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NAME AND ADDRESS DATE

*
 A CKNCV/LKJGEMENTS

The author wishes to express his gratitude to

Drs, John S 0 Gray and Fred S. Grodins for their

invaluable encouragement and advice throughout

the course of this study®

 NORTHWESTERN UNIVERSITY

THE DUAL NATURE OF THE MECHANISM OF EXERCISE HYPERPNEA

A DISSERTATION

SUBMITTED TO THE GRADUATE SCHOOL

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

for the degree

DOCTOR OF PHILOSOPHY

DEPARTMENT OF PHYSIOLOGY

By

Frederick Feng-tUIen Kao

Chicago, Illinois

December, 1951

1952
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 TABLE OF CONTENTS

Page

I* Introduction. 1

II. Theoretical Analysis of RespiratoryResponses toExercise. 5

A. The known principles of the simple respiratory

chemostat. 5
B. Modification of the respiratory chemostat. 16

G. Theories of the mechanism of exercise hyperpnea. 26

D. Experimental implications of the dual hypotheses. 30

III. Review and Critical Analysis of Experimental Literature. 39

A. Denervation experiments. 39

B. Passive exercise experiments. 92

C. Ischemia experiments. Ill

D. Vascular anastomosisexperiments. 134

E. Experiments attempting to Identify peripheral

chemoreceptors. 137

IV. Summary of Literature and Statement of Problem. 145

V. Experimental Methods. 147

A. General procedures. 147

B. Specific procedures. 148

VI. Experimental Results and TheirAnalysis. 152

A. Evaluation of the adventitious sensory stimulation

in electrically induced exercise. 152

B. Evaluation of the adequacy of the vascular

anastomoses. 168
 Page

C. The pathways involved in the regulation of

breathing during exercise. 173

D. Attempts to identify peripheral chemoreceptors. 190

VII. Discussion. 196

A. The adequacy of experimental procedures. 196

B. The mechanism of exercise hyperpnea. 205

C. The nature of the Hergoreceptor.n 212

VIII. Summary and Conclusions. 216

Bibliography.

Vita.
 I. INTRODUCTION

Although the most common and most Intense hyperpnea occurs in

exercise the system controlling this response is only imperfectly

understood. On the effector side the medullary respiratory centers

and their neural connection to the respiratory muscles and the

respiratory pump are undoubtedly concerned and reasonably well under­

stood, but almost complete ignorance prevails regarding the sensory

side of the control system. Any solution to this latter problem must

include at least l) identification of the stimulus concerned, and

2) identification of the mechanism 6y which it acts. The latter

involves localizing the receptors and establishing whether the

stimulatory agent is conducted from the muscles to a distant receptor

by the blood stream (humoral mechanism) or whether the receptor is

located in the muscles and its neural signal is conducted to the

brain by reflex paths (reflex mechanism).

There have been numerous suggestions made regarding the nature

of the stimulus responsible for the hyperpnea of exercise. For

example, Rosenthal (l) proposed a theory in which the blood oxygen

level controlled all respiratory responses, including that in exercise.

Subsequently, Haldane (2) suggested that the arterial blood or alveolar

carbon dioxide tension was the controlling stimulus in exercise.

Later, when the hydrogen ion theory of respiratory regulation became

popular, Haldane (3) proposed that this agent is responsible for the

hyperpnea of exercise. Unhappily for these theories, subsequent

evidence (4) revealed that neither the arterial blood oxygen, carbon

dioxide, nor hydrogen ion are altered in exercise, unless it is so

severe as to induce a metabolic acidosis (5, 34)* In order to avoid

 -2-

this difficulty, Henderson (6) proposed a new but unknown stimulus,

which he called “respiratory X” as the agent concerned, and which he

suggested was a chemical agent released from active muscles.

Nielsen (7), on the other hand, proposed that the arterial blood

carbon dioxide tension is the stimulus concerned, but that exercise

in some undisclosed fashion increases the sensitivity of the respira­

tory center to this agent.

It will be noted, that in each of the above cases, the stimulus

is presumed to be a blood borne chemical agent affected by exercise.

But Krogh and Lindhard (8, 9) claimed that a reflex mechanism must be

concerned, since they found that the respiratory response to exercise

occurred too promptly to depend upon a circulating agent. They pro­

posed that this reflex mechanism consists either of cortical irradia­

tion or of a peripherally elicited reflex. The former was subsequently

discarded as the primary factor, since the steady state ventilatory

response to voluntary exercise and that to electrically induced exercise

are identical (9, 10).

Four types of experiments have been performed in attempts to

distinguish between humoral and reflex mechanisms: 1) denervation

experiments, 2) ischemia experiments, 3) passive exercise experiments

and 4) vascular anastomosis experiments. The results of these experi­

ments have been uniform but the interpretations offered have been

contradictory. For example, five groups of investigators (11-15) have

observed a respiratory response to exercise after denervation (chordotomy),

but only three have interpreted the results to favor a humoral mechanism.

All investigators have observed a respiratory response to exercise

 -3-

during ischemia of the active muscles (1-

4* 16-20), but the results
were considered by some as proof for a reflex mechanism (14* 18-20),

and by others as proof for a humoral (14, 16, 17). In passive exercise,

a respiratory response has been observed by all observers (14* 20-2$).

Some have concluded (14* 21) that a proprioceptive reflex mechanism is

concerned in exercise, whereas others (14* 21-24) claim that the effect

is too small to be important in the normal respiratory response in

exercise. The two single vascular anastomosis experiments by two

groups of authors have not been properly performed* In one group the

carotid artery was anastomosed, the blood in which during normal exer­

cise does not change its gas composition, while the other group

anastomosed the iliac vein only. Both groups naturally obtained

ambiguous results. It is, therefore, clear that these four types of

experiments have not been conclusive.

The fact that respiratory responses to exercise persist after

interruption of either vascular or neural connections, suggests that

both humoral and neural mechanisms are concerned in regulating venti­

lation in exercise, and that the usual insistence upon a simple

"either-or” interpretation is •unjustified. Furthermore, it is already

well established l) that the blood hydrogen ion concentration, carbon

dioxide tension and oxygen tension are important agents in the control

of breathing, 2) that all of these agents operate by a humoral mechanism

and c) that whenever ventilation changes without a proportional change

in metabolism, this humoral mechanism will be called into play, as a

feedback element. Therefore, if a reflex be normally involved in

exercise, its interruption, instead of abolishing the response to

exercise, must provoke a response mediated by the humoral feedback

mechanism. Grodins and Morgan (15), recognizing these possibilities,

repeated the chordotomy experiments, but again were not successful

in accounting for the results in view of the complications introduced

by anesthesia and the acute chordotomy*

It is evident that a new experimental procedure is required which

will better serve to separate humorally mediated from neurally

mediated responses in exercise* It occurred to the author that this

might be accomplished by a properly designed cross-circulation experi-

I
ment, in which the circulation of the hind legs of a dog is exclusively

provided by a second dog, using abdominal aorta and inferior vena cava

anastomoses. In such a preparation the respiratory control systems

of both dogs are intact and in neither is the general circulation

appreciably disturbed, yet one dog can respond to the exercise only

through the original neural connections to the leg, whereas the other

can respond only through its humoral connections. This avoids the

circulatory disturbances induced by chordotomy, as well as the

ischemic complications produced by vascular occlusion. The purpose of

the present investigation was to utilize this preparation in an attempt

to elucidate the mechanism of the hyperpnea of exercise.

 -5-

XI. THEORETICAL ANALYSIS OF RESPIRATORY RESPONSES TO EXERCISE

A* The Known Principles of the Simple Respiratory Chemostat.

There are three stages in the continuous process by which the

oxygen and carbon dioxide gas exchange is accomplished between the

metabolizing cells and the external environment in mammals. The

first stage is the pulmonary respiration which supplies the alveoli

with air and which performs the actual gas exchange between the alveoli

and the blood stream. The second stage is the intermediate respiration

which transports the gases from the pulmonary circulation to the

metabolizing tissue. The third stage is the cellular respiration,

which deals with the gas exchange between the active cells and their

immediate environment. It is the first stage, the pulmonary respira­

tion, with which we are concerned at the present.

The fundamental function of pulmonary respiration is to provide

gas exchange for metabolic processes, as in the case of exercise; also

to regulate blood gas composition by compensatory adjustments, as in

anoxia (a decrease of oxygen contents in the tissues), hypercapnia

(an increase of blood carbon dioxide contents), and acidemia (an

increase of blood hydrogen ion concentration). It is also well

established that blood pressure and temperature alterations in the

body affect pulmonary ventilation. For the present, we will limit

ourselves to the discussion of the compensatory responses of the

pulmonary respiration.

In order to describe the regulation of breathing during compensa­

tory responses, a flow-control diagram is presented in Figure 1. In

 o

_I

r:

oxrtjxit signals
exchange surface

ta

cv

Q_ JUL
+*
I
' 1 _1
1_

I :G U - l -
this diagram, the pulmonary system is divided into two parts according

to its function: a) the mechanochemical system, which is the controlled

part, and b) the neural system, which is the controller part* For

each part, its structure (the anatomy) and the operation (the function)

are described separately* The latter is based on the multiple factor

theory (4-* 26-33) and only concerns steady state conditions*

The mechanochemical system includes three important structural

elements: a) a respiratory pump, b) a blood circulation, and c) a

gas exchange surface*

The respiratory pump consists of the elastic lungs and the

thoracic cage which are alternately expanded and contracted by the

action of the respiratory musculature, thus maintaining an alternating

flow of oxygen-rich and carbon dioxide-poor air into and carbon

dioxide-rich and oxygen-poor air out of the lungs* This is represented

in the diagram by a pump and an air chamber with an opening which

permits air to go in and out*

The cardiac pumps in the diagram represent the heart which pumps

the circulating blood* The carbon dioxide-rich and oxygen-poor blood

is brought to the pulmonary capillary bed (represented by the blood

chamber) from the veins by the right pump. The oxygen-rich and

carbon dioxide-poor blood is carried away from the blood chamber to

the systemic arteries by the left pump to supply the organs of the body.

The exchange of gases between the gas phase of the alveolar air

(air chamber) and the solution phase of the pulmonary venous blood

(blood chamber) takes place across a thin membrane, which is designated

in the diagram as the exchange surface. The transfer of gas across

 -8-

this exchange surface is accomplished by passive diffusion in accordance

with partial pressure gradients* Under normal conditions, oxygen goes

into the capillary blood from the alveoli while the carbon dioxide

comes out to the alveoli from the blood, and furthermore, there is

sufficient time available for the attainment of equilibrium so that the

arterial and alveolar gas tensions are essentially identical*

The operation of this mechanochemical system is described by

three fundamental relationships between four primary variables* The

latter include V (ventilation in L./min., BTPS), pCC^ (arterial carbon

dioxide tension in mm. Hg), pC^ (arterial oxygen tension in mm. Hg),

and H* (hydrogen ion concentration of the arterial blood in mpM/iiter).

The three relationships include: a) the ventilation equation for the

relationship of V as a function of pCC^; b) the alveolar equation for

the relationship of pCC^ as a function of pC^; and c) the blood buffer

equation for the relationship of pCC^ as a function of H*.

The tension of carbon dioxide in the alveoli depends upon the rate

at which carbon dioxide is transferred from the blood into the alveoli

and the rate at which the alveoli are ventilated with air. If carbon

dioxide is transferred at a constant rate, then an increase in

ventilation will reduce the alveolar pCC^j due to greater dilution of

the transferred carbon dioxide. This effect of ventilation on pCC^

is quantitatively expressed by the ventilation equation as follows:

pC02 = [47 MER‘RQ] U + [(B - 47) FC02] (1)

pC02 = arterial or alveolar carbon dioxide tension in mm. Hg.

MRR = oxygen consumption as multiples of the resting oxygen

consumption*
 -9-

VR = alveolar ventilation expressed as multiples of the

resting alveolar ventilation,

RQ = alveolar respiratory quotient,

FCO2 = the volumetric fractions of carbon dioxide in dry

inspired air,

B = barometric pressure in mm, Hg,

It is evident from this equation that the primary variables pCC^

and VR are inversely related. All the other factors, MER, RQ, FCC^j

and B, are parameters of this equation. In this diagram the relation­

ship between the primary variables is expressed in functional form,

and the parameters are listed separately.

The alveolar gas pressure is equal to the barometric pressure,

which is the algebraic sum of the partial pressures of carbon dioxide,

oxygen, and nitrogen. If pN£ (partial pressure of N2) is kept constant,

then a reduction of pCC^ will cause an increase in pC^. This important

relationship between the alveolar pCC>2 and pOq is described quantita­

tively by the alveolar equation as follows:

po2 = [(b - 4 7 )fo 2] - Pco2 ( 2)

pOp - = alveolar oxygen tension in mm. Hg,

PCO2 = alveolar carbon dioxide tension inmm.Hg,

FO2 - volumetric fraction of oxygen in thedry inspired air.

B = barometric pressure in mm, Hg.

RQ = alveolar respiratory quotient.

It is clear from this equation that the primary variable pOq is

 -10-

negatively related to the primary variable pCC^, so long as the

parameters (B, RQ, FO2) remain constant.

Since pC02 represents free carbonic acid in the blood, any

increase in pCC^ will tend to increase the hydrogen ion concentration

of the blood. The relationship between the H* and pC02 in the blood

together with all the factors that may influence the relationship is

described below as the blood buffer equation:

pc°2= gfi-l (16+ 2.302)(log H+ -1.59)+BHC03i7 +0.375 (02150-02)] 0)

K! = dissociation constant of E^CO^.

c< = solubility coefficient for carbon dioxide in Vol.$

under standard temperature and pressure*

0 - factor converting Vol*% to millimiero moles per

liter (muM/L.).

PCO2 = arterial carbon dioxide tension in mm* Hg.

H* = hydrogen ion concentration in mpM/L.

O^i^o = hemoglobin concentration in Vbl*$ oxygen combining

capacity*

BHCO3 = standard bicarbonate content at pH 7*41*

V * a[-_L

O2 = per cent oxyhemoglobin content in Vol.^,

In this equation pC02 and H+ are the primary variables and all the

rest are parameters for this equation. It is evident that pC02 and H*

are positively related.

Because of the awkwardness of this equation, for practical purposes,

the equation is approximated over any desired limited range by a linear

 -11-

equation of the following form:

H+ = apC02 + b

in which the coefficients, a and b, are functions of the above

parameters•

The application of the above three equations may be illustrated

"by the example of voluntary hyperventilation* In voluntary hyper­

ventilation, the increased ventilation is not accompanied by a

corresponding increase in metabolism so that in accordance with the

ventilation equation, the alveolar pC02 must fall. The decreased pCC>2

will in turn increase the alveolar p0£ as required by the alveolar

equation. As a result of the decreased pC02 the blood H* concentra­

tion decreases as required by the blood buffer equation. Thus, in

voluntary hyperventilation all three of these blood chemicals are

influenced, in a manner determined by the three equations.

The neural controller system* The above described mechanochemical

system has an elaborate neural system to control its operation. This

controller system will now be described. In the diagram the connec­

tions between the different parts of the controller system are desig­

nated by dotted lines because they represent pathways for the conduction

of impulses, or controlling signals, rather than for the flow of

material or energy. This system includes structurally a) the respira­

tory motor centers, b) the motor nerves, and c) the sensory nerves and

their chemoreceptors.

The box labeled "coordinator11 in the diagram represents the

respiratory motor centers located in the medulla. Functionally, they

 -12-

integrate all the sensory stimuli and then send out motor impulses

or controlling signals to the lung pump. The single line labeled

"ventilation control signal" in the flow-control diagram represents

all the nerves to the various respiratory muscles and diaphragm.

There are chemoreceptors strategically located in the body which

are sensitive to the blood pCC^j V®2> anc* hydrogen- ion concentration.

The chemoreceptors which are commonly named peripheral chemoreceptors

are located in the carotid and aortic bodies, the former innervated

by the ninth and the latter by the tenth cranial nerves. These

chemoreceptors are sensitive to concentration of free oxygen (pC^)

in the arterial plasma.

The chemoreceptors which are sensitive to the concentration of

hydrogen ion and pCC^ are located in the medulla presumably adjacent

to the respiratory centers, although they have not been anatomically

identified. These two chemoreceptors are presumably not directly

responsive to the arterial concentrations of hydrogen ion and carbon

dioxide, but to capillary or tissue fluid,concentrations. However,

in steady states, these various concentrations are probably in

equilibrium so that the arterial concentration may be used instead of

the unidentified effective concentrations.

The three chemical agents are thus stimuli capable of influencing

the controller system. It is necessary, therefore, to know the

quantitative effect of these three chemical agents on ventilation.

This has been described by the stimulus equation as reproduced below:

VR = 0.22 if + 0.262 pC02 + 4.72 x 10-9(104 - pOg)^’9 - 18 (4)

 -13-

YR =alveolar ventilation ratio.

H+ =arterial blood hydrogen ion concentration in mpM/L.

PCO2 =arterial carbon dioxide tension in mm* Hg.

pC>2 =arterial oxygen tension in mm. Hg.

In this equation, VR, pCC^, PO2’ anc^ ^ are ^ e Pri*aa*,y variables and

the numerical coefficients are the parameters (sensitivity coefficients).

This stimulus equation states that each of the three chemical

agents exerts a partial effect on ventilation, the actual total venti­

lation being the algebraic sum of the partial effects of the separate

agents. The partial sensitivity coefficient for If*' is 0.22, which

indicates the change in ventilation produced by unit change in arterial

hydrogen ion, all the other factors remaining, of course, constant.

The same is true for the PCO2 coefficient, 0.262. The partial

coefficient of oxygen assumes a complicated form but in principle, it

is essentially the same as the other two.

In discussing the operation of the mechanochemical system, it

has already been shown that ventilation affects the arterial blood

chemical agents. In discussing the neural control system we have shown

that the arterial blood chemical agents in turn affect the ventilation.

Thus, we have a closed-loop control system as may be seen by following

the circuit of the diagram. Disturbance in any of these three chemical

agents will result in a ventilatory response which tends to reduce the

disturbance imposed on the system. Therefore, this system is a

regulator which attempts to maintain the concentration of the chemical

agents (pCC^, p02, If*") in the blood constant by making appropriate

 -14-
adjustments of the ventilation. Such a chemical regulator may be

called a chemostat.

In general, a regulator has an input, or setting, which is the

level the regulator attempts to maintain, an output, which is the

actual level attained, and an error detector, which measures the

error or discrepancy between input and output, and generates control

signals to reduce the error. In the case of the respiratory chemo­

stat, inputs, or settings, may be considered to be the normal values

of 4-0 mm, Hg for the pCC>2, 38.9 mjaM/k* f°r and 104 mm. Hg for p02.

The outputs are the actual arterial levels of these three agents.

The chemoreceptors continuously record these outputs,, and the medullary

centers compare them with the desired inputs and generate appropriate

control signals for the respiratory pump. Note that there are three

separate and complete loops, one for each of the chemical agents, so

that the system is capable of responding to errors in any one of them.

It should be noted that most of the physiological factors tending

to disturb this system operate through parameters rather than directly

through the primary variables. This type of disturbance may be called

parametric forcing. For instance, breathing carbon dioxide is a

parametric forcing because it directly determines the value of FCO2

and only indirectly affects the blood PCO2 as a parameter for the

ventilation equation.

The operation of the chemostat may be illustrated with a typical

example of its response to factors tending to disturb the normal blood

levels, such as in carbon dioxide inhalation. The inhalation of

carbon dioxide of a tolerable range causes an increase in ventilation.

This is mediated through the increase of the alveolar-arterial carbon

dioxide tension (hypercapnia) which in turn augments the arterial

hydrogen ion concentration (acidemia) as required by the blood buffer

equation. Both the increased carbon dioxide tension and hydrogen ion

concentration acting through the chemoreceptors and central coordinator,

augment the ventilation. The increase of ventilation during carbon

dioxide inhalation is a compensatory action as evidenced by the fact

that the arterial carbon dioxide tension and hydrogen ion concentration

would increase more had the ventilation not increased. This compensa­

tory action protects the organism from carbon dioxide toxicity and

from excessive acidemia. For example, normal human beings can

tolerate 5 per cent carbon dioxide in the inspired air, since the

carbon dioxide tension rises only to 46.7 mm. Hg and the hydrogen ion

concentration to 46.1, because of the accompanied hyperpnea. However,

if the compensatory hyperpnea were absent, then, the arterial hydrogen

ion concentration would rise to 61.6 mpM/L. and carbon dioxide tension

to 75 mm. Hg, both of which are toxic levels. The compensation is not

perfect, however, for the arterial carbon dioxide tension and the

hydrogen ion concentration are slightly elevated. This increase in

carbon dioxide tension and hydrogen ion concentration is called the

steady state error of the control system.

Analogous responses of the chemostat to changes in hydrogen ion

concentration and oxygen tension of the arterial blood resulting from

metabolic disturbances in acid-base balance and anoxia respectively

can be illustrated with the aid of the flow-control diagram and the

above equations. Since the principles are essentially the same as in

the case of carbon dioxide inhalation, a detailed presentation

 -16-

seems unnecessary.

B. Modification of the Respiratory Chemostat.

Inadequacy of the simple respiratory chemostat. So far our

inquiry has been limited to the regulation of breathing at rest. Know­

ing that the pulmonary respiratory system at rest behaves essentially

as a chemostat and its average compensatory responses to carbon dioxide

inhalation, anoxia, and metabolic disturbances of acid-base balance

can be quantitatively described by the four equations of the multiple

factor theory, our next step is to employ these known principles to

an analysis of the regulation of breathing during exercise.

In exercise fixed values can be assigned to nearly all of the

parameters of the equations, e.g., for the ventilation equation

(equation (l)) B - 760 mm. Hg, for exercise at sea level; FCO^ = 0,

since the carbon dioxide in the atmospheric air is practically nil;

and RQ = 0.85 for average normal metabolic RQ. Thus, the ventilation

equation is simplified by substitution of these values to yield:

^ 4,0 MRR /c\

PC02 = vr~ (5)

In exercise, it is known that the arterial oxygen tension remains

within its neutral range so far as respiratory effects are concerned.

Thus, the alveolar equation is not required, and the oxygen tension in

the stimulation equation can be dropped.

If the exercising subject is considered to have a normal hemoglobin

level, and the severity of exercise is below that which either disturbs

the standard bicarbonate content, or produces a metabolic acidosis (as

 -17-

in the case of moderate exercise),then the buffer equation may be

approximated by the linear equation:

H+ = 0.65 pC02 + 13.5 (6)

Combining the simplified stimulus equation with the simplified buffer

equation yields:

VR = 0.4 pC02 - 15 (7)

Equation (7) has also been fitted empirically to experimental data on

carbon dioxide inhalation which represents respiratory responses to

carbon dioxide and hydrogen ion alone, in subjects with normal hemo­

globin level, with no alteration in the standard bicarbonate content.

Having two simple equations describing the behavior of the

chemostat, our next problem is to predict the behavior of ventilation

during exercise, assuming the ventilation is regulated by chemical

agents of the arterial blood (pC02? p02, B4")• By combining equations

(5) and (7),and solving for ventilation ratio, yields:

VR2 + 15 VR -16 MRR = 0 (8)

For various assumed values of metabolic rate, equation (8) can be

solved for ventilation. The predicted resultsyielding ventilation as

afunction of metabolic rate in exercise areplotted in Figure 2.

Alternatively, equations (5) and (7) can be combined to yield

carbon dioxide tension as a function of metabolic rate as follow's:

0.4 pC0| - 15 pC02 - 40 MRR = 0 (9)

 -1 8 -

10

6
H-

H*
h
VR + l^VR - 16MRR

metabolic rate ratio (MRR)

0 10

Figure 2. The predicted relationship between ventilation

ratio and metabolic rate ratio during moderate

exercise (chemical control only)Q

 -19-

Again for various assumed values of metabolic rate equation (10) can

be solved for carbon dioxide tension and the results thus obtained are

plotted in Figure 3«

The behavior of the relative ventilation equivalent for oxygen

(JZE-) as a function of the metabolic rate in exercise can also be

MRR
obtained by dividing equation (9) by MRR^ to yield:

fVR)2 + _ 16 , Q
MRR MRR MRR MRR

This function is plotted in Figure 4.

Equations (8), (9), and (10) constitute the responses of the

chemostat to the parametric forcing of exercise. In effect, they are

the responses to be expected, if the ventilation is under the exclu­

sive control of the three chemical agents of the blood. Figures 2, 3,

and 4 reveal that under these conditions the ventilation, the arterial

carbon dioxide tension, and the ventilation equivalent for oxygen must

all be curvilinear functions of the metabolic rate. Furthermore, the

rise in carbon dioxide tension must be accompanied by a rise in

arterial hydrogen ion concentration.

Our next problem is to determine whether this is what is experi­

mentally observed in moderate exercise. Data collected on 75 subjects

by 11 groups of investigators (16-18, 34-43-) show that a) ventilation

is a linear function of the metabolic rate, instead of the predicted

curvilinear response; b) that the ventilation equivalent does not

change with the metabolic rate, also in contrast to the above predic­

tion; and c) that the carbon dioxide tension and hydrogen ion concen­

tration are constant instead of curvilinear functions of the metabolic

 -20-

ro

0*k pC02 -15 p002 - 40 MRR * 0

metabolic rate ratio (MRR)

Figure 3# The predicted relationship between arterial p002

and metabolic rate ratio during moderate exercise

( chemical Control only )©

 -21-

1.00

0o80

-IS' 15 / VR n 16
MRR' MRR * MRR MRR ~

metabolic rate ratio (MRR)

0 2 k 6 8 10

Figure U. The predicted relationship between the relative

ventilation eqivalent for oxygen and metabolic

rate ratio during moderate exercise ( chemical

control only ).
 -22-

rate (10, 42-44)* (Figures 5-7). It is impossible, then, to escape

the conclusion that parametric forcing of the ehemostat cannot

account for the hyperpnea of exercise, or the conclusion that this

hyperpnea cannot be mediated by changes in the three chemical agents*

Therefore, the ehemostat as described at present is inadequate to

explain the hyperpnea of exercise*

Dual nature of the modified ehemostat* Since the simple ehemostat

cannot explain the hyperpnea of exercise, it becomes necessary to

modify it. Clues to the necessary modification are available in the

experimental data already presented. Since the ventilation increases

in direct proportion to the metabolism and this is accomplished 'with­

out any contribution from the three chemical agents,itIsapparent

that an additional stimulus must beinvolved and that itseffect on

ventilation must be directly related to the metabolic rate. This new

stimulus may now be called the exercise stimulus and may be symbolized

by MRR to which it is directly proportional under normal conditions*

It has already been shown experimentally by Carter (45) that the

partial effect of the exercise stimulus acts in an additive fashion

(rather than multiplicative) with the chemical stimuli. Hence, it

may be introduced as a primary variable into the stimulus equation to

yield the following:

VR = 0.4 pC02 + MRR - 16 (11)

By combining the new stimulus equation with the previous ventilation

equation (5):

pCOp = 4A, (5)

^ * VR
 -23-

STPD
in L./mino
rate
metabolic

ventilation in L./min. BTPS

o---------o---------o-------- o---------£-------- o-------- * °

§ S ^ cnj h
 -21*-

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rate ratio during moderate exercise ( observed )

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 -2 6 -

and solving for pC02 and VR alternatively, the following relationships

are obtained:

VR = MRR (12)

pC02 = AO (13)

J/R _ 1
MRR (n)

Theseare in agreement with experimental observations in moderate exercise*

It should be noticed that MRR appears both as a primary variable

in the stimulus equation and as a parameter in the ventilation equation*

Hence, the response of the modified ehemostat to exercise is the result

of both direct and parametric forcing. It is precisely this feature

which characterizes the modified ehemostat, which may therefore be

referred to as a dual system*

C* Theories of the mechanism of exercise hyperpnea*

An analysis of the mechanism of exercise hyperpnea involves, among

other things, an identification of the pathway by which muscular activity

influences the respiratory center. There have been numerous attempts

to determine whether the pathway concerned is humoral or reflex in

nature, but the conclusion from the experiments have been conflicting

and confusing, largely due to over-simplified concepts of the respira­

tory control system.

