

—

Function of Oxytocin

Milk is secreted continuously into the alveoli of the breasts, but milk does not flow easily from the alveoli into the ductile system and therefore does not continually leak from the breast nipples. Instead, the milk must be ejected from the alveoli and into the ducts before the baby can obtain it. This process is called "let-down" of the milk. It is caused by a combined neurogenic and hormonal

hormone oxytocin as follows: the baby suckles the breast, sensory signals are transmitted through somatic nerves to the spinal cord and then to the hypothalamus, there causing the pituitary gland to secrete oxytocin. This hormone flows in the blood to the breasts, where it causes myoepithelial cells that surround the outer walls of the alveoli to contract, thereby expressing the milk from the alveoli into the ducts. Thus, within 30 seconds to a minute after a baby begins to suckle the breast, milk begins to flow. This process is called milk ejection, or milk let-down. Suckling on one breast causes milk flow not only in that breast but also in the opposite breast. Also, it is especially interesting that the sound of the baby crying is often enough of an emotional signal reflex involving the

When

to

,

.

,

pituitary

cause milk ejection.

dimensions increase almost in proportion

At 12 weeks the length of the

fetus is approximately 10 cm; at 20 weeks, approximately 25 cm, and at term (40 weeks), approximately 53 cm (about 21 inches). Because the weight of the fetus is proportional to the cube of the length, the weight increases approximately in proportion to the cube of the age of the fetus. Therefore, the weight of the fetus remains almost nothing during the first months and reaches only 1 pound at 5.5 months of gestation. Then during the last trimester of pregnancy, the fetus gains tremendously, so that 2 months prior to birth the weight averages 3 pounds; at 1 month prior to birth, 4.5 pounds; and at birth, 7 pounds. to age.

TABLE 56-1 PERCENTAGE COMPOSITION OE MILK

Water

Human Milk

Cow's Milk

88.5

87.0

Fat

3.3

3.5

Lactose

6.8

4.8

Casein Lactalbumin and

0.9

2.7

0.4

0.7

0.2

0.7

other protein

Ash

56

Development of the Fetal Organ Systems Within

1

month

after fertilization of the

ovum,

the different organs of the fetus are already at formed, and during the next 2 to 3 months, most of the gross details of the different all

least partly

organs are established. However, cellular developof these structures is usually far from complete and requires the entire remaining months of pregnancy for full maturation. Even at birth the

Pregnancy; Lactation; and Fetal and Neonatal Physiology

^

679

excreting urine during at least the latter half of

pregnancy, and urination occurs normally in utero. However, the renal control systems for regulation of extracellular fluid electrolyte balances and acidbase balance are almost nonexistent until after midfetal life and do not reach full development until about a month after birth.

ment

those of the nervous system, the kidneys, and the liver, still lack full development, as is discussed in more detail later in the chapter. The Circulatory System. The human heart begins beating during the fourth week following fertilization, contracting at the rate of about 65 beats per minute. The rate increases steadily as the fetus grows and reaches approximately 140 per minute immediately before birth. Formation of Blood Cells. Nucleated red blood cells begin to be formed in the yolk sac and mesothelial layers of the placenta at about the third week of fetal development. This is followed a week later by the formation of non-nucleated red blood cells by the fetal mesenchyme and by the endothelium of the fetal blood vessels. Then at approximately 6 weeks, the liver begins to form blood cells, and in the third month the spleen and other lymphoid tissues of the body also begin forming blood cells. Finally, from approximately the third month on, the bone marrow forms more and more red and white blood cells while the other structures

ADJUSTMENTS OF THE INFANT TO EXTRAUTERINE LIFE

cells of certain structures, particularly

completely lose their ability to form blood

cells, ex-

cept for lymphocytes produced in lymph tissue. The Respiratory System. Obviously, respiration cannot occur during fetal life. However, respiratory movements do take place beginning at the end of the first trimester of pregnancy. Tactile stimuli or fetal asphyxia especially cause respiratory movements. The Nervous System. Most of the peripheral reflexes of the fetus are well developed by the third to fourth month of pregnancy. However, some of the more important higher functions of the central

undeveloped even at birth. Indeed, myelinization of some major tracts of the central nervous system becomes complete only afnervous system are

ter

still

approximately a year of postnatal

The

life.

Gastrointestinal Tract. Even in midpregnancy the fetus ingests and absorbs large quantities of amniotic fluid, and during the latter 2 to 3 months, gastrointestinal function approaches that of the normal newborn infant. Small quantities of meconium are continually formed in the gastrointestinal tract and excreted from the bowels into the amniotic fluid. Meconium is composed partly of residue from amniotic fluid and partly of excretory products from the gastrointestinal mucosa and glands. The Kidneys. The fetal kidneys are capable of

Onset of Breathing

The most obvious

effect of birth

on the baby

is

with the mother and therefore loss of this means for metabolic support. And by far the most important immediate adjustment required of the infant is to begin breathloss of the placental connection

ing.

Cause of Breathing at Birth. Following comnormal delivery from a mother who has not been depressed by anesthetics, the child ordinarily begins to breathe within seconds and has a completely normal respiratory rhythm within less than a minute after birth. The promptness with which pletely

the fetus begins to breathe indicates that breathing initiated by sudden exposure to the exterior

is

world, probably resulting from a slightly asphyxiated state incident to the birth process but also from sensory impulses originating in the suddenly cooled skin. However, if the infant does not breathe immediately, its body becomes progressively more hypoxic and hypercapnic, which provides additional stimulus to the respiratory center and usually causes breathing within a few seconds to a

minute after birth. Delayed and Abnormal Breathing at Birth Danger of Hypoxia. If the mother has been depressed by a general anesthetic during delivery, which at least partially anesthetizes the child as well, the initiation of respiration is likely to be delayed for several minutes, which illustrates the im-

—

portance of using as

little

obstetrical anesthesia as

who have had head trauma during delivery are slow to breathe or sometimes will not breathe at all. This can result from two possible effects: First, in a few infants, intracranial hemorrhage or brain contusion causes a concussion syndrome with a greatly depressed respiratory center. Second, and probably much more important, prolonged fetal hypoxia during delivery feasible. Also,

many

infants

can cause serious depression of the respiratory center. Hypoxia frequently occurs during delivery because of (1) compression of the umbilical cord, (2) premature separation of the placenta, (3) excessive contraction of the uterus, which cuts off blood flow to the placenta, or (4) excessive anesthesia of the

mother. Degree of Hypoxia That an Infant Can Tolerate. In the adult, failure to breathe for only 4 minutes

680

Endocrinology and Reproduction

often causes death, but a newborn infant often survives as long as 10 minutes of failure to breathe after birth. Unfortunately, though, permanent brain

impairment often ensues

if

breathing

is

delayed

more than

8 to 10 minutes. Indeed, actual lesions develop, mainly in brain stem areas, thus affecting many motor functions of the body. This is believed to

be one of the causes of cerebral palsy. Expansion of the Lungs at Birth. At

birth, the walls of the alveoli are held together by the surface tension of the viscid fluid that fills them. More than Hg of negative inspiratory pressure is re25 quired to oppose the effects of this surface tension and therefore to open the alveoli for the first time. But once the alveoli are open, further respiration can be effected with relatively weak respiratory movements. Fortunately, the first inspirations of the newborn infant are extremely powerful, usually caHg negative pable of creating as much as 50 pressure in the intrapleural space. Figure 56-7 illustrates the tremendous negative intrapleural pressures required to open the lungs at the onset of breathing. To the left is shown the pressure-volume curve (compliance curve) for the first breath after birth. Observe first the lowermost curve, which shows that the lungs do not expand at all until the negative pressure has reached — 40 cm water (— 30 Hg). Then as the negative pressure increases to - 60 cm water, about 40 ml of air enters the lungs. Then, to deflate the lungs, considerable positive pressure is required, probably because of the resistance offered by the viscid fluid in the bronchioles. Note that the second breath is much easier. However, breathing does not become completely normal until about 40 minutes after birth, as shown by the third compliance curve, the shape of which compares favorably with that of the normal adult. Respiratory Distress Syndrome Role of Sur-

mm

One

of the

infants

—

factant.

A

few

infants, especially

premature

infants,

develop severe respiratory distress in the early hours to several days following birth and frequently succumb within the next day or so. The alveoli of these infants at death contain large quantities of proteinaceous fluid, almost as if pure plasma had leaked out of the capillaries into the alveoli.

First

c60~

open

Second Breath

Breath

'

20 -

during inspiration. The surfactant

easily

se-

alveolar epithelial cells) do not begin to secrete surfactant until the last 1 to 3 months of gestation. Therefore, many premature babies (and a very few full-term babies) are born creting cells (the type

without

the

II

capability

of

secreting

surfactant,

which therefore causes both a tendency of the lungs to collapse and to develop pulmonary edema. The role of surfactant in preventing these effects

was discussed

in

Chapter

27.

Circulatory Readjustments at Birth

Almost as important as the onset of breathing at are the immediate circulatory adjustments

birth

that allow adequate blood flow through the lungs.

Because the lungs are mainly nonfunctional during not necessary for the fetal heart to On the other hand, the fetal heart must pump large quantities of blood through the placenta. As illustrated in Figure 56-8, most of the blood entering the right atrium from the inferior vena cava is directed in a straight pathway across the posterior aspect of the right atrium and thence through the foramen ovale directly into the left atrium. Thus, the well-oxygenated blood from the placenta enters the left side of the heart without going through the right ventricle and lungs. Instead, it is pumped by the left venfetal life,

is

it

pump much

tricle

blood through the lungs.

mainly into the vessels of the head and

fore-

limbs.

The blood entering the perior vena cava

is

right atrium

directed

from the su-

downward through

the

tricuspid valve into the right ventricle. This blood is

mainly deoxygenated blood from the head

gion of the fetus, and ventricle into the

it

is

pulmonary

pumped by artery.

re-

the right

Then almost

all

of the blood passes through the ductus arteriosus,

again not passing through the lungs but instead

descending aorta and through the two umwhere this deoxygenated blood becomes oxygenated. into the

bilical arteries into the placenta,

40

-40-20

adequate quantities of

substance normally secreted into the alveoli that decreases the surface tension of the alveolar fluid, therefore allowing the alveoli to

Changes

^

characteristic findings in these

surfactant, a

mm

mm

most

failure to secrete

is

.-- /L.

-^a --£*£_

40 Minutes

V

0-20-40-60-40-20 0-20-40-60-40-20 0-20-40-60 Pressure (cm

of water)

Figure 56-7 Pressure-volume curves of the lungs (compliance curves) of a newborn baby immediately after birth, showing (u) the extreme forces required for breathing during the first two breaths of life and (b) development of nearly normal compliance

curves within 40 minutes after birth. (From Smith: Sri. Am., 209:32. © 1963 by Scientific American, Inc. All rights reserved.)

in the Fetal Circulation at Birth.

The

basic changes in the fetal circulation at birth were discussed in Chapter 18 in relation to congenital

anomalies of the ductus arteriosus and foramen ovale that persist throughout life. Briefly, these are as follows: First, the tremendous blood flow through the placenta ceases, which approximately doubles the systemic vascular resistance at birth. This obviously increases the aortic pressure as well as the pressures in the left ventricle and left atrium. Second, the pulmonary vascular resistance decreases greatly as a result of expansion of the lungs. In the

56

Aorta

Ductus arteriosus

Lung

Foramen ovale

Ductus venosus

681

wall of the ductus arteriosus constricts markedly, and within 1 to 8 days the constriction is usually sufficient to stop all blood flow. This is called functional closure of the ductus arteriosus. Then during the next 1 to 4 months, the ductus arteriosus ordinarily becomes anatomically occluded by growth of fibrous tissue into its lumen. Ductus closure results from the increased oxygenation of the blood that flows through the ductus. In fetal life the Po 2 of the ductus blood is only Hg, but it increases to about 100 15 to 20 Hg within a few hours after birth. Furthermore, many experiments have shown that the degree of contraction of the smooth muscle in the ductus wall is closely related to the availability of oxygen. In addition, for reasons unknown the level of prostaglandins in the circulating blood decreases, and this, too, helps close the ductus. In one of several thousand infants, the ductus cular

Superior

vena cava

^

Pregnancy; Lactation; and Fetal and Neonatal Physiology

'

mm

mm

fails to close,

resulting in a patent ductus arteriosus,

the consequences of

which were discussed

in

Chap-

ter 18. Umbilical arteries

SPECIAL FUNCTIONAL PROBLEMS 56-8 Organization of the fetal circulation. (Modified from Arey: Developmental Anatomy. 7th ed. Philadelphia, W. B. Saunders Company, 1974.)

Figure

IN THE

A

most important

infant fetal lungs, the blood vessels had been compressed because of the small volume of the lungs. Immediately upon expansion these vessels are no longer compressed, and the resistance to blood flow decreases severalfold. Also, in fetal life the hypoxia of the lungs causes considerable tonic vasoconstriction of the lung blood vessels, but va-

unexpanded

when aeration of the lungs eliminates the hypoxia. These changes reduce the resistance of blood flow through the lungs as much as fivefold, which obviously reduces the pulmonary sodilation takes place

arterial pressure, the right ventricular pressure,

and the

right atrial pressure.

Closure of the Foramen atrial pressure

and the

high

Ovale. The low right

left atrial

pressure that oc-

cur secondary to the changes in pulmonary and systemic resistance at birth cause a tendency for blood to flow backward from the left atrium into the right atrium rather than the other direction, as occurred during fetal life. Consequently, the small valve that lies over the foramen ovale on the left side of the atrial septum closes over this opening, thereby preventing further flow. Closure of the Ductus Arteriosus. Similar effects occur in relation to the ductus arteriosus, for the increased systemic resistance elevates the aortic pressure while the decreased pulmonary resistance reduces the pulmonary arterial pressure. As a consequence, after birth blood begins to flow backward from the aorta into the pulmonary artery through the ductus arteriosus rather than in the other direction as in fetal life. However, after only a few hours the mus-

is

NEONATAL INFANT

neurogenic

control

newborn hormonal and

characteristic of the

instability of the various

systems.

This

results

partly

from immature development of the different organs of the body and partly from the fact that the control systems simply have not become adjusted to the completely

new way

of

life.

Cardiac Output. The cardiac output of the newborn infant averages 550 ml per minute, which is about two times as much in relation to body weight as in the adult. Occasionally, a child is born with an especially low cardiac output caused by hemorrhage through the placental membrane into the mother's blood prior to birth. Arterial Pressure. The arterial pressure during the first day after birth averages about 70/50; it increases slowly during the next several months to approximately 90/60. Then there is a much slower rise during the subsequent years until the adult pressure of 115/70 is attained at adolescence. Fluid Balance, Acid-Base Balance, and Renal Function. The rate of fluid intake and fluid excretion in the infant is seven times as great in relation to weight as in the adult, which means that even a slight percentage alteration of fluid intake or output can cause rapidly developing abnormalities. Also, the rate of metabolism in the infant is two times as great in relation to body mass as in the adult, which means that two times as much acid is normally formed, leading to a tendency toward acidosis in the infant. Finally, functional development of the kidneys

is

not complete until approximately

the end of the first month of life. For instance, the kidneys of the newborn can concentrate urine to

^

682

XIII

Endocrinology and Reproduction

only one and a half times the osmolality of the

plasma instead of the normal three- to fourfold in the adult. Therefore, considering the immaturity of the kidneys together with the marked fluid turnover and rapid formation of acid in the infant, one can readunderstand that among the most important problems of infancy are acidosis and dehydration. Liver Function. During the first few days of life, liver function may be quite deficient, as evidenced by the following effects: ily

4 6 8 10 1,2 2 Hours after birth!

2 1.

The

liver of the

newborn

is

deficient in form-

ing plasma proteins, so that the plasma protein concentration falls in the first few weeks of life to 1 g/100 ml less than that for older children. Occasionally, the protein concentration falls so low that the infant actually develops hypoproteinemic

Figure

56-9

after birth,

few days of

Fall in

and

4

6

8 10 12 1416 18 20

Days

after birth

body temperature of the infant immediately body temperature during the first

instability of

life.

edema. 2.

The gluconeogenesis function

of the liver

is

As a result, the blood glucose level of the unfed newborn infant falls to about 30 to 40 mg/100 ml, and the infant must depend on particularly deficient.

stored fats for energy until feeding can occur. The liver of the newborn often also forms too little of the factors needed for normal blood coaguits

3.

lation.

Metabolic Rate and Body Temperature. The normal metabolic rate of the newborn in relation to body weight is about two times that of the adult, which accounts also for the two times as great cardiac output and two times as great minute respiratory volume in the infant. However, since the body surface area is very large in relation to the body mass, heat is readily lost from the body. As a result, the body temperature of the newborn infant, particularly of the premature infant, falls easily. Figure 56-9 shows that in a normally cool room the body temperature of even the normal newborn falls several degrees during the first few hours after birth but returns to normal in 7 to 8 hours. Still, the body temperature regulatory mechanisms remain poor during the early days of life, at first allowing marked deviations in temperature, which are also illustrated in Figure 56-9. Nutritional

a corresponding decrease in immunity. Thereafter, the baby's own immunization processes begin to

form antibodies, and the

gamma

tration returns essentially to

globulin concen-

normal by the age of

12 to 20 months.

Endocrine Problems. Ordinarily, the endocrine system of the infant is highly developed at birth, and the infant rarely exhibits any immediate endocrine abnormalities. However, there are special instances in which endocrinology of infancy is important.

Need for Calcium.

In the

newborn

infant rapid

bones has only begun at birth, so that a ready supply of calcium is needed through-

ossification of the

out infancy.

Need for Iron. If the mother has had adequate amounts of iron in her diet, the liver of the infant usually has stored enough iron to keep forming blood cells for 4 to 6 months after birth. But if the mother has had insufficient iron in her diet, anemia likely to

Immunity. Fortunately, the newborn infant inhermuch immunity from its mother because many antibodies diffuse from the mother's blood through the placenta into the fetus. However, the neonate itself does not form antibodies to a significant extent. By the end of the first month, the blood gamma globulins, which contain the antibodies, have decreased to less than one half the original level, with its

Needs During the Early Weeks of

Life. Three specific nutritional problems occur in the infant, as follows:

is

Vitamin C Deficiency. Ascorbic acid (vitamin C) not stored in significant quantities in the fetal tissues; yet it is required for proper formation of cartilage, bone, and other intercellular structures of the infant. Furthermore, milk, especially cow's milk, has poor supplies of ascorbic acid. For this reason, orange juice or other sources of ascorbic acid are usually prescribed by the third week of life. is

supervene

in the infant after

about 3

months of life. Therefore, administration of iron in some form is desirable by the second or third months of life.

pregnant mother bearing a female child is with an androgenic (masculinizing) hormone or if she develops an androgenic tumor during pregnancy, the child will be born with a high degree of masculinization of its sexual organs, thus resulting in a type of hermaphroditism. 2. An infant born of an untreated diabetic mother will have considerable hypertrophy and hyperfunction of its islets of Langerhans. As a consequence, the infant's blood glucose concentration may fall to as low as 20 mg per 100 ml or even lower shortly after birth. Fortunately, the newborn infant, unlike the adult, only rarely develops insulin shock or coma from this low level of blood glucose concentration. 1.

If

treated

a

56

Pregnancy; Lactation; and Fetal and Neonatal Physiology

^

683

As

a consequence, respiratory distress is a cause of death. Also, the low functional

Because of metabolic deficits in the diabetic mother, the fetus is often stunted in growth, and

pressed.

growth of the newborn infant and

residual capacity in the premature infant is often associated with periodic breathing of the Cheyne-

tion are often impaired. Also, there

tissue maturaa high rate of

is

intrauterine mortality; and of those fetuses that do come to live birth, there is still a high mortality

Two

rate.

who

succumb to syndrome, which was de-

thirds of the infants

die

the respiratory distress scribed earlier in the chapter. 3. Occasionally, a child is born with hypofunctional adrenal cortices, some resulting from agenesis

glands or others from exhaustion atrophy, which can occur when the adrenal glands have been overstimulated. of the

Special Problems of Prematurity

All the problems just noted for neonatal life are severely exacerbated in prematurity. These can be categorized under the following two headings: (1)

immaturity of certain organ systems and (2) instahomeostatic control systems. Because of these effects, a premature baby rarely lives if it is born more than 2.5 to 3 months prior to

bility of the different

term.

The respiratory system is especially likely to be underdeveloped in the premature infant. The vital capacity and the functional residual capacity of the lungs are unusually small in relation to the size of the infant. Also, surfactant secretion

is

seriously de-

common

Stokes type.

Another major problem of the premature infant inability to ingest and absorb adequate food.

is its

the infant is more than 2 months premature, the digestive and absorptive systems are almost always If

inadequate. The absorption of fat is so poor that the premature infant must have a low fat diet. Furthermore, the premature infant has unusual difficulty in absorbing calcium and therefore can develop severe rickets before the difficulty is recognized. For this reason, special attention must be paid to adequate calcium and vitamin D intake. Immaturity of the different organ systems in the premature infant creates a high degree of instability in the homeostatic systems of the body. For instance, the acid-base balance can vary tremendously, particularly when the baby's food intake varies from time to time. And one of the particular problems of the premature infant is inability to maintain normal body temperature. Its temperature tends to approach that of its surroundings. At normal room temperature the baby's temperature may stabilize in the low 90s or even in the 80s. Statistical studies show that a body temperature maintained below 35.5° C (96° F) is associated with a particularly high incidence of death, which explains the common use of the incubator in the treatment of prematurity.

REFERENCES Reproduction and Lactation Blackburn,

and Loper, D.

S. T.,

A Clinical

ogy:

L.:

Fetal

Maternal, Fetal, and Neonatal Physiol-

Perspective. Philadelphia,

W.

B.

Saunders Co., 1992.

Drugs in Pregnancy and Lactation: A Guide to Fetal and Neonatal Risk. Baltimore, Williams & Wilkins Co., 1994. Compel, C, and Silverberg, S. G.: Pathology in Gynecology and ObstetBriggs, G. G.:

rics.

Lippincott Co., 1994. Reproductive Endocrinology. Philadelphia,

Philadelphia,

Cowan,

B.:

J.

B.

J.

B.

Lippincott

Co., 1994. Practice. Philadelphia,

W.

and

D.:

E.,

Raven

Neill,

J.

R.:

Maternal-Fetal Medicine: Principles and

Saunders Co., 1994. The Physiology of Reproduction.

Jr.,

al.:

and

more, Williams

W.

&

Bassett,

L.:

The Female Breast and

New

York,

&

Its

Disorders.

Wilkins Co., 1990.

Clinical Gynecologic Endocrinology

Tulchinskv, D., and

ders

Infertility'. Balti-

Wilkins Co., 1994. Little, A. B.: Maternal-Fetal Endocrinology'. Philadel-

B.

C, and

Co.,'

Bertrand,

J.

B.

Management

of

Lippincott Co., 1994.

Endocrinology: Physiology', Pathophysiology, & Wilkins Co., 1993. T, and Loper, D. L.: Maternal, Fetal, and Neonatal Physiol-

et al.: Pediatric

J.,

Clinical Aspects. Baltimore: Williams

Blackburn,

S.

ogy: A Clinical Perspective. Philadelphia, W. B. Saunders Co., 1992. Garland, T, Jr., and Carter, P. A.: Evolutionary physiology. Annu. Rev.

Hanson, M.

A., et 1:

al.:

The

Fetus and Neonate: Physiology and Clinical AppliNew York, Cambridge University Press,

Circulation.

1993. B.

Saunders

Co., 1990.

and Fox, W. W.: Fetal and Neonatal Physiology. Philadelphia, Saunders Co., 1992. Stark, J., and de Leval, M.: Surgery for Congenital Heart Defects. Philadelphia, W. B. Saunders Co., 1993. Strang, L. B.: Fetal lung liquid: Secretion and reabsorption. Physiol. Rev, Polin, R. A.,

and

Saunders Co., 1994. Jaffe, R. B.: Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Philadelphia, B. SaunS.

Neonatology': Pathophysiology and

Long, W. A.: Fetal and Neonatal Cardiology. Philadelphia, W.

Baltimore, Williams Speroff, L., et

phia,

B., et al.:

Newborn. Philadelphia,

cations. Vol.

B.

Press, 1994.

Mitchell, G. W.,

Yen,

the

Physiol., 56:579, 1994.

Creasy, R. K., and Resnik,

Knobil,

Avery, G.

and Neonatal Physiology

W

W.

B.

71:991, 1991.

1991.

QUESTIONS 1.

2.

Describe the fertilization of the ovum. Describe the transport and implantation of the devel-

oping morula and blastocyst.

3.

How

4.

In

do the early-developing morula and blastocyst derive their nutrition from the uterus? what ways

is diffusion

through the placental

mem-

684

^

XIII

Endocrinology and Reproduction

brane similar to diffusion through the respiratory

13.

membrane? 5.

Describe the diffusion of oxygen, carbon dioxide, and the various food substances through the placental

membrane. 6.

Explain the role of human chorionic gonadotropin in the

14.

few weeks

15.

maintenance of pregnancy during the

first

after fertilization. 7.

8.

What

are the functions of the estrogens gesterone secreted by the placenta?

How

does the mother respond

to

and the

pregnancy

pro-

16.

in rela-

17.

tion to each of the following factors: placental blood

flow and cardiac output, mother's blood volume, mother's nutrition during pregnancy, and formation of amniotic fluid? 9.