In the past, it has usually been assumed that only one pathway is

concerned and that it must be either exclusively humoral or exclusively

reflex. These unitary hypotheses have included a) the central reflex

 - 27-
bypothesis, b) the peripheral reflex hypothesis, and c) the humoral

hypothesis•

The central reflex hypothesis states that in voluntary exercise

cortical irradiation impulses are sent directly to the respiratory

center, as an accompaniment of the voluntary cortical impulses sent

to the activated muscles. This hypothesis must be rejected for the

steady state of exercise at least, because it has been shown that

the ventilation equivalent for oxygen is the same in exercise induced

by peripheral electrical stimulation of muscles as in voluntary

exercise.

The peripheral reflex hypothesis states that exercising muscles

produce an agent(s) which activates local receptors which in turn

send neurally conducted impulses to the respiratory center. As an

exclusive mechanism this hypothesis can be immediately rejected, since

it has been shown that exercise must parametrically force the respira­

tory control system through its effect on carbon dioxide production

(metabolic rate) and this effect is necessarily mediated humorally.

The humoral hypothesis states that exercising muscles produce an

agent(s) which is carried by the blood stream to a distant receptor,

which transmits impulses neurally to the respiratory center. Again,

as an exclusive mechanism this must be rejected. If the single

humoral mechanism consists of the parametric forcing produced by the

increase in metabolism, we have already shown this to be unable to

account for exercise hyperpnea. Any other humoral mechanism must

necessarily be in addition to this humoral parametric forcing, and

hence is not a unitary mechanism.

 - 28-

Xt should be clear from the above that the mechanism controlling

the respiratory response to exercise must be dual in nature. The

parametric forcing which results from the increase in carbon dioxide

production by the working muscles must operate through a humoral

pathway. The direct forcing by the primary exercise stimulus may

operate through a humoral or a peripheral reflex pathway. Hence,

two alternative dual hypotheses are possible. The humoral-humoral

hypothesis regards both direct and parametric forcing to be humoral,

whereas the reflex-humoral hypothesis regards the direct forcing to

be peripheral reflex and the parametric forcing to be humoral.

In order to illustrate these two dual hypotheses, a modified

flow-control diagram (Figure 8) is presented. This diagram differs

from the previous one for the simple ehemostat in several ways:

1) The three chemical feedback loops are incorporated into one, in

accordance with the simplified equations applicable to moderate

exercise. 2) The blood circulation loop is closed in order to incor­

porate the exercising tissue, and 3) the alternative hypothetical

pathways for the exercise stimulus are included.

The humoral-humoral hypothesis states that the normal exercise

stimulus which acts by direct forcing is produced by the exercising

muscles but is carried by the blood stream to receptors located at

a distance from the muscles. The increased gas metabolism, which

acts by parametric forcing, also is transported by the blood stream.

As subordinate hypotheses, the exercise stimulus may be a) one or all

of the three chemical stimuli, in which case the receptors must be

located in the venous circulation (pathway N-l in Figure 8), or b) some

 -29-
i

~1'CL-0 vol..

loral (.

<01

03 fU fc-;cd

-1) neural pathway iroin vei‘S to center

— ^

u nrV- L _

rI~~ %1-----
t■
CJ
 - 30-
other agent, in which case the receptors may be located anywhere

except the working muscles.

The reflex-humoral hypothesis states that the normal exercise

stimulus which acts by direct forcing is produced by the exercising

muscles, but acts on local receptors which transmit neural signals

to the respiratory center; in addition, the increased gas metabolism

which acts by parametric forcing is transported by the blood stream.

The receptors in the working tissue in Figure 8 are labeled "ergo-

receptors,1’ as a non-committal term; they may be chemical, thermal, or

propioceptive (motion or tension of muscle and tendon) in nature.

The neural route for conducting sensory impulses from these receptors

is represented by the dotted line, N, in Figure 8.

D. Experimental implications of the dual hypotheses.

In order to determine which of the alternative dual hypotheses

is the correct one, it is necessary to deduce their experimental

Implications, so that these may be checked against experimental obser­

vations. There have been four types of experiments performed in

studying the mechanism of exercise hyperpnea: a) denervation experi­

ments, b) passive exercise experiments, c) ischemia experiments,

and d) vascular anastomosis experiments.

Denervation experiments have consisted mainly of chordotomy in

animals to sever any possible neural connections between the working

muscles and the respiratory center. As indicated in Figure 8, this

procedure should interrupt the hypothetical reflex pathway for direct

forcing.
 -31-

According to the humoral-humoral hypothesis, this procedure

does not interrupt either the humoral pathway for parametric forcing

or the humoral pathway for direct forcing. Therefore, the ventilatory

response during exercise with denervation should be the same as that

without denervation.

According to the reflex-humoral hypothesis, this procedure

interrupts the reflex pathway for direct forcing but the humoral path­

way for parametric forcing is intact. Therefore, the ventilatory

responses during exercise after denervation should be identical with

those predicted for the simple ehemostat (see Figures 2-4), viz, a

reduced ventilation equivalent for oxygen and a respiratory acidosis.

It is clear then, in order to demonstrate whether the ventilatory

response to exercise after denervation remains the same as that to

normal exercise or whether the ventilatory responses follow the pre­

dicted behavior for the simple ehemostat, it is necessary to make a

quantitative comparison between the steady state values of the

ventilatory responses in denervated and non-denervated experiments.

The exercise should be moderate but not mild, because the difference

in responses with and without denervation cannot be demonstrated unless

the metabolic rate exceeds 4-00 per cent (see figure 2). It is essential

that the oxygen consumption be determined, in order to make compari­

sons at equal levels of exercise intensity. It is also essential that

either the ventilation or the arterial carbon dioxide tension and

hydrogen ion concentration be determined, in order to detect hypo­

ventilation and respiratory acidosis. It is of vital importance that

an abnormal stimulus should not be created by the experimental procedure,

 - 32-
e.g. metabolic acidosis or blood pressure changes, which are known

to exert their effects humorally. If electrically induced exercise

is employed, it is necessary to avoid abnormal sensory stimulation

which may affect ventilation reflexly.

Passive exercise experiments consist of inducing motion in a

limb by the application of external force, in contrast to active

exercise in which muscle force is used to produce the motion. This

procedure is actually a means of dissociating the motion of exercise

from the muscle tension and metabolism, for the latter two are much

reduced in passive exercise in contrast to the motion which is main­

tained. It offers the opportunity of determining whether the

respiratory responses are associated with the motion, or with the

tension or metabolism changes. Many investigators, however, have

erroneously assumed that passive exercise does not increase muscle

metabolism at all. Hence, they interpreted the slightest respiratory

response as being due to motion, and since the latter cannot be

transmitted humorally, they have concluded that a reflex must be

concerned. Since passive exercise does in fact increase muscle

metabolism (although much less than active exercise with equivalent

motion), this simple reasoning collapses.

The real application of the passive exercise experiment is not

in differentiating reflex and humoral mechanisms, but rather in

differentiating motion and muscle metabolism as the source of the

direct forcing stimulus. If the exercise stimulus is motion, then

passive exercise should yield as intense direct forcing as active

exercise having equivalent motion. If, on the other hand, the exercise
 -33-

stimulus originates in active muscle contraction or metabolism, then

passive exercise should yield a stimulus intensity which is as small

as the increase in metabolism. The first possibility is incompatible

with the humoral-humoral hypothesis, since motion cannot be conducted

humorally; the second, however, is compatible with either type of

hypothesis.

In determining the intensity of direct forcing produced by

passive as compared with active exercise, it is essential to bear in

mind that the magnitude of the ventilatory increase is not necessarily

a measure of the intensity of the partial exercise stimulus. For

example, if motion is the exercise stimulus, and its direct forcing

effect is transmitted reflexly, then in passive exercise the direct

forcing will be powerful, but the parametric forcing (due to minimal

increase in gas exchange) will be minimal; the resulting ventilatory

response will be small because of feedback inhibition resulting from

the respiratory alkalosis. Thus, the response will be hyperventila­

tory in nature, with an elevated ventilation equivalent for oxygen,

and a respiratory alkalosis; the potency of the motion stimulus will

be much more powerful than indicated by the actual ventilatory

response (see Figure 9).

If motion is not the exercise stimulus, then passive exercise

should merely act like a very mild type of active exercise; the small

respiratory response should be proportional to metabolism and no

changes in arterial composition should occur. Of course, if the

motion induced passively is different from that occurring in exercise,

then an abnormal stimulus may be involved and produce a hyperventilatory

 -3i*-

passive exercise
without feedback
inhibition
feedback
ventilation equivalent for oxygen

inhibition

actual observed during passive exercise

0 motion

Figure 9° The relationship between the

ventilation equivalent for

oxygen and motion during

passive exercise (predicted)

 -35-

response.

It is clear, then, in order to demonstrate whether the ventila­

tory responses to passive exercise is due to motion or due to actual

active exercise, it is necessary to make a quantitative comparison

between the steady state values of the ventilatory responses in

active and passive exercise of similar amount of motion. It is

essential that the oxygen consumption and the magnitude of motion be

determined, in order to make comparisons at equal levels of exercise

intensity. It is also essential that either ventilation or arterial

carbon dioxide tension and hydrogen ion concentration be determined,

in order to detect hyperventilation and respiratory alkalosis. It is

of vital Importance that production of abnormal stimuli or activation

of other types of receptors be avoided.

Ischemia experiments have consisted of a ligation of the blood

supply to the exercising muscles, so that no metabolic products can

gain access to the general circulation. As indicated in Figure 8,

this procedure should interrupt both the known humoral pathway for

parametric forcing and any hypothetical humoral pathway for direct

forcing.

According to the humoral-humoral hypothesis, the ischemia pro­

cedure should interrupt the humoral pathways for both parametric and

direct forcing. If the ischemia is complete, and no complications are

introduced by the ischemia, all responses to exercise should be

abolished. If the ischemia is incomplete, but no complications are

introduced by the ischemia, then the response although reduced should

be characterized by unchanged ventilation equivalent for oxygen and

 -36-

arterial composition, exactly as in the normal case. If the ischemia

introduces an abnormal stimulus (such as pain) or if it reduces gas

metabolism more than it reduces the unknown stimulating metabolite,

then the response should be characterized by hyperventilation as

revealed by an elevated ventilation equivalent for oxygen and

respiratory alkalosis. Thus, according to the humoral-humoral

hypothesis, no response, a normal response, or a hyperventilatory

response may occur in ischemia.

According to the reflex-humoral hypothesis, the ischemia pro­

cedure should interrupt only the humoral pathway for parametric

forcing. If no complications are introduced then a hyperventilatory

type of response should occur, whether the ischemia is complete or

incomplete. But complications are almost inevitable, for if the

exercise stimulus is either heat or a chemical agent, the ischemia

should prevent its removal, thus permitting its continuous accumula­

tion; the result will be that the local stimulus intensity will be

exaggerated and if ischemia is complete, a steady state will never be

attainedI The only non-accumulative stimulus is motion, but the

passive exercise experiments indicate that this is a very unlikely

stimulus. Furthermore, the development of pain will contribute to an

exaggerated local stimulus intensity. To make matters worse, it is

very possible that ischemia may impair muscle activity, so that with

a constant electrical stimulus the exercise will diminish, or that in

order voluntarily to maintain a constant work output more muscles will

be called into play. The almost inevitable result of these factors

must be an exaggeration of the local exercise stimulus In ischemic

 -37-

exercise, so that the respiratory response "will be hyperventilatory

as revealed by an elevated ventilation equivalent for oxygen and

respiratory alkalosis (possibly compensated in part by lactic acidosis).

It should be clear that the ischemia experiment Is decidedly

unsatisfactory for differentiating these two hypotheses. Regardless

of which hypothesis is correct, a hyperventilatory type of response

is possible and even probable.

The most ideal m y to test the humoral-humoral and the reflex-

humoral hypotheses is to perform experiments in which the neural and

the humoral pathways are dissociated but the normal environment of

the working muscles and the respiratory apparatus are preserved.

One way of doing this is by means of the vascular anastomosis experi­

ment. In order to do this successfully, two animals are needed. The

lower extremity of one animal Is perfused exclusively by the second

animal’s blood. The animal with the perfused leg is called the

’•neural" animal, because its perfused leg connects to its own body

only neurally. The second animal is called the ’’humoral” animal,

because the perfused leg is connected to it only humorally. The

perfused leg is then exercised. If the humoral-humoral hypothesis

were true, then there should be no ventilatory response to exercise

in the neural dog but a normal response in the humoral dog. If the

reflex-humoral hypothesis were true, then the humoral dog should

respond to the parametric forcing with a decrease in ventilation

equivalent for oxygen and a respiratory acidosis. The neural dog,

on the other hand, should respond only to the direct forcing; since no

parametric forcing is present in this dog, the feedback mechanism

 -38-

will inhibit its respiratory response, which should be accompanied

by an elevated ventilation equivalent for oxygen and respiratory

alkalosis*

In testing the dual hypotheses by means of vascular anastomosis

experiments, it is necessary to acquire the same information as for

denervation experiments, namely, quantitative determinations of the

steady state values of the ventilatory response in exercise and in

controls; oxygen consumption determinations in order to make

comparisons at equal levels of exercise intensity; arterial carbon

dioxide tension and hydrogen ion concentration determinations in order

to detect respiratory acidosis or alkalosis* It will be important

to provide adequate circulation for the exercised leg in order to

avoid ischemia complications.

 -39-

III. REVIEW AND CRITICAL ANALYSIS OF EXPERIMENTAL LITERATURE

The review of the literature consists of that dealing with the

four types of the experiments described above in addition to the

experiments attempting to identify peripheral chemoreceptors. The

presence of peripheral receptors implies that the primary direct

forcing stimulus is mediated reflexly.

A. Denervation experiments.

It should be recalled that in order to test the dual

hypotheses, the information required in denervation experiments must

Include the following:

1. Determination of oxygen consumption in the steady state.

2. Determination of ventilation or arterial carbon dioxide

tension and hydrogen ion concentre.tion in the steady state.

3. Determination of the above variables be made in animals

during exercise with and without denervation.

A. The exercise should be moderate but not mild.

5. If electrically induced exercise is used, its adventitious

sensory stimulation must be evaluated or avoided.

6, No abnormal stimuli should be produced.

In 1888, Geppert and Zuntz (11), were among the first to investi­

gate the mechanism involved In the regulation of breathing during

exercise. They postulated two possible routes for the transmission of

the normal exercise stimulus: l) the humoral route, and 2) the neural

route. They further proposed that the humoral agent may be physical,

e.g., body temperature, or chemical, e.g., the blood carbon dioxide or

 -AO-

oxygen content* The neural stimulus may arise peripherally in the

working muscles and be transmitted centripetally to the respiratory

center, or may arise from the cerebral cortex (later known as cortical

irradiation)•

In order to investigate these possibilities, the authors studied

the ventilatory responses to induced exercise of etherized dogs and

rabbits with chordotomy and that to voluntary exercise of an intact

dog. Voluntary exercise was produced in this dog by making it pull a

wagon. The induced exercise was produced by applying electrical

current to an unspecified region on the lower extremities of dogs and

rabbits. The current was described as tetanizing. The muscle response,

referred to as tetany, implies a type of exercise with impaired cir­

culation to the muscles. In all instances, where it was mentioned,

the duration of the induced exercise and that of the voluntary exercise

varied from two to eight minutes and the average values of the venti­

latory response during that whole period were given. These values

are, therefore, unsteady state values. The total volume of the

expired air of the animals was measured continuously by means of a

gas meter, connected to a tracheal cannula in animals which had been

tracheotomized. Samples of the expired air were collected through

the gas meter by means of a device specially designed to sample a

constant proportion of the expired air. The air samples were then

analyzed for their composition by a method not described*

Their results are summarized in Table 1, in which the oxygen

consumption, the respiratory quotient and the ventilation values were

provided by the authors while the ventilation equivalent for oxygen (VE)
 - 41-
Fh Fh U H
0 0
f i ra > fi ra ra 3 W
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b 03 H -H rH H *H H •H rH *H
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The respiratory responses to induced exercise in chordotomized animals

H H 00 43 43 4> -P -P -P -p
and that in intact dog to voluntas exercise. Geppert and Zuntz (11)

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is calculated by the following simple formula:

YJ2_ Ventilation in L./min. __

Oxygen consumption, 100 cc./min.

Since the operations and the stimulus in these animals are different,

for convenience of analysis, the results are placed into four cate­

gories: l) intact animal with voluntary exercise (Dog I), 2) two low

thoracic chordotomized animals with induced exercise (Dogs II and III,

and Rabbit I, the first part), 3) two low thoracic chordotomized

animals with additional nerve sections with induced exercise (Rabbit I,

the first part, and Rabbit II), and 4-) three cervical chordotomized

animals with induced exercise.

The results in the intact dog with voluntary exercise are plotted

in Figure 10, in which the diagonal line represents the average

resting VE value which is 2.08. The VE values during the two working

levels are slightly higher than that at rest. The oxygen consumption

in this dog ranged from 255 to 816 cc./min., reflecting an increase

in metabolic rate of 215 per cent.

The exercise produced in these three low thoracic chordotomized

animals was very mild, for the oxygen consumption of the three animals

increased from 39.9 to 57.5 cc./min., an increment of only U5 per cent.

The average ventilation increased slightly more, from 767 to 1,568

cc./min., ah increment of 105 per cent, so that the average VE increased

from 2.06 to 2.31. The ventilation and oxygen consumption of these

three animals are plotted in Figure 11, in which the three diagonal

lines represent the resting VE values of these three animals. In every

case, there is an increase of VE during induced exercise.

20

H*

H*

10

representing resting VE(=2.Q8) of

the dog with voluntary exercise

oxygen consumption in cc./min. STPD

0
0 200 Uoo 6oo 800 1000

Figure 10. Comparison of the range of oxygen consumption

in chordotomized dogs with induced exercise (0)

and that in intact dog with voluntary exercise(+)c

Geppert and Zuntz (11)

 -US-

Os

-P

TJ

•H

CO

-P

CM
Tt
§
CM
t
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&
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C3

-P
•H

ventilation in I*,/mxi, BTPS?

CM rH O
 -4-6-

In the two rabbits with low thoracic chordotomy and additional

nerve sections, the average metabolic rate during exercise increased

29 per cent, while the average ventilation increased 78 per cent and

the average VE increased from 2.49 at rest to 3.77 during exercise.

In the three cervical chordotomized rabbits, the oxygen consumption

increased 20 per cent during work, while the ventilation increased

41 per cent, resulting in a change of VE from 3.76 to 4.54.

On the basis of these observations, the authors concluded:

1) That the ventilatory responses to induced exercise and that

to voluntary exercise are the same, as revealed by the similar and

slight change in VE.

2) That the normal exercise stimulus is transmitted exclusively

humorally, as revealed by the Increase in ventilation even after

chordotomy.

3) That the humoral agent acts directly on the respiratory

center and not on the nerve endings of the lungs as revealed by the

similar increase in ventilation in those animals after the sensory

nerves from the lungs to the respiratory center were cut.

The authors were attempting to study the ventilatory response to

normal exercise. Since after chordotomy the animal cannot perform

voluntary movements, exercise must be induced. The induced exercise

might produce additional stimuli which would affect the ventilation,

and so conclusions cannot be drawn regarding the ventilatory response

to normal exercise. Realizing this, the authors attempted to perform

control experiments for the induced exercise but failed to do so with

similar animals. The voluntary work was produced in an intact,

 -47-

unanesthetized dog, while the induced exercise was produced in

chordotomized, anesthetized rabbits and dogs. Furthermore, the work

intensities of the induced and voluntary exercise, as judged by the

oxygen consumption increment, were markedly different. The authors

neither performed experiments in chordotomized dogs in which the

oxygen consumption increased 215 per cent, nor performed experiments

in intact dogs in which the oxygen consumption increased as little as

55 per cent. Therefore, it is unjustifiable to compare the ventilatory

responses to the induced and voluntary exercise in these experiments.

Even if exercise of similar intensity had been produced in dogs, the

results could not be used as controls for the rabbit experiments

because there may be species differences. Moreover, one cannot con­

clude anything from a comparison of results from a single experiment.

As for the statement of the mechanism during exercise being

humoral, the authors again did not provide the evidence. The fact

that the chordotomized animal is capable of making a respiratory

response to electrically induced exercise cannot support the conclu­

sion that the normal hyperpnea of exercise must be mediated humorally.

For the author1s conclusion to be valid, it is necessary to quanti­

tatively compare the ventilatory responses of intact and chordotomized

animals of the same species and under similar anesthesia. This, as

indicated above, the authors failed to do. Furthermore, as it will

be recalled, the ventilatory response to exercise after chordotomy

would not differ from that in intact animals unless the \rork level is

higher than 400 per cent. The highest work level ever produced by

these authors in the intact animal was 315 per cent, and in the
 -49-

Table 2. The blood gas compositions in chordotomized animals

during exercise. Geppert and Zuntz (11)

Blood iGases, Vol.56, STPD

02 C02
Animal Operation Rest Work Rest Work Source of Blood

Dog Chordotomy Tg 17.53 33.57 Carotid artery

17.33 17.63 36.49 35.01

Rabbit Chordotomy Tg 15.S3 16.04 53.71 39.06 Femoral artery

17.90 51.03

Rabbit Chordotomy Tg 19.21 19.28 46.49 19.29 Femoral artery

13.76 15.97

Rabbit Chordotomy Tg 10.90 37.34 20.63 Femoral artery

10.62 9.65 31.15 18.32
 -48-

chordotomized animals, only 4,5 per centt These authors produced mild

exercise, not moderate exercise.

Regarding the results observed in the low thoracic chordotomized

rabbits with additional nerve sections, the authors again did not

perform adequately controlled experiments, and hence one cannot draw

conclusions regarding the influence of the exercise stimulus on the

nerve endings of the lungs. Most important of all, the authors did

not demonstrate that there is a humoral agent in normal exercise for

the regulation of breathing.

In four additional experiments, the authors determined the arterial

oxygen and carbon dioxide content in four low thoracic chordotomized

animals, at rest, and during induced work, presumably of similar

degree and duration. The results are reproduced in Table 2. It was

found that during induced exercise, the arterial oxygen content

remained the same (average: rest, 16.08 vol.#; exercise, 15.66 vol.#;

statistically the difference is not significant); but the arterial

carbon dioxide content decreased on the average from 41.04 vol.# to

26.46 vol.#, which is significant at the 5 per cent level of

probability. The authors concluded that the exercise stimulus cannot

be the arterial oxygen content because it remained unchanged; nor can

it be the arterial carbon dioxide content, because it changed in the

wrong direction. Therefore, they concluded that the exercise stimulus

must be an unknown substance.

The decrease in arterial carbon dioxide content during induced

exercise is of special interest. Unfortunately, the ventilatory

responses in these four experiments are not recorded; however, clues

to the nature of the disturbance imposed on the experimental animals

can be found in the previous experiments. There are two possible ways

in which the arterial blood carbon dioxide content can be reduced:

1) t>y hyperventilation, 2) by metabolic acidosis. It is unlikely that

reduction of the arterial carbon dioxide content is due to hyper­

ventilation, because the ventilation equivalent for oxygen of the

previous animals changed so little. It is then most likely that there

was a metabolic acidosis, because in tetanizing the muscles, the local

blood circulation, and therefore the oxygen supply to the muscles, was

impaired. The metabolic acidosis thus created should increase the

ventilation equivalent for oxygen slightly, but it may be due to the

profound circulatory disturbance or shock that the animals were unable

to respond fully to the stimulation of the metabolic acidosis. The

presence of an abnormal metabolic acidosis in these animals invalidates

the second statement of the authors because it is knoxm that metabolic

acidosis exerts its effect humorally on ventilation. In normal

moderate exercise there is no metabolic acidosis. The production of

an abnormal stimulus by induced exercise which affects the ventilation

humorally does not illuminate the normal mechanism of exercise hyperpnea.

In summary, Geppert and Zuntz have shown that during the unsteady

state of induced exercise in denervated animals, there is an increase

in oxygen consumption and a slight increase in ventilation equivalent

for oxygen. The oxygen consumption of these animals with induced

exercise increased only to 45 per cent, while that in the one intact

animal with voluntary exercise (which also showed increase in oxygen

consumption and ventilation equivalent for oxygen) increased to

 -51-

215 per cent* The findings that the metabolic response of the animals

to induced exercise is low and that their arterial carbon dioxide

content during exercise is lowered are the result of a circulatory

disturbance imposed on the animals* This circulatory disturbance in

addition to the tetanic type of muscle contraction (abnormal exercise),

resulted in a metabolic acidosis* The lack of control experiment and

the production of an abnormal stimulus mean that the authors have

failed to demonstrate anything regarding the mechanism involved in the

regulation of breathing during normal exercise.

the above experiments were repeated by Kramer and Gauer (12), who

carried out their experiments on anesthetized cats (morphine-chloralose)

and rabbits (urethane) in which the chordotomy was performed at the

level of T]_2.-12* Exercise was induced by means of an inductorium with

the electrodes applied to the lower limbs of the animals. It was

mentioned that by this method a rythmical tetany was produced by one

second tetanus and one second pause. However, steady state of exercise

was not reached, because the longest duration of exercise was only four

minutes. Ventilation was recorded continuously by means of a small

gas meter. In two cats, the alveolar carbon dioxide tension and the

alveolar oxygen tension were recorded continuously by means of a gas

exchange recorder which is connected to a special designed device for

the collection of a constant fraction of the alveolar air. This

device was connected by a tracheal catheter, passing through the

tracheal cannula which was connected to the tracheotomized animal. The

gas exchange recorder was so designed to register continuously the

alveolar air tension in mm. Hg, calibrated and corrected for vapor
 -52-

pressure at 38 degree centigrade and the ambient atmospheric pressure

(4-6)• In one graph oxygen consumption in cc./min. was labeled along

the tracings, but the authors failed to describe whether the oxygen

consumption was calculated according to the tracings of the alveolar

oxygen tension or the recorder records the oxygen consumption directly.

No reference was given as to the detail design of the gas exchange

recorder, but only referred to as the "Reinschem Gaswechselschreiber.u

The arterial blood (carotid) pressure was recorded continuously by

means of a manometer. Their data are summarized in Tables 3 and 4.

Table 3 consists of the results of six cats and three rabbits,

in which the increase in respiration, oxygen consumption in per cent,

and the fall of blood pressure in per cent are provided by the authors.

The relative ventilation equivalent for oxygen is calculated. Since

the ventilation and oxygen consumption were given in per cent of

increment, each of them is added to a hundred to obtain the original

proportionality. Thus, by dividing the ventilation in per cent plus

100 by the oxygen consumption in per cent plus 100, the relative

ventilation equivalent for oxygen is obtained. In the cat experiments,

as shown in Table 3, during induced exercise, the increase in venti­

lation averages 102.5 per cent; the increase in oxygen consumption

averages 141*8 per cent resulting In an average fall in the relative

ventilation equivalent for oxygen from 1 to 0.853* The fall in blood

pressure during exercise averages 16.3 per cent. In the rabbit

experiments, during induced exercise, the ventilation increased 74*8

per cent on the average, the oxygen consumption 58.8 per cent, resulting

in a relative ventilation equivalent for oxygen of 1.10. The average

 -53-

Table 3* The blood pressure and ventilatory response to

induced exercise in chordotomized animals.

Kramer and Gauer (12)

% Inc. % Fall Rel. Vent.

Anesthesia and % Inc. in O2 in Equiv.
Animal Operation in Resp. Cons. B.P. for

Cat I Morphine-Chloralose 92 2A5 41 0.56

Chordotomy T-q „]_2 66 195 22 0.56
75 11A 11 0.82
Cat II tt
■ 106 133 9.5 0.88
AO 165 6.0 0.53
Cat III tt 170 133 17.0 1.16
AO 7A 11.5 0.85
Cat IV It
77 70 15 1.03
Cat V tt 90 90 17 1.00
25 70 8 0.7A
Cat VI II 290 255 22 1.10
160 158 16 1.01

Ave* 102.5 141.8 16.3 0.853

Rabbit I Urethane 144 55 41 1.58

Chordotomy Tn ? 50 62 33 0.93

Rabbit II tt 80 75 20 1.02
Rabbit III tt 0.87
25 A3 12.5

Ave. 7A.a 58.8 26.6 1.10

^Relative ventilation equivalent for oxygen = — ^

Oxygen consumption m %+100
 -54-

Table 4* The ventilatory responses to exercise in cats with

and without chordotomy (values taken from graphs)#

Kramer and Gauer (12)

°2 Alveolar
Cons# Vent# pC02
Animal Operation Condition cc/min# cc/min# mm. Hg VE B.P#

Gat I Chordotomy Rest 20 520 45 2.60 120

(Chloralose) T10 Exercise 32 970 40 3.03 100

Cat II Intact Rest 26.8 810 34 3.02 -

(Chloralose) Exercise 84.0 2,900 43 3.46 Incr.

 -55-

fall in blood pressure in rabbits during induced exercise was 26.6

per cent.

The relationship between the relative ventilation equivalent for

oxygen and the increase in oxygen consumption is plotted in Figure 12.

The data of cat IV in Table 3 were not used, because there is only one

set of values recorded during exercise. The data of the rabbits are

eliminated because they are of a different species; and besides, there

were no control experiments done by these authors on rabbits. There­

fore, only the data of the other five cats are used in analysis* To

each of these five cats, a resting value of the relative ventilation

equivalent for oxygen, which is unity, and the oxygen consumption

increment, which is zero, are added, so at least each cat has values

of one resting and two work levels. It Is then possible to do a

covariance analysis on these data. It was found by the covariance

analysis (47), that after the data had been found to be homogeneous,

a pooled r of -0.4-623 was obtained, which is not significant. There

is an apparent negative slope (-0.000895) for this group of data, but

it is also insignificant.

In one additional experiment on one cat, the arterial blood

pressure was determined during induced exercise when the spinal cord

was intact and also after chordotomy. It was found that the arterial

blood pressure remained the same during the first two minutes, then

rose slightly during exercise when the spinal cord x^as intact, but a

decrease of 20 per cent in blood pressure occurred during exercise

when the spinal cord was cut. This was depicted in a graph which shows

that when the cord of the animal was cut, there is a fall in blood
 -56-

1.0

Y= -0o000895 (± 0,177) X+Oo979

r® -O.U623

0,0

increase in oxygen consumption in

0 100 200 300

Figure 12c The relationship between the relative

VE and the increase in oxygen consump­

tion in animals during induced exercise,

Kramer and Gauer (12)

 -57-

pressure within the first 15 seconds of the exercise, then remained

at a constant low level for the remaining period of the exercise which

lasted for three minutes.

In another two experiments on cats, in addition to the variables

listed in Table 39 the alveolar carbon dioxide tension of the animals

was determined. The data which are taken from the graph are presented

in Table 4* Attempt was made to select an approximate value from the

tracings to best represent that in the graph. Gat I was chordotomized

at T^q* During induced exercise, its oxygen consumption increased

60 per cent (from 20 to 32 cc/min.), ventilation increased 85 per cent

(from 520 to 970 cc/min.), resulting in an increase in ventilation

equivalent for oxygen from 2.60 to 3*03. The alveolar carbon dioxide

tension dropped from 45 to 40 mm. Hg, while the blood pressure fell

from 120 to 100 mm. Hg. In the second cat, which was intact, the

oxygen consumption increased 210 per cent while the ventilation

increased 258 per cent, resulting in an increase in ventilation equiva­

lent for oxygen from 3.02 to 3*46. The alveolar carbon dioxide tension

increased from 34 to 43 mm. Hg, while the blood pressure increased

slightly. There is no calibration of the blood pressure on the graph,

so it was impossible to obtain a definite value of blood pressure

from it.

From these observations, the authors concluded that the stimulus

causing the increase in breathing during exercise is influenced by the

fall in blood pressure incident to the exercise. They further stated

that the fall in blood pressure could not be the sole stimulus,

because it had been established in man that the increase In breathing

 -58-

during exercise is accompanied by an increase in blood pressure.

In order to evaluate the authors1 statement, a multiple correla­

tion analysis (47) was carried out. The results are presented in

Table 5* The correlation between the increase in respiration and the

increase in oxygen consumption is 0.5681, which is significant at

5 per cent level of probability. The correlation between the increase

in oxygen consumption and the fall in blood pressure is 0.7514? which

is significant at the 1 per cent level of probability. The correla­

tion between the increase in respiration and the fall in blood pressure

is, however, not significant. The partial correlation of the increase

in oxygen consumption and the fall in blood pressure with respiration

kept constant is 0.7689 which Is significant at 1 per cent level of

probability, while the other two partial correlations (respiration and

oxygen consumption with blood pressure constant, and respiration and

blood pressure with oxygen consumption constant) are not significant.

Judging from the insignificant partial correlation between the increase

in respiration and the fall of blood pressure with oxygen consumption

kept constant, it is impossible to draw a conclusion that the blood

pressure affects the ventilation in these animals during induced

exercise. It should be clear, however, that this insignificant partial

correlation does not mean that the fall In blood pressure does not

influence the respiration at all, but simply that the experiments of

these authors do not demonstrate any such influence.

The fall in blood pressure during induced exercise is positively

correlated to the oxygen consumption which implies that at a higher

work level there is a larger drop in blood pressure. Unfortunately,

 -59-

Table 5. The correlation coefficients.

Variables Correlation P
V - MR 0.5681 P < 0.05

V - B.P. 0.3383 Insignificant

MR - B.P. 0.7514 P < 0.01

(V - B.P. # MR constant -0.1630 Insignificant

Partial (
(MR - B.P. • V constant 0.7689 P <0.01
Correlation (
(V - MR * B.P. constant 0.5045 Insignificant

N.B.

V = Ventilation increment in per cent.

MR = Oxygen consumption increment in per cent.

B.P. = Blood pressure increment in per cent.

 -60-

neither the exact work intensity of these animals, nor the relation­

ship between the work intensity and the oxygen consumption is revealed,

so the oxygen consumption of these animals has to be used arbitrarily

as an index of the work intensity. If there is adventitious stimu­

lation of the animals by the induced current, the animal's respira­

tion and blood pressure rather than the oxygen consumption would be

affected. This may be the case to explain the insignificant partial

correlation of oxygen consumption and respiration during the induced

exercise. The authors did mention that they failed to demonstrate a

linear relationship between the oxygen consumption and the respiration

of these animals during induced exercise, and, therefore, the relative

values in per cent are given. By doing this the scattering of the

individual animals is reduced, and by so doing the differences between

animals which may be attributed to the differences in the depth of

anesthesia or in degree of shock, etc., are masked.

As it will be recalled, in the previous part of this review,

according to our prediction, the relative ventilation equivalent for

oxygen and the metabolic rate ratio in chordotomized animals during

exercise should be negatively and curvilinearly related (Figure 4)*

The data obtained by these authors are thus treated and plotted in

Figure 12, which revealed an apparent negative correlation (r = 0.4623)»

which is not significant. The authors, however, did not commit

themselves as to the specific stimulus or mechanism involved in the

regulation of breathing during exercise. At any rate, it should be

clear that the behavior of the variables in Figure 12 is qualitatively

in agreement to what we have predicted.

 -61-

In chordotomized animals, as we predicted, the carbon dioxide

tension of the alveolar air and of the arterial blood should rise

during exercise. Cat I in Table 4 showed a decrease of alveolar

carbon dioxide tension with a rise in ventilation equivalent of oxygen.

It is probable that this animal also had circulatory disturbance

similar to that of Geppert and Zuntz (11). As a result of the circu­

latory disturbance, a fall in the blood pressure is apt to occur.

In the one control experiment in one intact cat (Cat II, Table 4)

the alveolar carbon dioxide tension did not fall (the resting carbon

dioxide tension was low) and the blood pressure increased a little

instead of falling. This may explain that in chordotomized animal,

the experimental procedure has caused circulatory disturbance in the

animals. Of course, one should not draw conclusions from the observa­

tions in one experiment. But it is well known that in intact animal

or man during exercise the blood pressure rises (48, 49)* Therefore,

the fall in blood pressure cannot explain the increase of breathing

during normal exercise. The authors' data cannot be used even to

explain the changes during induced exercise because there are no

adequate controls, besides the one determination in intact animal

during induced exercise.

From Kramer and Gauer's experiment, the following conclusions

appear justified,

l) In chordotomized cats, the increase in ventilation and the

increase in oxygen consumption during induced exercise tend to

behave not proportionally, therefore, resulting in a decrease in

the relative ventilation equivalent for oxygen.

 - 62-

2) There is a fall of blood pressure during induced exercise in

the chordotomized cats but the fall of blood pressure is not even

partially related to the increase in ventilation. Furthermore, the

blood pressure during normal exercise increases; therefore, the fall

of blood pressure in induced exercise cannot explain the mechanism of

normal hyperpnea.

3) It is probable that the cats of these investigators had

circulatory disturbances after chordotomy and, therefore, made it

difficult to illuminate the normal mechanism concerned in the regula­

tion of breathing during exercise.

The mechanism concerned in the regulation of breathing during

exercise was also investigated by von Euler and Liljestrand (13» 50),

who performed experiments on five chloralosed cats and one chloralosed

dog (0.05-0.1 gram of chloralose per kilogram of body weight intra­

venously). In three cats, which were chordotomized at the level of

Tj2> ventilation at rest and during induced exercise was recorded*

The exercise was induced by stimulating the peripheral end of the cut

cord and the ventilation was measured by an unspecified method for an

unspecified period beginning two minutes after the electrical stimu­

lation had been applied (unsteady state). The ventilation was

recorded after chordotomy at rest, and during exercise, and was repeated

after additional sinus denervation.

The results thus obtained are shown in Table 6 (the first three

cats). It was found in these three cats that after chordotomy the

ventilation averaged 0*442 liters per minute, BTPS at rest, while

during exercise the ventilation increased to an average of 1.036 liters

 -63-

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 -65-

per minute, BTPS, reflecting an increment of 135 per cent. After

sinus denervation, the resting ventilation on the average was 0,420

liters per minute, BTPS, whereas the ventilation during work on the

average was 0,875 liters per minute, BTPS, reflecting an increment

of 108 per cent. From these observations, the authors concluded that

the normal exercise stimulus is transmitted humorally and exerts its

effect either on the respiratory center or on the chemoreceptors

located in the carotid sinus, because the peripheral nerves innervating

the working muscles are cut.

First of all the authors did not perform any control experiments,

which should consist of determination of the ventilation in intact

animals to induced exercise, and that in intact animals to normal

exercise. The authors did not even provide the data on the oxygen

consumption in these experiments, so it is impossible to calculate

ventilation equivalents as a means of evaluating abnormal sensory

stimulation in these animals. It was said that the exercise was pro­

duced by electrical stimulation of the peripheral end of the cut

spinal cord, but the authors did not indicate whether the induced

exercise was rhythmic or tetanic. When the peripheral end of the cut

cord is stimulated, it should be possible to mobilize all the muscles

in both lower extremities. Yet the ventilation increase resulting

from the induced exercise is only 135 per cent. It Is then possible

that the animals were not responding properly to the stimulus, due to

shock, etc. Suppose, the ventilation of these three cats did increase

proportionally to oxygen consumption, still the ventilatory response

after chordotomy does not demonstrate that the response must be humoral,
 -66-

because the exercise was of a very low range*

In another two experiments on intact chloralosed cats (Gats IV

and V of Table 6), exercise was induced by a modulated stimulator with

electrodes applied to the abdomen and the back of the animal. Both

ventilation and oxygen consumption were determined with the aid of

a small Douglas bag at rest and during induced work when the animals

were intact and also after bilateral vagotomy and sinus denervation.

The duration of stimulation and the specific time for the determina­

tion of the ventilatory response were not mentioned. The results thus

obtained are given in Table 6. The average oxygen consumption of

these two cats at rest was 11.8 cc./min., STPD, x^hen they were intact,

and 12.5 cc./min., STPD, when they are denervated (bilateral vagotomy

and chemical sinus denervation). The average ventilation at rest was

0.121 L./min., BTPS, when intact, and 0.313- L./min., BTPS, when

denervated, resulting in an average ventilation equivalent for oxygen,

2.96 and 2,66 respectively. During induced exercise, the oxygen

consumption increased on the average to 32.5 cc./min., STPD, when

the cats were intact, reflecting an increment of 119 per cent, whereas

the ventilation increased on the average to 0.869 L./min., BTPS,

reflecting an increment of 106 per cent. After denervation, the

oxygen consumption in these two cats increased to 28.6 cc./min., STPD,

during exercise, an increment of 128 per cent, whereas the ventilation

increased to 0.631 L./min., BTPS, an increment of 85 per cent. The

ventilation equivalent for oxygen decreased from 2.96 to 2.61 during

exercise when the animals were intact, and from 2.66 to 2.11 during

induced exercise after denervation.

 -67-

It was mentioned that '•similar0 responses to induced exercise was

obtained after the spinal cord was transected at the level of L-^ No

data of such 0similar0 ventilatory responses were recorded. The authors,

however, concluded, °The experiments therefore give clear evidence,

that the increase in ventilation is not, to any considerable extent, due

to impulses travelling from the working muscles through afferent paths.

If such impulses are of any importance at all in this connection, it

must be very small. Since a great increase in ventilation after mus­

cular work was obtained, even when all influences through the vagi

and the sinus nerves were eliminated, it can hardly be doubted that

the effect is due mainly to a direct influence on the respiratory

center.0

The above conclusion was not supported by evidence. The authors

merely stated that similar response to induced exercise was obtained

after chordotomy. That the effect is undoubtedly due mainly to a

direct influence on the respiratory center implies something else is

also concerned, but they failed to indicate what that is. As noted

from the data, after the sensory denervation of the lungs, there was

a decrease in ventilation equivalent for oxygen. The significance of

this finding is not quite clear because for the first place, there are

too few experiments, and secondly, there may be other factors which are

disturbed after the sensory denervation. One of these factors may be

the carotid depressor which after denervation is unable to respond to

the circulatory disturbance which normally may cause the ventilation

to increase. The results in these two cats could be used as controls

for the first three experiments mentioned above but, unfortunately, the
exercise induced was by different methods#

There is one additional experiment performed by these authors on

a single chloralosed dog. The method of determining the ventilatory

responses is the same as that for Gats IV and V. Exercise was induced

by means of a modulated stimulator with the electrodes applied to the

hind legs of the animal. The ventilatory responses were determined at

rest and during induced exercise, and repeated after chordotomy and

sensory denervation. The data thus obtained are presented in Table 6

(Dog I). As shown in Table 6, the average resting value of oxygen

consumption of the dog when intact was 58.8 cc./min#, STPD, and that

of the ventilation was 3.26 L*/min., reflecting a ventilation equiva­

lent for oxygen of 5.57. This high ventilation equivalent for oxygen

at rest implies that the dog was not under a normal condition. This

may be due to inadequate anesthesia, etc. The oxygen consumption during

exercise when the dog was intact increased to 145.8 cc./min., STPD,

the ventilation increased to 6.49 X./min., BTPS, on the average,

resulting in a ventilation equivalent for oxygen of 4.62 which is

lower than that at rest. After chordotomy, the oxygen consumption of

this dog at rest x^as 67*4 cc./min., STPD, and increased to 266 cc./min.,

STPD, during exercise; the ventilation increased from 3.78 to 14.65

L./min., BTPS, reflecting a change in ventilation equivalent for oxygen

from 5.61 to 5.50. After additional denervation, during work the

oxygen consumption increased from 70.2 to 196 cc./min., STPD, the

ventilation increased from 3*19 to 8,41 L./min., BTPS, resulting in a

decrease in ventilation equivalent for oxygen from 4.55 to 4.30, The

data from this dog are also plotted in Figure 13. The upper diagonal
 -6$'-

dog intact
dog chordotomized
dog chordotomized and
vagotondzed

resting VE(=£.£7) /
when dog was intaket

presumably the normal VE

in anesthetized dog

oxygen consumption in cc0/min STPD

0 100 200

Figure 13» The relationship between ventilation and oxygen

consumption in one dog with induced exercise0

von Euler and Liljestrand (13)

 - 70-

line in this figure represents the resting ventilation equivalent for

oxygen when the dog was intact, the lower diagonal line represents the

normal ventilation equivalent for oxygen of anesthetized dogs (15, 51).

It is evident that the resting ventilation equivalent for oxygen as

well as the ventilation equivalent for oxygen during exercise were high,

although the latter is of a lesser degree* On the hasis of the obser­

vations in a single animal, the authors concluded, nthat the increase

In ventilation during muscular work can be explained neither by

efferent [afferent] nerves impulses from the working muscles, nor by

impulses from the receptors in the sinus or aortic regions. It there­

fore seems necessary to return to the old hypothesis of a direct

chemical stimulation of the respiratory center.n

The experiment on a single animal does not warrant this or any

other conclusion. Besides, this single animal had a high ventilation

equivalent for oxygen at rest which implies there was a disturbance

causing hyperventilation. The increase in ventilatory responses to

exercise after chordotomy does not mean normally the exercise stimulus

must be humorally mediated. In almost every instance of work the

ventilation equivalent for oxygen decreased after vagotomy and sinus

denervation$ yet these authors concluded this denervation has no

effect on ventilation, which evidently Is unjustified.

To sum up, von Euler and Liljestrand1s experiments have shown

that the ventilation equivalent for oxygen decreases during work after

vagotomy and sinus denervation. Since this also occurs in their

intact animals, and since the quantitative difference in ventilation

equivalent for oxygen cannot be demonstrated because there are too few
 -71-

adequately controlled experiments, any conclusion regarding the

significance of this decrease in ventilation equivalent for oxygen

would be hazardous* Their limited experiments have shown that after

chordotomy there is still ventilatory response to induced exercise

but this does not necessarily mean that in normal conditions the

neural mechanism is not concerned* Besides, the authors did not

perform control experiments for the induced exercise, so nothing can

be concluded from the authors1 data regarding the mechanism of normal

hyperpnea*

Comroe and Schmidt (14) observed the changes in ventilation

before and after cord transection following stimulation of the motor

nerve roots* Both cats and dogs were used. In the cat experiments,

the animals were anesthetized with chloralose (0.05 gram per kilogram

of body weight) intravenously or sodium barbital (0*35 gram per kilo­

gram of body weight) intraperitoneally. Ventral lumbar spinal roots

of the animal were exposed, using 11Sherrington*s method,'* The roots

were cut free on the central side, and placed on Insulated electrodes

raised above the cord to obviate escape of current. Stimulation was

produced by a thyraton stimulator, frequency being four per second.

Strength of the stimulation was adjusted so as to elicit maximal

muscular activity* In some cases only the seventh lumbar pair of

ventral roots were stimulated, in others the sixth lumbar and In a

few the first sacral was also added. Respiration was recorded by

means of a spirometer. The authors provided no detailed data but

stated that in 29 observations of the effects of the muscular exercise

thus induced in 15 cats, there was In every case "some" increase in

 - 72-
respiratory volume. After transection of the spinal cord in the

dorsal region in five cats, the "exercise” still increased breathing

"much as it had done before." Thus the authors concluded that the

hyperpnea of muscular exercise induced in cat by stimulation of

ventral spinal roots, is humorally mediated by liberation into the

blood stream of chemical products which act either on the respiratory

center or on chemosensitive nerve endings elsewhere than the leg.

Similar experiments were carried out by the same authors on dogs.

They stated that of 39 tests of ventral root stimulation in 11 anes­

thetized dogs, 35 showed definite respiratory stimulation, the increase

in ventilation varying from 8 to 200 per cent and averaging 62 per cent.

Transection of the spinal cord in the lower dorsal region completely

abolished the "polypnea," in each of the four dogs on which the point

was tested. It was said that the section of the dorsal lumbar roots

likewise abolished the effect in other animals. Based on these

observations, the authors concluded that the respiratory stimulation

associated with exercise induced by ventral root stimulation in dogs,

unlike the corresponding effect in cats, is essentially due to afferent

nerve impulses from the limbs.

As stated by the authors, in cats there was some increase in

respiratory volume and in dogs there was an average of 62 per cent

increment when those animals were stimulated. The authors also stated

that the strength of stimulation was adjusted so as to elicit maximal

muscular activity. It is clear, then, the ventilatory response to the

maximal stimulation was not adequate, because the ventilation during

"maximal" normal exercise can be easily produced to several times of

 - 73-
that at rest. As we know, the presence of ventilatory response to

induced exercise after chordotomy in cats, does not prove the normal

exercise stimulus is humorally mediated. The authors stated in dog

experiments there was sometimes no change or even depression of the

respiration when the roots were stimulated. It is probable that these

dogs had so much circulatory disturbance that they were unable to

respond properly to the electrical stimulation. After chordotomy,

there may be more disturbance so the "polypnea** would be abolished

even without electrical stimulation, or the animal may even cease to

breathe. If that is the case, the chordotomy not only eliminated the

peripheral nerve pathway, but also abolished respiration by circula­

tory disturbance. Therefore, no conclusion can be drawn in regard to

the normal mechanism of exercise hyperpnea.

Comroe and Schmidt provided no data for their statement. Their

statement implies that their animals had extensive disturbance imposed

by the experimental procedure that the animals could not respond

properly to stimulus. Their experiment, therefore, failed to demon­

strate the normal mechanism involved in the regulation of breathing

during exercise.

The mechanism involved in the regulation of breathing during

exercise was reinvestigated by Grodins and Morgan (15), using

chordotomized dogs. Realizing that after chordotomy, the chemical

control of the breathing will operate, and that the increase in

breathing during exercise in chordotomized animals must be accompanied

by an elevation of the arterial blood carbon dioxide tension and

hydrogen ion concentration, these authors determined these chemical

 -74-

agents in the arterial blood at rest and during Induced exercise in

chordotomized dogs (at Tj_q) In addition to the total ventilation and

oxygen consumption in the steady state. The dogs were anesthetized

with sodium barbital, 0.3 gram per kilogram of body weight intra­

venously. Oxygen consumption and total ventilation were recorded by

means of a Benedict-Roth metabolimeter. The exercise was produced by

means of a modulated stimulator with the electrodes applied per-

cutaneously to the hind limbs. Carotid blood samples were drawn

anaerobically at rest and during steady state of induced exercise,

and they were centrifuged to obtain plasma. The plasma carbon dioxide

content was determined by the manometric method and plasma hydrogen

ion concentration was determined with the aid of the glass electrode

which was kept at a constant temperature of 38 degrees centigrade.

The arterial carbon dioxide tension was then calculated from the

Kenderson-Hasselbalch eolation. Data of 46 experiments on ten

chordotomized dogs including 26 experiments on five dogs with blood

determinations were reported. The data are reproduced in Table 7

with additional calculated ventilation equivalent for oxygen, relative

ventilation equivalent for oxygen, metabolic rate ratio, and ventila­

tion ratio. The control experiments (induced exercise in intact dogs)

were reported in a separate article (52), which consists of 54 experi­

ments on ten dogs including 28 experiments on six dogs with blood

determinations* The methods used for the determinations in the control

experiments are identical with that in the experiments on chordotomized

animals. The data of the control experiments are reproduced in Table 8

with similar additional calculations.

 -75-
Table 7. Ventilatory response of chordotomized dogs to
induced exercise. Grodins and Morgan (15).
Vent. Arterial Arterial
%
Dog cc./min. L./min. pC02 H+ Rel.
No. STPD BTPS VE mm. Hg mpI'l/L. MRR m VE
1 78.3 3.16 4.02 1.00 1.00 ‘l.OO
224.0 6.72 3.00 2.86 2.13 0.77
78.3 3.01 3.86 1.00 1.00 1.00
249.0 6.90 2.77 3.18 2.29 0.72
2 74.8 2.97 3.97 1.00 1.00 1.00
117.5 ■ 4.25 3.63 1.57 1.43 0.91
78.4 3.27 4.17 1.00 1.00 1.00
149.5 5.26 3.52 1.91 1.61 0.84
64.1 2.97 4.63 1.00 1.00 1.00
157.0 4.08 2.61 2.45 1.38 0.56
3 97.9 3.02 3.09 1.00 1.00 1.00
182.0 5.17 2.84 1.86 1.71 0.92
4 78.4 2.84 3.63 1.00 1.00 1.00
252.0 7.58 3.01 3.22 2.66 0.83
76.6 2.78 3.63 1.00 1.00 1.00
301.0 8.32 2.75 3.94 2.99 0.76
5 116.0 6.90 5.96 1.00 1.00 1.00
267.0 18.60 6.98 2.30 2.70 1.17
104.0 8.62 8.27 1.00 1.00 1.00
303.0 14.00 4.62 2.92 1.62 0.56
6 150.0 5.25 3.50 50.6 56.2 1.00 1.00 1.00
303.0 10.10 3.63 57.1 62.3 2.02 1.92 0.95
153.0 4.30 2.81 53.7 57.5 1.00 1.00 1.00
385.0 9.74 2.53 57.8 61.5 2.52 2.26 0.89
125.0 2.80 2.24 52.4 54.3 1.00 1.00 1.00
320.0 8.10 2.53 57.2 56.8 2.56 2.89 1.13
7 108.0 7.20 6.67 46.8 51.2 1.00 1.00 1.00
270.0 13.13 4.87 49.8 68.3 2.50 1.83 0.73
126.0 7.10 5.64 53.8 59.5 1.00 1.00 1.00
395.0 14.30 3.62 58.7 66.0 3.14 2.01 0.64
8 67.7 3.88 5.74 36.0 38.9 1.00 1.00 1.00
175.0 9.44 5.38 34.3 51.2 2.59 2.43 0.94
60.6 2.98 4.92 38.6 41.7 1.00 1.00 1.00
205.0 9.99 4.87 41.8 54.8 3.38 3.34 0.96
64.I 3.36 5.24 38.7 43.6 1.00 1.00 1.00
219.0 12.60 5.76 36.5 48.9 3.42 3.75 1.10
9 73.5 5.10 6.92 49.3 53.7 1.00 1.00 1.00
219.0 10.00 4.57 51.8 56.2 2.98 1.98 0.66
73.5 6.13 8.33 41.6 47.8 1.00 1.00 1.00
228.0 11.20 4.92 52.4 60.2 3.11 1.82 0.59
73.5 5.51 7.52 45.2 48.9 1.00 1.00 1.00
238.0 10.20 4.33 50.1 56,2 1.85 0.57
10 410.0 10.60 2.58 53.2 51.2 4.15 1.84 0.45
89.1 6.25 7.01 48.7 48.9 1.00 1.00 1.00
 -76-

Table 8. Ventilatory response of intact anesthetized dogs to

induced exercise. Morgan and Grodins (52).