What

are

the

characteristics

of

preeclampsia

19.

20

newborn infant? Explain what happens

and

11

12.

Discuss the factors that increase uterine contractility toward the end of pregnancy. How does increased contractility lead to a possible positive feedback cycle that culminates in labor and birth of the baby? Describe the mechanics of parturition. What specific feedback mechanisms at the time of labor probably play major roles in enhancing the labor contractions and causing parturition to go to completion? Discuss the factors that cause growth and development of the breasts and of their glandular apparatus.

during lactation? Which organs of the fetus are not fully developed at the time of birth? Describe the onset of breathing. Why is surfactant important in this? Explain the changes in pressure in different parts of the circulatory system immediately after birth that cause the immediate closure of the foramen ovale and the closure over a period of hours and days of the ductus arteriosus. What are some of the special nutritional needs of the

18.

eclampsia? 10

Explain the hormonal mechanisms that prevent lactation before birth but cause it to begin immediately after birth. What is the role of prolactin in maintaining the capability of the breasts to secrete milk for many months if the baby continues to suckle? Explain the function of oxytocin in milk ejection. What are some of the metabolic drains on the mother

to the fetus

given an androgenic hormone or abetes during pregnancy. is

21

What rity,

are

some

the

mother

she has di-

of the special problems of prematu-

especially problems related

system and

when when

to the

to

the respiratory

maintenance of body temperature?

Sports Physiology

57

Sports Physiology

Sports Physiology

57 No other normal stresses to which the body is exposed even nearly approach the extreme stresses of heavy exercise. In fact, if some of the extremes of exercise were continued for even slightly prolonged periods of time, they might easily be lethal. Therefore, in the main, sports physiology is a discussion

comes from the relative times required for running the marathon race. In a recent comparison, the top female performer had a running time 12 per cent less than that of the top male performer. On the other hand, for some events, women have at times

—

men for instance, for the twoacross the English Channel, where the availability of extra fat might be an advantage for held records over

of the ultimate limits to

which most of the bodily mechanisms can be stressed. To give one simple ex-

way swim

ample: In a person who has extremely high fever, approaching the level of lethality, the body metabolism increases to about 100 per cent above normal. By comparison, the metabolism of the body during a marathon race increases to 2000 per cent above normal.

heat insulation, energy.

buoyancy,

and

extra

long-term

The hormonal differences between women and men certainly account for a large part if not most of the differences in athletic performance. Testosterone secreted by the male testicles has powerful anabolic effect in causing greatly increased deposition of protein everywhere in the body, especially in the muscles. In fact, even the man who participates in very little sports activity but who nevertheless is well-endowed with testosterone will have muscles that grow to sizes 40 per cent or more greater than those of his female counterpart and with a corresponding increase in a

The Female and the Male Athlete

Most

of the quantitative data that are given in chapter are for the young male adult, not because it is desirable to know only these values but because it is only in this class of athletes that relathis

complete measurements have been made. for those measurements that have been made in women, almost identically the same basic physiological principles apply equally as to men except for quantitative differences caused by differtively

strength.

However,

to the muscle mass vary between two and three quarters of the values recorded in men. On the other hand, when measured in terms

The female sex hormone estrogen probably also accounts for some of the difference between female and male performance, though not nearly so much as testosterone. Estrogen is known to increase the deposition of fat in the female, especially in certain tissues, such as the breasts, the hips, and the subcutaneous tissue. At least partly for this reason, the average nonathletic female has about 27 per cent body fat composition in contrast to the nonathletic male, who has about 15 per cent. This obviously is a detriment to the highest levels of athletic performance in those events in which performance de-

of strength per square centimeter of cross-sectional area, the female muscle can achieve almost exactly

strength to

ences in body size, body composition, and the presence or absence of the male sex hormone testosterone. In general, most quantitative values for women such as muscle strength, pulmonary ventilation, and cardiac output, all of which are related

—

—

mainly thirds

the same maximum force of contraction as that of the male between 3 and 4 kg /cm 2 Therefore, much of the difference in total muscle performance lies in the extra percentage of the male body that is muscle, caused by endocrine differences that we

—

discuss

A

.

later.

good indication

of the relative performance

capabilities of the female versus the

male athlete

pends upon speed or on Finally,

ratio of total

body muscle

body weight.

one cannot neglect the

hormones on temperament. There

effect of the sex is

no doubt that and that es-

testosterone promotes aggressiveness

trogen is associated with a more mild temperament. Certainly a large part of competitive sports is the aggressive spirit that drives a person to maximal effort, often at the expense of judicious restraint.

687

688

XIV

Sports Physiology

erally against a force of

THE MUSCLES IN EXERCISE Strength, Power, and Endurance of Muscles

The final common denominator in athletic events what the muscles can do for you what strength they can give when it is needed, what power they can achieve in the performance of work, and how

—

is

long they can continue in their activity. The strength of a muscle is determined mainly

by

its

size,

with a maximum

contractile force of be-

tween 3 and 4 kilograms per square centimeter of musThus, the man who is well laced with testosterone and therefore has correspondingly enlarged muscles will be much stronger than those persons without the testosterone advantage. Also, the athlete who has enlarged his muscles through an exercise training program likewise will have increased muscle strength. To give an example of muscle strength, a worldcle cross-sectional area.

weight lifter might have a quadriceps muscle with a cross-sectional area as great as 150 square centimeters. This would translate into a maximal contractile strength of 525 kilograms (or 1155 pounds), with all this force applied to the patellar tendon. Therefore, one can readily understand how it is possible for this tendon at times to be ruptured or actually to be avulsed from its insertion into the tibia below the knee. Also, when such forces occur in tendons that span a joint, similar forces are applied as well to the surfaces of the joints, or sometimes to ligaments spanning the joints, thus accounting for such happenings as displaced cartilages, compression fractures about the joint, or torn class

ligaments. The holding strength of muscles is about 40 per cent greater than the contractile strength. That is, if a muscle

is already contracted and a force then attempts to stretch out the muscle, as occurs when landing after a jump, this requires about 40 per cent more force than can be achieved by a shortening contraction. Therefore, the force of 525 kilograms calculated previously for the patellar tendon during muscle contraction becomes 735 kilograms (1617 pounds). This obviously further compounds the problems of the tendons, joints, and ligaments. It can also lead to internal tearing in the muscle itself. In fact, stretching out of a maximally contracted muscle is one of the best ways to insure the highest degree of muscle soreness. The power of muscle contraction is different from muscle strength, for power is a measure of the total amount of work that the muscle performs in a unit period of time. This is determined not only by the strength of muscle contraction but also by its distance of contraction and the number of times that it

contracts

each

minute.

Muscle power

generally measured in kilogram meters (kg-m) per minute. That is, a muscle that can lift a kilogram weight to a height of 1 meter or that can move some object lat-

1

kilogram for a distance of

minute is said to have a power of 1 kg-m/min. The maximum power achievable by all the muscles in the body of a highly trained athlete with all the muscles working together is approxi-

a meter in

1

mately the following: kg-m/min First 8 to 10

seconds

7000 4000 1700

Next 1 minute Next half hour

Thus, it is clear that a person has the capability of an extreme power surge for a short period of time, such as during a 100 meter dash that can be completed entirely within the first 10 seconds, whereas for long-term endurance events the power output of the muscles is only one fourth as great as during

power surge. Yet this does not mean that one's athletic performance is four times as great during the initial power surge as it is for the next half hour, because the efficiency for translation of muscle power output into athletic performance is often much less during rapid activity than during less rapid but sustained activity. Thus, the velocity of the hundred meter dash is only 1.75 times as great as the velocity of the 30 minute race despite the fourfold difference in short-term versus long-term muscle the initial

power The

capability.

measure of muscle performance is endepends on the nutritive support for the muscle more than anything else on the amount of glycogen that has been stored in the muscle prior to the period of exercise. A person on a high carbohydrate diet stores far more glycogen in muscles than a person on either a mixed diet or a high fat diet. Therefore, endurance is greatly enhanced by a high carbohydrate diet. When athletes run at speeds typical for the marathon race, their endurance as measured by the final

durance. This, to a great extent,

—

time that they can sustain the race until complete exhaustion is approximately the following: minutes

High carbohydrate Mixed diet High fat diet

240 120 85

diet

The corresponding amounts

of glycogen stored in the muscle before the race started explain these differences. The amounts stored are approximately the following:

gm/kg muscle

is

High carbohydrate Mixed diet High fat diet

diet

40 20 6

57

The Muscle Metabolic Systems

in

trates

Exercise

are present in

body; these were Chapters 45 through 48. However, special quantitative measures of the activities of three metabolic systems are exceedingly important in understanding the limits of physical activity. These three metabolic systems are (1) the

muscle as discussed

in all other parts of the in

detail

phosphagen system,

and

(3)

(2)

in

the glycogen -lactic acid system,

the aerobic system.

of

ATP

phocreatine (also called creatine phosphate) is another chemical compound that has a high energy phosphate bond, with the following formula:

two phosphate

radi-

designated by the symbol ~,

are high-energy phosphate bonds.

Each of these bonds mole of ATP un-

stores 7300 calories of energy per

der standard conditions (and as much as 12,000 calories under the physical conditions in the body, which was discussed in detail in Chapter 45).

when one phosphate radical is removed from the molecule, 7300 calories of energy that can be used to energize the muscle contractile process is released. Then, when the second phosphate radical is removed, still another 7300 calories becomes available. Removal of the first phosphate converts the ATP into adenosine diphosphate (ADP), and removal of the second converts this ADP into adenosine monophosphate (AMP). Therefore,

Unfortunately, the amount of ATP present in the muscles, even in the well-trained athlete, is sufficient to sustain maximal muscle power for only about 3 seconds, maybe enough for half of a 50meter dash. Therefore, except for a few seconds at

new

adenosine triphosphate be formed continuously, even during the performance of short athletic events. Figure 57-1 illus-

a time,

it

is

essential that

This can decompose to creatine and phosphate ion, as illustrated to the left in Figure 57-1, and in doing so releases large amounts of energy. In fact, the high-energy phosphate bond of phosphocreatine has more energy than the bond of ATP 10,300 calories per mole, in comparison with 7300. Therefore, the phosphocreatine can easily provide

—

Adenosine— PO B ~ P0 3 ~ PO" last

ADP

Creatine ~ PO,

Adenosine Triphosphate. The basic source of energy for muscle contraction is adenosine triphosphate (ATP), which has the following basic formula:

cals to the molecule,

first to

with the release of energy to the muscles for contraction. To the left-hand side of the figure are illustrated the three different metabolic systems that are responsible for reconstituting a continuous supply of adenosine triphosphate in the muscle fibers. These are the following: Release of Energy from Phosphocreatine. Phos-

The Phosphagen System

The bonds attaching the

showing the and then to AMP,

the overall metabolic system,

breakdown The same basic metabolic systems

689

Sports Physiology

enough energy to reconstitute the high energy bond of ATP. Furthermore, most muscle cells have two to four times as much phosphocreatine as ATP.

A

special characteristic of energy transfer

phosphocreatine to

II.

from

occurs within a small fraction of a second. Therefore, in effect, all the energy stored in the muscle phosphocreatine is instantaneously available for muscle contraction, just as is the energy stored in ATP. is

The combined amounts

that

it

of

cell

ATP and

cell

phosphocreatine are called the phosphagen energy system. These together can provide maximal muscle power for a period of 8 to 10 seconds, almost enough for the 100 meter run. Thus, the energy from the phosphagen system is used for maximal short bursts of muscle power.

The Glycogen -Lactic Acid System

The stored glycogen in muscle can be split into glucose and the glucose then utilized for energy. The

initial stage of this process, called glycolysis, occurs entirely without use of oxygen and therefore is

> Creatine + P0 3

Phosphocreatine

I.

ATP

"^

Glycogen-

Lactic acid

Energy for

muscle contraction

I.

Glucose Fatty acids

57-1 The three important metabolic systems supply energy for muscle contraction.

Figure

that

+ 0,

->C0 2+H 2

Amino acidsj Urea

690

XIV

Sports Physiology

to be anaerobic metabolism (see Chapter 45). During glycolysis, each glucose molecule is split into two pyruvic acid molecules, and energy is released to form four ATP molecules. Ordinarily, the pyruvic acid then enters the mitochondria of the muscle cells and reacts with oxygen to form still many more ATP molecules. However, when there is insufficient oxygen for this second stage (the oxidative stage) of glucose metabolism to occur, most of the pyruvic acid is converted into lactic acid, which then diffuses out of the muscle cells into the inter-

said

stitial fluid

and blood. Therefore,

in effect,

much

of

the muscle glycogen becomes lactic acid, but in doing so considerable amounts of adenosine triphosphate are formed entirely without the consumption of oxygen.

Another characteristic of the glycogen -lactic acid system is that it can form ATP molecules about 2.5 times as rapidly as can the oxidative mechanism of

onds provided by the phosphagen system, though somewhat reduced muscle power.

at

The Aerobic System

The aerobic system means the oxidation

—

—

minute are the following:

M of ATP/min

the mitochondria. Therefore, when large amounts of adenosine triphosphate are required for short to

moderate periods of muscle contraction, this anaerobic glycolysis mechanism can be used as a rapid source of energy. It is not as rapid as the phosphagen system, but about half as rapid. Under optimal conditions the glycogen -lactic acid system can provide 1.3 to 1.6 minutes of maximal muscle activity in addition to the 8 to 10 sec-

of food-

mitochondria to provide energy. That is, as illustrated to the left in Figure 57-1, glucose, fatty acids, and amino acids from the foods after some intermediate processing combine with oxygen to release tremendous amounts of energy that are used to convert AMP and ADP into ATP, as was discussed in Chapter 45. In comparing this aerobic mechanism of energy supply with the glycogen -lactic acid system and the phosphagen system, the relative maximal rates of power generation in terms of ATP generation per stuffs in the

Phosphagen system Glycogen -lactic acid system Aerobic system

On

the other hand,

4 2.5

when comparing

the systems

for endurance, the relative values are the following:

Time

Phosphagen TABLE 57-1 ENERGY SYSTEMS USED

Phosphagen system, almost

IN

8 to 10 seconds

system Glycogen -lactic acid system Aerobic system

VARIOUS SPORTS

entirely

100-meter dash

1.3 to

nutrients last)

lifting

Football dashes

Phosphagen and glycogen -lactic acid systems 200-meter dash Basketball

home run hockey dashes Glycogen -lactic acid system, mainly 400-meter dash Baseball Ice

100-meter Tennis Soccer

minutes

unlimited time (as long as

Jumping Weight Diving

1.6

Thus, one can readily see that the phosphagen system is the one utilized by the muscle for power surges of a few seconds, and the aerobic system is required for prolonged athletic activity. In between is the glycogen -lactic acid system, which is especially important for giving extra power during such intermediate races as the 200- to 800-meter runs.

swim

Glycogen -lactic acid and aerobic systems 800-meter dash 200-meter swim 1500-meter skating Boxing 2000-meter rowing 1500-meter run 1-mile run 400-meter swim Aerobic system 10,000-meter skating Cross-country skiing Marathon run (26.2 miles, 42.2 km) Jogging

What Types of Sports

Utilize

Which Energy Systems?

By considering the vigor

of a sports activity and duration, one can estimate very closely which of the energy systems are used for each activity. Various approximations are presented in Table 57-1. its

Recovery of the Muscle Metabolic Systems After Exercise

same way

that the energy from phosphoused to reconstitute adenosine triphosphate, so also can energy from the glycogen -lactic acid system be used to reconstitute both phosphocreatine and ATP. And then energy from the oxidative metabolism of the aerobic system can In the

creatine

can

be

57

—

be used to reconstitute all the other systems and also the the phosphocreatine, the ATP, glycogen -lactic acid system. Reconstitution of the lactic acid system means mainly the removal of the excess lactic acid that has accumulated in all the fluids of the body This is especially important because lactic acid causes extreme fatigue. When adequate amounts of energy are available from oxidative metabolism, removal of lactic acid is achieved in two ways: First, a small portion of it is converted back into pyruvic acid and then metabolized oxidatively by all of the body tissues. Second, the remaining lactic acid is reconverted into glucose mainly in the liver; and the glucose in turn is used to replenish the glycogen stores of the muscles. Recovery of the Aerobic System After Exercise. Even during the early stages of heavy exercise a portion of one's aerobic energy capability is depleted.

This results from two effects:

called oxygen debt stores of the

and

(2)

(1)

the so-

depletion of the glycogen

muscles.

Oxygen Debt. The body normally contains about 2 liters of stored oxygen that can be used for aerobic metabolism even without breathing any new oxygen. This stored oxygen consists of the folTlie

lowing: (1) 0.5 liter in the air of the lungs; (2) 0.25 liter dissolved in the body fluids; (3) 1 liter combined with the hemoglobin of the blood; and (4) 0.3 liter stored in the muscle fibers themselves, combined with myoglobin, an oxygen binding chemical similar to hemoglobin.

heavy exercise, almost all of this stored oxyused within a minute or so for aerobic me-

In

gen

tabolism. Then, after the exercise

quirements. In addition, about 9

is

liters

Alactacid oxygen debt = 3.5

Lactic acid

4

more

of oxy-

phosphagen system and oxygen portion of the oxygen debt, then for another hour at a lower level while the lactic acid is removed. The early portion of the oxygen debt is called the alactacid oxygen debt and amounts to about 3.5 liters. The latter portion is called the lactic acid oxygen debt and amounts to

body

is

reconstituting the

also repaying the stored

about 8 liters. Recovery of Muscle Glycogen. Recovery from exhaustive muscle glycogen depletion is not a simple matter. This often requires days, rather than the seconds, minutes, or hours required for recovery of the phosphagen and lactic acid metabolic systems. Figure 57-3 illustrates this recovery process under three different conditions: first, in persons on a high carbohydrate diet; second, in persons on a high fat /high protein diet; and third, in persons with no food. Note that on a high carbohydrate diet, full recovery occurs in approximately 2 days. On the other hand, persons on a high fat/high protein diet or on no food at all show extremely little recovery even after as long as 5 days. The messages of this comparison are (1) that it is important for an athlete to have a high carbohydrate diet before a grueling athletic event and (2) not to participate in exhaustive exercise during the 48 hours preceding the event.

12

16

20

24

oxygen debt = 8

28

32

36

liters

40

44

57-2 Rate of oxygen uptake by the lungs during maximal and then for almost 1 hour after the exer-

exercise for 4 minutes is

over. This figure

Nutrients Used During Muscle Activity

Although we have emphasized the importance of and large stores of muscle glycogen for maximal athletic performance, this does not mean that only carbohydrates are used for muscle energy it means simply that carbohydrates are used by preference. Actually, the muscles use large amounts of fat for energy in the form of fatty acids and acetoacetic acid (see Chapter 46) and also use to a much less extent proteins in the form of amino acids. In fact, even under the best conditions, in those endurance athletic events that last a high carbohydrate diet

—

longer than 4 to 5 hours, the glycogen stores of the muscle become almost totally depleted and are then of little further use for energizing muscle con-

liters

Minutes

cise

Figure 57-2 illustrates this principle of oxygen During the first 4 minutes of the figure, the person exercises very heavily, and the rate of oxygen uptake increases more than 15-fold. Then, even after the exercise is over, the oxygen uptake still remains above normal, at first very high while the debt.

over, this stored

gen must be consumed to provide for reconstituting both the phosphagen system and the lactic acid system. All of this extra oxygen that must be "repaid," about 11.5 liters, is called the oxygen debt.

debt.

691

is

oxygen must be replenished by breathing extra amounts of oxygen over and above the normal re-

Figure

Sports Physiology

demonstrates the principle of oxygen

traction. Instead, the muscle now depends upon energy from other sources, mainly from fats. Figure 57-4 illustrates the approximate relative usage of carbohydrates and fat for energy during prolonged exhaustive exercise under three different dietary conditions: high carbohydrate diet, mixed diet, and high fat diet. Note that most of the energy is derived from carbohydrate during the first few seconds or minutes of the exercise, but at the time of exhaustion, as much as 60 to 85 per cent of

692

XIV

Sports Physiology

High carbohydrate diet

Figure 57-3 Effect of diet on the rate of muscle glycogen replenishment following prolonged exer-

(From Fox: Sports Physiology. Philadelphia, Saunders College Publishing, 1979.) cise.

Hours

of

recovery

the energy is being derived from fats, rather than carbohydrates. Not all the energy from carbohydrates comes from the stored muscle glycogen. In fact, almost as much glycogen is stored in the liver as in the muscles; and this can be released into the blood in the form of glucose, then taken up by the muscles as an energy source. In addition, glucose solutions given to an athlete to drink during the course of an athletic event (in optimal concentrations of 2 to 2.5 per cent) can provide as much as 30 to 40 per cent of the energy required during prolonged events

such as marathon races. In essence, then, if muscle glycogen and blood glucose are available, these are the energy nutrients

100

CD

O) CO CO

real

endurance event one can expect

more than 50 per cent about the

CD

O) CO

fa

c;n--

so, for a

fat to

supply

of the required energy after

3 to 4 hours.

Effect of Athletic Training

on Muscles

and Muscle Performance

Importance

One

of

Maximal Resistance

of the cardinal principles of

ment during

athletic training is the following:

cles that function

exercised

Training.

muscle develop-

for

under no load, even

if

hours upon end, increase

Mus-

they are little

in

At the other extreme, muscles that contract at more than 50 per cent maximal force of contraction will develop strength very rapidly even if the contractions are performed only a few times each day. Utilizing this principle, experiments on muscle building have shown that 6 nearly maximal muscle contractions performed in three separate strength.

days a week give approximately optimal increase in muscle strength and without producing chronic muscle fatigue. The upper curve in Figure

57-5

illustrates the approximate percentage increase in strength that can be achieved in the previ-

ously 0)

CL

I 100

20 40 2 4 l-Seconds-rMinutes 1

2

Hours

-

Duration of exercise Figure

first

Even

sets 3

3

CD

>>

of choice for intense muscle activity.

57-4

Effect of duration of exercise as well as type of diet

on relative percentages of carbohydrate or fat used for energy by muscles. (Based partly on data in Fox: Sports Physiology. Philadelphia, Saunders College Publishing, 1979.)

untrained

training program,

young person by this showing that the muscle

resistive

strength

increases about 30 per cent during the first 6 to 8 weeks but almost plateaus after that time. Along with this increase in strength is an approximately

equal percentage increase in muscle mass, which is called muscle hypertrophy. In old age, many persons become so sedentary that their muscles atrophy tremendously. In these instances,

muscle training often increases muscle

more than 100 per cent. Muscle Hypertrophy. The basic

strength

size of a person's

57

693

Sports Physiology

The basic differences between the fast twitch the slow twitch fibers are the following: 1.

Fast twitch fibers are about

two times

and

as large

in diameter.

The enzymes that promote rapid release of enfrom the phosphagen and glycogen -lactic acid energy systems are two to three times as ac2.

ergy

slow twitch fibers, thus making the maximal power that can be achieved by fast twitch fibers as great as two times that of slow twitch fibers. 3. Slow twitch fibers are mainly organized for endurance, especially for generation of aerobic energy. They have far more mitochondria than the fast twitch fibers. In addition, they contain considerably more myoglobin, a hemoglobin-like protein that combines with oxygen within the muscle fiber; the extra myoglobin increases the rate of diffusion tive in fast twitch fibers as in

4

6

Weeks

of training

57-5 Approximate effect of optimal resistive exercise training on increase in muscle strength over a training period of 10 weeks.

Figure

determined mainly by heredity plus the level of testosterone secretion, which, in men, causes considerably larger muscles than in women. However, with training, the muscles can become hypertrophied perhaps an additional 30 to 60 per cent. Most of this hypertrophy results from increased diameter of the muscle fibers rather than increased numbers of fibers; but this probably is not entirely true, because a very few greatly enlarged muscle fibers are believed to split down the middle along their entire length to form entirely muscles

new

is

fibers,

thus increasing the

number

of fibers

slightly.

The changes muscle

fibers

numbers

that occur inside the hypertrophied

themselves

include

(1)

increased

of myofibrils, proportionate to the degree

of hypertrophy; (2)

up

mitochondrial enzymes; cent increase in the

to 120 (3)

as

per cent increase in as 60 to 80 per

much

components of the phosphagen

metabolic system, including both ATP and phosphocreatine; (4) as much as 50 per cent increase in stored glycogen; and (5) as much as 75 to 100 per cent increase in stored triglyceride (fat). Because of all these changes, the capabilities of both the anaerobic and the aerobic metabolic systems are increased, increasing especially the maximum oxidation rate and efficiency of the oxidative metabolic system as much as 45 per cent.

Fast Twitch

and Slow

Twitch Muscle Fibers

In the human being, all muscles have varying percentages of fast twitch and slow twitch muscle fibers. For instance, the gastrocnemius muscle has a higher preponderance of fast twitch fibers, which gives it the capability of very forceful and rapid contraction of the type used in jumping. On the other hand, the soleus muscle has a higher preponderance of slow twitch muscle fibers and therefore

used muscle is

to a greater extent for activity.

prolonged lower leg

oxygen throughout the fiber by shuttling oxygen from one molecule of myoglobin to the next. In addition, the enzymes of the aerobic metabolic system are considerably more active in slow twitch fibers of

than in 4.

fast twitch fibers.