02 Vent. Arterial Arterial

Dog cc ,/min. L./min. pCOp H+ Rel.
No. STPD BTPS VE ™ . Hg mul'l/L. MRR VR VE
1 80.0 2.70 3.37 1.00 1.00 1.00
142.5 5.16 3.63 1.78 1.91 1.07
80.0 2.91 3.64 1.00 1.00 1.00
295.0 9.22 3.13 3.69 3.17 0.86
80.0 3.01 3.76 1.00 1.00 1.00
392.0 10.35 2.64 4.91 3.44 0.71
80.0 2.83 3.54 1.00 1.00 1.00
477.0 10.70 2.24 5.97 3.78 0.632
2 67.6 2.45 3.62 1.00 1.00 1.00
124.5 4.00 3.22 1.83 1.63' 0.89
71.2 1.98 2.78 1.00 1.00 1.00
142.0 4.08 2.87 1.99 2.06 1.03
3 99.7 2.60 2.62 1.00 1.00 1.00
205.0 5.90 2.88 2.06 2.27 1.10
89.0 2.45 2.76 1.00 1.00 1.00
214.0 6.80 3.18 2.41, 2.77 1.15
4 92.5 2.62 2.84 1.00 1.00 1.00
221.0 5.47 2.48 2.39 2.09 0.87
81.8 1.51 1.85 1.00 1.00 1.00
253.0 5.60 2.22 3.10 3.74 1.21
78.3 2.48 3.17 1.00 1.00 1.00
285.0 6.38 2.24. .3.64 2,57 0.71
5 110.0 3.54 3.22 1.00 1.00 1.00
333.0 9.82 2.95 3.03 2.78 0.92
117.5 4.31 4.02 53.7 50.1 1.00 1.00 1.00
258.0 9.70 3.75 54.2 54.8 2.20 2.25 1.02
71.4 1.69 2.37 50.0 52.4 1.00 1.00 1.00
500.0 13.18 2.63 49.7 64.5 7.02 7.80 1.11
6 150.0 7.20 4.80 1.00 1.00 1.00
614.0 25.60 4.17 4.09 3.56 0.87
119.0 4.66 3.93 45.2 46.2 1.00 1.00 1.00
363.0 12.10 3.34 44.5 52.4 3.04 2.59 0.85
125.0 5.39 4-31 39.3 46.8 1.00 1.00 1.00
602.0 24.60 4.07 47.7 57.5 4.82 4-56 0.95
7 42.7 2.32 5.45 49.7 47.8 1.00 1.00 1.00
99.7 5.13 5.17 43.7 47.3 2.33 2.21 0.95
62.3 3.37 5.41 43.0 54.8 1.00 1.00 1.00
232.0 9.74 4.18 39.9 57.5 3.73 2.88 0.77
8 126.0 6.12 4.87 49.3 58,2 1.00 1.00 "l.OO
341.0 12.60 3.68 49.8 54.3 2.71 2.06 0.76
119.0 4.74 3.98 51.0 64.5 1.00 1.00 1.00
665.0 20.00 3.01 50.3 74.8 5.58 4.22 0.79
89.8 3.24 3.61 56.8 57.5 1.00 1.00 1.00
539.0 18.10 3.36 50.2 72.3 6.02 5.59 0.93
 -77-

Table 8* Continued,

Vent. Arterial Arterial

Dog %
cc./min, L./min, PCO2 H+ Rel.
No, STPD BTPS VE mm. Hg mpM/L. MRR VR VE
9 132.0 3.87 2.93 54.4 56.2 1.00 1.00 1.00
399,0 9.BO 2.45 56.2 61.5 3.02 2.53 0.84
114.0 2.76 2.42 57.7 57.5 1.00 1.00 1.00
417,0 12.10 2.89 56.8 65.3 3.66 4-38 1.19
10 73.5 4.67 6.36 49.6 53.7 1.00 1.00 1.00
293-0 11.90 4.07 50.9 63.0 3.99 2.56 0.64
73.5 4.67 6.36 50.4 54.9 1.00 1.00 1.00
293.0 12.70 4*34 40.0 53.7 3.99 2.73 0.69
73.5 3.90 5.30 54.1 53.7 1.00 1.00 1.00
304-.0 11.20 3.68 55.5 69.1 4.14 2.88 0.69
 -78-

Figure 14 represents the relationship between ventilation and

oxygen consumption both in intact and chordotomized dogs. The line

labeled (i) represents the regression equation fitted to the data of

the intact dogs and the one labeled (C) represents that fitted to

data of the chordotomized dogs. By comparing the slopes of these two

lines a t-ratio of 1.001 was obtained which is insignificant. However,

the intercept of the equation for line G on y axis is significant.

Figures 15 and 16 depict the relationship between the ventilation

ratio and metabolic rate ratio in the intact and chordotomized dogs

respectively. The diagonal lines in these two figures represent a

direct proportionality. As shown in these two figures, the values

during induced exercise mostly fall in the range lower than the direct

proportional line.

The relationship between the relative ventilation equivalent for

oxygen and the metabolic rate ratio in the intact and chordotomized

dogs is plotted in Figures 17 and 18 respectively. In both cases, as

shown by the fitting lines (covariance) to the data, there is a

decrease of relative ventilation equivalent for oxygen with increasing

metabolic rate ratio. In the chordotomized dogs the slope of the line

( R VE = f(MHR) ) is significantly lower than that in the intact dogs.

The resting ventilation equivalent for oxygen values in intact and

chordotomized animals are different. Using group comparison (47),

a t-ratio of 3.08 was obtained which is significant at the 1 per cent

level of probability.

In the Intact dogs, the correlation coefficient between the

arterial carbon dioxide tension and the metabolic rate is -0.179 which
ventilation in L./mino BTPS
 - 80-

ventilation
ratio
(VR)

metabolic rate ratio (MRR)

1 2 3 h 5 6 7

Figure l$m The relationship between ventilation ratio and

metabolic rate ratio in intact dogs during

induced exercise. Grodins and Morgan (52)

 - 81-

M
H*
U

H*

metabolic rate ratio (MRR)

1
1 2 3 U 5 6

Figure l60 The relationship between ventilation ratio and

metabolic rate ratio in chordotomized dogs

during induced exercise„ Grodins and Morgan (15)

 -82-

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 -83-

1.20
 -84.-

is not significant. The correlation between the arterial carbon

dioxide tension and the arterial hydrogen ion concentration for the

range of metabolic rate is also not significant (r = 0,065). The

correlation between arterial carbon dioxide tension and the metabolic

rate is negative but not significant (r = -0.179). The correlation

between the arterial hydrogen ion concentration and the metabolic rate

is significant at the probability level of 1 per cent. This implies

that the intact dogs during exercise had metabolic acidosis. In the

chordotomized dogs the correlation coefficient between the arterial

carbon dioxide tension and the metabolic rate is 0.703, the correlation

coefficient between the hydrogen ion concentration and the carbon

dioxide tension is 0.616, and that between the arterial carbon dioxide

tension and the metabolic rate is 0.765. All these three correlation

coefficients are significant at 1 per cent level of probability. This,

unlike that in the intact dogs, implies a respiratory acidosis during

the induced exercise.

From these observations, the authors concluded, "The observed changes

in the respiratory responses to exercise following transection of the

spinal cord conform to neither of the two limiting predictions based,

respectively, on the assumptions of an exclusively neural, or an

exclusively humoral pathway for the transmission of the exercise stimu­

lus in the intact animal. Under these conditions, no conclusion can

be drawn regarding the pathway or pathways actually utilized In the

normal animal," This conclusion was drawn because the results agreed

with neither of the two limiting predictions defining the possible

effects of chordotomy upon the ventilatory responses, viz, l) that no

alteration of the ventilation would be produced, thereby implying that

an "Intact central nervous pathway" was unnecessary for the normal

transmission of the exercise stimulus* (There is some important impli­

cations in this prediction. If there is no alteration of the ventila­

tion, yet there is elevation of the arterial carbon dioxide tension

and hydrogen ion concentration, then, one cannot imply that an intact

central nervous pathway is unnecessary, because normally the arterial

carbon dioxide tension and hydrogen ion concentration do not change

during normal exercise*). 2) That chordotomy would modify the normal

ventilatory response, thereby implying that an intact normal neural

pathway was essential for the normal transmission of the exercise

stimulus. The authors were cautious in extrapolating these results

on anesthetized dogs to normal dogs. From the behavior of the intact

dogs some peculiar responses during exercise were observed. It is

well knoxm that during normal moderate exercise, the ventilation is

so well adjusted that the arterial carbon dioxide tension and hydro­

gen ion concentration are not altered. The presence of metabolic

acidosis in the intact dogs during exercise makes it difficult to use

them as normal controls. Therefore, it is hazardous to draw any

conclusions regarding normal exercise. What is more difficult to

explain is the fact that respiratory acidosis occurred in these

chordotomized dogs during exercise. If the metabolic acidosis during

induced exercise is a result of the insufficiency of the oxygen

supply, it implies an insufficient regulatory system as far as oxygen

supply is concerned. Then, why does severer metabolic acidosis not

occur in the chordotomized dogs. It would not be due to the fact that
 -86-

the chordotomized dogs had a better regulatory system for oxygen

supply. If metabolic acidosis causes an elevation of the ventilation

equivalent for oxygen, then the relative ventilation equivalent for

oxygen as a function of the metabolic rate in the intact dogs should

be actually lower.

Qualitatively, the ventilatory responses in the chordotomized

animals are in agreement with that predicted if reflex-humoral hypo­

thesis were true, but the response in the intact dogs makes it hazardous

to conclude anything as to the normal mechanism during exercise.

Furthermore, these authors did not evaluate the abnormal sensory

stimulation during electrically induced exercise, it is impossible to

state that this reflex element, if there is any, is not due to the

abnormal stimulation.

There are no artificial denervation experiments in man. However,

Asmussen et al. (10) have investigated the ventilatory response during

exercise in a 57 year old male patient suffering from tabes dorsalis.

It was mentioned that in this patient all the kinesthetic sensations

controlling muscular movements and limb posture were completely

extinguished in the legs and In the lower part of the trunk and had

been so for seven years. The authors postulated that the increase in

breathing in man during normal exercise is of nervous origin and is

of two possible ways: namely, either due to increased cortical

irradiation impulses or due to Increase in reflex impulses from the

working muscles. In both cases the impulses must be closely correlated

to the work intensity, since the relationship between the ventilation

and the intensity of work In moderate exercise is linear. In this

 -87-

patient, the authors further stated, the cortical irradiation impulses

were separated* therefore, it was possible to study the assumptions

mentioned above*

Both
*
voluntary and induced exercise were produced in one normal

subject and in this patient* The induced exercise was produced by

means of a modulated stimulator, which was so designed as to produce

exercise imitating the natural voluntary muscular contractions* The

indifferent electrode was placed 011 the back of the subject, the

different electrodes ventrally on the thighs and dorsally on the

calves, so a rhythmic contraction and relaxation of the lower

extremities was produced* The working machine consists of an

angular lever equipped with pedals to which the feet were fixed* The

lever moved on a horizontal axis and the load of the work was varied

by means of a spring* Voluntary work was produced with the aid of the

same working machine, but no electrical stimulation. In addition to

this, the patient also performed voluntary work on a modified

ergometer* After the subject had exercised for 10 to 15 minutes, the

oxygen consumption and ventilation were determined by the Douglas bag

method* The alveolar carbon dioxide tension was then calculated, the

dead space being previously determined by an unspecified method.

The results thus obtained were presented in graphs which are

reproduced in Figures 19 and 20. Figure 19 represents the data

obtained from the normal subject; and Figure 20 represents that from

the patient* As shown in Figure 19, the relationship between the

oxygen consumption and ventilation during induced and voluntary work

is practically the same. The diagonal line in this figure represents

 oxygen consumption in cc./min« .STPD
200 400 600 800 1000 1200

Figure 1?0 The relationship of ventilation and alveolar pC02

oxygen consumption in a normal human subject

during electrically induced work («) and during

voluntary work (+)0 Asraussen et al (10)

 -89«
26

22
ventilation in L./min*BTPS

18

Hi

10

6 o+
alv„p(X)2 in inmHg.

36

32
w ty ^ ic o n s u ^ itio i^ in ^ ^ ^ ^ iiu S l^ D
200 Uoo 600 800 1000 1200
Figure 20. The relationship of ventilation and alveolar pOC>2

to oxygen consumption in a patient with tabes dorsalis

during voluntary work (+) (°) and during induced

work (.). Asmussen et al(lO)

 -90-

a ventilation equivalent for oxygen value of 2.2 which is reasonably

normal. The alveolar carbon dioxide tension during voluntary and

induced work also behaved in a similar way; i.e., stayed constant for

the range of oxygen consumption determined. Figure 20 shows the

relationship between the variables in the patient. The diagonal eye-

fitting line represents a ventilation equivalent for oxygen value of

2.6 which is higher than that of the normal subject. The alveolar

carbon dioxide tension shows a wide scattering, and a lower resting

value. The range of the oxygen consumption in this patient covers

from 220 to 800 cc./min., which is much shorter than that in the normal

subject (to 1300 cc./min,).

On the basis of these observations, the authors concluded that

during exercise, the mechanism of controlling the ventilatory response

must be of an exclusively nervous origin from the working muscles,

because in this patient whose ordinary kinesthetic sensations were

completely extinguished, the pulmonary ventilation during both kinds

of work increased in the normal way, i.e., corresponding to the oxygen

consumption.

If there is no cortical irradiation impulses involved during

induced exercise, the absence of this irradiation impulse is demonstrated

by the similarity of the ventilatory response diiring both induced and

voluntary work both in the patient and the normal subject. As for the

demonstration of the normal exercise stimulus being transmitted by

centripetal nerves from the working muscle to the respiratory center,

the authors accomplished none. Only because there is no possibility of

being a cortical irradiation mechanism, it does not mean necessarily

 -91-

that the mechanism must be of neural impulses. There are still ouher

possibilities. The authors failed to indicate if all the sensory

nerves in this patient were destroyed. If there were absolutely no

sensory connection between the working muscles and the respiratory

center, the exercise stimulus then must be carried by the blood stream.

As we have predicted, if the ventilatory response during exercise is

operated by the reflex-humoral mechanism, after the elimination of the

peripheral reflex mechanism, a decrease In ventilation equivalent for

oxygen must occur, and the decrement in ventilation equivalent for

oxygen increases when the oxygen consumption is high. This the authors

failed to show. On the contrary the ventilation equivalent for oxygen

in this patient on the average is higher than that of the normal

subject. It is probably that the sensory nerves which might be con­

cerned in normal exercise are not damaged and therefore in a sense,

this patient is normal as far as the ventilatory response to exercise

is concerned. Therefore, this experiment on this one patient failed

/ to show the mechanism of exercise hyperpnea.

Summary: In the theoretical analysis, it has been shown that, In the

steady state and in the absence of complications, the denervated

animal should respond to induced moderate exercise, a) according to

the humoral-humoral hypothesis, with an unchanged ventilation equiva­

lent for oxygen and unchanged arterial gas composition, and b) accord­

ing to the reflex-humoral hypothesis, with a reduced ventilation

equivalent for oxygen and respiratory acidosis.

From the literature dealing with denervation experiments, It was

found, with regard to the responses, that,

l) only one group of investigators determined the ventilation

 -92-

during induced exercise in the steady state;

2) only three groups of investigators determined the oxygen

consumption, only one of which determined it during the steady state;

3) only one group determined the arterial blood gas composition

adequately;

4) the group that determined the ventilatory responses during the

steady state showed a respiratoryacidosis and a decrease of ventila­

tion equivalent for oxygen in the denervated animal.

With regard to the stimulus,

1) all but one group produced very mild exercise;

2) no investigators ever demonstrated that the induced exercise

,fsimulates” voluntary exercise.

From this information, it is concluded that none of the observa­

tions can neither reject nor retain either of the hypotheses, but

those of one group favor a reflex-humoral mechanism. However, this

cannot be regarded as conclusive,because of the circulatory distur­

bances induced by theexperimental procedure, and because of the

failure of the authors to evaluate the abnormal sensory stimulation

by the electrical current utilized to induce exercise,

B. Passive Exercise Experiments,

It should be recalled that in order to differentiate motion from

others as a stimulus to ventilation in exercise, the information

required in passive exercise experiments must include the following:

l) Determination of the magnitude of motion during passive and

and active exercise.

 -93-
2) Determination of the oxygen consumption during the steady

state of exercise*

3) Determination of the ventilation or arterial carbon dioxide

and hydrogen ion concentration during the steady state of exercise.

4) No other stimuli except motion should be produced.

Harrison et al. (20) studied the effect of passive exercise on

ventilation in five anesthetized dogs with the hind leg separated from

the body, only the sciatic nerve and the femoral vessels were con­

nected. Passive leg movements were carried out at a rate of 300 per

minute. Ventilation was measured by means of a spirometer. The

authors stated that if there was any response in ventilation it was

immediate, which implies these responses were unsteady state. The

results thus obtained are reproduced in Table 9.

When both the femoral vessels and the sciatic nerve were intact,

during passive movements, the ventilation changed on the average from

3*07 L./min. to 3*38 L./min., an increment of 10 per cent, which by

paired comparison analysis revealed to be insignificant. When the

sciatic nerve was left intact, the femoral vessels clamped, the

ventilation changed on the average from 3*14 to 3.38 L./min., an

increment of 7 per cent, whereas when the sciatic nerve was cut, but

the femoral vessels were intact, the ventilation changed on the average

from 3.14 to 3.09 L./min., a decrement of 1.5 per cent. Both the

7 per cent increment and the 1.5 per cent decrement are shown

statistically not significant. On the basis of these results, the

authors concluded that the normal exercise stimulus is transmitted

exclusively neurally.
 -94-

Table 9* The ventilatory responses to passive movements in dogs.

Harrison et al. (20).

Leg amputated except Femoral vessels Sciatic nerve cut.

for intact femoral clamped. Sciatic Femoral vessels
vessels and intact nerve intact. intact,
sciatic nerves.

Vent., L/min. (BTPS?) Vent., L/min.

y iiL-L.11 •
ju (BTPS?)
' uj ;j Vent., L/min.
i y lU-Lii • (BTPS?)
1

Ani­ Before During After Before During After Before During After
mal Move­ Move­ Move­ Move­ Move­ Move­ Move­ Move­ Move­
No. ment ment ment ment ment ment ment ment ment

1 3.20 3.38 3.16 3.22 3.34 3.24 3.44 3.52 3.4s

2 3.58 3.79 3.64 3.86 4.09 3.83 3.85 3.82 3.82

3 2.30 3.05 2.35 2.64 3.19 2.77 3.81 3.77 3.67

4 4.26 4*41 4.33 4.15 4.19 4.03 2.98 2.76 2.57

5 2.02 2.26 2.04 1.82 2.06 1.78 1.62 1.60 1.60

Ave. 3.07 3.38 3.11 3.14 3.38 3.13 3.14 3.09 3.03

Column A B C D E F

Paired Comparison:

B - A P 0.10

D - C P > 0.05

F - E P > 0.30
 The authors conclusion is invalidated by the fact that no control

experiments were done. The control experiments should include deter­

mination of the ventilatory responses in dogs thus prepared to active

exercise. This would be one method of determining whether the passive

exercise produced is a form of active exercise or would the animals

thus prepared respond at all even to active exercise. The latter

aspect is important because after such drastic surgical procedure, the

animals may not be able to respond to any stimulus. Besides, the

authors did not make the determinations that are listed as requirements

in order to test the dual hypothesis, namely, the determination of the

magnitude of motion, the determination of oxygen consumption and

ventilation during steady state. Furthermore, the rate of motion was

300 per minute, which was practically violent shaking (abnormal

stimulus), but there was no significant change in ventilation. Hence,

it is unjustifiable to conclude anything regarding the mechanism of

hyperpnea in normal exercise.

Harrison1s experiment was repeated by Comroe and Schmidt (14)

who carried out their experiment on dogs and cats. The cats were

anesthetized with ehloralose (0.0$ gram per kilogram of body weight

intravenously) or sodium barbital (0.35 gram per kilogram of body

weight intraperitoneally). The dogs were anesthetized with sodium

barbital (0.35 gram per kilogram of body weight intravenously) or

ehloralose (0.03 gram per kilogram of body weight intravenously) and

morphine (2 mg. per kilogram of body weight subcutaneously).

The femur of the animal was disarticulated or transected and its

proximal end was fixed. The foot of the disarticulated limb was tied
 -96-

to a rod which was moved by an electric motor at a rate of 200 per

minute. The authors claim that this experiment was carried out on

19 dogs and 12 cats, but no complete data were presented. However,

the authors stated that in dogs the increase in ventilation was seen

11at least once" in each experiment during passive movements of the

leg. The increase in ventilation varied from 22 to 125 per cent, and

averaged 52 per cent. They concluded that this "increase*1 in venti­

lation is neural on the groiind that the ventilatory response persisted

when the femoral vessels were occluded and that the ventilatory response

disappeared when the spinal cord or the nerves to the hind legs are

sectioned. (No data.) They further claim that the knee joint is

^prominently" concerned because in six experiments in which continuous

flexion of one knee caused "distinct11 respiratory stimulation, and the

result was unaffected by division of all the quadriceps and hamstring

tendons. When 2 per cent procaine was injected into and around the

knee joint, shaking or flexion of the leg was "entirely" ineffective

until, about 30 minutes, the effects of the drug wore away and the

response returned. In one experiment, denervation of the knee was

accomplished by division of all nerves in the vicinity, and this also

abolished the effects of shaking or flexion.

In cats, the authors stated, the response was less consistent and

less marked than that observed in the similar experiments on dogs. In

cats the stimulation of breathing during passive movements began

after a latent period (implying that the animal was unable to respond

immediately or the effect on ventilation is not neural). However,

the authors continued, "Nevertheless, the effect was proved to be

 -97-

entirely reflex by its persistence during closure of the femoral

artery and vein (three experiments) and by its absence following

sections of the nerves to the legs (two experiments) or injection of

2 per cent procaine into the knee joints(two experiments)

In addition to the passive exercise experiments on cats and dogs,

Comroe and Schmidt performed passive exercise experiments on man.

The subject reclined on a table with his left leg hung free. His

left foot was tied to a rod which was driven by an electric motor at

a rate of 100 per minute. Ventilation was measured by means of a

gas meter at rest and during the one or two minutes of passive move­

ment (unsteady state). The authors claim that a total of 86 tests

were made on 50 subjects and highest increase in ventilation was

60 per cent.

The same experiments was carried out in four patients. The

ventilation due to passive movements was determined before and during

spinal anesthesia. The results from these four patients are repro­

duced in Table 10. The average increase in ventilation during passive

movement was 26.9 per cent without spinal anesthesia and 8.8 per cent

with spinal anesthesia, the latter is significantly higher than the

former. On the basis of all these observations, these authors claim

that the increase of breathing during exercise Is exclusively reflex

in origin, but this neural factor evidently only shares part of the

stimulus because the response to passive movement is small.

First of all, the statement that the ventilatory response to

passive movement is small is not supported by evidence. There was no

control experiment to evaluate the differences between the responses

Table 10. Per cent change in ventilation produced in
man by passive movement. Comroe and Schmidt (14)*

Before During
Spinal Spinal
Subject Anesthesia Anesthesia

1 +51 +15
+26 +11

2 +21 + 12.2
+29 +15.8

3 0 - 7
+ 5*2 + 6*6
+43 +2.5

4 +40 0

Averages 26.9 8.8

Paired comparison P < 0.02

to passive and active movements when similar amount of muscles were

activated. When the active exercise is of a small magnitude, the

ventilatory response is also small. The authors did not determine how

much of the muscle was activated and how much did the activation

correspond to active exercise. Secondly, to evaluate the exact potency

of the stimulation by passive movement, the inhibitory effect of

acapnia resulting from hyperventilation should be accounted for. This

the authors failed to do, and probably did not even realize the

significance of it. As for the human experiment, it is evident that

in these patients, the decrease in ventilation after spinal anesthesia

was irrelevant because the effect of spinal anesthesia alone on

ventilation was not determined. Besides, the authors obtained no

steady state values in the determinations and the oxygen consumption

was not recorded, and hence, it was impossible to know whether or not

the passive movements produced active exercise. Therefore, this

experiment does not contribute toward the knowledge of the mechanism

involved in the regulation of breathing during normal exercise.

Bahnson et al. (22) studied the effects of active and passive

limb movements upon respiration and oxygen consumption in man. The

subjects performed active exercise on an ergometer. Passive exercise

was produced by ^manual manipulation” of the legs or arms in subjects

in supine position or in subjects sitting upon a stationary bicycle

driven by an electric motor at a rate of 60 per minute for a period

of five minutes. Ventilation was measured by means of a Tissot

spirometer. Oxygen consumption was measured over a five-minute period

by a circuit method employing the Tissot spirometer and a Haldane gas

 - 100-
analyzer. The data are reproduced in Table 11 with additional calcula­

tions of ventilation ratio, metabolic rate ratio, and relative venti­

lation equivalent for oxygen.

As shown in the Table, the averaged ventilation during passive

exercise increased from 8.4-9 to 10.59 L./min., an increment of

25 per cent, while during active exercise, the ventilation increased

from 8.9 to 11.19 L./min*, an increment of 26 per cent. The oxygen

consumption during passive exercise increased on the average from

283 to 389 cc./min., an increment of 37 per cent, while that during

active exercise increased on the average from 294- to 4-06 cc./min.,

an increment of 38 per cent. It is clear that, as far as ventilation

and oxygen consumption are concerned, the responses are not different

whether exercise is active or passive, and both are of very low

magnitude. The relationship between the ventilation and oxygen con­

sumption during passive and active exercise is plotted in Figure 21,

which shows, so far as the slopes of the fitting lines to the data are

concerned, no significant difference. The relative ventilation

equivalent for oxygen in passive exercise is not significantly different

from that of active exercise.

The authors further mentioned that in three subjects, arterial

blood samples were collected before and during passive movements of

the limbs and that although the ventilation increased 6, 10, or 57 per

cent, there was no change in the arterial hydrogen ion concentration

and carbon dioxide tension. They further concluded that "since the

maximal effect noted in this study was an increase of 57 per cent,

and since active muscular exercise is capable of increasing ventilation

 - 101-

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Ventilatory responses to passive movements in man.

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 -102- *
15

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H-

(?) * passive exercise ^ ' active exercise

Y=3.06£(±0.U8)X -o.76 Y=2.£(±.£9) X+1.287

r=0.3i±22 r=0„7251i

oxygen consumption in cc./rairi.STPD?

0
0 100 200 300

figure 21. The relationship between ventilation and

oxygen consumption in human subjedfts during

passive and active exercise. Bahnson et al(22)

 -103-

as much as 1100 per cent, it is apparent that passive movements do

not play an important role in the production of hyperpnea in muscular

exercise*n

This experiment has shown that passive movement of the limbs is

just a mild form of active exercise. Hence, there is no change in

arterial gas composition because there is no hyperventilation in

normal mild exercise. The authors probably attempted to produce

maximal passive .exercise but the increase in ventilation was 57 per cent

at the most, which indicates that motion is not concerned in the regu­

lation of breathing during normal exercise. Therefore, this type of

experiment is valueless in studying the mechanism of exercise

hyperpnea.

Otis (23) studied the effect of passive exercise on ventilation

in three series of experiments. The first series was carried out on

nine human subjects lying supine on a table. The right lower leg

was moved by a lever driven by an electric motor in such a fashion

that the leg performed flexion and extension movements at a rate of

70 per minute. Oxygen consumption and ventilation was measured by

means of a recording spirometer with soda lime. The whole experiment

was divided into five five-minute periods as follows: 1) normal

breathing, 2) passive exercise, 3) recovery, 4) passive exercise,

and 5) recovery. The results are reproduced in Table 12.

Table 12
1 2 3 4 5
Ventilation in % of 100 ^ 97 1 13 140 t 51
normal control values
Oxygen consumption in %
of normal control 100 110 ±11 108 ± 11 120 ± 10 107 ± 16
values
 -104-

As one may notice, the oxygen consumption during passive exercise

increased as well as the ventilation. During the third (recovery)

period the ventilation is lower than normal, implying that full

recovery was not obtained. Since the investigators work on the

transient only, the decrease in ventilation below the normal resting

value during the third period may be due to the inhibition resulting

from hyperventilation, as evident by the ^proportionality of the

oxygen increment during the second period.

In a second series of experiments, a gas meter was used to

measure the ventilation. Passive exercise was produced in the same

way as in the first series of experiments. Alveolar carbon dioxide

tension was measured with the aid of an automatic alveolar air

sampler. Ten minutes were allowed for passive exercise. Six human

subjects were used and the results are reproduced in Table 13.