The number

of capillaries per

mass

of fibers

is

greater in the vicinicv of slow twitch fibers than in

the vicinity of fast twitch fibers. In summary, fast twitch fibers can deliver extreme amounts of power for a few seconds to a minute or so. On the other hand, slow twitch fibers provide endurance, delivering prolonged strength of contraction over many minutes to hours. Hereditary Differences Among Athletes for Fast Twitch Versus Slow Twitch Muscle Fibers. Some persons have considerably more fast twitch than slow twitch fibers, and others have more slow twitch fibers; this obviously could determine to

some

extent the athletic capabilities of different in-

dividuals. Unfortunately, athletic training has not

been shown to change the relative proportions of fast twitch and slow twitch fibers however much an athlete might wish to develop one type of athletic prowess over another. Instead, this seems to be determined almost entirely by genetic inheritance, and this in turn helps determine which area of athletics is most suited to each person: some people appear to be born to be marathoners; others are born to be sprinters and jumpers. For example, the following are recorded percentages of fast twitch versus slow twitch fiber in the quadriceps

muscles of different types of

athletes:

Fast Twitch

Slow Twitch

Marathoners

18

Swimmers

26 55 55 63 63

82 74 45 45 37 37

Average man Weight lifters Sprinters

Jumpers

^

694

Sports Physiology

XIV

RESPIRATION IN EXERCISE

3.8

Although one's respiratory ability is of relatively concern in the performance of sprint types of athletics, it is critical for maximal performance in endurance athletics. Oxygen Consumption and Pulmonary Ventilation in Exercise. Normal oxygen consumption for a young adult man at rest is about 250 ml/min. However, under maximal conditions this can be increased to approximately the following average

3.6

-

•

little

^s*^

3.4

O >

Training frequency

* =5 days/wk • =2 days/wk ° =4 days/wk

3.2 O

2.8

1_

L

Figure

Athletically trained average

3600 4000 5100

man

Male marathon runners

Figure 57-6 illustrates the relationship between oxygen consumption and pulmonary ventilation at different levels of exercise.

as

would be expected,

It is

clear

that there

is

from

this figure,

a linear relation-

round numbers, both oxygen consumption and pulmonary ventilation increase about 20-fold between the resting state and maximum intensity ship. In

of exercise in the well-trained athlete.

The Limits of Pulmonary Ventilation. How sedo we stress our respiratory systems during exercise? This can be answered by the following comparison for the normal young man: verely

liters/min

Pulmonary ventilation at maximal exercise Maximal breathing

100 to 110

150 to 170

capacity

Thus, the maximal breathing capacity is about 50 per cent greater than the actual pulmonary ventilation during maximal exercise. This obviously pro-

120 110

c

E 100 §

80

1

60

^r

*>^i

'

40

o

H

•jgi^''

20 o

-

Uf^

^^ r \

Severe

exercise ,

2

,

2.0

1.0

)

57-6

Moderate

i

i

3.0

i

i

i

4.0

consumptic )n (L/min)

on oxygen consumption and venGray: Pulmonary Ventilation and Its Physiological Regulation. Springfield, 111.,' Charles C Thomas,

Figure

Effect of exercise

tilatory rate.

1950.)

(From

J.

S.

•

8

i

10

i

12

'

14

of training

57-7 Increase

athletic training.

in Vo, max over a period of 7 to 13 weeks of (From Fox: Sports Physiology. Philadelphia. Saunders

College Publishing. 1979.)

vides an element of safety for athletes, giving them extra ventilation that can be called on in such conditions as (1) exercise at high altitudes, (2) exercise

under very hot conditions, and

(3) abnormalities in the respiratory system. The important point is that the respiratory system is not normally the most limiting factor in the delivery of oxygen to the muscles during maximal muscle aerobic metabolism. We shall see shortly that the ability of the heart to pump blood to the muscles is usually a greater limiting factor. Effect of Training on Vo 2 Max. The abbreviation for the rate of oxygen usage under maximal aerobic metabolism is Vo, Max. Figure 57-7 illustrates the progressive effect of athletic training on Vo2 Max recorded in a group of subjects beginning at the level of no training and then pursuing the training program for 7 to 13 weeks. In this study, it is surprising that the Vo2 Max increased only about 10 per cent. Furthermore, the frequency of training, whether two times or five times per week, had little effect on the increase in Vb Max. Yet, as was 2 pointed out earlier, the Vo, Max of marathoners is about 45 per cent greater than that of the untrained person. Part of this greater Vo, Max of the marathoner probably is genetically determined; that is, those persons who have greater chest sizes in relation to body size and stronger respiratory

measure of the rate at which oxygen can diffuse from the alveoli into the blood.

diffusing capacity is a

exercise i

1

6

muscles select themselves to become marathoners. However, it is also very likely that the very prolonged training of the marathoner does increase the Vo 2 Max by values considerably greater than the 10 per cent that has been recorded in shortterm experiments such as that in Figure 57-7. The O, Diffusing Capacity of Athletes. The 2

CD

75

1

4

Weeks

ml/min

man

o

3.0

levels:

Untrained average

•

expressed in terms of milliliters of oxygen that minute for each millimeter of mercury difference between alveolar partial pressure of oxygen and pulmonary blood oxygen pressure. That is, if the partial pressure of oxygen in the alveoli is 91 This

is

will diffuse each

mm

57

Hg

while the oxygen pressure in the blood

is

90

mm

Hg, the amount of oxygen that diffuses through the respiratory membrane each minute is the diffusing capacity. The following are measured mlfmin 23 48 64 71

80

The most startling fact about these results is the almost threefold increase in diffusing capacity bestate and the state of maximal exThis results mainly from the fact that blood

tween the resting ercise.

flow through many of the pulmonary capillaries is very sluggish or even dormant in the resting state, whereas in exercise increased blood flow through the lungs causes all the pulmonary capillaries to be perfused at their maximal level, thus providing far greater surface area through which oxygen can dif-

pulmonary capillary blood. from these values that those athwho require greater amounts of oxygen per

fuse into the It is

letes

695

crease an athlete's "wind." This is true for many reasons. First, one effect of nicotine is constriction of the terminal bronchioles of the lungs, which increases the resistance of air flow into and out of the

smoke cause increased fluid secretion into the bronchial tree, as well as some swelling of the epithelial linings. Third, nicotine paralyzes the cilia on the surfaces of the respiratory epithelial cells that normally beat continuously to remove excess fluids and foreign particles from the respiratory tract. As a result, much debris accumulates in the respiratory passageways and adds further to the difficulty of breathing. Putting all these factors together, even the light smoker will feel respiratory strain during maximal exercise, and the level of performance obviously may be reduced. Much more severe are the effects of chronic smoking. There are very few chronic smokers in whom some degree of emphysema does not develop. In this disease, the following occur: (1) chronic bronchitis, (2) obstruction of many of the terminal bronchioles, and (3) destruction of many alveolar walls. In severe emphysema, as much as four fifths of the respiratory membrane can be destroyed; then even the slightest exercise can cause respiratory distress. In fact, many such patients cannot even perform the athletic feat of walking across the floor of a single room without gasping for breath. Such is the indictment of smoking. lungs. Second, the irritating effects of

values for different diffusing capacities:

Nonathlete at rest Nonathlete during maximal exercise Speed skaters during maximal exercise Swimmers during maximal exercise Oarsmen during maximal exercise

Sports Physiology

also clear

minute have higher diffusing capacities. Is this because persons with naturally greater diffusing capacities choose these types of sports, or is it because something about the training procedures increases the diffusing capacity? The answer is not known; but one must believe that training does play a role, particularly endurance training. The Blood Gases During Exercise. Because of the great usage of oxygen by the muscles in exercise, one would expect the oxygen pressure of the arterial blood to decrease markedly during strenuous athletics and the carbon dioxide pressure of the venous blood to increase far above normal. However, this normally is not the case. Both of these values remain nearly normal, illustrating the extreme ability of the respiratory system to provide very adequate aeration of the blood even in heavy exercise, which illustrates another very important

THE CARDIOVASCULAR SYSTEM IN EXERCISE

Muscle Blood Flow. The final common denominator of cardiovascular function in exercise is to deliver oxygen and other nutrients to the muscles. For this purpose, the muscle blood flow increases drastically during exercise. Figure 57-8 illustrates a recording of muscle blood flow in the calf of a person for a period of 6 minutes during moderately strong intermittent contraction. Note not only the

point: The blood gases do not have to become abnormal for respiration to be stimulated in exercise. Instead, res-

stimulated mainly by neurogenic mechaChapter 29. Part of this stimulation results from direct stimulation of the respiratory center by the same nervous signals that are transmitted from the brain to the muscles to cause the exercise. An additional part is believed to result from sensory signals transmitted into the respiratory center from the contracting muscles and moving joints. All this nervous stimulation of respiration is normally sufficient to provide almost ex-

piration

nisms

is

in exercise, as discussed in

proper increase in pulmonary ventilation the oxygen keep the blood respiratory gases and the carbon dioxide almost normal. actly the to

—

Effect of Exercise.

It

—

Smoking on Pulmonary Ventilation in is widely known that smoking can de-

Minutes

57-8

muscle exercise on blood flow in the calf of a leg during strong rhythmical contraction. The blood flow was much less during contraction than between contractions. (From Figure

Barcroft

Effects of

and Dornhorst:

J.

Physiol., 109:402, 1949.)

696 great

XIV

Sports Physiology

—

— about

but also 13-fold during each muscle conpoints can be made from this study:

increase in

flow

that the flow decreased traction.

Two

(1) The actual contractile process itself temporarily decreases muscle blood flow because the contracting muscle compresses the intramuscular blood vessels; therefore, strong tonic muscle contraction can cause rapid muscle fatigue because of lack of delivery of enough oxygen and nutrients during

the continuous contraction. (2) The blood flow to muscles during exercise can increase markedly. The following comparison illustrates the maximal increase in blood flow that can occur in the well-

TABLE 57-2 COMPARISON OF CARDIAC OUTPUT BETWEEN MARATHONER

AND NONATHLETE

Stroke

Volume

Resting Nonathlete

Marathoner

(ml)

Heart Rate (beats/min)

75 105

75 50

110 162

195 185

Maximum Nonathlete

Marathoner

trained athlete.

ml/100

gm

muscle/min

put,

oxygen consumption, and cardiac output dur-

not surprising that all these are each other, as shown by the linear functions, because the muscle work output increases oxygen consumption, and oxygen consumption in turn dilates the muscle blood vessels, thus increasing venous return and cardiac output. Typical cardiac outputs at several levels of exercise ing exercise.

3.6 Resting blood flow Blood flow during maximal exercise 90

directly

Thus, muscle blood flow can increase a maxiof about 25-fold during the most strenuous exercise. Almost half this increase in flow results from intramuscular vasodilation caused by the direct effects of increased muscle metabolism, as was explained in Chapter 14. The other half results from multiple factors, the most important of which is probably the moderate increase in arterial blood pressure that occurs in exercise, usually about a 30 per cent increase. The increase in pressure not only forces more blood through the blood vessels but

mum

also stretches the walls of the arterioles

and further

reduces the vascular resistance. Therefore, a 30 per cent increase in blood pressure can often more than double the blood flow; this multiplies the great increase in flow already caused by the metabolic vasodilation at least another twofold. Work Output, Oxygen Consumption, and Cardiac Output During Exercise. Figure 57-9 illustrates

the

interrelationships

35 r

among work

out-

Dexter 1951

Douglas 1922 30

Christensen 1931

~15"

Donald 1955

CO

25

E c

E

I ^10

d. 20

f o

15

T3

re

10

re

TO

o.

E

en

to

are the following: liters /min

Average young man at rest Maximal output during exercise

young untrained man Maximal average output during

5.5

23

in

exercise in

30

male marathoner

Thus, the normal untrained person can increase cardiac output a little over fourfold, and the welltrained athlete can increase output about sixfold. Individual marathoners have been clocked at cardiac outputs as great as 35 to 40 liters /min, seven to eight times normal resting output. Effect of Training on Heart Hypertrophy and on Cardiac Output. From the foregoing data, it is clear that marathoners can achieve maximal cardiac outputs about 40 per cent greater than that achieved by the untrained person. This results mainly from the fact that the heart chambers of marathoners enlarge about 40 per cent; along with enlargement of the chambers, the heart mass increases 40 per cent or more as well. Therefore, not only do the skeletal muscles hypertrophy during athletic training but the heart does also. However, heart enlargement and increased pumping capacity occur only in the endurance types, not in the sprint types, of athletic training.

-o re

O

200 400

Work

600 800 1000 1200 1400 1600

output during exercise (kg-meters/min)

57-9 Relationship between cardiac output and work output (solid line) and between oxygen consumption and work output (dashed line) during different levels of exercise. (From GuyFigure

ton,

is

It

related

Jones,

Output and pany, 1973.)

and Its

Coleman: Circulatory Regulation. Philadelphia,

Physiology:

W.

B.

Cardiac Saunders Com-

Even though the heart of the marathoner is considerably larger than that of the normal person, resting cardiac output is almost exactly the same as that in the normal person. However, this normal cardiac output is achieved by a large stroke volume at a reduced heart rate. Table 57-2 compares stroke

volume and heart

rate in the untrained person

and

the marathoner.

Thus, the heart-pumping effectiveness of each

57

heart beat is 40 to 50 per cent greater in the highly trained athlete than in the untrained person, but there is a corresponding decrease in heart rate at rest.

Role of Stroke Volume and Heart Rate in Increasing the Cardiac Output. Figure 57-10 illustrates the approximate changes in stroke volume and heart rate as the cardiac output increases from liters/min to 30 its resting level of about 5.5 liters/min in the marathon runner. The stroke volume increases from 105 to 162 milliliters, an increase of about 50 per cent; whereas the heart rate increases from 50 to 185 beats per minute, an increase of 270 per cent. Therefore, the heart rate increase accounts by far for a greater proportion of the increase in cardiac output than does the increase in stroke volume during strenuous exercise. The stroke volume normally reaches its maximum by the time the cardiac output has increased only halfway to its maximum. Any further increase in cardiac output must occur by increasing the heart rate.

Relationship of Cardiovascular Performance to exercise, both the heart rate and the stroke volume are increased to about 95 per cent of their maximal levels. Since the cardiac output is equal to stroke volume times heart rate, one finds that the cardiac output is about 90 per cent of the maximum that the person can achieve. This is in contrast to about 65 per cent of

Vo 2 Max. During maximal

maximum

pulmonary

for

ventilation.

Therefore,

one can readily see that the cardiovascular system is normally much more limiting on Vo, Max than is the respiratory system, because oxygen utilization by the body can never be greater than the rate at which the cardiovascular system can transport oxygen to the tissues. For this reason, it is frequently stated that the performance that can be achieved by the marathoner mainly depends on his or her heart, for this is the most limiting link in the delivery of adequate oxygen to the exercising mus-

/

Stroke volume

^y— r

165

/

/

E 130

150

"S to itinued) endogenous production of, 304-305 mast cell release of, 286, 293 Hepatic duct, 532, 532, 534 Hepatic vein, 521-523, 522 Hering-Breuer inflation reflex, 338 Hering's nerve, blood pressure control

in,

Hyperkalemia, 617 Hyperopia, 401 -402, 402 Hyperpolarization, intestinal smooth muscle in, 512, 523 sinus nodal, 95, 98 Hypersensitivity, 295 immune response in, 295 Hypertension, 160-166 angiotensin in, 162-165, 162-265 definition of, 160 essential, 165-166, 266

718

Index

Hypovolemia, shock due

Hypertension (Continued)

non- salt-sensitive,

Goldblatt, 164-165, 265 to,

in,

ventricular axis deviation

due

of,

352

effects of, 178, 345,

220

erythrocyte production

volume-loading in, 262, 161-162 Hyperthyroidism, 612-613 cardiac output affected by, 172, 272 causes of, 612-613 of,

symptoms

due

to,

275,

276-277, 277 hypoventilatory, 344-345 neonatal, 679-680

oxygen therapy

613, 623

of, 613,

280-286 shock due

344-345 diffusion impairment with, 344-345, 345

to, 110,

345, 345

for,

shock causing, 178 tissue uptake defect

623

treatment of, 613 Hypertonicity, body fluids and, 207, 207,

in,

344-345

to,

263, I

263(t)

Hypoadrenalism, 622-623 Hypocalcemia, 251-252, 252, 636, 636,

I

643 Hypogastric plexus, 495, 496

Ileocecal sphincter, 529,

Hypoglycemia, 627, 631

innervation

effects of, 627, 631

growth hormone secretion due 602-603 Hypogonadism, amenorrhea due

volume

to,

to,

666

ovarian, 666

of

of,

Immune

behavior controlled by, 486, 486-487 blood flow in, 600, 600-601

151-152

control centers of, 486, 502, 502 feeding regulated by, 486, 502, 584

fever and chills effect on, 580, 580, 581

600-601, 603-605 inhibitory, 600-601 neurohypophysial, 603-605 releasing, 600-601 limbic system controlled by, 485, 485-487, 486 nuclei of, 486 osmoreceptors of, 241-242, 486

111-112, 186 Inspiratory area, brain stem location of,

of,

529, 519-520, 520

respiration control by, 337-338, 338, 339

519-520

Inspiratory volume, lung capacity and, to,

of, 292,

292

allergy and, 295 in, 288, 289, 290-294, 292, 293 288-294, 289, 293 blood group antigen causing, 295-298,

antibodies cells in,

296(t)

cell-mediated, 288-294, 289, 293. See also Monocytes; T cells. role in, 292,

292-293

humoral, 288-294, 289, 293. See also An-

B

tibodies;

314-316 pathway in, 435, 435 Insulation, body system of, 575 Insulin, 625-632 322, 324,

Insula, taste

toimmunity.

of,

446-447

reciprocal, 446,

transfusion reaction related to, 295-298 Immune response, 288-295. See also Au-

complement

of,

667-668 female, 667-668 vitamin E role in, 590 Inflammation, 284-286 growth factors in, 285, 285-286 macrophage role in, 285, 285-286 neutrophil role in, 285, 285-286 process of, 284-286

Injury current, heart affected bv, 222,

496, 497, 499(t)

complexes, kidney failure due

267 opsonization

177-178

to,

contraceptive induction

337-338, 338, 339

Ileum, 522 cecal junction

B

502, 502

circulation regulated by,

519-520 519-520

chyme through, 542

motility of, 529,

Hypokalemia, 617, 624 Hypoparathyroidism, 642 Hypophysis. See Pituitary gland. Hypotension, 155 Hypothalamus, 485-487, 599, 600, 604 adrenal gland axis with, 622, 621-622 anatomy of, 484-486, 485, 599, 604 autonomic system controlled by, 486,

hormones

band, 59, 60, 66 Iggo dome receptor, 384, 384 Ileocecal valve, 529,

Infertility,

infarction.

mechanisms and,

stages in, 620 Infundibulum, 486 Inhibin, gonadotropin secretion inhibited by, 664 ovarian cycle role of, 664 spermatogenesis regulated by, 655 Inhibition, lateral, 416-418, 417, 418 postsynaptic potential role in, 372, 372

transport defect with, 344-345

208 Hyperventilation, alkalosis due

See Neonate.

Infarction. See also Ischemia.

myocardial. See Myocardial

352 causes

Indusium griseum, 484

Infection, host defense

brain affected by, 178, 352

162-165, 262-265

diagnosis

343, 343

altitude related to, 344-345, 351-353,

160-166, 262, 265,

failure as, 268, 268(t)

renin

175-177,

Infant.

Hypoxemia, pneumonia causing, Hypoxia, 344-345

salt-sensitive, 166, 166

kidney response 266

to, 275,

276

166, 266

lymphocytes

cells;

Immunoglobulins.

288-294, 289, 293 memory cells in, 291, 292, 293 plasma cell role in, 290-291 precipitation as, 292 self-tolerance failure in, 294 T cells in, 288-294, 289, 293 Immunity, 288-295 in,

beta cell origin of, 625 brain not affected bv, 625, 627 cellular effects of, 625-627, 626 diabetes treated with, 632-633

metabolism affected by, 627-628, 628 feedback mechanism for, 630, 630 glucose relation to, 625-632, 626, fat

628-630 muscle cell affected by, 625-627 626 physiology of, 625-632, 626, 628-630 protein metabolism affected by, 629, 629 rate of secretion of, 629, 629-630, 630 receptors for, 625-627 regulation of, 629, 629-630, 630 Intellect, 471-480. See also Cognitive func',

tion.

association areas related

to,

471 -476,

472-474 Intercalated cells, renal tubular, 228, 229,

ovaries regulated by, 658, 664-665

acquired, 288-294

pain suppression by, 395, 395 pituitary regulated by, 485-487, 486

definition of, 288

Intercalated disc, 85

innate, 288

Intercellular cleft, capillary, 130, 232

maternal, 682 neonatal, 682

Intercostal muscles, ventilatory function of,

600-601 603-604, 604

anterior, 600,

posterior,

satiety regulated by, 486, 502,

584

temperature regulated by, 578, 578, 580, 580 testes regulated by, 655 thyroid regulated by, 622, 612 Hypothermia, 581 Hypothyroidism, 613-614 clinical features of, 613-614, 624 diagnostic testing in, 614 treatment of, 614 Hypotonicity, body fluids and, 207, 207, 208 Hypoventilation, acidosis due to, 263, 263(t)

hypoxia with, 345

Immunization, 294-295 Immunoglobulins, 291-293 B cell production of, 290-291 definition of, 291, 292 E,

311-312,322 Interleukins,

immune

response role

293 Interlobar arteries, 213, 223, 219(t)

Interlobular arteries, 213, 223, 219(t)

Interneurons, spinal, 441-442, 442

295

G, 291, 292 heavy chain of, 291, 292 light chain of, 291, 292

mechanism

260, 260

of action of, 292, 291-293,

292

plasma

cell production of, 291 thyroid-stimulating, 612-613

formation of, 653, 654 of Leydig, 652, 652 fetal

testicular, 652,

tumor

of,

Interstitium,

652-653

656

131-132

alveolar wall, 328, 329

Incus, 427, 428, 429

definition of,

Indicator dilution technique, 273, 173-174

fluid of, 4, 5,

Inducer substance, 28

652-653

Interstitial cells,

131-132

131-134, 131-137 "free," 132, 132, 210

of, 293,

719

Index

Ischemic heart disease, 111-112, 184-187

Interstitium (Continued) gel, 132,

210

atherosclerosis

184-185

coronary bypass in, 187 pathophysiology of, 222, 111-112,

increased, 220, 210-211, 245 structure of, 232, 132, 232 Intestine, 511

in,

-546

fetal,

184-187,286

blood flow to, 521-523, 522 calcium binding by, 635 carbon dioxide production in, 531 hypothalamic center related to, 486 large, 522, 529-522, 520-521 absorption in, 520, 520-521, 542-543 feces formation in, 542-543 secretions of, 524-525, 525(t), 535 membrane potentials in, 511-512

Langerhans, 596, 625, 626 anatomy of, 596, 625, 626 hormones of, 596, 625 Isocitric acid, 555 Isoleucine, 566 Isotonicity, 207, 207, 208 Isovolumic (isometric) contraction, 89 Isovolumic (isometric) relaxation, 89 Islets of

neural control

of,

glucose in, 223(t), 224-226, 226, 227, 229 hypertension and, 160-166, 262, 265, 266

medulla of, 213, 223, 220, 229, 238(t) hyperosmolarity in, 238(t), 238-241, 239-241 neonatal, 681-682 output curve of, 157-160, 25S, 259

233-234 polycystic disease

499(t), 523,

513-514 518-521, 529-522

secretions of, 524-525, 525, 525(0, 534,

535 of, 525(t)

225,

secretions of, 531

segmentation contractions

of,

529,

519-520

cells, 162,

389

223, 221-222,

539-541, 540-542 524-525, 525(t), 534,

in,

secretions of,

K

534-535 villi of,

wall

of,

Kallekrein, 147

511-512, 522, 539, 539-540, 540

Kallidin, 147

to,

394,

394 Intrinsic factor, 278, 527,

528

deficient production of, 278, 528, 543 parietal cell secretion of, 527, 528

pernicious anemia role of, 278, 528, 543 vitamin B v combined with, 278, 543 Inulin, membrane permeability to, 132(t), 216(t)

renal clearance rate of, 233, 233 Iodine, deficiency of, dietary, 613

thyroid utilization of, 607-608, 608 Ion channels, 34-43 active transport in, 35, 41 -43, 42, 43 current flow measurement in, 37, 37-38 diffusion in, 34-41, 35, 36 gating of, chemical, 37 voltage, 36, 36-38, 37 neuron membrane potential and, 370, 370-371 synaptic membrane and, 367-368, 368

Iridocorneal angle, 406, 406 401, 402, 425

muscle

Ketogenesis, 569 Ketoglutaric acid, 555 protein deamination role of, 569 Ketone bodies, brain utilization of, 587 Ketosis, starvation with, 587 Kidney, 212-270 acid-base balance and, 257-264, 258-262 and, 236-244, 237, 238(t), 240,

ADH

242(t), 247 aldosterone and, 231-232, 232(t), 246-247, 250, 250-251, 617

amino acids in, 225, 225-226, 227, 229 anatomy of, 212-214, 223, 224 arterial pressure control

and, 157-167,

25S-266

224,

of, 223(t),

248-251, 248-251 pregnancy complications of, 675 reabsorption in, 223(t), 223-233, 223(t), 248-251,

424, 497,

499-500

bicarbonate in, 254-264 acid-base balance and, 257-264,

258-261

corneal angle with, 406, 406 erythroblast ingestion of, 279, 279 674, 679, 682

hemoglobin structure and, 278, 278-279, 279

metabolism of, 278-279, 279 pregnancy requirement for, 674, 679, 682

body quantity of, 278 transport and storage of, 278-279, 279 Ischemia, brain affected by, 178 cardiac muscle affected by, 222, 111-112, total

185-187, 186 shock causing, 174-178, 276 toxins released due to, 176-177 vasomotor center response to, 155

mechanisms of, 227-229, 257-264, 258-261 blood flow in, 213, 223, 219(t), 219-222, transport

clearance by, 233-234 calculation of, 233, 233-234, 234 inulin and, 233, 233

measurement

of, 233, 233-234, 234 (para-aminohippuric acid) and, 233-234, 234 solute rates of, 234 cortex of, 213, 223, 229 creatinine in, 223(t), 229, 234 excretion by, 212-252, 225, 223(t), 224, 226

PAH

245-247

daily rates related

to,

221, 223(t), 248,

249, 258, 258 failure of.

239-241 dilute urine and, 236-237, 237

transport

mechanisms

of,

223(0,

224-226, 225, 227-230, 236-241, 237, 240 water excretion and, 236-241, 237-242 stones of, 267 of, 223-234 amino acids and, 225, 225-226,

tubules

227,

See Kidney

anatomy of, 223, 224, 214 bicarbonate and, 223(0, 227-229, chloride and, 223(0, 224-227, 227-229 collecting, 214, 224, 228,

failure.

228-229, 229,

238(0, 239-240 creatinine and, 223(0, 229 distal, 214, 224, 228,

251-252, 252, 634-635, 645 chloride in, 223(t), 224-227, 227-229 in,

control of,

concentrated urine and, 237-241,

257-264, 258-261

daily quantity of, 223(t), 258

calcium

239-242 sodium in, 223(0, 224-226, 236-241 clearance rate using, 233-234

229

222, 222, 242 of,

Iron, daily loss of, 279, 279

fetal,

tubular reabsorption

of, 223(t),

of, 230, 230-233, 231(0, 232(0 sodium and, 236-241, 237-242 urine concentration and, 237-241,

Keratin, 567

Intralaminar nuclei, pain pathways

circular

248-251

regulation

522, 522, 539, 539-540, 540

Intrafusal fibers, 441-442, 442

Iris,

mechanisms 227-229

236-241 potassium and, 248-251

small, 522, 518-520, 529

absorption

224,

248-251 transport

•

Juxtaglomerular 222

of, 268(t)

in, 223(t),

clearance rate using, 233-234 daily excretion of, 223(t), 248-251,

malocclusion affecting, 646 teeth in, 643-646, 645 Jejunum, 522 Joints, position-sensitive receptors in,

volume

potassium

Jaundice, neonatal, 297-298 Jaw, closing force of, 514

enteric system, 512, 512-513, 523

daily

214-222. See also Glomeru-

lar filtration rate.

J

512-514, 523

peristalsis in, 514, 524,

222, 221-222,

pain referred from, 396 phosphate in, clearance rate using,

519-520

autonomic, 496, 497,

of,

675, 679

filtration by,

microstructure of, 522, 523 mixing function of, 529, 519-520 motility of, 518-521,

Kidney (Continued) feedback mechanisms 222, 245-247

228-229, 229,

238(0, 239-240

glucose and, 223(0, 224-226, 226, 227, 229 heart failure affecting, 196-197, 210 hormonal regulation of, 231-232, 232(0, 246-247, 250, 250-251 hydrogen ion in, 224-226, 225, 227, 228 potassium and, 223(0, 224, 225, 227-229, 248-251, 249-251 proximal, 214, 224, 227, 227, 229 sodium and, 223(0, 224-226, 225, 227-230, 236-241, 237-241 transport mechanisms of, 214-215, 223-233, 236-241 active, 224-226, 224-226 countercurrent, 237-241, 239, 241

720

Index

hyperosmolality and, 237-241,

239-241

maximum

in,

226

passive (diffusion), 224, 226-227,

227 regulation

230-233,

of, 230,

231(f),

232t, 617

224 urea and, 223(0, 226-227, 227, 229, 238(t), 240 water in, 226-228, 236-241 excretion and, 236-241, 240, 241 transport of, 224, 226-228, 227 ultrafiltration in, 224,

Kidney

267-270

failure,

due

acidosis

to,

270, 270

acute, 267 intrarenal, 267

postrenal, 267

prerenal, 267 chronic, 267-270 end-stage, 267-268, 268, 268(t) glomerular filtration rate affected by,

polycystic disease

in, 268(t)

transfusion reaction causing, 296-297

maternal, 678, 678(t) milk containing, 678, 678(t)

Language, 456, 472-473, 475-476. See also Speech.

Broca's area role

in,

456, 473, 473, 474,

476

motor function

in,

naming function

456, 457, 473, 473, 476

in,

472, 473

reading comprehension area for, 472 Wernicke's area role in, 472, 473, 474 Larynx, 316, 515 epiglottal protection of, 515, 515 hypocalcemic spasm of, 642 speech articulation and, 317-318, 318, 476

swallowing mechanism

effect on, 515,

515

vision

pathways

in,

419, 419

Lateral inhibition, 416-418, 417, 418

269-270, 270

to,

anaerobic glycolysis role of, 557, 626, 689-690, 691 exercise role of, 689, 689-691, 691 fatigue caused by, 691, 691 Lactose, digestion of, 537, 538

testosterone effect on, 653 voice box anatomy and, 318, 318 Lateral geniculate nucleus, layers of, 419, 421

268-270, 269 metabolic acidosis in, 264 nephron loss in, 267-269, 268, 269

uremia due

Light, adaptation to, 412

Lactic acid, 691

Kidney (Continued)

Lateral lemniscus nucleus, 431

"Killer" cells, 294

Kilocalorie unit, 572

Lateral ventricle, cerebrospinal fluid in,

Kinetic energy, diffusion relation

to,

34-35,

36,40

504,

504-505

Leaflets (cusps), valvular, 90

scarring of, 190-191 Learning, hippocampus role in, 480, 488 reward-punishment center role in, 487 Lecithin, 564, 564 hepatic excretion of, 533 Lens, 400-405, 401-406

molecular, 34-35, 36, 40 Kininogen, 301 (t), 303 Kinins, blood flow control by, 147 Kinocilium, 450, 451 Korotkoff sounds, 123-124 blood pressure measurement and, 123-124, 224

accommodation (focusing) 401 -405, 424-425

origin of, 123-124

Krause's corpuscle, 377 Krebs cycle, 554-555, 555 Kupffer cells, 284

hemoglobin destruction

aging

of,

400-404,

by, 280

284 phagocytosis by, 280, 284 Kwashiorkor, 583

membranous,

450,

450-451

Lactase, intestinal, 537, 538 Lactate, extracellular fluid level of, 203, 204(t)

intracellular fluid level of, 203, 204(t)

plasma Lactation,

level of, 203, 204(t)

677-678

breast development

for, 677 oxytocin effect on, 595, 605, 678 prolactin stimulation of, 677, 677-678 rate of, 678

Lacteals, 522, 522, 540, 540

absorption

anatomy

in,

of,

of,

281-282

276, 281, 282

locomotion by, 18-19, 19, 282, 282-283 normal count of, 281 phagocytic function of, 281, 283-286 production of, 276, 281, 282 of,

276, 281, 281

Leukopenia, 286 Leukotrienes, 295 Leydig cells, 652, 652 LH. See Luteinizing hormone.

540, 540

Life expectancy, fitness role in, 699

540

Ligaments, eye lens suspended by,

of, 522,

chylomicron transport

in,

542

intestinal villus with, 522, 522, 540,

400-401,402,406 540

spiral, of cochlea,

appetite center

in,

584

association area of, 472, 473

behavior controlled by, 486-487, 487 hypothalamic control of, 485, 485-487, 486 pain center of, 487, 487 reward center of, 486-487, 487 Lingual nerve, 435, 435 Lipase, adipose tissue with, 560, 562, 628 enteric, 538 hormone-sensitive, 564, 628 lipoprotein, 560 pancreatic, 538, 538 triglycerides affected by, 564, 628 Lipid bilayer, 9, 22. See also Cell membrane. barrier role of, 9, 34-36, 35, 36 cholesterol in, 565 phospholipid in, 22, 565 proteins of, 9-10, 22, 34, 35, 36 solubility in, 9,

structure of,

35-36

9, 22, 35,

36

transport across, 34-43. See also

Mem-

brane transport. active, 34, 35,

41-43, 42,

43.

See also

Active transport. passive, 34-41, 35, 36. See also Diffusion; Osmosis.

transport of, 533, 542, 560-561 types of, 560

blood containing, 561 high density, 561, 565 low density, 561, 565

280-286

immature forms of, 281 increased, 285-287 life span of, 282

types

Limbic system, 484, 484-488, 485 anatomy of, 484

Lipoproteins, 561

differentiation of, 275, 276, 281,

genesis

Light chains, immunoglobulin structure and, 291, 292 myosin with, 62, 62, 77

628

Neutrophils.

Lacrimal glands, innervation of, 497, 500 Lactalbumin, milk containing, 678(t)

423, 427, 417-418 white, 413

lysis (mobilization) of, 562, 564, 619,

Leukocytes, 280-287. See also Basophils; Eosinophils; Lymphocytes; Macrophages;

absence of, 286 body defense role decreased, 286

for, 407-409, 407-411, 415-419, 428 retinal stimulation by, 409-413, 420, 422,

atheromatous deposits of, 565 digestion of, 538, 538-539 emulsification of, 533, 538, 538-539 insulin action affecting, 628, 628 liver synthesis of, 562-565

of,

lymphogenous, 286-287 myelogenous, 286-287

Labile factor, 301 (t) Labor, of birth, 675-677, 676 Labyrinth, bony, 428, 450

499-500 receptors

Triglycerides.

400-401, 401, 406 oscillation of, 425 refraction by, 400-403, 401-403 Leucine, 566 Leukemia, 286-287

intestinal bacteria in,

pupillary reflex and, 419, 424-425,

Lipids, 560-565. See also Cholesterol; Fat;

effect on, 401

cataract clouding of, 404

ligaments

color of, 422, 412-413, 423

428

transport role

types

of,

of,

561

561

very low density, 561 tract, 385, 393 Lithiasis, gallstone as, 533-534, 534 kidney stone as, 267 Liver, 522,522, 531-534 B cell processing in, 289, 290 bile secretion by, 531-533, 532 blood flow related to, 521-523 intestine and, 521-523, 522 reservoir function of, 127, 522, 522 splanchnic circulation role of, Lissauer

521-523,522 carbohydrate metabolism

in,

551-553,

627, 631

cholesterol secretion by, fatty acid

metabolism

533-534 562-563

in,

721

Index

Liver (Continued)

glucose metabolism

551-553, 627,

in,

631

glycogen storage lipid metabolism

macrophages

in,

552-553, 627, 631

in,

562-565

of, 280,

of, 127,

in,

568-570

norepinephrine secretion bv, 369, 483, 483 Loop of Henle, 213, 214, 214 anatomv of, 213, 214, 214 ascending thick, 214, 227-228, 228, 238(t) thin, 224, 227, 238(t)

in, 237-239, 239 descending, 214, 227-228, 228, 238(t) transport mechanisms in, 227-228, 228, 236-241, 237, 238(t), 239, 240 urinarv hvperosmolarity and, 237-240, 238(t), 239 Lumirhodopsin, 410, 410 Lung. See also Respiration; Respiratory tract;

countercurrent exchange

Ventilation.

acid-base regulation bv, 256-257, 257, 263, 263(t) altitude (high) effects in, 351-353, 352(t)

anatomy of, 316, 327-329, 327-329 asthma affecting, 344 atelectasis of, 343

blood flow in. See Pulmonary vasculature. compliance of, 312, 313 dead space of, 315-316 edema of, 322, 322 heart failure with, 196-197, 322

embolism

affecting,

emphysema

306-307 342-343

affecting, 342,

expansion and contraction 312,313 expiratory

volume

664-665 599, 600-601, 664

for,

654-655 Lymph nodes, anatomic locations of, 137 functional morphology of, 283-284, 284 testes regulated by,

522, 522

vitamin D in, 634-635, 635 Lobotomv, prefrontal, 475 Lochia, 677 Locomotion. See also Movement. cellular, 18-19, 19, 20, 282, 282-283 ameboid, 18-19, 19, 282 chemotaxis role in, 282, 282-283 cilia in, 19-20, 20 walking as, 447, 447-448 Locus ceruleus, 483, 483

ascending

hormone

releasing

of,

311-314,

of, 312, 314,

immune

of,

283, 289, 289

macrophages of, 283-284, 284 Lymphatic system, 137 anatomv of, 137-139

protein concentration

in,

139-140

intestinal villus lacteal in, 522, 522, 540,

540

macrophages of, 283-284, 284 nodes of, 283-284, 284. See also Lymph nodes.

pulmonarv function

related to, 321,

321-322, 322, 328 function

of, 135,

valves

of, 139,

139-140

of,

immune

276, 281,

complement

of,

289, 289-294,

293 life

span

of,

282 290

specificity of, T.

See

T

cells.

Lysine, 566 insulin secretion stimulated by, 630

blood

removal 296-298

by, 305,

clot

erythrocytic,

306-307

fetal,

immune

fluid

transfusion reaction causing, 296-298

679-680, 680 exchange in, 319-322, 321, 322 gas exchange in, 324-335, 325(t), 325-334 hyperbaric effects in, 355-359 inspiratory volume of, 312, 314, 314-316 membrane lining of, 327-329, 327-329 metabolic function of, 256-257, 257, 263,

response role

pneumonia affecting, 342, 343, 343 residual volume of, 314, 314-316 smoking effect on, 695 surface area of, 327-328 surfactant of, 313, 343, 680

volume

of, of,

314,

314-316

344

volumes and capacities of, 312, 312, 314, 314-316 measurement of, 314, 314 water loss from, 201, 202, 202(t)

652-654

reaction and, 286, 295 of,

304-305

activation of, 292, 293

heparin release by, 286, 293, 304-305 histamine release by, 293, 295 Mastication (chewing), 514-515, 515 Mechanoreceptors, 376-378, 377, 383-384, 384 Meconium, 679 Medial forebrain bundle, reward center in, 486, 487 Medial lemniscus, taste sense pathwav in, 435, 435 Medial lemniscus -dorsal column system, 385, 385-386, 386

Medial longitudinal fasciculus, 422, 423, 423 Median eminence, hypophysial, 600, 600, 621

Medulla oblongata, 483, 502 autonomic system controlled by, 502, 502 baro receptor system and, 153, 253 brain activation role of, 483, 483-484

10, 12

Cortisol stabilization of,

620

digestive vesicle and, 15, 15, 16, 283 Golgi apparatus and, 15, 15, 16, 16 pinocytosis role of, 15, 15

minute volume of, 315 neonatal, 679-680, 680

tuberculosis

292

circulatorv regulation bv, 150, 250, 252, 153,

2'53,

502

mechanisms of, 546 motor function role

shock affecting, 177, 178

263(t)

tidal

of, 292,

Lysoferrin, 15

Lysosomes,

cells, allergic

coagulation prevention role

281-282

response role

intracellular fluid level of, 35, 203, 204(t)

Magnocellular layer, 419, 421 Malabsorption, 545 vitamin B ]2 in, 278 Malic acid, 555 Malleus, 427, 428 Malocclusion, 646 Maltase, intestinal, 537, 538 Maltose, digestion of, 537, 538 Mamillary body, 484, 486, 502 hypothalamus and, 600, 604 Mamillotegmental tract, 484 Mamillothalamic tract, 484 Mammary gland, prolactin and, 599, 599 Mandible, closing force of, 514 teeth in, 643-646, 645 Masculinization, adrenal androgens in, 616 female neonate with, 682

Mast

138-140, 139

Lymphoblasts, 281, 281 Lymphocytes, 276, 281, 281-282 activation of, 289, 293, 293 B. See B cells. cloning of, 290 genesis

extracellular fluid level of, 35,

203, 204(t)

testosterone role in,

pump

280

inflammation role of, 285, 285-286 phagocytosis by, 283-286, 285 splenic, 284 Macula, 407-408, 450 retinal, 407-408, 408 anatomy of, 407-408, 408 visual cortex corresponding to, 420, 420 vestibular, 450, 450 Macula densa, 214, 214, 222, 222 sodium chloride effect in, 222, 222

Magnesium,

138-140, 139 chylomicron transport in, 542 circulatorv function and, 137, 138-140, 139, 202 fluid of, 138-140, 139, 202 blockage affecting, 209 edema prevention role of, 210, 210-211 flow rate of, 139, 139-140, 210, 210-211 formation of, 139-140 increased, 210, 210-211 capillaries of, 131, 138,

Lysis,

314-316

response role

by, 279,

hepatic, 280, 284

664-665 pulsatile secretion of,

protein metabolism

Macrophages (Continued) hemoglobin destruction

Lutein cells, 660 Luteinizing hormone, 599, 599 ovaries regulated bv, 658-661, 659,

284

neonatal, 682

sinuses

Lupus erythematosus, autoimmunity mechanism of, 294

of,

448, 448-449,

452-453, 453

M

respiratorv center of, 337-338, 338-340,

502

M antigen, heart valve damage due to,

190

482-483

rheumatic fever with, 190 streptococcal, 190

reticulospinal tract and, 448, 449, 449,

Macrocytes (erythrocytic), 277-278 Macrophages, 282-286 alveolar, 284 differentiation of, 276, 281, 282 genesis of, 276, 281,282

growth

factors released by, 285,

reticular formation and, 394, 448,

285-286

452-453, 453, 464 sensorv function role of, 364, 386, 386, 390 vomiting center in, 545-546 Megakaryocytes, 276, 281 fragmentation of, 299

722

Index

Menstruation (Continued) blood lost in, 664

Megakaryocytes (Continued) genesis

of,

276, 281, 299

platelet formation from, 299

648 sex chromosomes in, 648 Meissner's corpuscle, 364, 377, 383-384 Meissner's plexus, 512, 512 Melanin, 622 retinal, 409 Melanocytes, 622 Melanocyte-stimulating hormone, 622 Melatonin, pineal secretion of, 656 Membrane, basilar, 428, 430 cellular, 34-43, 47-57. See also Cell membrane. olfactory, 435-436, 436 tectorial, 430, 430 vestibular, 428, 450 Meiosis, definition

Membrane

of,

potential,

47-57

iron loss

279, 279

in,

menopause

666 ovarian cycle in, 658-661, 659, 663-664 Mental status, hypoxia affecting, 345, 352 psychosis and, 492-493 Meromyosin, 60 Mesencephalon, 483, 502 autonomic system control by, 502, 502 brain activation role of, 483, 484 motor function role of, 448, 448-449, 452-453, 453 vision transmission inhibited in, 419 Mesentery, capillaries of, 227 Metabolic rate, 572-574 affecting,

basal, 574, 609,

action, 50-55, 50-55. See also Action

369-372, 370, 371 dendritic, 373-374, 374

excitatory postsynaptic, 371, 371, 373

inhibitory postsynaptic, 371, 372

609-614

factors affecting, 573, 573-574,

measurement

potential.

basic physiology of, 47-56, 48-55,

intestinal

endometrium in, 663, 663-664 hypogonadism effect on, 666

573, 573

of,

nerve conduction role

of,

Metabolism, 551 -590 adrenal hormones affecting, 616-620 aerobic pathway in, 690(t), 690-692, 692 anaerobic glycolysis in, 557, 626, 690, 691

689-690 exercise effect on, 688-692, 690(t), 691,

55-56,

369-372

692 fatty acid,

560-563, 563

recording of, 56-57, 57 resting, 48-50, 49

growth hormone 601-603

rhythmic spontaneous discharge of, 54-55, 55 sensory receptor with, 376-378, 377, 378 slow wave, 78, 79, 511, 513 spike, 78, 78-79, 511-512, 513

lipid,

transport,

34-43

absorption of nutrients by, 540-543 active, 34, 35, 41-43, 42, 43. See also Active transport.

carbohydrates in, 17, 551-552, 625-627 countertransport as, 225, 226, 227 lipid bilayer structure and, 9, 11, 34, 35, 36 osmosis in, 39-41, 40 passive, 34-41, 35, 36. See also Diffusion. renal tubular, 224-227, 224-227 Memory, 364-365, 477-480 cognitive function role of, 475, 477-480, 478 consolidation of, 479-480, 488 emotional stimulus role in, 487 gene transcription in, 368 habituation vs. reinforcement of, 487 hippocampus role in, 480, 488 loss of, 480, 488 neural mechanism of, 368, 477-480, 478, 488 synapse role in, 477-480, 478 trace pathways of, 477 "working," 475 Memory cells, B, 291, 291, 293 immune response role of, 291, 291, 293 T, 293

Menarche, 658-659 Meninges, headache related to, 397 Menopause, 666 estrogen decrease in, 666 ovarian change in, 666 Menstruation, 658-661, 663-665 absence of, 666

affecting, 599, 601,

560-565, 563, 610 to,

583-584

thyroid hormones affecting, 609,

609-611

562-564 of,

affected by, 73 intestinal content of, 546

Methionine, 566

axon terminal

in, 71,

72

Microfilaments, cellular, 10, 14, 31 endocytosis role of, 14, 14-15 mitosis role of, 29, 31 Micropipettes, electrodes made from, 48,

50

pressure measurement with, 134, 134 Microtubules, 10, 13 cilia with, 19 mitosis role of, 31 Microvilli, intestinal, 539

264-267

reflex of, 264, 266,

of,

266-267

266

Migraine, 397-398

prodromal symptoms

of,

398

Milk, 677-678

cow

vs.

of,

human,

regurgitation from, 190, 190 stenosis of, 290, 190-191 Modiolus, 428, 430 Molecular kinetic energy, 34-35, 36 Molecular weight, diffusion and, 36, 36-37, 131-132, 132(t), 216(t) Monocytes, 276, 281, 281-282 of,

276, 282,

281-282 281-282

inflammation role of, 285, 285 span of, 282 phagocytosis by, 283-284, 285 Monoglycerides, digestion and, 538, life

absorption of, 541-542 digestion of, 537, 538 membrane transport of, 551-552 "Moon" face, 623, 623 Morula, 671, 672 Mossy fibers, 461 -462, 462

membrane

678, 678(t) 678, 678(t)

ejection (let-down) of, 678

Mineralocorticoids, 616-618 deficiency of, 622-623

71, 72

potential of, 72

neuromuscular junction role of, 71, 72 skeletal muscle with, 71-74, 72 smooth muscle with, 77, 77-78 Motor system, 363, 364, 441-470 brain stem role in, 448, 448-449, 452-453, 453 cerebellum in, 363, 364, 459-462, 459-465, 464 cerebral cortical areas of, 363, 364,

455-459, 456-458 intestinal

brain center control

composition

Mitral valve, 86, 89, 90 heart sound due to, 290, 190-191

Motor end-plate,

Micelles, 533, 538, 542

Micturition,

30-31

435, 436

Carbohydrates.

intermittent contraction affecting, 128

48, 50,

of, 29,

cell,

fat

Methacholine, neuromuscular junction

Microfibrils,

Mitral

absorbed as, 542 Monoiodotyrosine, 608, 609 Monosaccharides, 551 -557. See also

637

Metamyelocytes, 281 Metaphase, 29, 31 Metarhodopsin, 410, 410, 411 Metarterioles, 127, 127

Methane,

DNA

stages

538-539

Metals. See also Iron.

bone deposition

30-31

division with, 29, 29-31 replication in, 29, 29-31

genesis

respiratory quotient related

triglyceride, 560,

synaptic terminal with, 366 thyroxine effect on, 610

differentiation of, 276, 282,

567-570

protein,

structure of, 10, 12, 23

cell

carbohydrate, 551-558, 553-556, 689,

513

carbohydrate metabolism in, 554-556, 555, 556 electron transport chain of, 555-556, 556 energy production role of, 554-556, 556 energy-related reactions of, 27, 17-18, 28 fatty acid carried into, 562 intestinal epithelium with, 524, 525, 540 muscle fiber with, 60, 62, 66 sarcoplasmic, 60, 62, 66 shock effects in, 177, 178

Mitosis, 29,

neonatal, 682, 682

smooth muscle with, 511-512,

measurement of, 48, 48, 50, 50 motor end-plate and, 72

Membrane

609-614

Mineralocorticoids (Continued) excess of, 623-624 metabolic functions of, 616-618 Minute volume, 315 Mitochondria, 10, 12, 23 ATP formation in, 27, 17-18, 28 basic function of, 17, 17-18, 28

movement

role of, 514, 524,

518-521, 519-521 nerve fiber type in, 379, 379, 441 -442, 442 speech function and, 456, 457, 473, 473, 476

stomach emptying and, 516-518 Mouth, 522 bacteria of, 526

food processing by, 522, 514-515, 525 saliva function in, 526

723

Index

Movement. See

Muscle (Continued)

also Motor system.

basal ganglia role in, 465-469, 466 cerebellar function in, 463-465, 464 flicking,

467 467

patterns

of,

flailing,

and, 61, 64, 67, 689, 689 blood flow to, 180-182, 1 81, 695,

458-459, 465, 467 of,

calcium ion role in, 65-66, 66 contraction of, 60-70, 441-448, 688 cellular mechanism for, 60-70,