The ventilation during passive exercise on the average increased

from 6.34 to 7.3 L./min., BTPS, an increment of 16 per cent, while

the alveolar carbon dioxide tension on the average decreased from

41.1 to 38.8 mm. Hg, a decrement of 5.5 per cent. Both the increase

in ventilation and the decrease in alveolar carbon dioxide tension

are statistically significant. Qualitatively, the direction of

changes is in agreement with that in respiratory alkalosis. However,

the oxygen consumption was not recorded, nor was the work intensity.

It is, therefore, impossible to conclude anything in relation to the

mechanism of normal exercise hyperpnea.

In a third series of experiments, the subject was seated on a

bicycle with his feet on the pedals. A motor was coupled to the
 -105-

Table 13. Ventilatory responses to passive exercise in man.

Otis (23).

Alveolar pCOpj mm. Hg Ventilation* L./min,, BTPS

Subject Control Passive Exercise Control Passive Exercise
1 42.5 39.3 5.78 7.32
2 39.8 37.7 6.33 7.98
3 42.0 40.5 6.22 7.25
4 42.3 41.5 5.83 5.67
5 39.7 37.0 6.50 8.42
6 40.3 36.5 7.37 7.59

Averages 41.1 38.8 6.34 7.37

A B C D

Paired comparison:

A - B, P < 0.01

D - C, P <r 0.05

Table 14. Ventilatory responses to passive exercise in man.

Otis (23)

Alveolar pC02 mm. Hg Ventilation, L./min., BTPS

Sub.iect Control Passive Exercise Control Passive Exercise
1 38.2 37.9 8.29 9.29
2 37.3 35.4 7.84 8.63
3 36,8 38.2 7.62 10.04
4 36.5 41.1 7.79 9.16
5 35.5 30.7 8.01 15.67
6 40.3 38.2 7.21 12.38

Averages 37.4 36.9 7.79 10.86

A B C D

Paired comparison:

A - B, P > 0.50

D - C, P < 0,05
 -106-

rear wheel so that each pedal was driven at a rate of $0 revolutions

per minute. Ventilation and alveolar carbon dioxide tension were

determined by the same method as in the previous series of experiments.

The results are listed in Table 14.

As shown in Table 14» the ventilation during this kind of passive

exercise increased on the average from 7.78 to 10.86 L./min., BTPS,

an increment of 40 per cent, whereas the alveolar carbon dioxide tension

changed on the average from 37.4 to 36.9 mm. Hg, a decrement of

1.5 per cent. The increase in ventilation was significant, whereas

the decrease in alveolar carbon dioxide tension was not significant.

It seems peculiar that in the same subjects doing similar work

that their alveolar carbon dioxide tension increment was significant

in one series of determinations but not significant in another. It is

doubtful if the method of determining the alveolar carbon dioxide

tension was valid.

There are no determinations of oxygen consumption or record of

the magnitude of passive movement. There are no similar determina­

tions in the subjects performing active exercise. Therefore, these

experiments are valueless. However, they have shown that the maximal

ventilatory response was 40 per cent which indicates that motion is not

concerned in exercise hyperpnea.

Gardner and Jacob (24) claimed that joint reflexes do not play a

,rsignificant role" in the production of respiratory changes during

passive exercise* Their experiments were carried out on 10 cats and

25 dogs, the legs of which were passively flexed manually at a rate of

 -107-

150-300 per minute. In many of the animals other stimuli were used,

including movements of the trunk brought about by pushing on the hips

in such a way as to '’mimic11 transmission of movements during passive

flexion; trunk movements brought about by rubbing the sides of the

thorax; rubbing a tracheal cannula in the tracheal wound; massaging

the cut skin and muscle edges. All these stimuli were carried out for

period of one minute. They further claim that in "some” of the

animals, section of the vagus nerve was carried out. In two dogs the

right hind limb was amputated at the thigh, except for femoral

vessels and sciatic nerve, and the effect of passive flexion of the

knee xjas studied. Some animals were decerebrated and some were

prepared with denervated knee joints. Respiration was recorded by

means of a pneumograph, which unfortunately only registered the

amplitude of chest motion where the instrument was attached, but not

the ventilation. Thus, applying different stimuli In different

conditioned animals, the authors reported the average changes in

respiratory rate in percentage as follows: l) The respiratory rate

increased on the average 2.5 per cent In normal cats during passive

motion. 2) In decerebrated cat, the rate increased on the average

18 per cent during passive motion. 3) In dogs during passive motion,

the respiratory rate increased on the average 16 per cent. 4) In

dogs with denervated knee joints the respiratory rate increased

23 per cent.

From these results, the authors concluded that joint reflexes do

not play a significant role in the production of respiratory changes

during exercise in animals. They even extrapolated their results from

 -108-

animals to man and concluded that limb reflexes are unimportant in the

regulation of respiration during exercise In man.

These authors did not perform experiments on man. As for the

animal experiments, the investigators did not perform control experi­

ments. Furthermore, they used too many kinds of stimuli and all were

not classified in their report. Some stimuli do not have any rela­

tionship to normal exercise. As for responses they even failed to

determine the ventilation. These experiments are useless as far as

respiratory physiology is concerned.

Liljestrand and Stenstroem (25) investigated the effect of

massage and passive movement on ventilation on two human subjects.

Massage was carried out on the abdomen and the muscles of the lower

extremities. Passive movement was done by extension and flexion of

the lower extremities at a rate of 20-30 per minute. Ventilation

was recorded by means of a spirometer and expired air samples were

collected for analysis of oxygen and carbon dioxide. The oxygen con­

sumption and alveolar carbon dioxide tension were then calculated.

The duration of the experiments ranged from two to four minutes;

therefore, the determinations were unsteady state values. The data

are reproduced in Table 15 > which shows the averaged ventilation

during muscle massage was 9*29 L./min., during belly massage was

9.14 L./min., and during passive exercise was 8.97 L./min., the

averaged resting value being 5.33 L./min. The oxygen consumption

increased on the average from 229.6 cc./min. to 319 cc./min. during

muscle massage, to 272 cc./min. during belly massage, and to 351 cc./min.

during passive movement. The average resting value of oxygen consumption

 - 109-

Ventiiatory responses in man during massage and passive

movements* Liljestrand and Stenstroem (25).
During muscle massage

Duration Ventilation 02 Consumption Alveolar pCOo

min. L*/min. (BTPS?) cc/min, (STFD?) mm. Hg
2.7 7*46 283 38.9
2 2.9 7.93 302 38.2
3 2.6 9*60 353 34.1
4 2.6 9*42 350 32.7
5 2.6 13*64 363 26.6
6 2.8 12.33 350 24.7
7 2.6 9.29 323 32.8
8 2.5 10.12 326 29.8
9 2.9 7.40 303 36.8
.0 3*0 8.29 323 32.2
.1 2.9 8.35 291 34.5
.2 3*4 7.17 295 34.5
1 2*4 10.49 331 28.6
2 2*4 10.81 321 27.9
3 2.8 7.01 256 36.4
4 2*9 9.24 328 33.5
5 2.6 9.54 337 31.6
6. 2.8 9.11 305 29.4
Ave. 9.29__________319 32*4
During belly massage
T 2.9 5.75 229 37.9
2 2.5 5.72 238 37.5
3 2.8 5.93 240 38.9
4 2.8 7.41 296 35.7
5 2.9 6.93 285 34.9
6 2.9 6.30 256 34.4
7 2.6 6.35 294 38.2
a 2.8 7.22 287 —

1 2.1 22.30 292 18.0

2 2.2 16.19 283 18.7
JL 2.6 10.41 295 28.6
Ave. 1 9*14 272 32.3
During passive movement
T 2.5 9.46 431 38.7
2 2.5 9.89 413 35.8
3 2.8 8.78 381 37.5
4 2.6 10.11 440 37.4
5 2.8 6.49 345 40.6
6 2.9 7.17 354 39.8
7 2.6 7.89 338 36.8
8 2.7 7.53 338 36.7
9 2.8 8.44 378 36.2
L0 2.9 8.49 367 35.3
1 3.0 7.46 270 37.8
2 3.0 7.82 264 36.8
3 2.5 12.99 321 29.2
2.6 13.11 278 26.7
Ave. 8.97 351 36.1
 -llO-
was 229.6 cc./min. The average alveolar carbon dioxide tension was

39.1 mm. Hg, and decreased to 32.4 mm. Hg during muscle massage, to

32.3 mm. Hg during belly massage and to 36.1 during passive exercise.

The nature of the stimulus to ventilation incident to muscle and

belly massage is not known. It may be an abnormal stimulus as far as

exercise is concerned, because it produces pressure rather than motion.

During passive movements both ventilation and oxygen consumption

were increased resulting in a ventilation equivalent for oxygen of 2.56,

which is higher than the resting ventilation equivalent for oxygen of

2.28. The increase in oxygen consumption implies that the authors

have produced active exercise, which increased ventilation to 70 per cent.

The small increase in ventilation equivalent for oxygen during passive

exercise does not mean necessarily that motion was concerned. In

order to imply that motion is the factor, it is necessary to demonstrate

that no abnormal stimuli are produced and the determination of the

ventilatory responses should be in steady state. This the authors

failed to do; therefore, their experiments are useless in studying

whether motion is concerned in exercise.

Summary; In the theoretical analysis, it has been mentioned that the

passive exercise experiment is a means of differentiating motion from

other factors as a stimulus to ventilation during exercise. If motion

is demonstrated to be responsible for the regulation of breathing

during exercise, a reflex-humoral mechanism is implied, since the

motion cannot be transmitted humorally.

From reviewing the literature dealing with passive exercise, the

following conclusions appear justified;

 -111-
With regard to the stimulus,

1) There is not a single passive exercise experiment in which the

magnitude of motion was determined in both active and passive exercise.

2) Many authors even failed to attempt to recognize what the

stimulus during passive exercise should be, so instead of using

passive motion, some investigators used massage and many other

types of irritation, implying that these stimuli simulate those in

normal exercise without showing the evidence of it.

3) Many authors did not even determine the oxygen consumption.

With regard to the responses,

l) The determinations of the respiratory responses were made at

any time between one and ten minutes of passive exercise, but no one

has shown how soon a steady state response would be attained during

passive exercise.

However, from the available data, it has been found that during

passive exercise the relationship between ventilation and oxygen con­

sumption is the same as that during active exercise, implying that

motion is not concerned as a stimulus in exercise.

C. Ischemia Experiments.

For analyzing the observations in ischemia experiments, attention

is called to the unliklihood of reaching a steady state and to the

production of abnormal stimuli during exercise with ischemia. As for

the determination of the responses, it should be recalled that steady

state condition is essential* Both the intensity of stimulus and the

magnitude of the ventilatory responses should be measured during

exercise with and without ischemia.

 -112-

Asmussen and Nielsen (19) reinvestigated the ventilatory response

during exercise with ischemia in human subjects. Ventilation was

measured by means of a gas meter. Alveolar air was sampled by the

Scholander apparatus (53) and analyzed for the carbon dioxide tension.

For arresting the circulation to the legs, pneumatic cuffs were used.

The ventilatory response during voluntary (ergometer) and induced

exercise by modulated stimulator with and without ischemia was

studied. The results are presented in graphs, and hence are reproduced

in Figures 22 and 23. Figure 22 represents the observations on a sub­

ject during voluntary exercise. As shown in this figure, during the

two-minute ischemia the ventilation remained unchanged when the work

level was 824 mKgm/min. and increased when the work level was

412 mKgm/min. After the pressure was released the ventilation went

up in both instances. The alveolar carbon dioxide tension which was

recorded only when the work level was 412 mKgm/min. decreased during

ischemia and increased above the resting value when the ischemia was

released. The authors have specifically mentioned that during volun­

tary exercise with ischemia there was no "ischemic pain" but only

growing numbness and an increasing difficulty in moving the legs. The

subject had to "exercise harder" in order to keep the work output

constant.

Figure 23 represents the observations made on one individual in

which the work was induced. In this one instance, as shown in this

figure, the ventilation decreased about 70 per cent during ischemia.

It is interesting to note that the work intensity which was expressed

arbitrary units showed a transient increase, then a marked decrease

 -113-

Hcuffs inflated"*
alv.
P°°2 1*1*
in mraHg.

60 c"

2*0

vent*
L./min.
BTPS
20

0
-1.3 0.6 0
> 0.6 1.8 0

time in minutes
Figure 22. Ventilation(two lower sets of curves) and

alveolar pOC^ in work before,during and after

blocking of the circulation to the legs by

means of blood pressure cuffs. The curve

showing the alveolar pCX>2 is from the work

experiments at Ul2 rakgm.mino

Asmussen and Nielsen (if)

 -liu-

cuffs inflated

work in ✓
arbitrary
units

ventiLation during work

resting ventilation

0.6 1.2

Figure 23* Ventilation during electrically induced work

before and during blocking of the circulation

to the working muscles by means of blood

pressure cuffs. Upper curve represents the

work in arbitrary units0

Asmussen and Nielsen (19)

 -115-
during the last part of the 2.U minute exercise, although the electri­

cal stimulation was kept constant. There was no pain during ischemia

with induced exercise, but the muscles simply diminished their contrac­

tion in spite of the continued electrical stimulation.

The decrease in the work intensity during ischemia might furnish

clues as to the nature of this type of experiment and its uselessness

for investigating the mechanism of normal exercise hyperpnea. The

pertinent question would be: What is the potency of exercise stimulus

during ischemia? In this one instance of induced exercise, the

muscles involved were still the same but the contractions were smaller,

while in voluntary exercise, the individual had to adjust the muscles

involved in order to obtain a constant work output. If the intensity

of electrical stimulation represents the exercise stimulus, then, the

muscle contraction is decreasing gradually and this can explain the

decrease in ventilation in this present case. If the external work

accomplished be the intensity of the exercise stimulus, then, actually

the number of muscle units must be increased during ischemia in order

to accomplish the same amount of work. If normally, there is a

neural element locally involved in transmitting the exercise stimulus,

this neural element is mobilized to a greater extent and hence increased

the exercise stimulus. If this is the case, the work output xiould

not be a reliable exercise Index. Therefore, it is probable that this

type of experiment is of no value in elucidating the pathways involved

in normal exercise hyperpnea.

The same authors (Asmussen et al. (18)) performed ischemia experi­

ments also at an earlier time on human subjects performing voluntary

 -116-

work. A steady state of work was assumed to have been reached after

the subject has worked on an ergometer for 15 minutes. Ventilation

was determined with the aid of a Douglas bag during this steady state.

While the subject was still working, the circulation to the legs was

cut off by pressure cuffs inflated to 250-300 mm. Hg. The ventilation

was then measured within one to five minutes after the pressure was

on. The data thus obtained on three subjects are presented in Table 16.

In addition, data on subjects with and without ischemia at rest were

also obtained and hence are reproduced in Table 17.

As shown in these two tables, the resting oxygen consumption was

on the average 256 cc./min. STPD and 254* CG./min. STPD for subjects

No. 1 and No. 3 respectively. The oxygen consumption during work

without ischemia Increased according to the intensity of work. The

oxygen consumption during work with ischemia increased to a much less

degree at the corresponding work level. This increment of oxygen

consumption during work with ischemia implies that the ischemia was

incomplete, or other muscles beyond the ischemia were exercised. The

ventilation during work without ischemia increased proportionally to

the oxygen consumption, resulting in an average ventilation equivalent

for oxygen of 2.17. During work with ischemia the ventilation

increased to the same magnitude as during normal exercise, resulting

in an elevated ventilation equivalent for oxygen of 3.56 on the average*

In subject one determinations on five different work levels were made.

As shown in Table 16, in this subject the ventilation equivalent for

oxygen increased as a function of the work intensity.

From these observations, the authors concluded that the hyperpnea

 -117-

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Ventilatory responses in man during exercise with ischemia.

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 -118-

during exercise is regulated exclusively neurally because during

exercise with ischemia the oxygen consumption decreased but the venti­

lation remained the same.

From these authors1 later work which has been discussed previously,

it has been indicated that during exercise with ischemia a steady state

of exercise (as far as the exercise stimulus is concerned) cannot be

reached. These determinations in this article are all unsteady state.

As the authors mentioned, there were increasing ischemic pains, which

were increasing throughout the experiments, and in higher work

intensity the ischemia was only carried no more than one minute, because

of the pain. It is obvious then that this type of experiment can

never reach a steady state condition. Hence, it is a very unsatisfactory

method of dissociating the humoral and the neural pathways concerned

in exercise hyperpnea.

More recently, Asmussen and Nielsen (54) studied the effect of

ischemic blood on ventilation, in order to show that blood during work

contains substances with a pronounced stimulating effect on ventilation.

Two young, well-trained human male subjects were used. Each subject

was allowed to work on a chair ergometer at 1340 mKgm/min, for ten

minutes. After cessation of work, the blood in the legs was trapped

by inflating a pair of blood pressure cuffs which prior to work had

been placed proximately on the thighs, and the subject thereafter

placed his legs in a slightly elevated position on a high stool. After

15 minutes, the pressure in the cuffs was released. Respiration was

determined with the aid of the Douglas bag method starting four minutes

before the inflation and two minutes after deflation of the cuffs.
 -119-
The data are reproduced in Table 18,

Table 18, Ventilatory responses to 11auto transfusion.”

Asmussen and Nielsen (54)

Mean values from six experiments on each subject (S and W)

Before Release _____ After Release

Min. Min. Min. Min. Min. Min.
4-2 2-0 0-0.5 0.5-1.15 1.15-1.8 1.8-4

Subject S
Vent,., L./min. 9.8 9.6 26.6 35.9 26.3 13.4
r

Alv. co2, % 4.08 4.11 5.16 4.62 4.30 4.24

Alv. pC02, mm. Hg 29.1 .29.2 36.8 34.3 30.9 30.2

R.Q. 0.81 0.82 0.86 1.38 1.46 1.12

Subject W
Vent., L./man. 12.7 13.0 23.5 37.6 24.5 13.5
Alv. co2, % 3*66 3.59 4.64 4.45 4.06 4.15

Alv. p002, mm. Hg 36.2 35.4 33.0 31.8 29.0 29.4

R.Q. 0.86 >0.90 0.80 1.23 1.42 1.03

As shown in Table 18, in these two subjects, the resting ventila­

tion after exercise before the release of the pressure was on the

average 9.6 and 13.0 L./min BTPS respectively. These figures are

higher than the normal resting values, implying that the authors worked

on the recovery period of exercise. The average alveolar carbon dioxide

tensions were on the average 29.2 mm. Hg and 25.6 mm. Hg respectively,

which are lower than normal values, implying a hyperventilation. After

the release of pressure there was an increase in both the alveolar

carbon dioxide and the ventilation, the latter increased to 26.6 and

27.5 L./min. BTPS respectively; the former to 36.8 and 33.0 mm. Hg
 -120-
respectively.

It is probable that the trapped blood became hypercapnial, anoxic

and acidic, which when perfused to the respiratory center causes an

increase in ventilation. In order to prove that this humoral agent(s)

is concerned, it is necessary to determine if it is present during

normal exercise. It is known that during normal moderate exercise,

the increase in breathing is not due to the arterial carbon dioxide

tension, hydrogen ion concentration or oxygen tension, because they

do not change in moderate exercise. Then, the increase in ventilation

by ”auto transfusing” work blood which may render the arterial blood

hypercapnial, acidic and anoxic cannot explain the increase in

breathing during exercise. The production of an abnormal stimulus

does not explain the normal phenomen where the abnormal stimulus does

not exist. Hence, this type of experiment is of no help in studying

the mechanism of normal exercise hyperpnea.

Barman et al. (16, 17) have investigated the ventilatory responses

to exercise during Ischemia in three human subjects. Ventilation was

measured by an unspecified method in five conditions: 1) at,rest,

2) at rest with the circulation of both arms cut off at the level of

the distal insertion of the deltoids, 3) during exercise of the flexors

of the hand with the circulation normal, 4) during the same exercise

continued to exhaustion with the circulation cut off, and 5) immediately

after restoration of the circulation. The exercise consisted of

squeezing an inflated rubber bulb with each hand sixty times per minute

at a rate of irork of 12 meterKilograms per minute for one and one-half

minutes, or squeezing a bulb with one hand and moving an ergograph with
 -121-
the other. Sphygmomanometer cuffs inflated to a pressure of 200 mm. Kg

were used to cut off the circulation. The results thus obtained are

reproduced in Table 19.

The resting ventilation in these three subjects was on the average

9.07 L./min., BTPS, while the ventilation at rest plus ischemia was

on the average 9.27 L./min, BTPS, the latter being significantly

higher than the former. During exercise without ischemia, the

average ventilation went up to 9.98 L./min., BTPS, whereas during

exercise with ischemia, the average ventilation went up to 9.71 L./min.,

BTPS, the latter being significantly lower than the former. The venti­

lation immediately after the cuffs were released averaged 16.1 L./min.,

BTPS, which is significantly higher than that during exercise with

ischemia.

From these observations, the authors concluded that the normal

exercise stimulus must be of chemical-humoral origin and not a reflex

origin, because: l) the ventilation during exercise with ischemia is

lower than that without ischemia, and 2) there is an increase in

ventilation when the circulation Is restored.

On the basis of the unsteady state values obtained by these

authors, it has been shown that the ventilation during exercise with

ischemia is significantly lower than that without ischemia. This

favors, at least qualitatively, an additional mechanism being Involved

besides the humoral feedback mechanism in the regulation of breathing

during exercise. The fact that the ventilation during exercise with

ischemia is lower than that without ischemia can be explained by the

humoral feedback mechanism. The primary stimulus mechanism still remains

to be explained.
 -122-

Table 19. Pulmonary ventilation in liters per roinute of normal

subjects under conditions stipulated. Barman et al, (16, 17)

Resting
Resting Exercise Exercise First Minute
Plus No With After Exercise
Subject Resting; Ischemia Ischemia IscheEiia With Ischemia
1 6.90 7.00 8.10 7.30 12.4
7.50 8.20 8.90 8.90
7.20 8.00 8.50 8.50 13.0
6.40 7.60 7.60 7.00 12.2
6.SO 7.SO 8.10 7.80 14.5
6.SO 7.50 9.00 8.10
6.70 6.90 6.80 7.10 13.5
6.70 6.70 7.30 7.30 12.5
6.72 7.20 7.20 7.20 16.0
7.00 7.80 7.20 7.00

2 6.70 9.00 8.90 8.90 12.3

6.74 7.74 8.40 7.90 12.3
7.SO 8.20 7.90 9.10 13.1
6.SO 7.60 7.70 7.80
6.SO 6.90 8,60 9.10
7.95 8.20 8.45 8.00
6.75 6.80 7.43 6.75
7.SO 7.85 7.85 6.20 12.8
8.10 8.00 9.90 9.00
7.80 8.00 9.50 10.00 15.0
6.90 8.10 9'.10 8.00

3 6.80 8.10 8.50 8.20 ,0

6.50 7.10 8.80 8.20 12.0

Ave". STPD 7.50 7.66 8.25 8.02 13.3

BTPS 9.07 9.27 9.98 9.71 16.1

(A) (B) (0) (D) (S)

Paired comparison between (B) and (A) P < 0.01

Paired comparison between (C) and (D) P < 0,05

Paired comparison between (E) and (d ) P <•0,01

 -123-
The increase of breathing after restoration of circulation can

be explained by the elevation of known chemicals that affect venti­

lation in the arterial blood, but they are abnormal stimuli and do

not exist during normal moderate exercise.

These authors performed additional experiments on the same three

subjects who exercised with their legs. The subjects walked on a

motor driven treadmill at a grade of 8.5 per cent and a speed of

3.5 miles per hour until a steady state was reached. While still

walking the circulation of both legs was cut off by inflating, to a

pressure of 200 mm. Hg, sphygmomanometer cuffs placed around the legs

at the level of the distal insertion of the gluteal muscles. After

one and one-half minutes, the pressure ivas released and the subject

continued to walk until the previous steady state was reached,

usually within ten minutes. Ventilation and oxygen consumption

(Haldane analysis) were determined during the steady state of exercise

without ischemia, during ischemia for one and one-half minutes, and

finally after the release of pressure. The data thus obtained are

reproduced in Table 20 with calculated ratios to cut down the

scattering of the data.

As shown in Table 20 the oxygen consumption during exercise with­

out ischemia was on the average 1.720 L./min. STPD, while the venti­

lation was on'the average 50.1 L./min. BTPS, resulting in a ventilation

equivalent for oxygen of 3.01. During exercise with ischemia the

oxygen consumption was on the average 1.248 L./min, STPD, while the

ventilation was on the average 46.8 L./min. BTPS, reflecting a ventila­

tion equivalent for oxygen of 3.80, which is higher than the former*
 - 124-

I
<D to to t-vO CA CM vO \0
PA CM xQ CA ^ -q-ua O
Barman et al. (16, 17)

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Ventilatory responses to exercise with ischemia in man.

cti
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2 0 ® • • • • • • • • • * *
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Table 20.

H H O O to CM UA A H A
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 -125-

These observations on the ventilatory responses during exercise with

ischemia were unsteady state values. In the first minute after the

pressure was released, the ventilation increased to 70.7 L./min. BTPS

and the oxygen consumption to 1.911 L./min. STPD, reflecting a

ventilation equivalent for oxygen of 3*06, which Is practically the

same as that during exercise without ischemia.

On the basis of these observations, the authors concluded that the

stimulus to ventilation during exercise must be of humoral and not

of reflex origin because: l) after the release of the ischemia, even

though the nervous connections remain unaffected, there is a marked

increase of ventilation which must be caused by chemical-humoral

stimuli, and 2) even though the nervous connections remain intact,

11totaln ischemia of the legs during walking causes a decrease in the

pulmonary ventilation.

First of all, there was an oxygen increment during exercise with

ischemia, implying that the ischemia was Incomplete due to either

incomplete obstruction of the vessels, or to the mobilization of

muscles beyond the place where pressure was applied. Jhe increase of

breathing after the release of the ischemia does imply that some

chemical-humoral factor which when released stimulates breathing. It

is obvious that during ischemia the local blood is rendered hyper-

capnial, anoxic, acidic, either one of which may stimulate respiration

humorally, if they are present in the arterial blood, but none of

them exist during normal moderate exercise. As for the second reason

the authors proposed, they neglected that the metabolic rate during the

period of ischemia also decreased. However, an unsteady state high

 -126-

ventilation equivalent for oxygen resulted during ischemia, which implies

that either abnormal stimuli xrere present, or that the humoral feed­

back mechanism was not operating, or both. Since this is an unsteady

state behavior, it is unnecessary to postulate what the cause was.

However, it can be stated that if there were no abnormal stimuli pro­

duced by ischemia the decrease of ventilation may be due to the humoral

feedback system.

It is clear that this experiment has contributed no additional know­

ledge toward the illumination of the mechanism of exercise, hyperpnea.

There are also fragmentary data concerning ischemia experiments.

For example, Harrison et al, (20) have performed various kinds of

experiments including ischemia to investigate the mechanism involved

In the hyperpnea of exercise. They carried out their experiment on

four human subjects who performed voluntary exercise consisting of

rapidly opening and closing the hands and/or rotating the feet. Venti­

lation was recorded with the aid of a spirometer before and during work

(duration not specified) with circulation intact or impeded by pressure

cuffs inflated to 200 mm. Hg and placed around the proximal portions

of the extremities. The data are reproduced in Table 21.

In two subjects who performed work using both hands and feet, xbLth

the' circulation intact, the average ventilation increased from 7.28 to

15.23 L./min., an increment of 110 per cent. In the seme subject,

performing similar work with the circulation to the extremities cut

off, the ventilation on the average increased from 7.10 to 14-.26 L./min.,

and increment of 100 per cent. In treating- all the resulrs obtained

from the four subjects together, it was found that the increase in
 -127-

Table 21, Ventilatory response to exercise with ischemia in man,

Harrison et al. (20),

Ventilation
Portion of L./min. (BTPS?) Increment
Condition Subj. Body Moved Before During in %

Voluntary movement 1 Hands and feet 7.70 12.06 57

with circulation
intact 2 Hands and feet 6.85 18.40 168

3 Feet 7.24 8.73 20

4 Hands 7.56 -12.30 62

Voluntary movement 1 Hands and feet 7.70 13.20 71

with circulation
impeded by 2 Hands and feet 6.49 15.32 137
pressure
3 Feet 8.32 8.52 2.5

4 Hands 8.36 14-10 69

 -128-

ventilation during work with the circulation intact was significant

but that with the circulation cut off was not significant. From these

observations the authors concluded that the increase of breathing

during exercise is exclusively due to a neural stimulation.

These authors have carried out no control experiment to evaluate

the ventilatory changes, if any, due to ischemia alone. From one of

the tracings recorded, the authors used the value of ventilation of

the first minute of exercise. This, of course, is unsteady value

and, therefore, cannot be used to compare quantitatively with the

steady state values. Furthermore, the authors performed two few

experiments, only two had similar xx>rk. Hence, this experiment is

not conclusivei

Comroe and Schmidt (14) performed ischemia experiment to

investigate the possibility of the reflex from the limbs being a

factor in the regulation of hyperpnea of muscular exercise. Exercise

of the right forearm and hand was produced by flexion of the fingers

at a rate of 60 per minute, each effort raising a weight of 1360 gram

of a distance 5-7 cm. (about 4*9 mKgm/min.). Ventilation was deter­

mined by means of a gas meter in 11 subjects under five conditions:

1) resting control which consists of two minutes of observations after

a steady state had been shown to be present* 2) occlusion of the

circulation in the right arm by inflation of pressure cuffs to a

pressure higher than the systolic arterial level* 3) exercise of the

right forearm and hand with circulation intact* 4) repetition of the

exercise with the circulation cut off (terminated as soon as any

unpleasant sensations were experienced, often in less than two minutes—

 -129-

unsteady state); 5) cessation of the exercise without restoration of

the circulation. The differences in ventilation in percentage between

the control and each of the other four conditions cited above were

reported and hence are reproduced in Table 22. The average change of

these 22 determinations on these 11 subjects are as follows: l) from

control to exercise, 14 per cent; 2) from control to ischemia alone,

1.0 per cent; 3) from control to exercise plus ischemia, 28 per cent;

4) from control to continued occlusion after exercise, 14 per cent.

Except for the change from control to ischemia alone, all the other

changes are significant. Since pain sensation occurred during exercise

with ischemia in most of the cases, the authors concluded that the
r

larger increase in breathing during exercise with ischemia was caused

by the pain stimulation.

From the authors* data, it should be evident that the range of

the exercise intensity used by the authors was extremely small. The

increase in breathing during •'normal11 exercise in the present experi­

ment was merely 14 per cent, which is almost negligible in comparison

with the 1000 per cent increase in breathing during normal exercise.

Since the authors have only obtained unsteady state values and since

an abnormal stimulus was produced which affects the breathing, their

experiment is, therefore, of no value in demonstrating the mechanism

involved in normal exercise hyperpnea.

Delucchi (55) investigated the effect of ischemia on ventilation

in human subjects during work and at rest. The work consisted of a

continuous push on a rudder bar i^eighing 10 or 20 pounds for five

minutes, using one leg. Subjects breathed 100’per cent oxygen and
 -130-

Table 22. Ventilatory response in man during exercise with ischemia.

Comroe and Schmidt (14).

Subject Per Cent Change in Ventilation

1 2 3 4
1 0 -12 +23 +35
0 0 0 0
+12 0 +16 +16
2 +50 -8 +61
+15 +5 +16 +23
+13 0 +30 +20
+30 0 +45 +20
+37 0 +40 +61
+25 -13 +28 +12

3 0 -14 -16 0
-10 0 +15 +25
0 0 +75 +30

4 +40 +14 +32 0

+36 +12 +84 +26

5 0 +25 -22 +12

+30 0 +29 -3

6 0 0 +33 +7

7 -8 0 +13 +3

8 +10 +12 +31 0

9 +20 0 +28 0

10 +11 0 +7 +3

11 +27 +2 +35 -4

N.B.
1= Changefrom control to exercise•
2= Changefrom control to ischemia alone.
3~ Changefrom control to exercise plus ischemia.
4= Changefrom control to continued occlusion after exercise.
 -131-
their ventilation was recorded by a gas meter. The pressure was

applied to the leg at the proximal end to a pressure of one-half or

two-thirds the systolic pressure by means of a sphygmomanometer cuff.

Their results are reproduced in Tables 23 and 24.

As shown in these tables, the resting ventilation averaged

8.15 L./min, BTPS, in one series of experiments and 8.01 L./min. in

another. When pressure was applied to one-half the systolic blood

pressure, there was practically no change in breathing. However, when

the pressure was up to two-thirds the systolic blood pressure, the

resting ventilation decreased to 7.38 and 7.15 L./min. BTPS respectively.

In comparing the resting ventilation and that with two-thirds systolic

blood pressure, by group comparison analysis, it was found the venti­

lation decreased significantly when pressure was applied. During work

at a level of 10 pounds, the ventilation increased on the average to

8,95 L./min, BTPSwhen no pressure was applied, but increased to

9.16 L./min. BTPSwith one-half systolic blood pressure, and increased

to 10.25 L./min. BTPS with two-thirds systolic blood pressure. The

increase in ventilation during work with two-thirds systolic pressure

was significantly higher than that without pressure. During work at

a level of 20 pounds, the ventilation increased to 9.85 L./min. BTPS

with no pressure, to 9.99 L./min. BTPS with one-half systolic pressure

and to 10.75 L./min, BTPS with two-thirds systolic pressure.The

increase in ventilation was higher with two-thirds systolic pressure

than that without pressure.

The greater increase in ventilation during work with a higher

pressure may be due to: 1) the generation of a new stimulus that affects
 - 132-
Table 23. Ventilatory responses in man during exercise with ischemia.
Delucchi (35).

Ventilation, L./min.
Rest Push 10 Pounds
(A}” (B) ' " ' T e r ....
'

Plus Plus
Vascular Vascular
One-half Two-Thirds Obstruction Obstruction
No Systolic Systolic Ho (1/2 sys- (2/3 sys­
Obstruc­ Blood Blood Obstruc­ tolic blood tolic blood
Subi. tion Pressure Pressure tion pressure) pressure)
1 5.08 4.76 4.93 6.83 6.93 8.10 ■
2 9.94 9.79 9.04 9.96 9.96 10.32
3 6.17 6.98 5.16 6.76 6.77 7.94
4 7.43 6.95 6.85 7.76 7.14 7.54
5 6.31 6.24 4.95 6.47 6.05 7.17
6 5.36 5.71 5.24 5.85 7.86 8.76
7 6.78 7.10 6.50 8.06 8.21 8.71

Ave. 6.72 6.79 6.10 7.39 7.56 8.48 STPI

8.15 8.21 7.38 8.95 9.16 10.25 BTP£

Table 24. Ventilatory responses in man during exercise with ischemia,

Delucchi (55).

Ventilation, L./min.
Rest Push 20 Pounds
(D) (E) (f1
Plus Plus
Vascular Vascular
One-half Two-Thirds Obstruction Obstruction
No Systolic Systolic No (1/2 sys- (2/3 sys­
Obstruc­ Blood Blood Obstruc­- tolic blood tolic blood
Sub;]. tion Pressure Pressure tion pressure) pressure)
1 5.88 5.90 5.55 7.66 7.93 8.71
2 7.28 8.04 7.07 9.04 8.35 9.73
3 6.31 6.24 4.95 8.23 8.26 8.62
4 7.43 6*95 6.85 8.54 8.89 9.50
5 6.17 6.98 5.16 7.20 7.94 8.57
6 6*44 6.22 5.19 7.23 7.09 7.63
7 6.78 7.10 6.50 9.00 9.38 9.43
Ave. 6.61 6.78 5.90 8.13 8.26 8.88 STPD
8.01 8.21 7.15 9.85 9.99 10.75 BTPS

Paired comparison: B -A P > 0.10 uj - D P > 0.40

C -A P < 0.02 F - D P < 0.01
 -133-
ventilation. This may be pain, or any discomfort, etc., and/or 2) the

fact that when obstruction is present, ’'fatigue11 may easily result.

Thus, in order to perform the same amount of work during pressure,

gradually more muscles must be mobilized and hence ventilation is

augmented.

At any rate, either of the above possibilities defies the useful­

ness of this type of experiment in studying the regulation of breathing

during normal exercise.

Summary: In the theoretical analysis, it has been shown that, in

ischemia experiments, a steady state response is not likely to be

attained, since the circulation is obstructed with resulting accumula­

tion of stimulating substances, except for motion. However, motion

has been previously shown not to be the factor responsible for the

regulation of breathing during exercise. If a steady state response

could be attained, then, in an uncomplicated ischemia, the subject

should show: a) according to the humoral-humoral typothesis, that

the ventilatory responses remain unchanged, and b) according to the

reflex-humoral hypothesis, show an elevated ventilation equivalent for

oxygen, whether ischemia is complete or not, but with no complications.

The testing of these hypotheses with the observations from the

ischemia experiment would be unnecessary, since the responses under

these conditions are unreliable.

From the literature dealing with ischemia experiments, it was

found that:

With regard to the stimulus,

l) No investigators ever performed experiments long enough to

 - 134-
permit a steady state to be reached, if it can be attained at all.

2) In induced exercise, the work intensity decreased gradually

even when the electrical stimulus was maintained at a constant level.

3) In voluntary exercise, one had to "work harder" gradually

in order to keep the work output constant even for one to five minutes.

With regard to the response,

1) No investigators ever determined the ventilation during

steady state.

2) Pain or numbness is inevitably produced even when the duration

during exercise with ischemia was only one minute.

Because of the fact that a steady state of response cannot be

attained and that an abnormal stimulus is produced, it is concluded that

the ischemia experiments are unreliable in studying the mechanism of

the exercise hyperpnea.

D. Vascular Anastomosis Experiments.

It should be recalled that in order to test the dual hypotheses,

proper vascular anastomosis must be performed to dissociate completely

the neural and the humoral pathway. In addition, the following

information should be acquired:

1) Determination of the oxygen consumption of both animals in

the steady state of exercise and at rest.

2) Determination of ventilation or arterial blood gas composi­

tions in both animals during steady state of exercise and at rest.

3) Abnormal stimuli must be avoided.

There are two articles located in the literature dealing with

 -135-
experiments related to what we defined previously as vascular anastomo­

sis experiments. One is by Heyrnan et al. (56), who performed their

experiments on dogs. A dog’s head completely separated from its body

was perfused with a donor dog’s blood through the carotid arteries

and jugular veins. The donor dog was induced to exercise by tetanizing

or modulated current. ’’Respiration" was measured by recording the

movements of the larynx or nostrils of the perfused head. The venti­

lation on the donor dog was not recorded. It was found that the

laryngeal or nostril twitching of the perfused head increased when the

donor dog was exercised. Based on this experiment, the authors

claimed that ventilation during exercise is increased through

humoral agents.

This experiment is very inadequate for the following two reasons:

1) There was no measurement of ventilation, but only the laryngeal

twitching. 2) The vascular anastomosis was carried out on the

carotid arteries and the jugular veins. During moderate exercise the

known chemical agents stimulating respiration in the carotid artery

do not change. In the authors’ experiment, if the donor dog’s

ventilation during the induced exercise was adequate, its arterial

blood should be neutral, no stimulating effect on ventilation. It

is very probable that the donor dog’s head Is not adequately supplied

by blood because of the improper anastomosis and, therefore, the dog

may be hypoventilating, rendering its blood hypercapnic. Thus, this

experiment again falls in the same category of producing an abnormal

stimulus which is mediated humorally. This experiment, therefore, is

of no value in demonstrating the normal mechanism of exercise hyperpnea.

 -136-

The second of such anastomosis experiment was performed by

Kramer and Gauer (12) in two chloralosed cats in which the venous

circulation of the hind extremities of these two cats were crossed.

The lower extremities of the donor dog was stimulated by tetanizing

current for four minutes. Ventilation was measured by means of a

gas meter, the alveolar carbon dioxide tension and the oxygen con­

sumption were recorded continuously by means of the so-called

"Reinschem Gaswechselschreiber." One experiment was done and the

results were presented in two graphs. In the recipient animal, there

was increase in the alveolar carbon dioxide tension, no change in

oxygen consumption, but decrease in ventilation. In the donor dog

there was increase in alveolar carbon dioxide tension, Increase in

ventilation, and increase in oxygen consumption.

The anastomosis procedure in this experiment is not adequate

because only the veins were crossed; hence, the neural and the

humoral pathways are not completely separated. Therefore, Kramer and

Gauer*s experiment is not conclusive regarding the mechanism involved

in exercise hyperpnea.

Summary: In the theoretical analysis, It has been shown that in the

steady state of uncomplicated, properly performed vascular anastomosis

experiments, the humoral animal should show: a) according to the

humoral-humoral hypothesis, a normal response, and b) according to

the reflex-humoral hypothesis, a response similar to that predicted

for the parametric forcing, a decrease in the ventilation equivalent

for oxygen with a respiratory acidosis. The neural animal, 011 the

other hand, should show: a) according to the humoral-humoral hypothesis,

 -137-
no response, and b) according to the reflex-humoral hypothesis, a

response to direct forcing, which should be accompanied by an elevated

ventilation equivalent for oxygen and respiratory alkalosis.

From the literature, no experiments have been found regarding

proper vascular anastomosis. Hence, it becomes necessary to perform

the proposed experiments to test our dual hypotheses.

E. Experiments Attempting to Identify Peripheral Chemoreceptors.

Since the experiments so far performed have been unsuccessful in

revealing the normal mechanism involved in exercise hyperpnea, it

becomes necessary to review the literature dealing with the identifi­

cation of peripheral chemoreceptors, the existence of which implies a

neural mechanism. It is well established that there are central

chemoreceptors (57) and also chemoreceptors located along the aortic

arch (58) and the carotid sinuses (59), which when stimulated affects

ventilation. For convenience, all of these known chemoreceptors are

considered as central. By peripheral chemoreceptors, then, we mean

those responsive to hydrogen ion concentration, to carbon dioxide

tension, and to oxygen tension changes and located in the extremities,

along the venous side of the circulation or in the working tissues.

Literature concerning the identification of peripheral chemo­

receptors is meager* Comroe and Schmidt (14) have attempted to

demonstrate peripheral chemoreceptors in the limbs of animals. They

performed three types of experiments. The first type of experiment

consisted of cross perfusions in which blood from a donor dog was

circulated through one or both hind limbs of the recipient dog by

 -138-
means of a perfusion pump. These experiments were performed to test

the ability of blood rendered anoxic, hypercapnic, and acidic "by

appropriate manipulation of the donor" to cause a reflex hyperpnea

in the recipient. The authors claimed that no signs of any such

effect were seen. Since there are no data given, it is impossible

to evaluate the authors’ statement.

The second type of experiment was claimed to be "auto trans­

fusion" experiments which consisted of injection into one femoral

artery of blood collected from the opposite femoral vein during

"exercise," ischemia, and "exercise" plus ischemia on the side of

collection. Usually 5 to 20 cc. of blood were collected and then

was injected into the profunda femoris, the main artery being clamped

above the point during the injection. The authors stated that although

the appearance of the collected blood indicated complete change to

"reduced hemoglobin," there was no effect on breathing, when the

blood was injected into the opposite femoral artery. Since only

5 to 20 cc. of blood was used, it is doubtful if the response can be

observed. Furthermore, the authors presented no data; hence, an

analysis was not possible.

The third type of experiment consisted of intrarterial and

intramuscular injections of various chemical substances, hydrochloric

acid, lactic acid, etc. The authors claim that acids were active

when injected in concentrations of 0.1N or stronger but thrombosis of

the artery frequently followed repeated injections. The threshold

was said to be about pH 6.7 which was effective only weakly and

occasionally in cats. The injections were made with the arterial

 -139-
inflow cut off and the response was observed after the circulation

was restored# The fact that the response was observed after the

circulation was restored implies a central effect. Even if the

effect of the injected acid is local, it is still necessary to dis­

tinguish whether it is due to chemoreceptors acting locally, or due

to pain irritation. Therefore, these experiments are not conclusive

in regard to the identification of local chemoreceptors#

Ischemia at rest makes the local blood anoxic, hypercapnic, and

acidic. If there were any chemoreceptors responding to these changes

and affecting ventilation, an effect on ventilation should be observed,

provided no abnormal stimulus is produced by the ischemia# In review­

ing the fragmentary literature dealing with this problem, different

results were found. For example, Conroe and Schmidt (14.) performed

experiments in man by occlusion of the circulation in the right arm

by inflation of the cuffs to a pressure higher than the systolic level.

Ventilation was measured by measuring the expired air in a gas meter.

The results thus obtained are reproduced in Table 25. The average

increase in ventilation during ischemia was 1 per cent, which is

statistically not significant, implying no evidence of local chemo­

receptors.

Barman et al. (16, 17), on the other hand, revealed a significant

change in ventilation when ischemia was produced in both arms in man#

They performed their experiments on three human subjects. Ventilation

was measured at rest and at rest with ischemia. Ischemia was pro­

duced by cutting off the circulation of both arms at the level of the

distal insertion of the deltoids by sphygmomanometer cuffs inflated

 -14.0-

Table 25. Ventilation changes due to ischemia of right arm

at rest in man. Comroe and Schmidt (14)*

% Change in Ventilation
Subject During Ischemia

1 -12
0
0
2 -8
+5
0
0
0
-13
3 -14
0
0
4 +14
+12
5 +25
0
6 0
7 0
8 +12
9 0
10 0
11 +2

Average 1%

Insignificant P > 0.50

 -141-

Table 26. Ventilatory response to ischemia of arms at rest in man.

Barman et al. (16, 17).

Ventilation Resting
Expt. L./min. Plus
Subject_____ No.____ Resting Ischemia
1 1 6.90 7.00
2 7.50 8.20
3 7.20 8.00
4. 6.40 7.60
5 6.80 7.80
6 6.80 7.50
7 6.70 6.90
8 6.70 6.70
9 6.72 7.20
10 7.00 7.80

2 1 6.70 9.00
2 7.74 7.74
3 7.80 8.20
4 6.80 7.60
5 6.80 6.90
6 7.95 8.20
7 6.75 6.80
8 7.80 7.85
9 8.10 8.00
10 7.80 8.10
11 6.90 8.10

3 1 6.80 8.10
2 6.50 7.10

Average 7.09 7.69

Paired comparison P< 0.01

 -142-

to a pressure of 200 mm* Hg* Their data are reproduced in Table 26.

The ventilation increased on the average during ischemia from

7*09 L*/min. to 7.69 L*/min., which was significant* This significant

increase in ventilation during ischemia-implies some kind of stimulus

was produced but not necessarily chemical. It may be pain that stimu­

lates the ventilation*

Ischemia was also produced in the legs in man. Asmussen et al. (18)

studied the effect of Ischemia on ventilation by blocking the circula­

tion to the legs by means of pneumatic cuffs inflated to a pressure of

250 to 300 mm. Hg. Ventilation was measured in two subjects at rest

and at rest with ischemia. The results are reproduced in Table 27.

Table 27. Ventilatory responses to ischemia of legs at rest in man.

Asmussen et al. (18).

No, of Ventilation O2 Consumption

Subj. Condition Expt. l./min., BTPS cc./min., STPD VE
1 Rest 9 5.66 t 0.06 256 t 2.1 2.2

Rest with ischemia 6 5.25 £ 0.09 237 t 2.1 2.2

2 Rest 9 6.93 t 0.12 254- £ 1*2 2.7

Rest with ischemia 12 6.26 t 0.05 231 £ 1*4- 2.7

As shown above, there is a decrease in both ventilation and oxygen

consumption during ischemia, but the ventilation equivalent for oxygen

(VE) stayed constant.

Delucchi (55) has studied the total ventilation after partial

obstructing of the blood vessels to the right leg at rest. Pressure

was applied by means of pressure cuffs Inflated to a pressure one-half

 -143-

or two-thirds of the systolic pressure. Ventilation was measured by

means of a gas meter. The results are presented in Table 28.

Table 28. Ventilation changes due to ischemia of right leg at

rest in man. Delucchi (55).

Ventilation,
v L./min.
9 xj • / iixj-xx#
One-Half Two-Thirds
No Systolic Systolic
Subject Obstruction Pressure Pressure
1 5.08 4.76 4.93
2 9.94 9.79 9.04
3 6.17 6.98 5.16
4 7.43' 6.95 6.85
5 6.31 6.24 4.95
6 5.36 5.71 5.24
7 6.78 7.10 6.50
8 5.88 5.90 5.55
9 7.28 8.04 7.07
10 6.31 6.24 4.95
11 7.43 6.95 6.85
12 6.1? 6.98 5.16
13 6.44 6.22 5.19
14 6.78 7.10 6.50
Averages 6.67 6.78 5.99 STPD

8.07 8.21 7.25 BTPS

The ventilation of these 14 subjects at rest averaged 8.07 L./min.

when one-half systolic pressure was applied to the right leg, the

average ventilation was 8.25 L./min., which was not significantly

different from that without pressure. The ventilation decreased on

the average to 7.25 L./min. when two-thirds systolic pressure was

applied, which was significant,

Delucchi1s observations are irrelevant because there was no com­

plete obstruction and it was doubtful if ischemic blood was produced.

In summary, experiments performed in animals by nauto transfusion,,f

and injection of acids, to Identify peripheral cheraoreceptors are

 - 144-
inconclusive. Ischemia produced by pneumatic cuffs inflated to

pressures from 200 to 300 mm. Eg on human arms increased, decreased,

or did not change ventilation, Ischemia produced in human legs by

pressure cuffs also showed equivocal results in ventilation. Hence,

all the available experiments in this regard are not conclusive. To

Identify peripheral chemoreceptors necessitates a procedure of two

steps, l) to produce the chemical changes locally and observe their

effects on ventilation when the circulation to the central chemo­

receptors is blocked. It is also necessary to avoid the production

of other abnormal stimulus, e.g. pain, which stimulates ventilation

peripherally. 2) to identify the chemical changes in the local

peripheral tissue or venous circulation during exercise. No authors

have carried out such a study.

 -145-
IV. SUMMARY OF LITERATURE AND STATEMENT OF PROBLEM.

The literature dealing with the following four types of experiments

has been reviewed in order to obtain information regarding the mechanism

involved in exercise hyperpnea: 1) denervation experiments, 2) passive

exercise experiments, 3) ischemia experiments, and 4) vascular anas­

tomosis experiments.

The denervation experiments have been inconclusive with regard to

the mechanism of exercise hyperpnea because of the inadequacy of the

determinations in most of the experiments* In those experiments in

which proper determinations were made, the animals showed circulatory

disturbance; also abnormal stimuli were not evaluated. Therefore,

these experiments also have been inconclusive with regard to normal

exercise and inadequate to test the dual hypotheses.

The passive exercise experiments, which are more a means of

differentiating motion from other exercise stimuli, have revealed that

motion is probably not concerned as a stimulus in normal exercise

hyperpnea.

The ischema experiments have shown that during exercise with

ischemia a steady state response cannot be attained, and that an

abnormal stimulus to ventilation is Inevitably produced. Hence, this

type of experiment is not satisfactory in studying the mechanism of

exercise hyperpnea.

The vascular anastomosis experiments seem to be the most ideal

means of dissociating the humoral and neural pathways, and of preserving

the normal environment for the working muscles, but no investigator

 - 146-

has performed this type of experiment in the proper way. Hence, our

dual hypotheses cannot be tested by the observations so far obtained

from this type of experiment.

In addition, literature dealing with identification of the

peripheral chemoreceptors has been reviewed. It has been found that

no investigators have employed the proper procedure in attempting

an experiment for identifying the peripheral chemoreceptors.

Hence, the present study has been undertaken to investigate:

1) The dual nature of the mechanism of the exercise hyperpnea.

2) The abnormal sensory stimulation, since electrical current

is used in inducing exercise.

3) The existence of peripheral chemoreceptors In the working

muscles.
 - 147-
V. EXPERIMENTAL METHODS

The experimental methods are divided into two categories, general

procedures and specific procedures.

A. General Procedures.

Experimental animals and their preparation. Mongrel dogs weighing

from ten to twenty kilograms were used in the present study. The

animals were fasted twelve hours before use. They were anesthetized

with sodium pentobarbital, intravenously, 30 mg. per kilogram of body

weight. Supplementary doses were given at two-hour intervals when the

experiment was continued longer than three hours.

Method of producing exercise. The animal was fixed in the supine

position. An iron bar, 0.5 cm. in diameter, was inserted through the

soft tissues at the knee joint. This bar was then fixed horizontally

in a frame so as to lift the knee joint to a position higher than the

abdomen. A weight of 1.3 kilograms was fixed by a pully system to the

Archillis tendon of the animal. Exercise was Induced by means of

60 cycles alternating current modulated sinusoidally at 50 per minute,

delivered to the muscles of the hind limb by means of two needle

electrodes. One electrode was inserted into the tibialis anticus

muscle and the other into the quadriceps. For inducing exercise of

both lower extremities four needle electrodes were used. These

electrodes were placed, two in each limb, in the same sites as

described. The movements produced were extension and flexion of the

lox/er portion of the hind extremity with the knee joint as the fulcrum.

A step input current stimulus was used in all instances to induce

exercise.
 -14B-

Method of determining the responses. After tracheotomy, a

cannula was Inserted into the trachea, which was connected to a

Benedict-Roth metabolimeter, filled with 100 per cent oxygen, to

obtain a record of oxygen consumption and ventilation* The values of

oxygen consumption and ventilation were expressed as STPD and BTPS

respectively*

B* Specific Procedures.

Method of evaluating the adventitious stimulation of ventilation

in induced exercise. In order to evaluate the adventitious stimula­

tion of ventilation in induced exercise, both motor nerve root stimula­

tion and peripheral stimulation were carried out in the same dogs. The

animal was fixed in a prone position with the two hind extremities

hanging in the natural position. The spinal cord of the animal was

exposed at L^ - Ly and the seventh lumbar ventral roots were freed

from the cord and coated with a layer of liquid paraffin. The current

was delivered to the peripheral end of the severed ventral roots from

the same stimulator by means of German silver electrodes with a

resistance of $0,000 ohms in the output circuit. The peripheral end

of the nerve root during stimulation was completely isolated from the

tissues to avoid current spread. The movements produced in this type

of experiment were extension and flexion of the lower extremities

simulating running movements. The same animal thus prepared was also

stimulated alternatively using root stimulation with electrodes applied

peripherally to the aforementioned sites.

Method of dissociating neural and humoral pathways. In order to

dissociate the neural and humoral pathways and to preserve the normal
 -149-

environmenb for the working muscles, vascular anastomoses (cross

circulation) were carried out. The dog whose lower extremity was

exercised is called the '•neural*1 dog. Its exercising leg is perfused

with the blood of the donor or "humoral" dog. Three types of vas­

cular anastomoses were used.

Type A . The cephalic ends of the left external iliac artery and

the left common iliac vein of the humoral dog were connected to the

peripheral ends of the corresponding vessels on the right side of the

neural dog. The internal iliac arteries of both animals were tied.

The right posterior extremity of the neural dog was perfused and

exercised in this type of experiment. Figure 24 illustrates the

general scheme of the vascular anastomoses.

Type B. The cephalic end of the abdominal aorta of the humoral

dog was connected at the level of the fourth lumbar vertebra to the

peripheral end of the right external Iliac artery of the neural dog,

whose right internal iliac artery was tied. The cephalic end of the

inferior vena cava of the humoral dog was connected at the level of

the fourth lumbar vertebra to the peripheral end of the right common

iliac vein of the neural dog. The right posterior extremity of the

neural dog was perfused and exercised In this type of experiment.