61-63,65-69

464-468 position-sensitive receptors and, 389, 445, 452

posture maintenance

as,

463-465, 464

reflexes associated with, 447,

447-448

sterotyped, 453

writhing, 467 writing as, 465-468

MSH

(melanocyte-stimulating hormone), 622 Mucosa, 539, 540 gastric, 527,

527-530

large, 535,

512

542-543

small, 512, 534, 539,

with, 435-436, 436

respiratory tract coated with, 317 saliva containing, 525

vaginal, 667

407 190-191

190,

"blowing," 190

phonocardiography of, 190, 190-191 Muscle, 59-93, 687-699 anabolic steroid effect on, 654, 687, 698 birth labor contraction of, 675-677, 676

bronchial, 316

action potential of, 85-87, 87, 95

calcium ion effects in, 87, 92-93 conduction velocity and, 86, 95, 95-97, 97 depolarization wave of, 100-102, 101 potassium ion effects in, 92 refractoriness in, 86, 107, 107-108, 108 syncytium of, 85 of, 87,

59-65, 60-64

92-93

400-401, 401, 406 parasympathetic control

of,

401, 424,

nerve junction with, 71, 72, 441-443, 442,444 remodeling of, 69-70, 692-693 sarcomere of, 59-60, 60, 64 strength of, 688, 692-693, 693 maximum, 69, 688 summation in, 68-69, 69 tetanization in, 68-69, 69 transverse (T) tubules of, 61, 65, 66, 67 smooth, 74-80

78-79 autonomic nerve endings in, 77, 77-78 contraction of, 74-80 of, 77, 78,

516-518

',

311-312,312 511-512,522 oculomotor, 422, 422-423 papillary, 89-90, 90 intercostal, intestinal,

piloerector, 496 skeletal,

59-70, 687-699

actin filaments of, 59-65,

60-64

action potential of, 65-67, 66

oxygen demand depolarization

affecting,

wave

183-184

100-102, 202 85-87, 86, 87, 185-187, of,

refractoriness in, 86, 207, 107-108, 208

properties

of,

of,

75-80, 76

75-76

tissue factors causing,

in,

80

79-80

74-75, 76, 77 microstructure of, 74, 74-75, multiunit, 74, 74-76, 77

76,

77

77-78 79-80

of, 77,

of,

unitary, 74, 75, 77

spasm

448 abdominal, 448 carpopedal, 636, 636 drug-induced, 74 headache due to, 398 hypocalcemic, 251, 636, 636, 642, 643 local cramp as, 448 spinal reflex role in, 448 stapedius, 427 tensor tympani, 427 testosterone effect on, 654, 687, 698 thyroxine effect on, 611 urinary bladder with, 264, 266 uterine, 675-677, 676 ventilatory function role of, 311-312, of,

312, 694,

694-695

of,

186-187 59-67 morphology of, 59-60, 60-62, 66 neuromuscular junction in, 71-74, 77, 77-78 scar tissue in, 286,

sarcoplasmic reticulum role

syncytial, 75, 85, 86, 511

glucose metabolism in, 626, 626, 688, 689 glycogen storage in, 552-553, 626, 689, 689 insulin effects in, 625-627 626

294 electrocardiography of, 222, 111 heart failure due to, 272, 193-196, 294 pathophysiology of, 111-112, 185-187, 286 recovery stages of, 286, 186-187, 194, 195 rupture of, 186 Myocardium, 85-87, 185-187, 696 angina pectoris of, 187 blood flow to, 183, 183-185 atherosclerosis affecting, 184 decreased, 222, 111-112, 183-185, 286 nervous regulation of, 184

mechanism

non-neural stimulation

gastric wall,

80

80

cricoarytenoid, 318

691-697 eye accomodation bv, 400-401, 401, 424, 497

186-187

muscle fibers 696

effects in,

detrusor, 264, 266 exercise effect on, 687-699, 689, 690(t),

of, 286,

"latch" effect in, 76

neuromuscular junction

424, 497, 499(t)

71,

cardiac output affected by, 272, 193-196,

fibers of, 74,

ciliary,

294

cardiac muscle affected by, 222, 111-112

myofibrils of, 59-60, 60-62, 64, 693 myosin filaments of, 59-65, 60-64

hormonal

of,

neuron sheath in, 55, 55-56, 56 Myeloblasts, 281, 282 Myelocytes, 281, 282. See also Leukocytes. genesis of, 276, 281, 282 Myenteric plexus, 522, 512, 523 Myenteric reflex, 514, 521 Myocardial infarction, 111-112, 185-187

anatomy

morphology of, 59-60, 60 motor end-plate of, 71, 72 motor unit of, 68

calcium regulation

mechanism

drug therapy in, 74 neuromuscular junction and, 74

72

action potential of, 78,

cardiac, 85-93, 86, 87, 95

DNA

Myasthenia gravis, autoimmunity

neuromuscular junction axon with,

67-68, 68, 693 of,

Mutation, 30 cancer caused by, 31-32 repair and, 30

of, 588 nerve classification and, 379, 379

59-60, 60, 442, 693

microstructure

lubricant function of, 525, 652, 667

T tubules

fibers of,

511-512, 512

Muscle spindle, 364, 377, 442, 444 innervation of, 364, 442, 442-443, 444 motor end-plate and, 71-74, 72, 77, 77-78 structure and function of, 364, 442, 442-443, 444

Myelination, loss

fatigue of, 69, 688, 691-693, 692

latent period in, 68, 68

intestinal secretion of, 525, 534, 535

fiber,

693

fast vs. slow, 68,

isometric twitch characteristics of,

gastric secretion of, 527, 527

Murmurs,

walk-along theory of, 63, 63 denervation effect on, 70 energy for, 61, 64, 67, 689, 689 excitation of, 65-67, 66, 441-444, 442

539-540

Mucosal gland, 511, 512, 535 Mucus, airway, 317 bowel movement with, 535

membrane

isometric vs. isotonic, 67-68, 68 spinal reflex causing, 443-445, 444

intrafusal, 442, 442, 443 hypertrophy vs. atrophy of, 69-70, 692-693, 693

lesion of, 543-545, 544 intestinal, 511,

force of, 69, 688

extrafusal, 442, 442, 443

atrophic, 278, 528, 543

Muller

visceral, 75, 79,

695-697

planning, timing, and sequencing

olfactory

Muscle (Continued)

ATP

Myofibrils,

72,

skeletal muscle and, 59-60, 60-62, 64 Myoglobin, iron present in, 278

membrane

permeability

to, 132(t),

216(t)

molecular weight of, 132(t) Myopia, 402, 402 Myosin, 62, 62 heavy chain of, 62, 62 light 'chain of, 62, 62,

Myosin

filaments,

77

59-67

cardiac muscle fiber with, 85

endocytosis role mitosis role

morphology

of, 24,

14-15, 19

of, 29, 31 of,

60-63, 62

of, 59-65, 75-77 59-65, 60-64, 66 smooth, 75-77, 76 platelet with, 299 Myosin kinase, 77 Myosin phosphatase, 77 Myxedema, 614, 624

muscle contraction role skeletal,

724

Index

N NADH,

556,

Nerve

556-557

anaerobic glycolysis role of, 557 carbohydrate metabolism and, 556, 556, 557 electron transfer role of, 556, 556 Narcosis, helium and, 358 nitrogen-related, 356 "rapture of the depths" as, 356 Nasal glands, innervation of, 497 500 ,

Nasal sinuses, headache related 398 Natriuresis, 160,

to,

397,

243-244

157-160, 258, 159, 163, 164, 166, 244, 244 atrial peptide causing, 232, 232(t) hypertension and, 162-164, 162-166, 166, 244, 244 Near-sightedness, 402, 402 Neck, proprioceptors of, 452 Neonate, 679-683 circulatory system of, 680-681, 681 complications in, 681-683, 682 arterial pressure role in,

development of, 678-679 hypothyroidism in, 614 jaundice in, 297-298 fetal

physiology of, 679-683, 681, 682 premature, 683 respiration in, 679-680, 680 Rh antigen affecting, 297-298 Neoplasia, ACTH secretion by, 623 germinal epithelial, 656 granulosa cell, 666 interstitial cell, 656 mutation causing, 31-32 ovarian, 666 parathyroid-secreting, 642-643 prostate gland with, 656 testosterone production by, 656 Neospinothalamic tract, 393, 393-394 Neostigmine, 74 Nephron, 213, 214, 214. See also Kidney, tubules

of.

anatomy

of,

kidney

213, 214, 214

failure and,

267-270, 268 in, 223-231,

mechanisms 224-230

transport

Nernst equation, 39, 47 Nerve, cochlear, 428, 430, 430 facial, 526-527, 527 glossopharyngeal. See Glossopharyngeal newe. Hering's, 153, 253, 155 lingual, 435, 435

416-417, 419, 429 phrenic, 383, 383 pudendal, 265, 265 trigeminal, 575 vagus. See Vagus nerve. Nerve fibers, 47-57. See also Neuron(s). A type, 379, 379, 393, 393-394, 394 adrenergic, 496, 496-499, 497 C type, 379, 379, 393, 393-394, 394 cholinergic, 496, 496-499, 497 climbing, 461-462, 462 conduction physiology of, 55-56, 56, 97, 379, 379. See also Conduction. diameter of, 379, 379 endings of, 363-364, 364, 377, 442, 444 optic, 406,

arteries with, 153, 253 free, 364, 377,

383

hypophysial, 600, 603-604 intestine with, 513, 523

fibers (Continued)

muscle with, 71-74, 72, 77, 77-78, 442, 442-444, 444 types of, 364, 376, 377, 383-384 enteric, 522, 512-513, 523 fast, 379, 379, 393, 393-394, 394 mossy, 461-462, 462 myelinated, 55, 55-56, 56, 379, 379 pain conduction by, 393, 393-394, 394 parasympathetic, 495-497, 496 propriospinal, 442, 442 slow, 379, 379, 393, 393-394, 394 spinal tracts of, 385-390, 457-461 afferent (sensory), 385, 385-390, 386,

390

455-461, 457,

efferent (motor), 441,

458, 461

pain transmission

393-394,

in,

393-395 sympathetic, 495-499, 497 unmyelinated, 55, 55-56, 379, 379 vestibular, 450, 450-451, 452, 453 Nervous system, 363-507. See also Brain; Spinal cord.

autonomic. See Autonomic nervous system; Parasympathetic nervous system; Sympathetic nervous system.

basic organization of, 363-365, 364

bronchioles controlled by, 316-317 circulation regulated by, 120, 220, 149-155, 250, 252, 253, 254 fetal development of, 679 integrative function of, 363-365, 364,

471-480 471-480

intellectual function of,

ischemia response of, 155 motor function role of, 363, 364, 441-470. See also Motor system. niacin deficiency affecting, 588 pain pathways of, 392-399, 393-396 parasympathetic. See Parasympathetic nervous system.

sensory function role of, 363, 364, 376-437. See also Sensory system; specific sense,

sympathetic. See Sympathetic nervous system.

thiamine deficiency affecting, 588 Neurohypophysis, 603-605, 604

Neuromuscular

junction,

71-74

71-74, 72, 73, 78 basic phvsiology of, 71-74, 72, 73, acetylcholine

77-78 drug effects

in,

77,

Neuron(s) (Continued) inhibition of, 372, 372-373, 381, 381, 383 membrane potential of, 47-57, 369-375. See also Membrane potential. motor, 364, 379, 441 -442, 442, 444 alpha, 379, 441, 442 anterior, 441-442, 442, 458, 458 gamma, 379, 441, 442 nodes of Ranvier in, 55, 55-56, 56, 377 postganglionic autonomic, 495-497 postsynaptic, 367-368, 368, 380-382 preganglionic autonomic, 495-497 respiratory group of, 337-338, 338, 339 retinal, 407, 415-419, 426, 428 rhythmic discharge of, 383, 383 spontaneous, 54-55, 55 second messenger activation of, 367-368, 368 sensory, 364, 376-390, 379 synapse of, 365-375. See also Synapse. threshold for firing of, 52-53, 371-372, 373 summation and, 372-373, 373 tactile receptor and, 376-377, 377 vesicle streaming in, 73, 369 Neuropeptides, neuron synthesis of, 369 sleep controlled by, 369 Neurotransmitters, 368-369. See also specific substances,

autonomic system secretion of, 497-498 axon varicosities containing, 77, 77-78 basal ganglia with, 468, 468-469 of, 482-484, 483 brain stem secretion of, 482-484, 483 depression psychosis role of, 492-493

brain activation role

enteric system secretion of, 513

excitatory vs. inhibitory, 367, 482-484,

483 intestinal innervation and, 513 retinal neuron release of, 415 smooth muscle, 77-78 types of, 368-369 Neutrophils, 276, 281, 281-282

defensive properties of, 282, 282-283 genesis of, 276, 281, 282 increased, 285

inflammation role of, 285, 285-286 phagocytosis by, 283-286 Newborn. See Neonate. Niacin, 587(t), 588 daily requirement for, 587(t) Nicotine, neuromuscular junction affected by, 73

in,

73-74

ventilation affected by, 695

microstrucrure of, 71-73, 72 motor end-plate in, 71, 72, 77, 77-78 myasthenia affecting, 74 skeletal muscle cell with, 71-74, 72, 73 smooth muscle cell with, 77, 77-78 Neuron(s), 55. See also Nerve fibers. automaticity in, 54-55, 55 cerebellar, 461-463, 462

formed by, 380-383, 380-383 convergence in, 381, 381 divergence in, 380-381, 381

Nicotine adenine dinucleotide. See NADH. Nicotinic acid, 588 Night blindness, 410 Nipple, suckling stimulus of, 678 Nitric oxide, biological effects of, 145 glomerular filtration affected by, 220 vasodilator action of, 145 Nitrogen, artificial climate containing,

reciprocal inhibition in, 381, 381

354-355 decompression sickness due to, 357, 357-358 hvperbaria and, 356, 357, 357-358

reverberatorv (oscillatory), 382, 382,

narcosis (rapture of the depths)

circuits

383, 477, 492

sustained output in, 382, 382-383, 383 electrode stimulation of, 56-57, 57 excitation sequence of, 369-372, 370,

371,373,373-374,374 facilitation of, 373, 380,

due

356

382

gigantocellular, 483, 484

non-protein, 269-270, 270 kidney failure and, 269-270, 270 partial pressure of, 324, 325(t) Nociceptors, 364, 376, 379, 392-393 Nodes of Ranvier, 55, 55-56, 56, 377 Noise. See Sound(s).

to,

725

Index

Norepinephrine, 146, 496-498 adrenal gland secretion of, 500-501, 616 autonomic system role of, 496-499 brain activation by, 483, 483 chemical structure of, 497 duration of action of, 498 enteric neuron secretion of, 513, 513 enzyme destruction of, 498 intestinal function role of, 513, 513 receptors

for,

498-499

secretion of, 369, 483, 483,

smooth muscle

496-498

inhibition by, 78, 80

vs. epinephrine, 498-501 Nose, air warming in, 326, 317 gland innervation in, 497, 500

olfactory

membrane

relation to, 435,

435-436 respiratory function of, 316, 317

sinuses related

to,

397, 398

Nucleolus, 10, 13, 13-14 Nucleotides, codon role of, 23-25, 25, 26, 26(t)

DNA structure and, 22-24, 23-25 RNA structure and, 24-26, 25, 26 Nucleus cell

(cellular), 10, 13,

13-14

division (mitosis) and, 29, 29-31

physical structure

Nucleus

of, 10, 13,

13-14

(neural), abducens, 423

arcuate, 486

auditory pathway and, 431, 431-432 brain stem, 448, 449, 452-453, 453, 483 caudate, 364, 466, 467, 467-468 cerebellar,

460-462, 462

dentate, 453, 461

dorsomedial, 486 Edinger-Westphal, 424, 424-425 fastigial, 453 gigantocellular, 483, 484 hypothalamic, 486 intralaminar, pain pathways to, 394, 394 lateral geniculate, layers of, 419, 421 vision pathways in, 419, 419 oculomotor, 423 olivary, sound direction and, 433 paraventricular, 486, 604 perifornical, 486 periventricular, 395, 395, 486, 486 preoptic, 242, 486 pretectal, eye reflexes and, 419, 419, 423 raphe, 395, 395, 483, 484 sleep controlled by, 489, 490 red, 453, 461, 464 reticular, 448, 449, 452-453, 453 salivatory, 435, 435, 526-527, 527 subthalamic, 364, 465, 466 supraoptic, 486 taste sense pathway in, 434-435, 435 trochlear, 423 ventromedial, 486, 486 vestibular, 423, 452-453, 453 Nutrition, 572-574, 583-584. See also Diet; Feeding; Food. calories and, 572-574,

583-584

energy requirements related to, 572, 572-574, 583-584 excessive, 586 exercise physiology related to, 573-574, 688-692, 692 fetal, 671, 672, 674 maternal, 674, 678, 682 neonatal, 674, 682 obesity relation to, 586 pregnancy affecting, 674 Nystagmus, cerebellar, 465

O

Osmosis (Continued) renal tubular, 224, 226, 227, 22S, 230

Obesity, 586

childhood overnutrition role feeding regulation in, 586 genetic factors in, 586 psychogenic, 586 Occipital lobe, 420

in,

586

language comprehension role of, 472, 474, 476 visual cortex in, 420, 420-421, 423, 457 Occipitotectal tract, 423

Ocean diving, 355-359, 356-358 hyperbaria related

355-359, 356, 357 Oculomotor nucleus, 423 Odontoblasts, 644 Odorant substances, binding of, 436 fecal, 543 Ohm's law, blood flow calculation with, to,

117, 117

Olfaction. See Smell.

Olfactory bulb, 435, 436, 437, 484 Olfactory membrane, 435, 435-437, 436 Olivary nucleus, sound direction and, 433 Olivocerebellar tract, 460

Oncogenes, 31-32 Opercula (of insula), taste pathway in, 435, 435 Operon, gene activation role of, 28, 28-29 Ophthalmoscope, 405, 405 Opiates (endogenous), 395, 395 pain inhibition by, 395, 395 Opsonization, bacterial destruction by, 292, 292 complement role in, 292, 292 Optic chiasm, 419, 419, 486 hypothalamus and, 600, 604 Optic disc, edema of, 506 Optic nerve, 419, 419 retina with fibers of, 406, 407, 407,

416-417 Optic radiation, 419, 419 Optic tract, 419, 419 Oral cavity, 512 bacteria of, 526 food processing by, 512, 514-515, 515 saliva function in, 526 Oral contraceptives, 667-668 Organ of Corti, 428, 428, 430, 430 Organelles, 10-18, 10- 18 Orgasm, female, 667 male, 652 Ornithine, urea formation role of, 569 Oscillating

neuron

circuits, 382, 382, 383,

477 Oscilloscope, action potential on, 50,

56-57, 57 Osmolality, 40-41, 206 definition of, 206 osmotic pressure relation to, 40-41, 204(t), 206 sodium and, 236-242, 237-241 urinary, 236-242, 237-241 vasopressin effect on, 242, 241-242 Osmolarity, 206 body fluid compartments and, 204(t), 206 definition of, 206 Osmole unit, 40-41, 206 Osmoreceptors, 241-242 Osmosis, 39-41, 206-208 definition of, 206 intestinal absorption by, 540-541, 542 mechanisms of, 39-41, 40, 206

Osmotic pressure, 40, 40-41, 206-208 bodv fluid compartments and, 204(t), 206-208, 207, 208

Bowman's

217-218

capsule, 227,

exchange role

capillary

132-138, 233,

of,

209 capillary filtration and, 209

definition of, 40, 132, 206

glomerular, 227, 217-219, 228, 219(t) kinetic energy role in, 34-35, 36, 40

mathematical calculation

of,

206, 209

membrane

of,

38-41, 39,

40,

transport role

132-138

normal value

number

for, 41, 204(t)

of particles related to, 40-41,

135 osmolality relation to, 40-41, 204(t), 206 peritubular capillaries with, 230,

230-231, 231(t) plasma colloid relation to, 132-138, 233, 209 plasma solutes and, 132-138, 233, 204(t), 206 pulmonary function and, 322, 321-322, 322 van't Hoff law related

to, 206 39-41, 40 Ossicular system, 427-428, 428 Osteoblasts, 637-640, 638 estrogen effect on, 662

water role

in,

638-639 parathormone activation

Osteoclasts, 638,

of, 640,

642

Osteocytes, 637

membrane system

of,

640

Osteolysis, 639-641

bone remodeling

role of, 638 parathyroid hormone in, 639-641, 640 rapid phase of, 640 slow phase of, 640 Osteomalacia, 642, 643 Osteon, 637, 638 Osteoporosis, 643 causes of, 643 Osteoprogenitor cells, 639 Otic ganglion, 497, 527 Otoliths, vestibular, 450, 450 Oval window, 427, 428, 429 Ovaries, 658-668 follicles produced by, 658-661, 659 hormone production by, 596, 662,

661-664 hyperfunction of, 666 hypofunction of, 666 hypothalamic regulation

of,

658,

664-665 668

infertility related to,

menopause and, 666 menstrual cycle and, 658-661, 663,

663-665 pituitary regulation of, 658-661, 659,

664-665 puberty and, 658-659, 665 steroids of, 662, total

number

661-664

of ova in, 658

tumor of, 666 Overbreathing, alkalosis due Ovulation, 658, 659, 660 absence of, 668

Ovum,

659,

to, 263, 263(t)

659-661

fallopian tube transport of, 670-671 fertilization of, 651,

670-671, 672

menopause and, 666

726 Ovum

Index

(parietal) cells, 527, 527-530, 528 hydrochloric acid produced by, 527-530, 528 Oxyphil cells, 639, 639 Oxytocin, 595, 605 milk ejection induced by, 678 parturition role of, 675 uterine contraction induced by, 675

Oxyntic

(Continued)

production of, 659, 659-661 progesterone effect on, 674

sperm penetration

of, 651, 670,

671

uterine implantation of, 671, 671 Oxaloacetic acid, 554-555, 555 citric acid cycle role of, 554-555, 555 Oxalosuccinic acid, 555 Oxidation, citric acid cycle with, 555-556, 556 phosphorylation coupled with, 555-556, 556 water formation by, 555-556, 556

Oxygen, 324-335 altitude (high) and, 351-355, 352, 352(t),

353 blood flow regulation related to, 142-143, 143, 180-184, 503 brain blood flow and, 502-503 calorie equivalent of,

Pwave,

88,

392-399

birth labor causing, 677 cardiac, 187, 396,

396-397

ischemic disease causing, 187 Cortisol secretion due to, 621, 621 descriptive names for tvpes of, 392 fast, 392-394, 393, 394

headache causing, 397, 397-398 hypothalamus and, 395, 395 396

exercise and, 270, 329-333, 330, 341, 341,

nerve pathways

393-395, 393-395

receptors for,

278,

332, 332-334, 351, 352

membrane

permeability

to, 35,

326-330,

respiratory quotient related

583-584 muscle blood flow related 694, 694-697

to,

to,

180-181,

myocardial blood flow and, 183-184 for, 6(t),

6-7

temperature-related, 392-393, 393,

341 saturation level of, 142-143, 143, 332, 332-333, 343, 352, 352(t) tension (partial pressure) of, 324-334

325(0, 325-327, 326,

of,

329, 330 extracellular level of,

6(t),

6-7, 35, 330,

331-332,332 672 high, 356 fetal,

intracellular level of, 35, 333, 333

low, 344-345, 351-355, 352, 352(t), 353, 503 toxicity of, hyperbaria causing, 356,

Oxygen Oxygen

of, 275,

358

329-334, 332-334

debt, 691, 691

therapy, 351 -353 altitude effect treated with, 351 -353, 352, 352(t), 353

pH

640-641 treatment using, 642 vitamin D regulated bv, 634-635, 635, 641 Paraventricular nucleus, 486, 604 oxytocin secretion by, 604, 604

387

hydrochloric acid produced by, 527-530,

528 Parieto-occipitotemporal association area, 472,

472-473

Parkinson's disease, 468-469 Parolfactory area, 484, 485, 485 Parotid gland, 512, 525 innervation of, 497, 500, 526-527, 527

of, 525(0, 530 regulation of, 531, 532 hormones secreted by, 596, 625-633. See also Glucagon; Insulin.