Type C. The cephalic end of the abdominal aorta of the humoral

dog was connected at the level of the fourth lumbar vertebra to the

peripheral end of the same vessel at a corresponding level in the neural

dog. In addition, the cephalic end of the Inferior vena cava of the

humoral dog was connected to the peripheral end of the inferior vena

cava of the neural dog at the level of the fourth lumbar vertebra.
 - 150-
Humoral dog Neural dog

Figure 2h
Brain Brain
Diagram showing the

circulation of the
IT
vas cular-anas tomosed

dogs
i
Lungs Lungs
RV - right ventricle
-J— T-i- -^skr- T— T—4
LV = left ventricle

RA. = right atrium

RV LA. = left atrium RV

AA = abdominal aorta

IV =s inferior vena cava

IA = iliac artery

ILV= iliac vein

AA
 -151-

Both posterior extremities of the neural dog were perfused and exercise

in this type of experiment.

The connections between the vessels were made with glass cannulae

and tygon tubing, the diameters of which were selected to fit the

lumen of the anastomosed vessels. The glass cannulae were coated

internally with a thin layer of Dri-film after scrupulous cleansing.

The blood of all dogs used in these experiments was cross matched

as a check against possible agglutination reactions. Each pair of

animals used was approximately of the same weight. An abdominal

approach was used in exposing the vessels for anastomosis. Incisions

were made with a cautery unit. Using this procedure, blood loss was

negligible after an experiment of six to seven hours duration.

Before the vessels were anastomosed, heparin (0.5 mg. per kilogram

of body weight) was injected intravenously into both dogs. Supple­

mentary doses of heparin were given at two hour intervals. Shortly

after the administration of heparin, the vessels were connected and

tied, and the perfusion procedure was initiated. The perfused extrenw-

ity(ies) was exercised for 15 minutes after the resting steady state

values of ventilation and oxygen consumption had been obtained. The

exercise was repeated at 30 minute Intervals.

Method of identifying peripheral chemoreceptors. The procedures

used for the experiments attempting to identify peripheral chemo­

receptors were the same as those already described for the anastomosis

experiments* Instead of exercising the neural dog, hox/ever, the

humoral dog rebreathed air in a three liter closed circuit for eight

minutes. The effect on ventilation was studied in both the neural and

the humoral dogs.

 -152-
VI. EXPERIMENTAL RESULTS M D THEIR ANALYSIS

For analysis, the experimental results are divided into four

parts: A. Evaluation of the adventitious sensory stimulation In

electrically induced exercise, B* Evaluation of the adequacy of the

vascular anastomoses, C. The pathways Involved In the regulation

of breathing during induced exercise, D. The indentification of

peripheral chemoreceptors•

A. Evaluation of the adventitious sensory stimulation in electrically

induced exercise.

In order to evaluate the adventitious sensory stimulation In

electrically induced exercise, the ventilatory responses were deter­

mined In the same animal with exercise Induced by (l) spinal motor

root stimulation and by (2) peripheral direct stimulation. Thirteen

experiments were performed in five dogs. An analysis was carried out

to study both the transient and the steady state behaviors.

1. Transient behavior. The general trend of the time curves

of the measured (ventilation, V; oxygen consumption, O2) and derived

(ventilation equivalent for oxygen, VE) variables.

Peripheral stimulation•

The time course of the variables of the dogs with exercise

by peripheral stimulation are plotted in Figure 25s In which each curve

represents the average values from the 13 experiments in five dogs.

Stimulation was started at zero time and continued at a steady intensity

for 15 minutes. The variables were also followed for ten minutes before

and after exercise. The curves show:

a. The oxygen consumption increases immediately after the

 -153-

Sc&8 * •irpn/*»i ut uoT^ifauaA

O ro CN cd O

(HJS* •irpn/*oo ux uoTq.dmnsuoo ua&Cxo

vn h
o h
va

ro
started
stimulation

c+
H*

VJ\

H-
stimulation

H-
H-
OP

Hj Vn.
O
CL
(D O
^ TO
vn c+ '•
 -154-

the exercise is started and rises to a peak value in two minutes.

Then it decreases gradually to reach a steady state.

b. The ventilation increases immediately and reaches

a peak value in the first minute of exercise. Then it decreases

and attains a steady state.

c. The ventilation equivalent for oxygen increases in the

firstminute of exercise (P < 0.01 by paired comparison analysis of

the ventilation equivalent for oxygen at rest and during the first

minute of exercise), then decreases and attains the resting value.

d* After the cessation of exercise, the fall in oxygen

consumption and ventilation begins immediately, but does not reach

the original values within ten minutes.

Spinal motor root stimulation.

In this group of experiments, the exercise was induced by

stimulating the ventral spinal roots (the seventh lumbar motor

nerve, right or left or both, see Table 30) which were cut free from

the spinal cord* The averaged values of oxygen consumption, venti­

lation and ventilation equivalent for oxygen for 13 experiments

in five dogs are plotted in Figure 26. It shows:

a. The oxygen consumption increases immediately after

exercise is started. It reaches a peak value and then decreases

gradually to reach a steady state.

b. The ventilation also increases immediately and reaches

a peak value. From the kymograph tracing, it was observed that

the ventilation increased in every experiment from the first breath

after stimulation was started. The ventilation attained a steady

 - 155-

S c IIQ ' 'U T t t l / 'q UT UOTq.BTfq.U0A

ro {=- os CD

(H IS * *UTm//*D 0 UT uot^dTnrisuoo ueBJhco

vn VA

ro

vn.

H-

H-

ro
On

H-

VA

vn VjJ
 -156-

state well within the period of observation.

c. The ventilation equivalent for oxygen increases in the

first minute of exercise (P < 0,01, by paired comparison analysis of

ventilation equivalent for oxygen at rest and during the first minute

of exercise), then decreases to reach the resting steady state value.

The general time course of the ventilation equivalent for oxygen is

practically identical with that observed in peripheral stimulation,

d. The behavior of oxygen consumption and ventilation

during recovery is identical with that observed in peripheral stimu­

lation.

It should be emphasized, however, that the time curves in

Figures 25 and 26 are plotted from average values. They show that

all animals reached a steady state within the period of observation.

Furthermore, during the unsteady state, the ventilatory responses to

both peripheral and motor root stimulation show: (l) an immediate

rise and (2) an overshoot. These average curves, however, do not

represent the average time required to reach the steady state because

they may be distorted by the behavior of the animal requiring the

longest time to reach the steady state value.

2. Steady state behavior. The complete data of the steady state

values are presented in Tables 29 and 30.

Peripheral stimulation.

a. Ventilation as a function of oxygen consumption.

The steady state values of ventilation and oxygen con­

sumption in the experiments in which exercise was induced by peripheral

stimulation are plotted in Figure 27. An over-all regression line

 -157-

Q)
>
-P
un CM UN
NO
UN H
NO O
ON
UN
CO O i— 1 O UN UN i 1 —
cm o O H CM ON o
o o o On O On o o o O O O ON
H • • * • « • • • • • • • •
<D rH rH H o rH O rH H H rH rH rH o
P3

•H <D
ON to
UN
rH
ON
H On "t O CN ON ON nO -<?- n O
on I>- O n ON !> ON ON ON rH CM
• • • 9 • • • • * • • •
S. ON on ON ON ON ON CM ON ON -<r CM ON ON
O I
•P H ^
do -p o o CO ■sf cm UN CO UN ON ON ON ON NO
>a)'h t
ao
> on
*
o\ O
• a CO O
• •
rH
•
NO
«
CM
•
ON ON
• •
CO O
*
ON
• •
ON o n ON ON ~4- CM ON ON -<r CM ON ON

\D !>
Peripheral Stimulation

CO £> Ch UN ON UN CO nO ■sf O
"t O ON
ON ON
ON O
ON
!> CM
CO
CO ON
NO
ON 'H
ON
HT ON ON
« • • « • • * • • • • • •
H rH r-i H rH CM rH H H rH rH rH rH

vO H
ON 60
Z> rH NO UN c- ON
UN
O Z>
ON CO
CM
ON
■Nj- nO
!> rH
C" NO
• • • • * • • • • • * ♦ «
ON m CM ON UN ON UN E"- c- UNo

O O H ON nO UN nO z> oo No "■t rH ON
o
♦ rH• Z>• CO O
. •
ON
.
nO
• o
• . 0• nO
• ON* NO•
Table 29.

cm on (V rH CM CM CM "t UN CM ON ON

H ON t> CM nO UN rH NO CM n Q NO H O
i— 1 ON n O CO CO J> ON CO CM vO ON {> O
on o NO -H- £> UN CM CM CO ON UN nO O
• • • • • • • • • • • • •
H iH rH H rH CM rH rH rH rH rH <H CM

O
.
O
•
O
•
CM n O O
« • •
UN
• O
■ O
•
O
• O
• O• O
•
—
i 1 UN
i
—1 !> ON rH n
-Qd-
CO H
nO
UN ON
IN~
nO
nJ
ON
- CD
O
NO £> ON CM rH
H
CM
H rH
r~1 H H H CM rH H CM

O• O « CM• • ON• E>9 UN

• CM
• O♦ O• UN
• UN• O •
'-t CM CO
CO ON CO
ON H nO
UN UN
ON
ON
UN CO
CM rH
rH
ON
rH
ON
On O
O rH
i
—1 rH H —
i 1 tH
-0P
ccf
.U>

H cm ON H CM ON rH rH CM ON rH CM ON a
o
£erf
a)
t>o * M H -p
o o H M M > CO
Q S —1 M
I *
 -158-

0
-p p p
0 d <y <y
P3 p£ Oh ps f£j
S -P
CO A- A- P A-
►5" P~ hf P ►S' JS" JT P1 P P
I "00 CH xa H- A xa xa a o to to A rH
«J CD o m- p OH
O O' ■00
XA tQ tA O W rl P OH a
P
CD P
!> H O O O' o o o o• O
•
o
•
PS -P r—I rH rH O O O H rH H rH rH H

> « ^ O' o HD A P o
% £3 ^ (— 1 tov O
*H CD P A in- p O n E> A P
•
rH 'st
a a
OH
•
P* toa
cn E^\ 0 (V 0| P OH OH oh a Hi
M O£?'i
-P J-cv—'
SO -P P HD P O to H Hi HD HD CH HD P
0 <H
>
0 to O x a
0 • • •
HD o Hi
• • •
OH
•
OH O
• •
OH
•
H
♦
4• HD
•
PS Hi OH OH OH OH P P OH OH OH Hi Hi
Roots Stimulation

i a
P O O r~> O EA O HD OH HD p XA HD XA HD OH to
P *H *H fH o m xa P rH XA xa rH CH EA O OH HD
S3 P p > to OH OH CV A O O HD a P O n to HD
0 d d x— ' • • • • • a • • • • • * •
> H PS H rH A 1— 1 A a rH iH rH i— 1 H H H

a
o *o
P 0
P CO P O XA H OH P xr\ XA P EA to xa OH Hi
cS Ph O xr\ NO H XA A- no XA p P to• HD HD
I
—Irl P • • • «r
• • • • • • • •
•HPQ © P OH HD Hi OH P P xa p HD P OH P
P X
0 w
n
> •£H
Table 30,

P g p O ON o OH ON rH to OH XA ON OH to r-
d\ 0 0
XA' HD HD
• • •
O HD OH
* • • OH
•
P• p• P
•
P• CH
•
n-•
p
Hi Hi C\2 Hi i—1 Hi Hi OH rH P Hi rH Hi

P ON XA XA EA n- IA ON ON rH OH HD P
Hi XA P OH C\i Hi Hi o HD XA O O OH
HD Hi Hi OH OH OH OH HD Hi P ON P HD
CO 0 * • • • .♦ * • • • a • • a
H H A? H Hi A Hi i— 1 H P P P P

o q *h Hi O O P o O O A p O XA A XA
•rl ft O a • a a • « a * a * • • •
P Erl U OH XA OH to to I— 1 rH OH ON HD SI p
Ac0 0 P HD un- Hi Hi i— 1 HD P l> P p HD
g K P P P P i— I P P P P H p P
HJ
r a I
• P-
r1
M
£ .P3
C
O S Hi Hi XA CD O O A A to P O OH XA
o \ P a * • a a • • a • • • • a
O 0 to to OH XA XA XA XA o A OH A A o
Hi O 0 to to O XA XA XA XA o P A i> to o
O p P P p 0
P
P a d
o e; -O
CO
• p p Hi 0H I— I Hi OH P p A OH P A OH
O 0 r“
s
■X3
S Q
cO
0
tiO • H P
III

>
IV

CO
II

o o
Q A! *
6

5
H*

Y = 0.03U69 (io.0026l)X + 0.123

r = 0*9383

oxygen consumption in cc./min.,STPD

0
0 100 200
Figure 27. The relationship between ventilation and

oxygen consumption in experiments in which

exercise was induced with peripheral

stimulation. ( 5 dogs, 12 experiments)

 -160-

V = 0,03469 MR + 0.123 (15)

was fitted to the data, where V is the total ventilation in liters per

minute, BTPS, and MR is the oxygen consumption in cc. per minute, STPD.

The correlation coefficient, r, is 0.93S3> which is significant at the

one per cent level of probability. The regression line has an

intercept of 0.123 which is not significantly different from zero, and

the regression coefficient does not differ from that of a direct

proportion through the mean point.

The same data were analyzed by covariance analysis (47).

After establishing the homogeneity of the individual dog regressions,

a pooled correlation coefficient, r = 0.9644> and a pooled regression

coefficient, b = 0.03656, were obtained. Both are significant at the

one per cent level of probability.

b. Ventilation ratio (VR) as a function of the metabolic

rate ratio (MRR) •

In order to minimize the scattering of the data, the

variables are expressed as ratios, VR and MRR, which are plotted in

Figure 28. The linear regression curve fitted (47) to these data is:
*
VR = 0.9804 (10.0261) MRR + 0.0363, with r = 0.99 (16)

where VR is the ventilation ratio and MRR, the metabolic rate ratio.

The intercept, 0.0363 does not differ significantly from zero (P > 0.30),

and the slope of the regression line does not differ significantly

from unity (P > 0.40).

Since the resting values of VR and MRR are always unity,

a regression line is also fitted to the data, using the resting values
3

I = 0.98014 (±0.026l)X + 0.0363

r = 0.99

metabolic rate ratio (MRR)

0
0 1 2 3

Figure 28<, The relationship between the ventilation ratio and

the metabolic rate ratio in experiments in which

exercise was induced with peripheral stimulation#

(5 dogs, 13 experiments)
 - 162-
as origins. (Method, p. 105, in reference (4-7)) Thus a direct

proportional line is obtained passing through the origin.

VR = 1.0002 (t0.0299) MRR, with r = 0.9951. (16a )

Both r and b are significant at one per cent level of probability.

c. RVE (relative ventilation equivalent for oxygen) as a

function of metabolic rate ratio (MRR) •

The relative ventilation equivalent for oxygen, RVE

(VE during exercise divided by VE at rest) is plotted as a function

of MRR in Figure 29. An overall regression line was fitted to the

data. The slope, b = 0.00093, is not significant from zero. The

correlation coefficient, r = 0.0081, is also not significant. The

average value of RVE for the total range is 1.015. By paired compari­

son of the difference between the resting RVE, which is unity, and

RVE during exercise in each individual experiment, a t ratio of

0.44-04 (B > 0.50) was obtained, which implies that the RVE values are

not significantly different from one.

Spinal motor root stimulation,

a. Ventilation as a function of oxygen consumption.

The steady state values of ventilation and oxygen con­

sumption in the experiments in which exercise was induced by spinal

motor root stimulation are plotted in Figure 30. A regression line

V = 0.3125 MR + 0.1577 (17)

was fitted to the data, where V is the total ventilation in libers

per minute, BTPS, and the MR the oxygen consumption in cc. per minute,
 -163-

1.20

CD
Co
1.00 c+
H-
<
CD

0.80

r = 0o008l

b = 0.00093

sb= 0.0163

average RVE = 1.01515

metabolic rate ratio (MRR)

0 1 2

figure 29« The relationship between the relative ventilation

equivalent for oxygen and the metabolic rate ratio

in experiments in which exercise was induced with

peripheral stimulation. ( 5 dogs, 13 experiments)

7

ct-
H-

T = 0.03125 (+0.00259)X+0.l577
1

oxygen consumption in cc./min*,STPD

0
0 100 200

Figure 30. The relationship between ventilation and

oxygen consumption in experiments in which

exercise was induced with spinal motor root

stimulation. ( 5 dogs, 13 experiments)

 -165-

STPD. The correlation coefficient is 0.926, which is significant at

the one per cent level of probability. The intercept, 0.1577, is not

significantly different from zero. Using analysis of covariance, the

individual dog regressions proved to be homogeneous and the pooled

regression and correlation coefficients were 0.0339 and 0.9555

respectively.

b« VR as a function of MRR.

The variables are expressed in ratios, VR and MRR, and

are plotted in Figure 31. An overall regression line

VR = 0.9643 MRR + 0.0346, with r = 0.99 (13)

was fitted to the data. The intercept 0.0523 is not significantly

different from zero (P > 0.40). The slope does not differ significantly

from one (P > 0.30).

The regression line fitted to this group of data, using

the technique for calculation of regression passing through the

origin is

VR = 0.9307 MRR + 0.0191, with r = 0.991 (13A)

Both r and b are significant at the one per cent level of probability,

c. RVE as a function of MRR.

The relationship between RVE and MRR is plotted in

Figure 32. The correlation coefficient, r, is 0.O9B3 and regression

coefficient, b, is 0.00931, neither 01 which is significantly greater

than zero. The average RVE for the observed range of MRR is 1*00939.

Using paired comparison analysis (RVE at rest and RVE during exercise
 -166-
3

H-

X = O.98O7(±Oo O.O390)X-O*O191

metabolic rate ratio (MRR)

0
0 1 O 3

Figure 31# The relationship between the ventilation ratio and

metabolic rate ratio in experiments in which exercise

was induced with spinal motor root stimulation.

( $ dogs, 13 experiments)
 -167-

1.20

2
c**
H*
1.00 «
(D

r = 0.0983
0.80
b = 0,00931

sb= 0c0193

average RVE = 1.00939

metabolic rate ratio (MRR)

0 1 2

Figure 32. The relationship between the relative ventilation

equivalent for oxygen and the metabolic rate ratio

in experiments in which exercise was induced with

spinal motor root stimulation. ( 3 dogs, 13 expts)

 -168-

in each individual experiment), it was found that the EVE is not

significantly different from one (P > 0.50).

Comparison of the responses between peripheral and motor root

stimulation.

a. The unsteady state behavior.

In the unsteady state, the overshoot of the ventilation

equivalent for oxygen is higher in peripheral stimulation than in

root stimulation. By group comparison analysis9 it was found that

the ventilation equivalent for oxygen between the two groups at rest

does not differ significantly (P > 0.20), while that during the first

minute of exercise differs significantly (P < 0.05).

b. The steady state behavior.

A summary of correlation and regression analysis of

the results in experiments with induced exercise by peripheral and

by spinal motor root stimulation is presented in Table 31? As shown

in this table, the comparison of the slopes dealing with the variables

in these two conditions show that as far as the relationships between

these variables in the steady state are concerned, exercise produced

by peripheral stimulation cannot be distinguished from exercise

produced by motor root stimulation.

B. Evaluation of the adequacy of the vascular anastomoses.

With regard to the adequacy of the vascular anastomosis procedure

it is essential to know the adequacy of the circulation in the perfused

leg of the animal, since the performance of work by the muscles-depends,

along with many other things upon the supply of oxygen through the

circulatory system. If there is ischemia in the perfused leg during

 -169-

Summary of correlation and regression analysis of data from Tables 29 and 30

pj
o
w
•H 03 O o o
CO to VO
ft, « • •
PP+M o o o
So
o A A A
o
ON
to to vo
02 ON O
O CO 02
Pi O
• o• O
o rO «
•
P
H m o o o
CO' + 1 +1 +1 +1
fit # Jis
CO Z> *
H o o
-P CO to t>
to o• ON
• o
o•
p o o
o o
o
ftj
Pi
Pi
o & ©
-tO & *■
O co
02 $
CO B
ri
Om £ O o
o O Pi
O
pH Pm
vO
CO p
Em -P
j?
•H
02 r—1
cv O vO CO Pi H
Pi o 02 r~I CD • H
o o* O» O I—1 rcOd
•H •9
-P
cd
o o g PO
+ 1 +1 +1 Em • a1
Pi
A
#
nQ
to tn o CD
•H n£>
oz Z>
nQ
o <P
-P
CO
O
o O O Pi O
•rl o
CO
o o• o P •H i©H
H M o o cd -P
\'H - H K
©*
cd o H o Pi CCS
Pi * .p -p r—I
CD pi pu cd CD -H H
& * 5fC & Sm cd -P£
A
*H H O Pi Pi ©
i
Pi cm CO o J > aJJ
CD ii- ON 02 •rl
PH o ON H0 p O P cd P
cd cti
o o H Pi .- I p c3
•H © T-lrQ P Pi o
© -rl
P Exo P ctJ cd
ca P i— 1 O <H
CD © ©
H > o > S Ph Pm Pi
p 6 II II II II II
*H tab
Pi *H
•cHd f^-A
tiOra
Table 31.

Pi I > f ^11 •h d
CtJ CO H
¥ 5>C
> >
 -170-

induced exercise, then, as a result of insufficient supply of oxygen,

the work output should be decreased even if the current used to

induce exercise remains constant, and a steady state of exercise is

unlikely to be attained. Since oxygen consumption in the steady

state of exercise is a measure of work, it is then possible to

determine the ■oxygen consumption in relation to the current input

stimulus during exercise in intact and perfused legs. This procedure

was carried out in 12 experiments, seven of which were in intact dogs

and five in, perfused animals. The data thus obtained are presented

in Table 32, and plotted in Figure 33.

As shown in Figure 33, the regression line fitted to the data

from the intact animals is,

02 = 3.9388 I + 98.44, with r = 0.978 (19)

where 02 is the oxygen consumption in cc. per minute, STPD, and I is

the current in milliampere• Both the r (0.978) and the b (3*9368)

are significant at the one per cent level of probability.

The regression line fitted to the data from the experiments on

the perfused leg is

02 = 2.871 I (10.218) + 90.3, with r - 0.952 (20)

where 02 and I are the same as designated in equation (19), but the

oxygen consumption was determined on the humoral dog, which was per­

fusing the exercising leg with its blood. Both equation (19) and

equation (20) are fitted by pooling the slopes for each individual

dog chat had more than two determinations. All those dogs than had
 -171-

Table 32* Steady state oxygen consumption in relation to the step

input current in intact dogs and in perfused dogs.

Intact Leg Perfused Leg___

Dog Current O2 Consumption Dog Current - O2 Consumption*
No. milliaurpere cc./min. STPD No. milliampere cc./min. STPD
1 0 89.0 1 0 130.0
2 98.0 27 204.0
8 136.0
15 193.0 2 0 82.4
14 107.5
2 0 85.O 0 ' 80.5
4 111.0 .17 106.5
0 92.0
- 12 165.0 3 0 71.7
12 107.5
3 0 99.5 0 71.7
9 128.0 13 107.5

4 0 '125.2 4 0 113.8
11 161.0 5 162.2
0 106.0
5 0 89.0 13 153.2
25 195.0 -
5 0 81.5
6 0 95.0 20 145.0
18 150.0

7 0 96.7
22 161.0

*02 Consumption measured by the increase of oxygen consumption of

the humoral dog in steady state, plus the resting oxygen consump­
tion of the neural dog.
 - 172-

300

(.) intact dogs. Y = 3.9388 (±0.175) X «* 98.UI

r = 0.978

200 ( 7 dogs, 18 detns)

H*

100

(+) perfused dogs ( 5 dogs, 16 detns)

Y = 2.871 (±0,2l8)X + 90.93

r = 0.952

current in millianpere (I)

0 5 10 15 20 25

figure 33. The relationship between oxygen consumption and

stimulating current intensity in intaet and

perfused dogs with peripheral stimulation in

the steady state.
 -173-
only two determinations were considered as one dog.

By comparing the slopes of the equations (19) and (20), a t ratio

of 1.9922 was obtained (P > 0.05), which is insignificant at the five

per cent level of probability. Since the differences in responses

of intact and perfused animals, as far as oxygen consumption are con­

cerned, are not significantly different, it is interpreted that the

blood supply in the perfused leg is probably adequate.

C* The pathways involved in the regulation of breathing during

induced exercise.

For studying the pathways involved in the regulation of breathing

during induced exercise, an experiment has been designed to separate

the humoral pathway from the neural and to preserve the normal

environment of the exercising muscles. This was done by perfusing

the exercising leg of the ’’neural’' dog with the blood from the

’’humoral” dog. Thus, the humoral effect of exercise on ventilation

should be limited to the ’’humoral” dog, while the neural effect remains

with the "neural” dog. We are certain that there is no neural

influence on the humoral dog and also that there is neural influence

on the neural dog. However, there might be humoral influence on the

neural dog, as a result of failure to ligate all the vessels draining

from the exercising muscles. The evidence that the humoral influence

on the neural dog was not significant consists of a) during exercise

the neural dog showed no significant increase in oxygen intake, and

b) during the time when the humoral dog showed great increase in

ventilation due to rebreathing, the neural dog showed no significant

response in ventilation (more in detail later). Ihiowing that the

 -174-

separation of the pathways is adequate, we will proceed to analyze

the behaviors of the humoral and the neural dogs.

1. The behavior of the humoral dog.

Twelve experiments were performed on six pairs of dogs.

Complete data of the steady state values are presented in Table 33.

Analyses were carried out inboth the unsteady and steady states.

Unsteady state behavior. The general trend of the time -

courses of the variables? ventilation (V), oxygen consumption (MR)

and ventilation equivalent for oxygen (VE).

In four of the 12 experiments, the exercise was con­

tinued for 10 to19 minutes; therefore, they are excluded for study­

ing the transient behaviors. The variablesof the remainder, eight

experiments which all were continued for 15 minutes, have been

averaged and plotted In Figure 34* The stimulus was started at zero

time and lasted for 15 minutes at a steady intensity, The curves

show:

a. Both ventilation and oxygen consumption rise

gradually in a similar fashion to reach a steady state within five

minutes of exercise.

b. The ventilation equivalent for oxygen gradually

decreases to reach a steady state within five minutes of exercise.

c. There are no overshoots in any of the responses

determined in the humoral dog,

d. After the cessation of exercise, the fall in oxygen

consumption and ventilation begins immediately but does not reach the

original values within 10 minutes.

 -175-
a
o u•
•H CD •
mrfP
e ft H—1 rOl
3 *BH r ON LA LA LA LA LA LA LA LA LA
H rl H H rl rl H H H H
O O
u-\ y CM cm M O
cm o r l
ON tON ON cm
y O
t A xCO
L' ON
N 0 xO
O0n LA y xO
P3 o• 9 • to• 0J0O
• • ♦ • • ON•
cm 0 0 00 O N
CM y
y• y•
O O o o o o o o O o o
o cm o LA cm ON ON o o o o o
CM 0A nO cm nO 00 ON cm r l to cm ON
G? r l« r|
•• CM
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9 c m
• CM9 cm LA
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H rl rl rl H rl rl H rH rH rl rl

<
tD
o
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•>H 0 0 P y yQ
x LA to xO O CM O vO xQ CM LA
rrf)hp M la• * • y• O• cm
CM • r l• LA
• rH• y• O• y•
cm cm y cm y -y y LA LA cm y y
s s?
-P u
s p - p
® Vt to CM CM xO to 00 00 00 CM y CM L LA y
i> 0 00m y• \Q* r l• LA • r l• H• xO• A
• y• A- • cm
•
P3 cm cm -t y y y "4* xO LA cm LA xO
Humoral Dog

©
CO to ON xO CM cm 00
•Ph *H to LA o y o 00
*dP E
PhQ pO y• y• y• O• xO• LA
« • ON
• LA
• y• CM
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© 0 cv CM cm LA xO xO y LA LA cm 00 r l
rl
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Table 33*

-eP
rf*gH -p
o to CM ON xO rl rl cm
O v\ 02 ! • y
%• • y• £>• a* • cm
• CM ON9 CM
Eh * © CM CM CM cm LA lT\ cm y y CM xO y
*A &

O *oH
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rl erf<—' o CM O LA cm rH o
o o o O LA o
o prf o m CO o y LA o cm CM y rl
-e9 CM « • • • y• • LA
cm xQ cm9 cm• LA rl
rf-0PV§
rl
S-- r l• • •
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0 erf
& &
5t5
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0
P h *H O• O• O* O• CM• • LA
C-M* LA • tn
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LA m O♦
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0 0 0 y0
o xQ O o "M
to y LA c O O CM
d • X r l r l rl H rl H H CM
OO *fHl w
Mh
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tion

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rl CM
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 •xJo-

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exercise

vn

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 -177-

Steady state behaviors.

a. Ventilation as a function of oxygen consumption.