Parturition,

blood flow related to, 521-522 islets of Langerhans in, 596, 625, 626 removal of, 628, 628-629, 629 Pancreatic duct, 532, 534 Paneth cell, 534 Pantothenic acid, 587(0, 589 deficiency of, 589 Papilla of Vater, 534, 534 Papillary muscles, 89-90, 90 Papilledema, 506 Para-aminohippuric acid (PAH), 233-234, 234

placental,

intestinal

Parafollicular cells, 641

Parahippocampal gyrus, 484, 485, 485 in, 493 Parasympathetic nervous system, 496-500, 497

Paranoia, neurotransmitter role

acetylcholine secretion

in,

496-497

hypoxia treated with, 345, 345

bronchioles controlled by, 316-317 cardiac innervation by, 91-92, 92, 98-99

of,

642-643

of,

secretion of, 525-527, 526, 527

anatomy

treated with, 345, 345

tumor

Parathyroid hormone, 639-641 calcium metabolism role of, 252, 635, 639-641, 642 chemistry of, 639 deficiency of, 642 excess of, 642-643 regulation of, 634-635, 635, 641, 642 renal tubule regulated bv, 232, 232(0,

Pars intermedia, 622

525(t)

hyperbaria and, 356

pulmonary edema

265, 497

Paraterminal gyrus, 484 Parathyroid gland, 639-641 anatomy of, 639, 639 histology of, 639, 639 hypertrophy of, 641, 643 rickets role of, 641, 643

Parietal (oxyntic) cells, 527, 527-530, 528

to, 515 Paleocerebellum, 461 Paleospinothalamic tract, 393, 394 Pancreas, 522, 532 anatomy of, 596, 625, 626 bicarbonate secreted by, 530-531 cell types of, 625, 626 enzymes secreted by, 530-531, 532,

Palate,

"tone" due to, 501 urinary bladder innervated by, 264-265,

Parietal lobes, 387,

396-397 swallowing relation

visceral, 396,

daily

326-327, 330, 331 pure, 351-353, 352, 352(t), 353 respiration control and, 340, 340-341,

transport

withdrawal from, 446, 446-447

538-539,539 volume of,

level of, 6(t), 6-7, 325(t),

alveolar level

392-393

398-399, 399

metabolism of, calorimetrv related to, 572-573 carbohydrate stores and, 583-584 fat stores and, 583-584

normal

for,

364,

487, 487

slow, 392-394, 393, 394

329, 330

nonlethal limits

for,

for,

referred, 395-397, 396 reflex

lipid bilaver solubility of, 35

intestine regulated by, 497, 513, 523, 521,

526-527, 527

to, 392,

hemoglobin binding capacity

defecation controlled by, 521, 522 eye innervation by, 424, 424-425, 497 gastric innervation by, 497, 529

100-102, 101

Pacinian corpuscle, 364, 377, 377-378, 378, 384 PAH (para-aminohippuric acid), 233-234, 234

increased sensitivity limbic system center migraine, 397-398

694-695

by, 401, 424,

penile erection controlled by, 651-652

332-334 exchange of, 324-332, 329-331 691, 691, 694,

muscle controlled

424, 497, 499(0

saliva secretion regulated by, 497,

analgesia (endogenous) of, 395, 395 angina pectoris with, 187

572-573

(Continued) ciliary

522, 523 norepinephrine and, 496-499

Pain, 187,

carbon monoxide displacement of, 334 cardiac output and, 169, 170, 173, 173 consumption of, 169, 170, 173, 180-184, 341, 341, 696, 696 depressed level of, 341 -345, 343, 345, 503 diffusion of, 324-332, 329-331, 694-695 dissociation curve for, 332, 332, 353 erythrocyte binding of, 275, 329-332,

Parasympathetic nervous system

496-500, 497

675-677

hormonal

factors in, 675

labor of, 675-677, 676

mechanics

675-677, 676

of,

676-677

Parvocellular layer, 419, 422 Patch-clamp technique, 37, 37-38

Patent ductus arteriosus, 290, 191-192, 292 phonocardiography of, 290 Pellagra, 588

Pelvic nerves, urinary bladder and, 265,

265 651, 651-652 651-652 erectile tissue of, 649, 651, 651-652 sex act role of, 652, 651-652

Penis,

anatomy

blood flow

of, 649,

to,

652,

Pentagastrin, 530 Pentose phosphate pathway, 557 Pepsin, formation of, 528 protein digestion role of, 539, 539 Pepsinogen, 528-530 activation of, 528

529-530 529-530 Peptic chief cells, 527, 527-530 gastric secretion of, 528,

regulation

of,

727

Index

Peptic ulcer, 543-545 bacterial infection causing, 544, 544

causes of, 543-545, 544 Peptidases, protein digestion role 539 small intestinal, 534, 539 Peptide bond, 567

RNA translation

of, 539,

Phonocardiography (Continued) valvular murmurs in, 290, 190-191 Phosphate bond, high energy, 17, 551, 552, 572, 689 Phosphates, bone structure role

636-640 buffer system based on, 256,

using, 27

dietary sources

Peptides, atrial natriuretic, 232, 232(t)

634-638

sleep controlled by, 369

pregnancy affecting, 674, 678, 682 renal excretion of, 640-641 vitamin D relation to, 634-636, 635 Phosphocreatine, chemical structure of, 571 energy transfer role of, 571-572, 572, 689, 689 exercise physiology role of, 689, 689 Phospholipids, 560, 564. See also Lipid

518-521

diarrhea role of, 519, 520 esophageal, 515, 516

reflex related to, 514, 521

ureteral, Peritonitis,

265-266

extracellular fluid level of, 35, 203

448

insulin action affecting, 628

Periventricular nucleus, 395, 395, 486, 486 Permeability,

35-36

138, 138

diffusion related

to,

35-36, 38, 130,

132(t)

role of,

209-210

glucose transport role of, 625-627, 626 insulin effect on, 625-627, 626 lipid bilayer and, 35-36 membrane transport role of, 35-36, 38 oxygen transport role of, 35 Peroxidase, tyrosine iodination by, 608 Petit mal seizure, 492, 492 pH. See also Acid-base balance. acidotic level of, 254, 262, 263(t) alkalotic level of, 254, 262, 263(0

alveolar ventilation and, 256-257, 257,

339 blood flow control by, 147 carbon dioxide relation to, 256, 335, 339 duodenal, 531 extracellular fluid level of, 6(t), 6-7, 35 gastric secretion level of, 525(t), 527, 528 Henderson-Hasselbalch equation and, 256 hydrogen ion concentration and, 254, 256, 339 intestinal secretion level of, 525(t)

intracellular fluid level of, 35

nonlethal limits

normal

6-7, 254

for, 6(t),

level of, 6(t), 6-7, 35, 254,

pancreatic secretion level

257

of, 525(t)

salival, 525, 525(t)

sperm tolerance

intracellular fluid level of, 35, 203 platelet with, 302, 303, 303

capillary function and, 130-132, 132(t),

edema

structure role of, 9-10, 22, 565 chylomicron formation by, 542 dietary, 538 cell

518-521, 519-521

level of, 650

Phagocytosis, 14, 14-15, 19, 281 eosinophil role in, 286

macrophage role in, 283-286, 285 mechanisms of, 14, 14-15, 283-286 monocyte role in, 283-284, 285 neutrophil role in, 283-286 Pharyngoesophageal sphincter, 515 Pharynx, 316, 515 swallowing mechanisms related to, 515,

515-516 Phenylalanine, 566 Phonation, 318, 328

Phonocardiography, 88, 190 normal, 88, 189-190, 290

of, 564, 564 Phosphoric acid, DNA role of, 22-23, 23 Phosphorylase, 553, 553 Phosphorylation, glucose in, 553, 553, 627 oxidative, 555-556, 556

types

Photopsin, 411-412 Photoreceptors, 407-409, 407-411,

415-419,428 Phrenic nerve, 383, 383 Physostigmine, 74 Pia mater, 505, 505

bone and, 639 Pigment, carotenoid, 587 retinal, 407, 408-409, 422, 412-413, 423 Piloerection, 576, 579 Pineal gland, 596, 656 Pinocytic vesicles, 540 Pinocytosis, 24, 14-15, 19 Piruicytes, 603 Piezo-electric effect,

Pituitary gland,

595-605

adrenal gland axis with, 622, 621-622 anatomy of, 596, 599, 599, 604 anterior, 595, 599, 599-603, 604 ovarian cycle regulation by, 658-661,

664-665 to, 600, 600-601 hormones of, 595, 599, 599-605 hypothalamic control of, 485-487, 486 ovarian axis with, 658-659, 664-665 659,

blood flow

posterior, 595, 599, 600,

603-605, 604

thyroid gland axis with, 622, 611-612

671-674 anatomy of, 671, 672 chorionic, 672, 673, 673-674

Placenta,

diffusion across, 672

hormones secreted pregnancy

role of,

672-674, 673, 677 671-674, 672, 673 by,

separation and delivery of, 676-677 Placenta spongiosa, 672 Plaque, atheromatous, 184-185, 565 calcified,

565

cholesterol in, 565 dental,

645-646

Plasma. See under Blood.

Plasma

cells,

282,281-282

antibody formation by, 290-291, 293

B

cell

Plasmalemmal

vesicles, 232

282 aggregation of, 299-300, 300 coagulation role of, 299-301, 300, 303,

Platelets, 276, 281, 281,

deficiency of, 305-306 genesis of, megakaryocyte

in, 299 299 normal count of, 281, 299, 306 physiology of, 299-300 vascular wall plug formed by, 299-300, 300 Pleasure, limbic center for, 486-487, 487

half-life of,

Pleural fluid, fluid exchange related

to,

322, 322

bilayer.

516-518

intestinal, 514, 514,

291 response role of, 290-291, 293 Plasma membrane. See Cell membrane. of, 281,

immune

303-306

intracellular level of, 34, 35, 203, 204(t)

Peptones, 531, 539, 539 Perforins, 294 Periaqueductal gray area, 395, 395 Perifornical nucleus, 486 Periodontal membrane, 644 Periosteum, 638

gastric,

261, 262

634

of,

cells (Continued)

genesis

Plasmin, 305

extracellular level of, 34, 35, 203, 204(t),

neuropeptide, 369

Peristalsis,

of,

Plasma

origin of, 291

lung surrounded by, 311, 322, 322 lymphatic drainage of, 311, 321-322, 322 pressure of, 311-312, 322, 322 ventilatory function and, 311, 322 Plexiform layer, retinal, 407, 407 Plexus, Auerbach's, 522, 512, 523 choroid, 504, 505 hypogastric, 495, 496 Meissner's, 522, 512 myenteric, 522, 512, 523 sacral, 265, 265 submucosal, 522, 512, 523 venous, under skin, 127 Pneumonia, 342, 343, 343 hypoxemia in, 343, 343 Pneumotaxic center, 337-338, 338, 502 respiration control by, 337-338, 338, 502 Podocytes, 216, 226, 222 Poiseuille's law, 119 Poisoning, carbon monoxide, 334 Polycythemia, 120, 203 Polymerase, RNA, 24-25, 25

Polymorphonuclear 281-282

cells,

276, 281,

genesis of, 276, 281, 281-282 Polypeptides, 539, 539 Polysaccharides, 537 Pons, 395, 424, 459

autonomic system control by, 502, 502 brain activation role of, 483, 484 motor function role of, 448, 448-449, 452-453, 453

pneumotaxic center

in, 337-338, 338 sensory function and, 364, 424 Pontocerebellar tract, 460 Portal vein, 521-523, 522 Postcentral gyrus, 387, 387 Postganglionic fibers, 495-499, 496 gastrointestinal regulation by, 512-513, 523 Postsynaptic neuron, 367-368

memory

role of, 478,

478-479

second messenger activation of, 367-368, 368 Posture, cerebellar maintenance of, 463-465, 464 reflexes associated with, 447,

447-448

Potassium, 6-7, 248-251, 617 aldosterone regulation of, 232, 232(t), 250, 250-251, 251, 617 cardiac muscle affected by, 92, 94-95 daily intake and loss of, 223(t), 248-251,

248-251 deficiency

of, 617,

624

+

728

Index

Potassium (Continued) excess of, 617

366-367, 372, 372-373 memory role of, 478, 478 physiology of, 366, 366-367, 372, inhibitory,

exercise effect on, 698 extracellular fluid and,

6(t),

6-7, 34, 35,

of,

248-251, 248-251

synthesis of, 598

Proaccelerin, 301 (t)

urea formation related to, 569 Proteoglycans, interstitial filaments 232 of bone, 636 Proteoses, 531, 539, 539

Proelastase, 539, 539

Prothrombin, 300-301

Pretectal nucleus, 419, 429, 423

248 kidney and, 223(t), 224, 225, 227-229, 248-251, 250 membrane transport of, 36, 41 -43, 42, 225 neuron potential role of, 47-53, 48-52, 370, 370-371, 371

Prevertebral ganglia, 512-513, 523 Principal cells, 22S, 229, 249, 249

normal

6-7

for, 6(t),

level of, 6(t), 6-7,

Proerythroblasts, 277

pregnancy

35

role of, 673,

Progestins, 662, 663

tubular reabsorption

Prolactin, 599, 599

of, 223(t), 224, 225,

248-251, 248-251, 617 urinary, 223(t), 248-251, 248-251 Potassium channel, 36, 36 activation of, 36, 51, 51-52 active transport in, 36, 41-43, 42 of, 36, 36, 42, 51,

51

neuron membrane with, 47-52,

49, 51

membrane

and, 367-368, 368 Potassium-sodium "leak" channel, 48-49, 49 P-Q interval, 101, 102 P-R interval, 101, 102 Precapillary sphincter, 127, 128 intermittent contraction affecting, 128 tissue blood flow control by, 244, synaptic

144-145 Prednisone, 616 Preeclampsia, 675 Prefrontal association area, 473, 474, 475

lobotomy affecting, 475 working memory in, 475

activator

Progesterone, 659, 661, 661-663 parturition role of, 675, 677 placental secretion of, 673, 673-674

saliva containing, 526

gating

hormone

inhibiting

for,

600-601, 678

677-678 pregnancy role of, 677, 677-678 Proline, RNA codons for, 25 Prometaphase, 29, 31 Promoter sequence, gene control by, 24, 28-29 lactation stimulated by, 677,

of,

Prehippocampal rudiment, 484

extracellular fluid level of, 34, 35, 203,

acids stored as, 567, 568 buffering function of, 256

membrane

structure and, 9-10, 22,

contractile.

See Actin filaments; Myosin

daily requirement

deamination

for,

resistance in, 119

intracellular fluid level of, 34, 35, 203,

See under Gases; and under

specific gas.

364, 383-385, 384

Presynaptic terminal, 366, 371, 374 dendritic, 373-374, 374 excitatory,

of,

216(0, 216-219,

affecting, 601, 629, 629

366-367, 372, 371-372, 374

diastolic,

damping

122-124, 223 122-124, 223

in, 122,

pressure contours

factors affecting, 598, 601, 629,

654, 687, 698

Punishment

223 of,

122, 223

center, limbic, 487,

487

Pupil, 401, 402

intestinal transport of, 542,

567

diameter

of,

innervation

401, 425 of,

424, 425, 497, 499(t)

reflexes related to, 419, 424, 424-425,

formation

of,

568

transport role 36, 42, 43

497, of,

34-43, 35,

567-570 619-620 energy derived from, 569-570

metabolism

122-124 122-124

systolic,

hole-forming, 294

membrane 406-407

Pulp, dental, 644, 644, 645 arterial,

204(t)

osmotic. See Osmotic pressure.

blood volume of, 327-328 320-321, 327-332,

fluid

Prepuce, 649 Presbyopia, 401 Pressure, baroreceptors

blood. See Blood pressure.

total

Pulses,

growth hormone

liver

329-332

115-116, 226, 320,

328-332 exchange and, 319-322, 320-322 gas exchange and, 326, 320-321, 327-332, 328-332

570, 583

of,

fibrous,

hormonal

in,

capillaries of, 326,

filaments.

567 glomerular filtration 22S

See

pressure level

320-322

204(t)

for.

329-332 exercise affecting, 270,

reservoir function of, 127

Premature contractions, 105-106 atrial, 105-106, 106 ventricular, 105-106, 206 Premature neonate, 683 Preoptic area, heat-sensitive neurons in, 578 hypothalamic, 486 Preoptic nucleus, thirst center in, 242

Baroreceptors.

depression as, 493 neurotransmitter role in, 492-493 Pteroylglutamic acid, 587(t), 589 Ptyalin, salival, 525, 537, 538 Puberty, 655, 658-659, 665 female, 658-659, 665 male, 653, 655 Pudendal nerve, micturition and, 265, 265 Pulmonary artery, low pressure receptors in, 155 pressure in, 328, 319, 320 Pulmonary membrane, 327-329, 327-329 Pulmonary valve, 86, 89, 90 Pulmonary vasculature, 115-116, 226 blood flow in, 115-116, 319-322 dynamics of, 319-322, 320-322,

34, 35, 36

cellular formation of, 568

Prekallikrein, 301 (t), 303

tactile,

28,

542

569 deficiency of, 583, 587 dietary, 583-584, 587 digestion of, 539, 539

partial.

Psychosis, 492-493

amino cell

300, 302, 302, 303,

29

565-570

absorption

for,

phagocytosis using, 283

Promyelocytes, 281 Pronucleus, female, 670, 672 male, 670, 672 Prophase, 29, 31 Propriospinal fibers, 442, 442 Prorenin, 162 Prostaglandins, 147 Prostate gland, 649 cancer of, 656 hypertrophy of, 655 secretion of, 650 semen and, 650-651 Protein,

complex

of, 132,

303 coagulation role of, 300, 300-301, 302, 303 formation of, 300-301 molecular weight of, 300 Protoporphyrin, 278 Pseudopodium, cell locomotion role of, 19,

673-674, 677

Preganglionic fibers, 495-499, 496 Pregnancy, 670-683 complications of, 675, 682-683 fetal development during, 678-681, 681 hormonal factors during, 672-674, 673 initiation of, 670-672, 672 maternal physiology in, 674-675 milk production following, 677, 677-678 neonatal physiology and, 681-683, 682 nutrition during, 674, 678, 682 parturition and labor of, 675-677, 676 placenta role in, 671-674, 672, 673

intraocular, 406,

plasma containing, 568

structure of, 366, 371, 374

intracellular level of, 34, 35, 203, 204(t),

nonlethal limits

583

partial,

371-374,374

203, 204(t)

regulation

Protein (Continued) obligatory loss of, 569-570

Presynaptic terminal (Continued)

of,

Cortisol effect on,

.

exercise effect on, 688-692, 692 insulin effect on, 629, 629

respiratory quotient related

to,

583-584 starvation effect on, 587, 587

499-500

DNA containing,

22-23, 23 Purkinje cells, cerebellar, 461-463, 462 Purkinje system, 94-99, 95-97 Purines,

conduction in, 96-97 Purpura, thrombocytopenic, 305-306 Putamen, 465-467, 466, 467 motor function and, 364, 465-467, 466, 467 PVC (premature ventricular contraction), 105-106, 206

729

Index

Pylorus, 516 'innervation

of,

496, 497, 499(t)

peptic ulcer and, 543-545, 544 of, 517-518 stomach emptied through, 517-518 Pyramidal cells, 472

sphincter

cerebral cortical, 388, 457-459, 471, 472

morphology of, 471, 472 Pyramidal (corticospinal) tract, 455-459, 457, 458 Pyridoxine, 587(t), 589 daily requirement for, 587(t) deficiency of, 589 containing, 22-23, 23 Pyrimidines, Pyrogens, aspirin therapy related to, 581 fever and chills due to, 580, 580-581

DNA

Pyrophosphate, bone affected by, 637 Pyruvic acid, 554 acetyl Co-A produced from, 554 anaerobic pathway role of, 557, 690 glycolytic production of, 554, 554 metabolism of, 554, 554

Receptors (Continued) light wave, 407-409, 407-411, 415-419, 418 mechanoreceptor, 376-378, 377 383-384, 384 membrane transport role of, 42, 42, 43 muscarinic, 498 muscle spindle, 364, 442, 442-445, 444 neuromuscular junction, 71-73, 72, 78 nicotinic, 498 norepinephrine, 498-499 olfactory (smell), 435-436, 436 pain (nociceptor), 364, 376, 379, 392-393 photoreceptor, 407-409, 407-411, 415-419, 418 position-sensitive, 364, 389, 445, 452 pressure (intravascular), 152-155, 253, 254 pressure (tactile), 364, 376-378, 377, 383-385, 384 rate of stimulus and, 378, 378 sensory, 364, 377, 378, 384, 430, 434, 436 synaptic function role of, 366, 367 371 T cell, 291, 293, 293 taste (gustatory), 434, 434, 435 temperature-sensitive, 376, 392-393, 393, 398-399, 399, 577-578 touch, 364, 377, 383-385, 384 triiodothyronine binding by, 609-610 vibration, 384-385, 427-428 Red blood cells. See Erythrocytes. Red flare, urticarial, 295 Red nucleus, 453, 461, 462, 464 Reentry mechanism, 207, 107-108 ,

Q

wave, 88, 100-102,102 QRS complex, 88, 100-102, 202 bundle branch block affecting,

110, 111

current of injury affecting, 111, 111-112

prolonged, 110, 111 PVC effect on, 105-106, 106 Q-T interval, 102

due to, 441 -448

207,

fibrillation

R

Reflex(es),

107-108

arterial pressure controlled by, 253,

R wave,

100-102, 101 Radial artery, pulse in, 123 Radioactive products, bone deposition 637

153-154, 254 autonomic, 501

88,

of,

baroreceptor, 253, 153-154, 254 carotid sinus, 253,

153-154

Radioimmunoassay, 598-599 hormone measurement using, 598, 598-599 technique of, 598, 598-599 Rage, behavioral signs of, 487 hypothalamic center for, 486 limbic center for, 487, 487 Ranitidine, stomach ulcer treated with, 544 Ranvier nodes, 55, 55-56, 56, 377 Raphe nucleus, 395, 395, 483, 484

chewing, 514-515, 525 cough due to, 317 crossed extensor, 446, 447 decerebrate animal with, 447, 447-448 defecation, 520-521, 521 duodenocolic, 521 eye with, 419, 424, 424-425, 497,

sleep controlled by, 489, 490 "Rapture of the depths," 356

gastrocolic, 521

Reading, cortical area used in, 472, 473, 474, 474, 476 Reagins, 295 Receptors, 377. See also Baroreceptors;

intestinal, 514, 518, 519, 520, 521

acetylcholine, 71-73, 72, 78, 496, 497, 498

phenomenon

in, 378,

378

aldosterone, 618 antigen bound to, 293, 293 auditory, 428, 430, 430

autonomic, 496, 497, 498-499 B cell, 291, 293, 293 cellular endocytosis and, 14, 14, estrogen, 662-663

expanded

tip,

364, 377,

383-384

hair cell (auditory), 428, 430, 430 hair end-organ (tactile), 377, 384

hormonal, 596-597, 597 Iggo dome, 384, 384 insulin,

625-627

kinesthetic, 364, 389, 445, 452

galloping,

knee

jerk as,

"mark

446-447

447-448

Hering-Breuer (lung

Chemoreceptors.

adaptation

499-500 flexor (withdrawal), 446,

inflation),

338

445

micturition, 264, 266, 266 myenteric, 514, 517, 518, 519, 520, 521 myotatic, 443-445, 444 patellar, 445 peristaltic, 514, 517, 518, 519, 520, 521 posture and locomotion, 447, 447-448

499-500 rhythmical stepping, 447 sex act and, female, 667 male, 651 sound attenuation by, 427 spinal cord role in, 441-448, 442, 444,

damped,

444, 444 dynamic, 443, 444 negative, 444

443-444

vascular resistance

in, 219(t),

219-220

Renal vein, 213, 213, 215 pressure and resistance in, 219, 219(t) Renin, 162 hypertension and, 162-165, 162-165 renal output affected by,

262-265

162-166 substrate for, 162 Repolarization, ECG

101-102 heart muscle

wave due

fiber in,

to, 202,

100-102, 202

neuronal, 50, 50 Repressor operator, gene control by, 28,

28-29 Reproductive system, 648-683. See also Fertilization.

female, 658-661, 659, 670-683. See also Pregnancy.

male, 648-656, 649-652 pineal gland role in, 656 Residual body, cellular pinocytosis with, 15, 25 Residual volume, lung with, 324, 314-316 Resonators, voice with, 318, 328 Respiration, 311-346. See also Ventilation. acid-base balance regulated in, 256-257, 257, 263, 263(t) acidosis and, 263, 263(t) alkalosis and, 263, 263(t)

altitude effect on, 351-355, 352, 352(t),

353 Cheyne-Stokes, 341-342 control of, 337-342, 338-341 dyspneic, 345-346 exercise effect on, 320, 320, 330, 330-331, 333, 341, 342, 694-696, 696

time," 447, 447

446,447 stretch, 443-445, 444

static,

swallowing, 515-516 taste-related, 435, 435 Refractoriness, myocardial, 86, 207, 107-108, 208 Regulons, gene transcription role of, 29 Reissner's membrane, 428, 429 Remodeling, bone in, 638-639 muscle in, 69-70, 692-693 Renal artery, 213, 223 blood pressure in, 219(t), 219-220 constriction of, 164-165, 265 Goldblatt hvpertension related to, 164-165, 165

gas exchange

pupillary, 419, 424, 424-425, 497,

19, 19

Reflex(es) (Continued)

in,

324-332, 329-332, 335

694-696 mechanics of, 311-316, 312-314 muscles of, 311-313, 322 neonatal, 679-680, 680 periodic, 341-342 rate of, 315-316, 337-338 swallowing inhibition of, 515-516 Respiratory center, 337-341, 502 drugs affecting, 341-342 nerve impulses generated by, 383, 383 neuroanatomy of, 337-338, 338-340, increased, 263, 263(0,

502 respiration controlled by, 338-340,

338-342, 502 swallowing effect on, 515-516 Respiratory distress syndrome, neonatal, 343, 680

surfactant lacking

in, 343, 680 Respiratory exchange ratio, 335 Respiratory quotient, 335 metabolic energy source related

583-584

to,

730

Index

Respiratory

anatomy drugs

tract,

316-318 316-318 316-317

affecting,

bone

membrane lining of, 327-329, 327-329 mucus coat of, 317 nervous control

of,

316-317

Resting potential, 48-50, 49, 369-372, 370 cardiac muscle fiber with, 85 intestinal smooth muscle with, 512, 533 measurement of, 48, 48 physiology of, 48, 48-50, 49, 369-372, 370, 371 Resuscitators, artificial respiration using, 346, 346 tank (iron lung), 346, 346 Reticular formation, 394, 448, 482-483 activation-excitatory area of, 482-484, 483 inhibitory area of, 483, 483 pain pathways of, 394, 394 sleep theory related to, 489 vision transmission inhibited in, 419 Reticulocytes, 277 Reticuloendothelial system, 283-284, 284 Reticulospinal tract, 449, 449, 453, 453 Retina, 407-413, 415-419 anatomy of, 406-408, 407-409, 416 blood flow to, 409 color detection by, 412, 412-413, 413,

417-419 examination

of,

416-417 of,

neural circuitry

of, 407, 408, 411,

Running, calories used in, 573(t), 573-574 Rve, gluten enteropathy caused by, 545

optical principles related to, 400, 402,

402, 405 photochemistry of, 409-413, 410-413 photoreceptors of, 407-409, 407-411, 415-419, 428

pigment layer

of,

407,

408-409

structural elements of, 407-409,

407-409

Retinal (pigment), 409-410, 420, 422,

vision photochemistry role of, 410, 420

477

486-487, 487

antigen, 297

affected by, 297-298 transfusion reaction due to, 297-298

294 heart affected by, 190-191 Rhodopsin, 409-411, 420, 422 Rhythm method, 667 Rhythmicity, neural, 54-55, 55, 383, 383 fever,

588-589

daily requirement for, 587(t) deficiency of, 588-589

Ribose, RNA role of, 24 Ribosomes, 20, 11, 26 endoplasmic reticulum with, 27, 27 intestinal cell with, 524, 525 protein synthesis by, 26, 26-27, 27 RNA translation by, 26, 26-27, 27 subunits of, 26-27, 27 Ribs, ventilatory function of, 311-312, 322

532 pancreas regulated by, 531, 532 liver stimulated by,

Secretory granules, 20, 26, 16-17

491-492 grand mal, 491-492, 492

Seizures,

petit mal, 492, 492

Semen, 650-651 composition sperm count

of,

650

of,

650-651

Semicircular canals, 450, 451, 451-452

cerebral cortical areas of, 363, 364,

corticofugal signals of, 390 in, 427-433, 428-433 language and, 472, 473, 474, 474,

hearing

of, 525(t)

hygiene related

to,

526

475-476

of, 525, 525(t)

525-527

nerve fiber types

in,

379, 379

Salivary glands, 512, 527 innervation of, 497, 500, 526-527, 527 secretions of, 525-527, 525-527

receptors of, 364, 377, 384, 430, 434, 436 smell in, 435, 435-437, 436. See also

435 Salivatory nucleus, 435, 435, 526-527, 527 Salt, exercise loss of, 698 iodized, 613 physiologic solution of, 208, 208

spinal cord nerve tracts in, 385, 385-390,

taste reflex control of, 435,

Sarcomere, 59-60, 60, 64 Sarcoplasm, 59-60, 62 composition of, 59-60 mitochondria of, 60, 62

redculum

newborn

651

386-389, 387, 432, 432

524-527 daily volume

Saliva,

433-434 Sarcolemma, 66

412-413, 423

Riboflavin, 587(t),

fluid response to,

208, 208

Salty taste,

Retinol, 587 circuits, 382, 382, 383,

body

in,

Scuba diving, 358, 358-359 Scurvy, 589-590 Sea, diving under, 355-359, 356-358 hyperbaria related to, 355-359, 356, 357 Seasons, pineal gland affected by, 656 Second messengers, glycogenolysis role of, 630-631 hormone action mediated bv, 597, 597-598 postsynaptic neuron activation by, 367-368, 368 Secretin, amino acid sequence of, 529 duodenal secretion of, 531, 532

Semilunar valves, 89, 90 Seminal vesicle, 648-649, 649 Seminiferous tubules, 648-649, 649, 652 Sensitization, memory related to, 477-479, 478 synaptic, 477-479, 478 Sensory system, 363, 364, 376-437 cerebellum in, 363, 364

Saccule, 450, 450

secretion of, 525-527,

416-417

Rheumatic

,

pH

415-419, 426, 418

center,

24-28

acid),

anticodons of, 26, 26 chemical structure of, 24-25, 25 codons of, 25, 25-27, 26(t) DNA transcription to, 23-26, 25 messenger, 25, 25-27 ribosomal, 26, 26-27, 27 synthesis of, 24-25, 25 transfer, 25-26, 26, 27 Rods (of eye), 408-411, 416-417 neurophysiology of, 426, 416-417, 428 photochemistry of, 407-412, 408-411 total number of, 416 Round window, 427, 428, 429 Rubrospinal tract, 453 Ruffini's end-organ, 377 384 Rugae, gastric, 526

oral

optic nerve fibers in, 406, 407, 407,

Reward

RNA (ribonucleic

Saline solution,

407-408, 408 microstructure of, 407, 415-416, 426, 428

Rh

calcium level in, 643 parathyroid hypertrophy in, 641 treatment of, 643 RNA polymerase, 24-25, 25

Sacral plexus, 265, 265

layers of, 407, 407, 415-416, 426

Reverberating

sexual sensation

effects of, 643

S cells, 531 S wave, 88, 100-102,202

405, 405

foveal region of, 404, 407-408, 408,

macula

Scrotum, 649

Rickets, 643

326,

of, 326,

of, 60, 62,

calcium ion

in,

RNA codons

55

Sclera, 402, 406

Sclerocorneal junction, 402 Sclerosis, cardiac valvular, 190-191 glomerular, 268, 268

myocardial, 286, 186-187 Scotopsin, 409

to,

177-178 485

for,

25

Serotonin, 483, 484

Scalp,

cell,

due

area, limbic, 484, 485,

Serosa, intestinal, 511, 522

65-67, 66

axon myelination by, 55, 55-56, 56 motor-end plate role of, 71

thermal, 364, 393, 393, 398-399, 399 touch in, 364, 377, 383-385, 384 vision in. See Eye; Vision.

Serine, 566

neural centers for, 486, 502, 584 Scala media, 428, 429, 429 Scala tvmpani, 428, 429, 429 Scala vestibuli, 428, 429, 429

Schwann

433-435, 434, 435. See also

Taste.

Septum

smooth muscle contracdon and, 80 Satiety, hypothalamus role in, 486, 502, 584

493

386, 390 taste in,

Sepsis, shock

66

headache related to, 398 Schizophrenia, neurotransmitter role

Smell.

in,

memory synapse

role of, 478, 478 pain perception and, 369, 392, 395, 484 production and release of, 369, 483, 484 sleep controlled bv, 489 Sertoli cells, 649, 649 Set-point, temperature and, 578, 578, 580, 580 Sex, 648-656, 658-668, 670 athletic ability and, 687 chromosomal determination of, 648, 670 female, 658-668, 670

secondary characteristics

of, 661,

662-663 male, 648-656, 649-653, 670

secondary characteristics of, 653-654 Sex act, 651-652 female role in, 666-667 hypothalamic center related to, 486

731

Index

Smell, 435-437

Sex act (Continued) lubrication

male

651-652

role in, 651,

656 Sex chromosomes, 648, 670 Sex hormones, 652-656 athletics and, 687, 698 pineal gland role

in,

and

hypothalamic center Shock, 174-178

ventilation affected by, 695 for,

580

486, 579

Snail (Aph/sia),

memory synapse

of,

of, 541, 541,

compensatory factors in, 175-176 hypovolemic, 175, 175-177, 176

aldosterone regulation

542-543

of, 72,

diffusion rate and, 38-41, 39, 40

225

172 congenital heart disease with, 191-193, 192

191-192, 192

cardiac muscle function and, 86, 87 exercise effect on, 698 extracellular fluid and,

6(t),

6-7, 34, 35,

Sickle cell disease, 277, 280 crisis of, 280 Simple cells, visual cortex role Sinus node, 95

of,

422

cardiac rhythmicity controlled by, 94-96,

95,98

intestinal transport of, 541, 542,

electrophysiology

pacemaker

of,

94-96, 95

hepatic, 522, 522 affecting,

body heat

transfer by,

darkening

of,

239-241

575-576 575, 575-576

622

glabrous, 383 in,

622

pain receptors in, 364, 392-393, 398-399 red flare of, urticarial, 295 tactile receptors in, 376-378, 377, 383-384, 384 temperature sensitivity of, 364, 392-393, 393, 398-399, 399 testosterone effect on,

653-654

venous plexus under, 127 vitamin A deficiency affecting, 587-588 vitamin D formation in, 643 water loss from, 201, 202, 202(t)

488-490

basic theories

489-490 489-490

neuropeptide control paradoxical, 489 of, 488,

slow wave form

266 tubular reabsorption and, 223(t),

224-226, 225, 227-230, 237-241, 240 water excretion and, 236-241, 237-241

membrane membrane

permeability to, 132(t), 216(t) transport of, 36, 41-43, 42, 43

neuron potential role of, 47-53, 48-52, 370, 370-371, 372 nonlethal limits

for, 6(t),

6-7

level of, 6(t), 6-7, 35 osmolality and, 236-242, 237-241 retinal rhodopsin decomposition and,

normal

410-411,422

of,

369, 490

489, 490, 491

of,

sweating loss

577

of, 577,

urine concentration and, 223(t), 236-244, 237, 240, 244, 246

488-489, 491

thyroxine effect on, 611 pores, capillary, 131, 216, 226

Slow waves,

hypertension and, 262-264, 162-166,

saliva containing, 526 of,

brain centers for, brain waves in, 491, 491 cyclic nature of, 490

stage

daily excretion and, 264, 223(t)

622

127, 575,

78, 79

gastric wall with, 517 intestinal smooth muscle with, 511, 513 Slow-reacting substance of anaphylaxis, 295, 344

wasting of, 616-618, 623-624 water metabolism and, 236-244, 237-241

Sodium channel,

36, 42, 43

activation of, 36, 51,

51-52

active transport in, 36, 41-43, 42, 43

all-or-none principal

of, 37,

37

cardiac muscle function and, 86, 87, 95 current flow measurement in, 37, 37-38 fast, 86,

gating

94

of, 36,

inactivation

208

placental secretion

674, 677

of,

672, 674, 677

of, 672, 674,

677

Somatostatin, delta cell origin of, 625 pancreatic secretion of, 625 Somatotropin. See Growth hormone. Sound(s), 427-433. See also Hearing. attenuation reflex related to, 427 decibel unit for, 431, 433 directional aspect of, 432-433

frequency

of, 427,

429-432, 430

heart with, 88, 189-191, 290 Korotkoff, 123-124, 224

loudness

of, 427, 431 place principle related to, 430-431 tapping, antecubital artery with, 123, 224

Sour

taste,

433-434

saliva secretion caused by, 526

heart failure affecting, 197 hyperosmolarity and, 237-241,

nasal, 397, 398

to,

intracellular fluid and, 34, 35, 203, 204(t) Natriuresis.

Sinuses, carotid, 153, 153-154

blood flow

542-543

kidney and, 224-226, 225, 226. See also

role of, 98

self-excitation in, 95, 98

ACTH

of, 239-242, 243-244, 244, 246 glucose cotransport with, 43, 43, 225, 225-226, 226 hypertension and, 162-164, 162-166, 266 intake of, 162-164, 262-264

regulation

192-193

right-to-left, 192,

saline, 208,

pregnancy role

203, 204(t)

left-to-right,

isotonic, 207, 207, 208

Somatomammotropin,

158, 159, 163, 164, 166

Shunt(s), cardiac output affected by, 172,

Slit

hypotonic, 207, 207, 208 43, 225,

blood pressure regulation and, 157-166,

stages of, 174-178, 176

permeability related

Solutions, hypertonic, 207, 207, 208

262-264

spinal transection causing, 448

membrane

35-36

Solutes. See also Osmotic pressure.

of, 232, 232(t),

angiotensin action and, 162-164,

REM

to,

623-624

progressive, 176, 176-178

Sleep,

Solubility,

adrenal hormones affecting, 616-618,

246-247, 616-617 amino acid cotransport with,

melanin

73

renal tubular, 224, 225

ADH and, 236-242, 237, 240, 247

irreversible, 177

177-178

buffer and,

244-256 Sodium-potassium pump, 41 -42, 42 neuron membrane potential and, 47-50, 49,52

Sodium, absorption

acetylcholine channel role

Skin,

478,

Sodium hydroxide, bicarbonate

478

aldosterone role in, 618 cardiogenic, 185-186, 196 circulatory function in, 174-178, 175, 176, 618

septic,

slow, 86, 94

by, 73

chills with, 580,

(Continued)

"leak" channel as, 49, 49, 95 neuron membrane with, 47-52, 49, 51, 370, 370-371, 372 postsynaptic, 367-368, 372

Smoking, neuromuscular junction affected

female, 662,661-664 male, 652-656, 653 Shivering, fever

Sodium channel

food aversion role of, 437 intensity gradation of, 436 neural pathways for, 435, 435-437 "primary" sensations in, 436 receptors for, 435-436, 436

652, 667

for,

36-38, 37,

of, 36, 51,

51, 52

51-52

Space

travel,

353-355

physiologic effects related

to,

353-355,

354 Spaces of Fontana, 406 Spasm, muscle. See under Muscle. Speech, 317-318, 318. See also Language. articulation of, 317-318, 318, 465, 476 Broca's area relation

456, 473, 473,

to,

474, 476 cerebellar function in, 465 cortical areas related to, 456, 457, 473,

473, 474, 476

dysarthria affecting, 465 failure of, 456, 465, 474,

motor function aspects

476 of,

456, 457, 465,

473, 473, 476

427-428 anatomy and, 317-318, 318

self-sensitivity to,

voice box

Sperm, 648-651 count of, 650-651 cytology of, 648-649, 649, 650 ejaculation of, 652, 651-652 flagellum of, 20, 670, 672 formation of, 648-651, 649 life span of, 650, 670 maturation process of, 649, 649 motility of, 649-650, 670 ovum penetration by, 651, 670, 672 pH tolerance of, 650 storage of, 649

X and Y chromosomes

of,

648, 670

Sphenopalatine ganglion, 497 Sphincter(s), anal, 496, 497 esophageal, 515-516 lower, 516 upper, 515

732

Index

Sphincter(s), anal (Continued)

519-520

ileocecal, 519,

of Oddi, 532, 533, 534 precapillary, 227, 128, 144

pyloric,

517-518

urethral, 265, 265

urinary bladder, 265, 265, 499(t)

Sphingomyelin, 564 neuron myelination with, 56 Spike action potentials, 78, 78, 511-512,

S-T segment, 88, 101 myocardial infarction affecting, 222, 111-112 Stapes, 427, 428, 429 ankylosis of, 433, 433 metal prosthesis for, 433 Staphylococcal infections, host defense against, 284 Starches, digestion of, 537, 538

smooth muscle with, 511-512,

intestinal

586-587

food store depletion

dome

cells, committed, 275 hematopoietic, 275-277, 276, 277, 282

Stem

gray matter of, 385, 385-386 laminae of, 385 nerve tracts in, 385-390, 457-461 afferent (sensory), 385, 385-390, 386, 390 anterolateral, 385, 385, 389-390, 390 corticospinal (pyramidal), 442,

lymphoid, 276, 289 osteoprogenitor, 639 pluripotential, 275-277, 276 Stercobilin, 543 Stereocilia, cochlear hair cell with, 430,

430 vestibular hair cell with, 450, 451 Stereopsis, visual, 404-405, 405,

455-459, 457, 458

column -medial lemniscal, 385, 385-386, 386 efferent (motor), 441, 455-461, 457, dorsal

Stereotypy, brain stem role Sterility,

neospinothalamic, 393, 393-394 paleospinothalamic, 393, 394 reticulospinal, 449, 449, 453, 453 spinocerebellar, 385, 459-465, 460, 461, 464 vestibulospinal, 423, 449, 449, 453,

453 Reflex(es).

transection of, 447, 447-448,

579-580

white matter of, 385, 385, 389 Spinal nerves, 250, 496, 497

252

vitamin E role Steroids,

in,

590

616-624

adrenal, 616

chemical structure of, 616, 627 metabolic effects related to, 616-620 renal tubule and, 232, 232(t), 246-247,

621-622

anabolic, 687, 698 ovarian, 662, 661-664 testicular, 652-654, 653

absorption

composition

514

sympathetic system relation to, 495, 496 urinary bladder innervation and, 264-265, 265 Spindles, mitotic, 29, 31 sleep brain wave with, 491, 492 Spinocerebellar tract, 385, 459-465, 460, 461, 464 tract, 385, tract,

386

385, 386, 390

daily

of,

volume

527-530

of, 525(t)

excessive, 543-545, 544

feedback inhibition of, 529-530 hormonal factors and, 529-530 neural regulation of, 529 neutralization of, 531, 544 pH of, 525(t), 527, 528

anatomy of, 522, 526, 516-518 emptying of, 517-518 hormonal

rate regulation for,

blood flow related

to,

521-522,

522

macrophages

284

299 284 Sports, 687-699. See also Exercise. endurance for, 688, 690, 692 female vs. male affected by, 687 physiology of, 687-699, 689, 690(t), platelet destruction in, of, 284,

691-697 types of, 573(t), 690(c), 693, 695 Sprue, 545

517-518 of,

insulation by,

interstitial fluid pressure in, 134-135 Sublingual gland, 525-527, 526, 527 Submandibular ganglion, 497, 527 Submandibular gland, 525-527, 526, 527 Submucosa, intestinal, 511, 522 Submucosal gland, 511, 522 Submucosal plexus, 522, 512, 523

Subneural

clefts, 71, 72 Substantia gelatinosa, 385 Substantia nigra, 465, 466, 468

dopamine production by, 483, 483-484 Subthalamic nucleus, 364, 465, 466 Succinic acid, 555 Suckling, hypothalamus stimulated by, 678 Sucrase, intestinal, 537, 538 Sucrose, digestion of, 537, 538 permeability

to, 132(t)

527-530,

of, 527,

528 pain referred from, 396, 397 of, 527,

529-530 516-518

receptive relaxation of, 516 ulcer of, 543-545, 544

intracellular fluid level of, 35

Summation, 371-373, 373 muscle fiber with, 68-69, 69 spatial, 372-373, 373, 379, 379-380 temporal, 373, 380 threshold for firing and, 371-373, 373 Superior colliculus, 419, 419 Supraoptic nucleus, 486, 604

hormone

secreted by, 604,

313

527-530

oxyntic (parietal) cells

peristalsis in,

body

lack of, 343, 680

atrophic, 278, 528, 543 lesion of, 543-545, 544

peptic (chief) cells

tissues,

Surfactant, alveolar surface tension and,

516

innervation of, 496, 497, 499(t), 512-513, 523 mixing function of, 517 527,

Subcutaneous 575

604 Surface tension, 313 alveolar, 313 principle of, 313

hunger contractions of, 584 inflammation of, 278, 528, 543

of,

ACTH secretion due to, 621, 622 adrenal gland response to, 620, 621, 622 alarm response due to, 501-502 Cortisol release due to, 621, 622 sympathetic system reaction to, 501-502 Stria medullaris thalami, 484 Stria terminalis, 484 Stroke. See also Heat stroke. cerebrovascular block causing, 504 motor cortex affected by, 459 Stroke volume output, 89 exercise effect on, 170, 697, 697 Strontium, bone deposition of, 637 Stuart factor, 301 (t) Subarachnoid space, 504, 504, 505, 505 Subcallosal gyrus, 484

antidiuretic

factors in, 518

food storage function

mucosa of,

306-307 Stress,

204(t)

527-528, 528, 529

Spiral ligament, 428

284

369

against, 284 Streptokinase, thrombus removal by,

membrane

gastrin effect on, 518

Spirometry, 314, 324 Spleen, anatomy of, 284, 284 blood reservoir function of, 127 erythrocyte destruction in, 279-280, 284,

in, 73,

Streptococcal infections, host defense

Sulfates, extracellular fluid level of, 35,

Spiral ganglion, 428-430, 430, 432

intestinal

105, 205

539

in,

kidney, 267 "Streaming," axoplasm

'

250-251

secretion of, 622,

acid secretion of, 517,

intestinal innervation by,

Spinothalamic

of,

667-668

Stokes-Adams syndrome, Stomach, 516-518

496, 497

circulatory regulation and, 149-152, 250,

Spinocervical

453

contraceptive induction

250,

reflexes of, 441-448, 442, 444, 446, 447.

of, 250,

in,

423-424

female, 667-668

458, 461

anatomy

569-570

Steatorrhea, 545

cerebrospinal fluid and, 504, 504-505

See also

586-587, 587

in,

Statoconia, vestibular, 450, 450

pattern, 492, 492

Spinal cord, 385-390, 457-461 analgesia system of, 395, 395

pulp

in,

obligatory protein loss

523

Spike and

136-138

Starling equilibrium,

Starvation,

523

Stones, gallbladder, 533-534, 534

527,

neonatal, 680 Sustentacular cells, olfactory membrane with, 436 Sertoli type, 649, 649 vestibular membrane with, 450

Swallowing, 515-516 brain stem center for, 515, 525 esophageal stage of, 525, 516

mechanisms

of,

525,

515-516

pharyngeal stage of, 515, 525 Sweat gland, 576-577, 577 acclimatization of, 698 innervation of, 496, 500, 576-577, 577 secretion mechanism of, 576-577, 577

733

Index

Sweating, abolition of, 579 daily output of, 201, 202, 202(t) evaporation related to, 576, 576 exercise with, 698 fever and chills with, 580, 580 hypothalamic center for, 486, 576

Temperature (Continued)

Systole (Continued)

coronary blood flow

phonocardiography

in, 183, of, 88,

183

189-191, 290

399,

set-point

sodium

mechanism

for,

576-577, 577

loss in, 577, 577, 698

sympathetic system control

of,

576, 577

T3 See T4 See T cells,

433-434 Swimming, calories used in, 573(t), 573-574 Sympathetic nervous svstem, 150, 495-503, Sweet

.

Triiodothyronine.

.

Thyroxine.

genesis

of,

293-294

276, 281, 282, 289,

immune

response role

496-497 alarm response of, 501-502 anatomy of, 150, 495-496, 496,

"killer,"

in,

288-294, 289,

by, 293

290

suppressor, 293, 293, 294

496, 499(t)

T

circulation regulated bv, 120, 120,

T wave,

defecation controlled by, 521, 522 exercise response of,

tubules, 62, 66

cardiac muscle fiber with, 87, 92-93 skeletal muscle with, 62, 65, 66, 67

149-155, 150, 151,155, 154 coronarv arteries and, 184, 499(t)

180-182

88,

101 Tachycardia,

100-102, 202 atrial, 106,

206

ventricular, 106, 207

499(t)

glomerular

Talking. See Speech.

intestine regulated bv, 496, 513, 514, 520,

Tamponade, cardiac, 186 Taste, 433-435

filtration rate and, 220, 245 heart failure compensation and, 194, 194

521, 523 norepinephrine secretion

496-499 penile ejaculation controlled by, 651-652 in,

renal excretion and, 220, 245, 499(t)

sweating controlled by, 496, 500, 576, 577 "tone" due to, 151, 501 urinarv bladder innervated bv, 264-265, 265, 496, 499(t)

Synapse, 365-375, 366, 371, 380-383 acetylcholine formation and release 72,73 anatomy of, 72, 366, 366-368, 371 cleft of, 366, 367,

in,

371

375 facilitation in, 477-479, 478 fatigue affecting, 374 affecting,

gutter of, 71, 72 inhibition

mechanism

in,

371, 372, 381,

381, 382

memory

role of,

neuromuscular,

477-480, 478 71, 72

skeletal, 71, 72, 73

smooth, 77, 77-78 neuron circuits and, 380-382, 380-383 one-wav conduction principle for,

365-366 physiology

of, 366, 366-375, 372 neuron with, 408, 408, 411, 415, 418 sensitization in, 477-479, 478

retinal

transmitter substances

for,

368-369. See

also Neurotransmitters. vesicles related to, 71, 72, 73, 366,

366-367 Syncope, atrioventricular block causing, 105

Syncytium, definition of, 511 heart muscle as, 85, 86 intestinal smooth muscle as, 511 Systole, 88, 88, 89

88 blood pressure level in, 115, 226, 122-124, 223, 224

coli,

membrane, 430, 430 643-646 caries of, 645-646 chewing function of, 514

Tectorial

Teeth,

of, 514 deciduous, 644, 645 demineralization of, 645 fluorine effect on, 646 formation and eruption of, 644-645, 645 histoanatomy of, 643-644, 644, 645 malocclusion of, 646 mineralization of, 644, 645

closing force

Teloglial cells, 72

Telophase, 29, 31

Temperature, 574-581 atmospheric, body affected by, 577, 577 pain related to,' 393, 393, 398-399, 399 receptors affected by, 392-393, 398-399, 399. 577-578 "core," 574, 577, 577 extracellular fluid range of, 6(t), 6-7 heat conservation related to, 578-579 heat loss related to, 575-576, 576, 578, 578 heat production related to, 574, 574-575, 578, 579 high, 580-581 control center

in,

578, 580 486, 502

regulation by, 578, 578, 580, 580 low, 581

descent

of, 653, 673 gonadotropin regulation of, 654-655, 673 hormone secretion by, 652-654, 653 hypothalamic regulation of, 655 pituitary regulation of, 654-655 spermatogenesis in, 648-649, 649

for, 6(t),

of,

656

Testosterone,

652-654

chemical structure of, 652-653, 653 developmental effects of, 653-655, 656, 673 feedback inhibition of, 655 fetal secretion of, 653, 654,

intracellular

mechanisms

of,

654

metabolism of, 652-653, 653 muscle development due to, 654, 687, 698 tumor production of, 656 Tetany, contraction frequency in, 68-69, 69 drug-induced, 74 hypocalcemic, 251, 636, 636, 642, 643 larynx affected by, 642, 643 rickets with, 643 Tetralogy of Fallot, 292, 192-193 Thalamic syndrome, 397 Thalamus, basal ganglia relation to, 466 brain activation role of, 482, 483

damaged, 471 limbic system role of, 466, 484, 485, 485 motor function and, 364, 464 nuclei of, 466, 484, 485, 485

pain pathways to, 394, 394, 397 sensory function and, 364, 385-386, 386, 389-390, 390 spinal tracts to, 364, 385-386, 386, 389, 390 taste sense pathway in, 435, 435 ventrobasal complex of, 386, 386, 389, 390, 394 Theca cells, 659 Thermogenesis, 572, 578, 579 epinephrine causing, 579 Theta waves, 490, 491, 492 Thiamine, 587(t), 588 daily requirement for, 587(t) deficiency of, 588 Third ventricle, 504 cerebrospinal fluid in, 504, 504, 505 pain suppression and, 395, 395 thirst center in, 242

242-243 and, 242-243

ADH 6-7

673

functions affected by, 653-654

Thirst,

neonatal, 682, 682, 683

nonlethal limits

520

athlete and, 687, 697

aversion related to, 435 chemistry of, 433-434 dietary preference related to, 435 neural pathways of, 434-435, 435 primary sensations of, 433-434 receptors for, 434, 434, 435 saliva secretion related to, 526-527, 527 Taste buds, 434, 434 total number of, 434 Tears, neural stimulation of, 497, 500

hypothalamus and,

579

Testes, 649

rumor

atrial,

eye innervation bv, 424, 424-425, 496,

in, 574,

578, 578, 580,

Tentorium cerebelli, 504 Terminal cisternae, muscle with, 66

receptors on, 293, 293 self-antigens and, 289, 294 specificity of,

for,

Temporal lobes, auditory areas in, 432, 432-433 intellectual function in, 472-474, 472-474, 476 olfactory areas in, 435, 437 Tendon reflex, 445, 445-446 Teniae

294

"memory" 499(t)

bronchioles controlled bv, 316, 496 cardiac innervation bv, 91-92, 92, 98-99,

atrial,

of,

293

acetylcholine

drugs

289-290

helper, 293, 293

496

'

276, 281, 289

cytotoxic, 293,

taste,

577-578 mechanism

580 thyroxine role

rate of, 576

secretion

normal, 6(t), 6-7, 574, 574 range of, 574, 574, 682 receptors sensitive to, 392-393, 398-399,

decreased, 242-243, 243(t)

734

Index

hypothalamic center for, 242, 486, 502 increased, 242-243, 243(t) osmolaritv affecting, 242-243, 243(t) stimuli for, 242-243, 243(t) threshold for drinking and, 243 Thorax, compliance in, 313 lymphatic drainage of, 311 ventilatory function and, 311-312, 322 Thought, 471 -480 association areas and, 471 -476,

472-474

472-474

complex, 473-474, 475 memory role in, 475, 477-480, 478 neural mechanisms of, 473-474, 477 prefrontal lobotomy effect on, 475 Wernicke's area role in, 473, 473-474, 474 Threonine, 566 Thrombin, 300-301 coagulation role of, 300, 300-301 formation of, 300, 300-301 molecular weight of, 301 Thrombocvtopenia, 305-306 idiopathic, 306 platelet level in, 306 purpura due to, 305-306 Thromboplastin, 301(t), 302, 302-303 Thrombosis, 306 coronary, 111-112 cardiac muscle affected by, 222, 111-112 electrocardiography and, 111, 111-112 drug therapy for, 306-307

secretion of, 608. 608-609 transport and latency of, 609

calcitonin secretion by, 641

cold exposure enlargement

of,

579

feedback regulation of, 611-612, 622 growth and, 610 hormones of, 607-611, 608, 611. See also Tliyroxine; Triiodothyronine.

hyperfunction of, 612-613, 623 hypofunction of, 613-614, 624 inflammation of, 613-614 iodine transport in, 607-608, 608 metabolic functions affected by, 609,

609-611 nodules of, 613-614

613-614

Th\Toid-stimulating hormone, 599. 599,

622,611-612

releasing

hormone

utilization in, 331, 333, 333 pain receptors of, 364. 393, 393, 398-399, 399 subcutaneous, body insulation by, 575 interstitial fluid pressure in, 134-135

TNT

(tumor necrosis

factor), 285,

285-286

Tobacco, neuromuscular junction affected by, 73 ventilation affected by, 695 Tongue, neural pathways from, 434, 434-435, 435 salivary secretion role of, 526-527, 52~

swallowing mechanism related

to,

515,

515 taste receptors of, 434, 434, 435 Tonotopic mapping, auditory cortex with,

432, 432-433 Touch sense, 364, 377, 383-385, 384 Trabeculae, intraocular, 406, 406-407 Tract(s), alimentary, 522.

See also Gastroin-

599, 600, 622, 612

Thyrotoxicosis, 612-613

Thyrotropin-releasing hormone, 622, 612 Thyroxine, 607-614 chemical structure of, 609 deficiency of, 613-614, 624 excess of, 612-613, 623 formation of, 607-608, 608. 609

receptors

for,

609-610

regulatory mechanisms for, 612, 611-612 secretion of, 608, 608-609 7

transport

and latency

of,

609

Tripeptides, 539 Tristearin, 560 , Trochlear nucleus, 423 Trophoblastic cells, ovum implantation role of, 671, 672 placenta formation from, 671, 672 uterine, 671, 672 Tropomyosin, 63, 63 Troponin complex, 63, 63 Trypsin, 530, 539, 539 Tryptophan, 566 dietary deficiency of, 583, 588 TSH (th\Toid-stimulating hormone), 599,

599^622,611-612 releasing

hormone

for,

599, 600, 622, 612

Tuberculosis, 344

optic, 419,

Tubocurarine, 73-74 Tubules. See also T tubules. dentinal, 644 Tumor necrosis factor (TNF), 285, 285-286 Tumors. See Neoplasia.

respirators'.

Turbinates, nasal, 326, 317

testinal tract.

See Biliary neural. See Spinal

biliary.

tract.

cord, neroe tracts in;

specific tracts,

429 See Respiratory tract. urinary, 212-213, 223 Tractus solitarius, blood pressure control

taste sense

pathway

in,

'

377 Transferrin, iron metabolism role 279 by, 376-378,

of, 279,

Transfusion, 295-298

and, 296, 296(t) adverse reaction to, 295-298 B agglutinins and, 296, 296(t) hemolysis due to, 296-298 Rh agglutinins and, 297-298 Transport. See Active transport; Diffusion;

Membrane transport; Osmosis. Transverse tubules. See T tubides. Tremor, intention, 465 Parkinson's disease causing, 468-469 thyroxine related to, 611 Tricarboxylic acid cycle, 554-555, 555 Tricuspid" valve, 86.89, 90 Trigeminal nerve, 525 560-564

ATP

formation and, 562, 563 blood containing, 561 carbohydrate conversion to, 563-564, 628 chemical structure of, 560 chylomicron formation by, 542 of,

iodination

of,

608, 608

435, 435

Transduction, blood pressure conversion by, 118, 118 retinal transducin mechanism of, 411 stimulus conversion to nerve impulse

digestion

Tympanic membrane, 427-428, 428 sound transmission by, 427-428, 428 Tyrosine, 566

and, 150, 153 saliva secretion and, 527, 527

Triglycerides, for,

formation of, 607-608, 608, 609 metabolic effects of, 609, 609-611

331-333

A agglutinins

colloid of, 608, 608

'

325, 331-332,

Triiodothyronine, 607-614 chemical structure of, 609 deficiency of, 613-614, 624 excess of, 612-613, 623

oxvgen

and

hemostatic disorder causing, 306-307 platelet stickiness and, 299 role of, 22-23, 23-25 Thymus gland, 596 immune response role of, 289, 289-290 T cell processing in, 289, 289-290 Thyroarytenoid muscle, 318 Thyroglobulin, 607-608, 608 excess of, 613 Thyroid cartilage, 318 Thyroid gland, 607-614 anatomy of, 599, 607, 608 antibodies to, 612-613

499(t)

Tissue factor, 301 (t), 302, 302-303 Tissue plasminogen activator, 305, 306-307 Tissues, circulation regulated bv, 116, 142-146, 243, 143t, 244 in,

fat

protein conversion to, 564 Trigone, of bladder, 264-266, 265, 496, 497,

Tickle sensation, 384, 389 Tidal volume, 324, 314-316

femoral, 306-307

Thromboxanes, Thymine, DNA

absorbed as, 542 metabolism of, 560, 562-564, 628

metabolic effects of, 609, 609-611 regulatory mechanisms for, 632, 611-612

gas diffusion

cerebral cortex in, 471 -476,

Thyroiditis,

Triglycerides (Continued)

Thyroxine (Continued)

Thirst (Continued)

538-539

energy derived from, 560, 562-564, 563

U Ubiquinone, electron transfer role of, 556, 556 Ulcer, stomach affected by, 543-545, 544 Ultrasonography, blood flow measurement with, 227, 117-118 Doppler, 227, 117-118 Umbilical arteries, 671-672, 672 Umbilical cord 72 Umbilical veins, 671-672, 672 Umbilicus, pain referred from, 396 Unconsciousness, G force causing, 354 Uncus, 484, 485, 485 Uracil, RNA role of, 24 Urea, ammonia conversion to, 569 excretion of, 223(0, 238(0, 240, 269-270 formation of, 569 membrane transport of, 36, 223(0, 227, 229, 238(0 plasma level of, 204(0 protein deamination and, 569 renal failure and, 269-270, 270 renal tubule and, 223(0, 226-227, 227. 229, 238(0, 240 urinarv, 223(0, 238(0, 240 Uremia, 269-270, 270 Ureter, 213, 223 ,

anatomy

of, 223,

innervation

of,

265.

265-266

265, 496. 499(0

+

Index

Vagus nerve (Continued)

Ureter (Continued) pain referred from, 396

265-266 urine transport in, 265-266

515-516 taste sense pathway

Urethra, 213, 223

anatomy

of,

213, 265, 265

semen in, 652 sperm in, 648, 649,

Valves,

male,

264-265, 265, 559 brain stem control of, 502, 502 emptying of, 264-267, 265 female, 559 hypothalamic center related to, 486 innervation of, 264-265, 265, 496, 497, 499(0, 502 pressure in, 266, 266 sphincter of, 265, 265, 499(0 Urinary tract, 212-213, 223 Urine. See also Glomerular filtration rate; Micturition.

with, 265-266, 266 251, 251 -252, ,252, 634,

filling

640-641 237-241, 239-241 dilute, 236-237, 237 fetal excretion of, 675, 679 formation of, 214-216, 215, 237-241 glucose loss in, 632 osmolality of, decreased, 236-237 237 increased, 237-241, 239-241 output of, 236-241 feedback mechanisms in, 221, concentration

of,

',

221 -222, 222, 241 in,

endometrium

of, 663,

663-664

electrocardiography and, 88 open-close cycle of, 88

phonocardiography of, 290, 190-191 rheumatic lesion in, 190-191 lymphatic vessel with, 239, 139-140 venous, 226, 126-127 Valvulae conniventes, 539, 539 Van't Hoff law, 206 Vapor pressure, 324-326, 325(0 Varicosities, venous, 126-127 Vas deferens, 648-649, 649 secretion of, 650 Vasa recta. See also Arterioles, renal. countercurrent exchange in, 240-241, 242 hyperosmolar urine and, 240-241, 242 Vascular compliance, 120, 122, 125 arterial, 120, 122 measurement of, 120 venous, 120, 125, 127 Vascular resistance, 117-120 arterial pressure regulation and, 159, 259, 262

blood flow physiology and, 117-120,

measurement

118-119 neonatal, 680-681 pathology affecting, 171-172, 272 physics of, 117-120, 117-120 pulmonary, 119, 127 reduced, 171-172, 272 renal circulation and, 218-220, 219(0, of,

222 total peripheral, 119,

171-172

anesthesia (spinal) affecting, 151, 252

angiotensin in, 262, 162-163 exercise causing, 180-182 local tissue blood flow and, 146-147

swallowing mechanism related 525

to,

515,

migraine headache due to, 397-398 nervous regulation of, 250, 150-152, 252 sympathetic control of, 250, 150-152,

Vaccines, 294-295

memory cells and, 291 Vagina, 658, 659 estrogen effect on, 662 Vagus nerve, 497 cardiac suppression by, 92, 92, 98, 250, 151 circulatory regulation by, 92, 98, 149, 250, 151, 153, 253

esophageal peristalsis controlled by, 525, 516 gastric secretion regulated by, 497, 529 intestinal innervation by, 497 513 ,

osmoreceptor and, 242, 241-242 physiologic function of, 600, 604-605 regulation of, 242(0, 604-605 renal tubules and, 229, 232, 232(0, 237, 238(t), 242,

247

secretion of, 146, 242(0, 600, 603-604,

604

sodium and, 236-242, thirst and, 242-243

tone related to, 128, 151, 252 vascular wall injury causing, 299 Vasodilation, 147 agents causing, 147 allergic reaction with, 295 exercise causing, 181-182 fever and chills with, 580, 580 local tissue blood flow and, 143, 147 nervous regulation of, 250, 150-152, 252 sympathetic control of, 250, 150-152,

247

124-127 blood volume contained

Veins, 115-116,

Vasomotor anatomy

center, 250, of, 150, 250,

150-152, 252 252

ischemic response of, 155 shock depression of, 176 tone associated with, 128

in, 226, 120,

120, 127

circulatory function and, 115-120,

116-120, 124-127, 225, 226 in, 120, 220 coronary, 282, 185, 285, 186 diameter of, 119, 229

compliance

exercise effect on, 181

hydrostatic effects in, 125, 226 innervation of, 149-152, 250, 252 intestinal, 521-523, 522 myocardial, 182, 185, 186 damming of, 285, 186 pressure in, 124-127, 226 pressure-volume curve for, 120, 220 pump function of, 124-127, 226 valves in, 226, 126-127 incompetent, 126-127

126-127

299-300, 300 353-354, 354 centrifugal force related to, 353 deceleratory, 354, 354 nerve conduction, 55-56, 96-97, 97, 379, 379 pain signal and, 393, 393, 394 in,

Velocity, acceleratory,

Venous plexus, body heat transfer 575-576 skin-associated, 575, 575-576

by, 575,

Ventilation, 311-316. See also Respiration. of,

257, 257, 263,

263(0 alveolar, 315-316, 326, 324-327, 325-329, 339 control of, 337-342, 338-341 decreased, acidosis with, 263, 263(0 hypoxia with, 344-345 exercise effect on, 341, 342, 694,

gas exchange 335

in,

694-695

324-332, 329-332,

increased, alkalosis with, 263, 263(0

measurement

252

237, 240

urine concentration and, 237, 238(0, 242,

acid-base balance role

252

V

604-605 increased, 242(0

wall injury repair

postpartum involution

progesterone effect on, 663 Utricle, 450, 450 Uvula, 515

247 fluids regulated by, 237, 238(0, 242, 247,

varicose,

viscosity role in, 229,

677

diuresis regulated by, 237, 238(0, 242,

venous, 120, 125, 225

parturition role of, 675-677, 676 of,

blood pressure affected by, 605 decreased, 242(0

units of, 118-119

119-120 Vasoconstriction, 146-152 agents causing, 146-147, 162

estrogen effect on, 662 ovum implantation in, 671, 671 oxytocin effect on, 675

vasoconstriction regulated by, 250, 150-152, 252 vasodilation regulated by, 250, 150-152,

Vasopressin, 146

229, 220

248-251, 248-251 sodium in, 241-244, 244, 246 water output in, 201, 202, 202(0 regulation of, 236-241, 237, 238(0, 239-241 Urobilin, fecal color due to, 543 Urogenital diaphragm, 265 Urticaria, 295 Uterus, 658, 659 birth contractions in, 675-677, 676

potassium

anesthesia (spinal) affecting, 151, 252 definition of, 128, 151, 252

252

89-90

cardiac reserve affected by, 297 circulatory effect of, 191

of, 213,

in,

435, 435

cardiac, 86, 89-90, 90

651, 652

sphincter of, 265, 265 Urinary bladder, 213, 213

bladder calcium

in,

Valine, 566

female, 559

anatomy

Vasomotor center (Continued)

mastication and, 514-515, 525 respiratory control and, 338, 340, 340 swallowing mechanisms and, 525,

peristalsis of,

735

of, 314, 324 mechanics of, 311-316, 312-314 normal values for, 311-312, 322, 324,

314-316 smoking effect on, 695

work

of,

311-313, 312

736

Index

Ventricle, 86,

95-97 183-185,

to, 183,

acuity

abnormal, 104-112 normal, 88, 100-102,202 electrophysiology of, 94-98, 95-97 electroshock therapy of, 107-108, 209 escape beat of, 92, 98, 105 fibrillation of, 106-108, 108, 109 myocardial infarction with, 186 hypertrophy of, 110, 220 output curve for, 91, 92 premature contraction of, 105-106, 206

binocular aspects

pressure in, 88, 89, 91, 92 pump function of, 85, 86, 88, 89, 92, 92 tachycardia of, paroxysmal, 106, 207 volume of, 88, 89 Ventrobasal complex, 386, 386, 389, 390 pain pathways to, 393, 394 Ventromedial nucleus, 486, 486 Venules, 115-116, 226 blood flow in, 227, 127-128 circulatory function of, 115-120, 116-120, 127, 127-128 intestinal villus with, 522, 522, 539-540,

540 Vermis, cerebellar, 460, 461

of,

283 14-15, 25.

intracellular, digestive, 15, 25, 16,

pinocvtic /phagocytic, 24,

283

421

421-422, 422 emmetropic, 402, 402, 405 equilibrium role of, 452 far-sighted, 401-402, 402 glaucoma affecting, 407 contrast analysis

16-17

transport, 16, 26

plasmalemmal, 232 synaptic, 71, 72, 73, 366,

366-367

acetylcholine release by, 72, 73, 367

neuromuscular junction

role of, 71, 72,

73 recycling of, 369

369

of, 73,

Vestibular system, 450-453

anatomy of, 450, 450-451, 451 membranous labyrinth of, 428,

450,

450-451 neural pathways related to, 423, 448, 452-453, 453, 460, 463 Vestibulocerebellar tract, 460 Vestibulocerebellum, 463 Vestibulospinal tract, 423, 449, 449, 453, 453 for,

384-385,

membrane,

504, 505,

Vibration, tactile receptors

427-428 Villus, arachnoidal

505

539-540, 540 540

intestinal, 522, 522,

lacteal of, 522, 522, 540,

image fusion in, 419, 421, 423-424 language comprehension role of, 472, 473, 474, 476

and angles

lines, borders,

loss of, 407,

in,

616

female neonate affected by, 682 testosterone role

in,

652-654

Viruses, host response to, 284, 292,

292-293 neutralization

near-sighted, 402, 402

292-293

photochemistry position, form,

of,

415-425, 416-424

in,

of, 496,

497,

pain referred from, 396, 396-397

119-120 blood flow related to,

Viscosity, 229,

229,

to, 229,

119-120, 203 119-120, 203

39 ion channel gating role 37

421

membrane 587-590

medullary center

410,

588-589

589-590

635, 642, 643

of,

cells, 417 Wakefulness, brain waves related to, 490, 490-491, 492 raphe nucleus lesion causing, 490 sleep cycle and, 490-491, 492 Walk-along theory, 63, 63 Walking, calories used in, 573(t), 573-574 cerebellar function in, 463-465, 464

reflexes associated with, 447, 447-448 Warfarin, 306

Warmth

receptors, 364, 393, 393, 398-399,

399 Water, 201, 202, 202(t). See also Fluids. absorption of, 540-543, 542 altitude effects and, 351

angiotensin and, 262, 163-164 arterial pressure and, 157-160, 258, 259,

244,244 acid cycle formation 555-556, 556

citric

of,

555,

daily intake of, 201, 202, 202(t) deficit of,

dehydration

as,

242-243, 633,

681-682 urine concentrated due

to,

237-241,

237-241 diabetic loss of, 632, 633

related to,

of,

264

daily loss of, 201, 202, 202(t)

and maternal, 682 Vitamin D, 587(t), 590, 634-635 bone mineralization role of, 641 calcium metabolism role of, 634-635,

excess

to,

W

587-588

Vitamin B 6 '(pyridoxine), 587(t), 589 daily requirement for, 587(t) deficiency of, 589 Vitamin B,,' (cobalamin), 587(t), 589 daily requirement for, 587(t) deficiency of, 589 erythrocyte requirement for, 277-278 gastritis affecting, 278, 543 pernicious anemia role of, 278, 543 Vitamin C, 587(t), 589-590 daily requirement for, 587(t) of,

545-546

W

deficiency of, 588 Vitamin B, (riboflavin), 587(t), 588-589 daily requirement for, 587(t) of,

36-39,

588

night blindness relation to, 410 vision photochemistry role of, 410, 420 Vitamin B, (thiamine), 587(t), 588 daily requirement for, 587(t)

deficiency

for,

metabolic alkalosis due

pantothenic acid as, 587(t), 589 pregnancy and, 674 Vitamin A, 587(t), 587-588 daily requirement for, 587(t) of,

of, 36,

Vomiting, 545-546

589-590

acid as, 277-278, 587(t), 589

deficiency

36-39,

of, 36,

transport role

to, 39,

37, 39

for, 587(t)

deficiencies related to,

deficiency

autonomic innervation 498-500, 499(t)

testosterone effect on, 653 Voltage, electromotive force relation

403 Visual purple, 409 daily requirement

301, 305, 306,

phonation role of, 318, 328 swallowing mechanisms and, 515 Voice, 317-318, 328. See also Speech. articulation and phonation with, 317-318,328 language processing areas and, 472, 473, 474, 476 laryngeal anatomy and, 317-318, 328 pubertv change in, male with, 653 self-sensitivity to, 427-428

refraction errors affecting, 401-403, 402,

folic

of,

warfarin competition with, 306 Vitreous humor, 402, 405-407, 406 Vocal cords, 326, 328 cough reflex and, 317

401-405

409-413, 420-423

and motion

daily requirement

Viscera, 496, 497

hematocrit related

of,

optical principles of, 400-405,

compounds of,

422

fetal

androgens

Virilization, adrenal

in,

410

neurophysiology night, 410

deficiency

placental, 671, 672

in,

for, 587(t)

589-590 prothrombin formation and, 301

412-413, 423, 417-419, 420,

niacinic, 587(t),

secretory, 20,22, 26,

daily requirement

404-405, 405,

deficiency

Vitamin(s), 587(t),

Vesicles, acetylcholine transport in, 72, 73

coagulation role of, 301, 305, 306 colon bacteria production of, 543

423-424 color, 422,

for, 587(t)

Vitamin K, '587(0, 590

astigmatic, 403, 403 of,

590

deficiency of, 589-590

404, 404, 407-408, 408

deviation in, 110, 220 electrocardiography and, 100-112

E, 587(t),

daily requirement

plasma level of, 229, 119-120 water and, 229, 119-120 Vision, 400-425. See also Eye.

electrical axis of, 110, 220

streaming

Vitamin

Viscosity (Continued)

coronary blood flow 185

for,

634-635

589-590, 643

641

parathyroid hormone regulation 634-635, 635 regulation of, 634-635, 635 skin formation of, 643 treatment using, 642

of. See also Edema. urine diluted due to, 236-237, 237 excretion of, 157-160, 236-241, 237-241 intestinal processing of, diffusion role in, 540-543, 542 secretion in, 525, 534, 535 kidney and, 236-241 diuresis and, 157-160, 258, 259, 244, 244

excess

587(t)

of,

737

Index

Wernicke's area (Continued) complex thought in, 474, 474 electrode stimulation of, 474

Water (Continued) excretion and, 236-244, 240, 241

transport

mechanisms and,

224,

226-228, 227 tubular reabsorption and, 224,

226-228, 228

membrane

permeability

X cells, 417, 419, 421 X chromosome, 648, 670

interpretive function of, 472, 473, 474,

to, 132(t),

216,

216(t)

osmotic pressure role of, 39-41, 40 renin and, 164-165, 165 respiratory gases and, 324-325, 325(t) thirst for, 242-243, 243(t) vapor pressure of, 324-326, 325(t), 351 Weakness, Addison's disease with,

622-623 Weightlessness, 355 Wernicke's area, 471-474, 473, 474 aphasia and, 476

474 language processing in, 472, 473, 474 Wheat, gluten enteropathy caused by, 545

White blood cells. See Leukocytes. White matter, spinal cord tracts in,

Y cells, 417, 419,422 Y chromosome, 648,

385,

670

385, 389

Word Word Work

blindness, 474, 476 formation. See Speech.

Z

output. See also Exercise.

anemia

affecting,

cardiac output related to, 169, 170 Writing movement, basal ganglion role

465-468

disc, 59, 60, 66

Zona pellucida, 651, 670 sperm penetration of, 651,

280 in,

Zonules, 400

Zymogen

granules, 525

670, 671

ISBN 0-721b-32^-A

90071

9

780721"632995