The steady state values of ventilation and oxygen

consumption in all the 12 experiments are plotted in Figure 35* A

linear covariance analysis revealed the individual dogs to be

homogeneous so that a pooled r and b could be calculated for the

total data. The former value is 0,8376 and the latter 0.03279, both

significant at the one per cent level of probability. The average

regression line fitted to the data is

V = 0.03279 MR + 1.28$ (21)

where V is the total ventilation in liters per minute, and MR the

oxygen consumption in cc. per minute. The positive intercept, 1.28$,

is not significantly different from zero (P < 0.10). If we accept

a 10 per cent level of probability, the positive intercept, 1.28$,

is then significantly different from zero, and the significant positive

intercept implies that the line is curvilinear, since physiologically,

it must include the origin. The slope, 0.03279, which is apparently

lower than that of peripheral stimulation in intact dogs (see Figure 27,

b = 0.036$6), does not differ significantly from the latter (P > 0.$0).

b. VR as a function of MRR.

The relationship between VR and MRR of the humoral

dogs is plotted in Figure 36. An overall linear regression line

VR = 0.5735 MRR + 0.44-15, with r = 0,9781 (22)

is fitted to the data, where VR Is the ventilation ratio and MRR the
10 - 178-

Cd

2 T = 0.03279 (±0.01538)1+1.285

r =• 0.8376

oxygen consumption in cc./min.,STPD

0
0 50 100 150 200

Figure 35® The relationship between the ventilation

and oxygen consumption in the humoral

dogs during induced exercise in the

steady state, ( 5 dogs, 11 experiments)

 -179-

2.0

0*7652 VR2 - 0*0835 VR + 0*3088 - MRR <* 0

metabolic rate ratio (MRR)

1.0
1.0 1.5

figure 36o The relationship between the ventilation ratio

and the metabolic rate ratio in the humoral

dog during induced exercise in the steady state.

( 5 dogs, 11 experiments)
 -ISO-
metabolic rate ratio. The intercept, 0.-441$, is significantly different

from zero (P < 0.01),which implies a curvilinear relationship between

VR and MRR. The slope of the regression line, 0.5735, is significantly

lower than that obtained in intact dogs with peripheralstimulation

(P < 0.01) (see Figure 28). A curvilinear regressionequation

0.7562VR2 - 0.0835VR + 0.308S - MRR = 0 (23)

was fitted to the data. It was found that the curvilinearity of the

regression equation is significant (P < 0.01).

c. RVE as a function of MRR.

The relationship between the RVE and MRR is plotted

in Figure 37. The regression line fitted to the data Is

RVE .= -0.261 MRR + 1.267, with r = -0.9258 (24)

where RVE is the relative ventilation equivalent for oxygen, MRR the

metabolic rate ratio.Both r and b are significant at the one per cent

level of probability. The slope, b =0.261, is significantly lower

than that in intact dogs exercised by peripheral stimulation, (see

Figure 29) (P < 0.01)

As far as the ventilation, oxygen consumption, and

ventilation equivalent are concerned, the behavior in the humoral dogs

is different from that in the intact dogs.

2. The behavior of the neural dog.

Both the unsteady state and the steady state behavior of the

responses of the neural dog were analyzed..

1.00

H-

-0„26l(±o.0237) X + 1.267
-0.9258

metabolic rate ratio (MRR)

0 1 2

Figure 37* The relationship between the relative ventilation

equivalent for oxygen and the metabolic rate ratio

in the humoral dogs during induced exercise in

the steady state*, ( £ dogs, 11 experiments)

 -182-

Unsteady state behavior. The general trend of the variables,

oxygen consumption (MR), ventilation (V), and ventilation equivalent

for oxygen (VE), with respect to time*

Curves similar to those in Figure 34 s.re drawn in

Figure 38, representing the general trend of the responses in the

neural dog. These curves were obtained from the data for the same

eight experiments in which the responses of the humoral dog were

studied. The curves show;

a. The oxygen consumption rises significantly above

the resting level in the first minute of exercise* ‘

The average

resting oxygen consumption was 98.6 cc./min* and that of the first

minute of exercise, 158.7 cc./min. Using paired comparison analysis,

a t ratio of 4*0357 was obtained, which is significant at the

one per cent level of probability. However, during the steady state of

exercise the oxygen consumption does not differ significantly from

the resting value (P > 0.30). If there were vascular connections

between the exercising limb and Its own body, there should be an

increase in oxygen consumption in the neural dog. Since there was

insignificant Increment in oxygen consumption In the oxygen consumption

in the neural dog, it implies that no such connection exists.

b. The ventilation rises very rapidly to a peak value

in the first minute of exercise. Then it decreases sharply and

oscillates during the remainder of the exercise period. It should be

emphasized that the curves are average values. It is possible that

the Individual dogs do not oscillate with the same frequency. Therefore,

the averaged curve here presented shows only a qualitative phenomenon

 -183-

Sctia t*uV^/*rl ut uox^T'J-uaA

fr- Q\ co

T ll/° 0 0 UT U O T q .d lJ T lB 1 1 0 0 u a " 1' A’x o

£ H co
Q Vr o

Uj Ov

U
ooj

H-

vn
 -184-
which may be distorted or cancelled by the non-uniform behavior among

the individual dogs. However, it has been noted that this average

curve simulates that of the individual ones.

c. The curve of ventilation equivalent for oxygen

reflects the changes in the ventilation curve. It increases to a

peak value in the first two minutes of exercise and then oscillates

in harmony with the ventilation curve.

It has been found that the ventilation equivalent

for oxygen during the first minute of exercise was well correlated

with the resting ventilation equivalent for oxygen (r = 0,9214)

(Figure 39).

d. After cessation of exercise, the ventilation

decreases immediately but does attain the resting value with the ten

minute period of observation. The oxygen consumption shows an

insignificant fall (P > 0.10) in the first minute after the exercise

is stopped.

Steady state behavior. The data obtained from the neural

dogs during the steady state of exercise are presented in Table 34*

a. Ventilation (V) as a function of oxygen consump­

tion (MR).

The ventilation of the neural dog during exercise

oscillates, so in each dog, the ventilation values were plotted against

time and the average value of ventilation at rest and during the last

five to seven minutes of exercise were taken from the graph. The

ventilation values thus obtained are plotted In Figure 40? showing

their relationship to the nMR.u The latter was calculated by adding

 - 185-

12

10

&
3-
&
C*
cr
CD

f*
•i
CO
c*-
p.
§
c+
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o
CD
fe
o
H*
CO

resting VE
0
0 6 8

Figure 39. The relationship between the resting

ventilation equivalent for oxygen and

the ventilation equivalent for oxygen

in the first minute of exercise in the

neurHl dogs*
 * -186-
* ix! X X
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 -18-7-

10

c
H+
*
6

H*

oxygen consumption in cc0/mino,STPD

0
0 50 100 150 200

Figure I4G. The relationship between the ventilation

and oxygen consumption in the neural dogs,

( 5 dogs, 11 experiments)
 -188-

to the resting MR value of the neural dog the increment of MR of the

humoral dog during the steady state of exercise, i.e., MR of neural

dog at rest plus (MR of the humoral dog during the steady state of

exercise - MR of the humoral dog at rest). The justification of this

procedure involves the assumption that this 1IR thus calculated

represents the exercise stimulus in the neural dog during induced

exercise (detail discussion is given later)•

An analysis of covariance was carried out. After

showing that the individual dogs were homogeneous, a pooled r and a

pooled b were obtained. The former is 0.451 and the latter 0.0238,

neither of which is significant.

b. Ventilation ratio (VR) as a function of metabolic

rate ratio (MRR),

The values of the oxygen consumption and ventila­

tion obtained from the neural dogs by the method just described are

expressed as ratios in VR and MRR. Their relationship is plotted

in Figure 41. An overall regression line

VR = 0.8739 MRR + 0.1611, with r = 0.771 (25)

is fitted to the data. Both r and b are significant at the one per cent

level of probability, while the intercept, 0.1611, is not significant.

The slope, 0.8739, is significantly lower than that obtained in

intact dogs with exercise by peripheral stimulation (b = 0.9804) at

the 10 per cent level of probability.

 - 189“

2.0
Y = 0,8739(^0.0U71) X + 0.1611
<1
C
D
3
c+ r= 0.7709
H’
1
&-'
c+
H*
O
3
4
tu
c-
H+
O
<
1-5 to

metabolic rate ratio (MRR)

1-0
1.0 2.0

Figure i^l. The relationship between the ventilation

ratio and the metabolic rate ratio ( see

text for the calculation of the MRR) in

neural dogs during induced exercise.

( 5 dogs, 11 experiments)
 -190-

c. Relative ventilation equivalent for oxygen (RVE)

as a function of MRR.

The relationship between RVE and MRR is plotted in

Figure 42. An overall regression line

RVE = 0.7733 MRR + 0.2643, with r = 0.894 (26)

is fitted to the data. Both r and b are significant at the one per cent

level of probability.

Thus, as far as VR as a function of MRR is concerned,

if we accept the 10 per cent level of probability as an arbitrary

criterion for testing the null hypothesis, and also as far as

RVE = f (MRR) is concerned, the neural dog responded differently from

the intact dog during exercise by peripheral stimulation.

A summary of the statistical analysis is presented in

Table 35.

D. Attempts to identify peripheral chemoreceptors.

.Five experiments were done in three pairs of dogs to attempt

to identify peripheral chemoreceptors. The results are presented in

Table 36, and the average values are plotted in Figure 43.

As shown in Figure 43, the ventilation of the neural dog remains

more or less unchanged while that of the humoral dog rebreathed. The

ventilation of the humoral dog, however, shows a significant increase

even in the first minuue. Using paired comparison analysis, it was

found that the ventilation of the neural dog decreased 0.35 L./min.,

BTPS, during the first minute while the humoral dog was rebreathing,

but this decrement in ventilation is not significant (P > 0.40).

 -191-

1.80

l«6o

Y = 0.7733(±0«099)X+0.26U3

r = O.89U

1.00

metabolic rate ratio (MRR)

0 1 2

Figure 1*2. The relationship between the relative ventilation

equivalent for oxygen and the metabolic rate ratio

in the neural dogs during induced exercise.

( ^ dogs, 11 experiments)
 -192-

Summary of correlation and regression analysis of data from Tables 33 and 34

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 -193-

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 Figure ]|3o The ventilatory response

in both neural and

30
humoral dogs while
I the humoral dog
C*
H +
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f&
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P*
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3
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3

S'
20
03

10

vent* of neural dog

vento of humoral dog

time in minute

- 1 0 1 2 3 ^ 5 6 7 8

rebreathing--------- ---------— — —
 -195-

The humoral dog during its first minute of rebreathing showed an

increase of 4<>2 L./min., DTPS in ventilation, which is significant at

the five per cent level of the probability.

The implications of this finding are as follows: a) there are

no chemoreceptors (those resulting from rebreathing) in the peripheral

limb that are comparable to the central chemoreceptors; b) there are

no significant vascular connections ffom the perfused limb to its own

body# If there were such connections, then, there must be detectable

changes in ventilation while the humoral dog was breathing.

 -196-

VII. DISCUSSION

A.The Adequacy of the Experimental Procedures.

In the present study exercise was induced by electrical stimula­

tion, and the method used for dissociating the neural and humoral

pathways was by vascular anastomosis. Accordingly, it is necessary

to evaluate: l) the adequacy of the Induced exercise, and 2) the

adequacy of the vascular anastomosis.

1. The adequacy of the induced exercise.

The major purpose of the present study was to investigate

whether the normal exercise stimulus normally ismediated neurally or

humorally. In the procedure of electrically induced exercise, it is

possible that local electrical stimulation of ventilation is produced.

Hence, it would be impossible to attribute the results to normal

exercise. In order to evaluate the abnormal sensory stimulation of

ventilation in induced exercise, experiments have been carried out to

observe the ventilatory responses in the same animal with exercise

by peripheral stimulation and also by spinal motor root stimulation.

In the motor root stimulation experiments, the sensory stimulation in

the local exercising muscles should be limited to that resulting from

exercise and should not have any adventitious sensory stimulation

from the electric current.

In the transient state, ventilation increased immediately

both in peripheral stimulation and in spinal motor root stimulation.

Since the ventilation equivalent for oxygen in peripheral stimulation

is higher than that in spinal root stimulation, in the first minute

 -197-
of exercise, one may infer that there probably is some local sensory

stimulation of ventilation* Hox^ever, this adventitious sensory

stimulatory effect is completed within the first minute of exercise,

because there is no significant difference in the ventilation equiva­

lent for oxygen in the second minute of exercise induced by motor

root and peripheral stimulation.

It has been observed that during spinal motor root stimula­

tion, the ventilation increased in every experiment from the first

breath after stimulation was started. The first breath usually takes

place no less than three seconds after the stimulation. This is of

special interest in studying the mechanism of exercise hyperpnea.

Since any metabolite or humoral agent resulting from exercise cannot

be effective in such a short time, a reflex mechanism must be involved

in the regulation of breathing during exercise. The initial change

in ventilation in root and peripheral stimulation is both in rate and

depth. It should be emphasized that in our present study no panting

was observed in any of the experiments.

In the steady state, it has been demonstrated that as far

as the relationships between ventilation and oxygen consumption,

VR as f (MRR) and RVE as f(MRR), are concerned, the responses in

peripheral stimulation do not differ significantly from those in

motor root stimulation. Equations (lf>) and (17) show that while the

ventilation of the animal during root stimulation increased 0.0339

L./min. per cc. increase in oxygen consumption, the corresponding

increment in ventilation in the same animals during peripheral stimu­

lation was 0.0366 L./min. per cc. increase in oxygen consumption.

 -198-
The difference is not significantly different. In addition, in both

spinal motor root and peripheral stimulation experiments, the rela­

tionship beWeen ventilation and oxygen consumption is rectilinear and

directly proportional. By expressing the ventilation as a ratio (VR)

and oxygen consumption as a ratio (ERR), it was found that the slopes

of VR - f(MKR) fitted to the data observed in motor root stimulation

(b = 1,0002) and those in peripheral stimulation (b = 0.981) are not

statistically different. The slopes of RVE = f (MRR) in these two

kinds of experiments are also statistically insignificant.

Electrically induced exercise has been widely used in

studying the regulation of breathing during exercise, but data con­

cerning the evaluation of abnormal sensory stimulation resulting from

this type of induced exercise are meager. Gomroe and Schmidt (14)

attempted to induce exercise by electrical stimulation of the spinal

motor root in dogs. In their experiments there were no comparisons

made between the responses from motor root and peripheral stimulation.

However, they claim that an 11immediate*’ Increase in ventilation upon

root stimulation had been observed and the changes were mainly In the

rate of breathing. These authors have not observed the ventilatory

responses in dogs in the steady state.

Our observations confirm studies of others with regard to

the relationship between oxygen consumption and ventilation. The

comparison Is shown in Table 37, in which one group of investigators

carried out their studies in voluntary exercise. As shown in this

table, as far as the relationship between the oxygen consumption and

ventilation Is concerned, the responses in dogs with exercise by

 -199-

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 -200-

peripheral stimulation, by motor root stimulation, and by voluntary

exercise are identical in the steady state.

Our immediate question is how do the observations on dogs

compare with those observed in man. The observations on the transient

ventilatory response to induced exercise and to voluntary exercise

are also fragmentary. Krogh and Lindhard (8, 9) have observed that

in man, the ventilation increased nimmediately (or within less than

a second) when muscular work is induced, and usually there is an

immediate augmentation both of the respiratory rate and of the depth.n

Since the increase in ventilation is so sudden that it cannot be due

to a humoral mechanism, they postulated that it is due to the

irradiation impulses from the motor cortex* This theory was rejected

subsequently. They have observed also the transient ventilatory

responses in man during voluntary exercise. From the tracings the

authors presented, it \/as found that the ventilation during voluntary

exercise increased both in depth and in rate in the same fashion as

that representing the responses to induced exercise. Evidently these

authors have neglected the fact that, since in the transient state

the ventilatory response during induced and voluntary exercise was

identical, the cortical irradiation impulses probably are not

concerned in the regulation of breathing during exercise.

Nielsen (7) has also studied the transient ventilatory

response in man during voluntary exercise, and has shown an increase

in the ventilation equivalent for oxygen within the first two or three

minutes of exercise.

The ventilatory responses during the steady state of induced

 -201-
and voluntary exercise have been studied by Krogh and Lindhard and

Asmussen et al. in man. Figure 14 represents the relationship between

the ventilation and oxygen consumption in man during the steady state

of induced exercise. The regression line fitted to the data is

V (L./min.) = 0.02576 MR (cc./min.) + 0.89,. with r = 0.866 (27)

Both b and r are significant at the one per cent level of probability

but the intercept, 0.89, is not significant. 'The regression

coefficient, b = 0.02576, corresponds to a ventilation equivalent for

oxygen of-2*576 which is practically the seme as that observed during

the same type of voluntary exercise.

Asmussen et al. (10) have obtained identical ventilatory

responses in man during induced and voluntary exercise. Their results

have been presented in Figure 19.

Thus, it can be stated that during the transient state of

induced exercise in dogs, the ventilatory responses are qualitatively

the seme, whether the exercise was induced by motor root or peripheral

stimulation; during steady state, the ventilatory responses are not

significantly different, as far as the relationship between ventilation

and oxygen consumption is concerned. The exercise thus produced also

simulates that observed in man during voluntary work during the steady

and the unsteady state. , The immediate increase in breathing during

exercise with'motor root stimulation implies that a peripheral neural

mechanism is involved in the regulation of bres.thing during exercise,

at least in the transient state.

 -202-

H*

Y = 2.576(± 0.371) X +0.8?

r = 0.866

10

oxygen consumption in 100 cc./min.,STPD

0 10 20

Figure iuu The relationship between ventilation and

oxygen consumption in human subjects with elect­

rically induced exercise. ( J subjects,

18 determinations) Xrogh and bindhard(9)

 -203-
2* The adequacy of the vascular anastomosis.

There are at least two aspects involved in the evaluation of

the adequacy of the vascular anastomosis. This experiment was

designed to l) dissociate the humoral and neural pathways and 2) to

preserve the normal environment of the exercising muscles.

With regard to the first aim, the success of the experimental

procedure depends upon the completeness of the separation of the two

pathways. It is clear that the humoral animal had no neural connections

with the exercising leg of the neural animal and that the neural

animal had neural connections with its own body. However, it is

important to know whether there aye humoral connections between the

exercising leg and its own body. For the latter, there was no direct

evidence obtained; but there were two types of observations in

relation to this pertinent question. In the neural dog during steady

state of exercise there was no significant increase in oxygen consump­

tion. If there were any humoral connection between the exercising leg

and its body, a significant increase in oxygen consumption of the

neural animal should occur. Secondly, in the experiments in which

attempts were made to identify peripheral chemoreceptors, while the

humoral animal was rebreathing, the neural animal showed no significant

change in ventilation, even during the time the arterial blood to

the perfused leg was the same color as the venous blood. If there

were significant vascular connection between the exercising leg and

its own body, while the humoral dog was rebreathing the ventilation of

the neural dog should increase. Thus, we can infer that no significant

vascular connection existed between the exercising leg and its main
 -201-

body. Therefore, the separation of the pathways was considered

complete and adequate.

With regard to the adequacy of preserving the normal environ­

ment of the exercising muscles, experiments had been performed to

determine the oxygen consumption in relation to the current stimulus

in intact and perfused muscles. It seems evident that if the exercising

muscles are not supplied adequately by oxygen, exercise may not reach

a steady state and the magnitude of work (using oxygen as index)

would be lower in the perfused muscles than the intact muscles at a

given level of stimulus. As shown in Figure 33> the oxygen consumption

per unit change of electrical current stimulus is 3.9338 cc./min. in

intact muscles and 2.871 cc./min. in perfused muscles. These values

do not differ significantly. Thus, we may infer that the circulation

in the perfused muscles was probably not different significantly from

that in the intact muscles.

If the oxygen supply to the perfused leg was inadequate, then,

as a result of muscle contraction metabolic acidosis might be produced.

The ventilatory response in the humoral dog should be that of a

metabolic acidosis. However, the result of a metabolic acidosis was

unlikely, judging from the ventilatory responses of the humoral dog.

This will be discussed in a detailed fashion later.

From the observations mentioned above, it was inferred that

vascular anastomosis was adequate for separating the humoral and

neural pathways and for preserving a normal environment for the

exercising muscles.
 -205-
B* The Mechanism of Exercise Hyperpnea*

In this part of the discussion, we will discuss our observations

and test their compatibility with the dual hypotheses.

1. The behavior of the humoral dog.

During the unsteady state of exercise, there wasno over­

shoot in ventilation or the ventilation equivalent for oxygen. Com­

parison of these observations with those from the intact dog, when

exercise was induced by peripheral or motor root stimulation, implies

that the overshoot during the transient state of exercise is a neural

effect.

In the steady state, as shown in equation (21), the increase

in ventilation in L./min. per cc. of oxygen consumption is 0.0328

in the humoral dog, which is apparently lower than that in intact

animals (b = 0.0366). The reason that they are not significantly

different may be, l) the small range of oxygen consumption, 2) the

variation in the depth of anesthesia, which may cause a wide scatter

of the data, and 3) the high ventilation equivalent for oxygen of the

humoral dog at rest which can be explained by the fact that great care

was exercised with the humoral dog to avoid overly deep anesthesia*

By expressing VR as a function of MRR, it was shown that

the relationship between these two variables is curvilinear with the

concavity of the curve downward. A rectilinear equation was also fitted

to the data, the slope of which is significantly lower than that in

intact animals. By expressing RVE as a function of MRR, it was shown

that a significant negative correlation exists. These relationships

are different from those observed in intact dogs during exercise and
 -206-

they are qualicabively compatible with those predicted for the responses
due to parametric forcing.

2. The behavior of the neural dop.

During the unsteady state of exercise in the neural dog, there

was an increase in oxygen consumption in the first minute of exercise.

This may be due to the change in the mid-position of the chest in the

neural dog as a result of an incrase in ventilation. It is known that

during exercise the cardiac output is increased. If the circulation of

the pulmonary system is increased in the initial stage of exercise, and

the mid-position of the chest is changed, then, just by a purely physio-

chemical process, the oxygen consumption should be increased.

The ventilation equivalent for oxygen during the first one

or two minutes of exercise increased to a much greater magnitude than

that during exercise in intact dogs. It is interesting to note that

the initial increase in the ventilation equivalent for oxygen is a

function of its resting value. (Figure 39)

For studying the steady state behavior in the neural dog a

longer exercising period is necessary. Based on the values obtained

from the graphs, it was shown that the ventilation is poorly correlated

with the oxygen consumption. It is rather hazardous to conclude

anything from these observations, since it is a well known fact that

during normal exercise ventilation is well correlated with oxygen con­

sumption. The poor correlation between the ventilation and oxygen con­

sumption in the neural dog may be due to the same reasons as for the

humoral dog. The two high initial values of ventilation equivalent for

oxygen skewed the data to a square shaped scattering. If these two

 -207-
determinations were excluded., then a correlation, r = 0.8033 is

obtained, which is significant at the one per cent level of probability.

It has been demonstrated, however, that the increase in ventilation

in the neural dog during exercise was statistically significant.

(P < 0.01, paired comparison analysis).

When the ventilation and metabolic rate values are expressed

as ratios, the scattering of the data in the neural dog is minimized

considerably. As shown in Figure 41, the correlation coefficient

between the variables VP and MRR is significant and the slope,

VP = f(MRR), is significantly lower than that in intact dogs at the

ten per cent level of probability. By expressing RVE as a function of

MRR, it was shown that a significant positive correlation coefficient

and a significant regression coefficient were obtained.

If we accept, l) the ten per cent level of probability in

comparing the slopes, VR = f(MRR), between that obtained in the neural

dog and that in the intact dog, and 2) the significant positive linear

relationship of RVE = f (MRR) in the neural dog as a criterion, then

the observations in the neural dog are different from those in the

intact dog. The ventilatory behavior in the neural dog during exercise is

qualitatively compatible with that predicted for the responses due to

direct forcing.
3. The compatibility of the observation with the hypotheses.

In the theoretical analysis, we have postulated two alternative

dual hypotheses to interpret the regulation of breathing during exercise,

l) a humoral-humoral hypothesis end 2) a reflex-humoral hypothesis. It

has also been predicted that according to a humoral-humoral hypothesis,

 -208-

there should be no ventilatory response to exercise in the neural dog

but a normal response to exercise in the humoral dog. Our observations

were: 1) in the neural dog there were ventilatory responses to exer­

cise, and 2) in the humoral dog, the ventilatory responses to exercise

were not normal. Hence, the humoral-humoral hypothesis is rejected.

According to the reflex-humoral hypothesis, the humoral dog

should respond to the parametric forcing with a decrease in ventila­

tion equivalent for oxygen and a respiratory acidosis. The neural

dog, on the other hand, should respond only to the direct forcing,

since no parametric forcing is present in the latter, the feedback

mechanism will inhibit its respiratory response, which should be

accompanied by an elevated ventilation equivalent for oxygen and

respiratory alkalosis. Our results observed in the humoral dog show

a decrease in ventilation equivalent for oxygen. The arterial blood

gas compositions were not determined, so we do not know whether or

not respiratory acidosis was present. The behavior of the ventilatory

responses in the humoral dog is qualitatively compatible with that

predicted for a respiratory acidosis. Our results observed in the

neural dog show an elevated ventilation equivalent for oxygen. The

arterial blood gas compositions were not determined. Therefore, again

we have no evidence that there was respiratory alkalosis. At any

rate, our results are qualitatively compatible with the reflex-humoral

hypothesis; the humoral-humoral hypothesis, according to our observa­

tions, is rejected.
It should be emphasized, however, that our predictions are

based on observations from human subjects. In order that our predictions

 -209-
from human data be applicable to the ventilatory behavior in dogs the

assumption must be made that qualitatively the mechanisms of exercise

hyperpnea in man and in dogs are the same.

4-* Possible objections to the reflex-humoral hypothesis.

So far we have provided only qualitative evidence that a

reflex-humoral mechanism is being utilized in the regulation of

breathing during exercise. Before this conclusion can be considered

to be established, quantitative observations should be made, which

include l) the determination of the sensitivity coefficient of the

animal employed for the experimental procedure, 2) the determination

of the blood gas compositions, and 3) the determination of the

potency of the exercise stimulus, if it is identified. None of these

are known at the present time.

Before experiments with quantitative determinations can be

performed, it is necessary to know whether or not the ventilatory

response observed in the humoral and neural dogs of the present

experiment was due to abnormal stimuli. Let us first inquire into

the possibility of an abnormal stimulus existing in the humoral dog

and predict what should happen under such a condition. If the cir­

culation in the perfused leg were not adequate, it is possible that

a metabolic acidosis would result. Thus, the humoral dog would

respond to the increased arterial hydrogen ion concentration which is

mediated humorally. The ventilatory response in the humoral dog

under such a condition would be a high ventilation equivalent for

oxygen and a metabolic acidosis, which consists of an elevated arterial

hydrogen ion concentration and a decrease in the arterial carbon

 -210-
dioxide tension. The best way of knowing whether metabolic acidosis

exists in the humoral dog is to determine the arterial blood gas com—

positions and to calculate the relations of these two variables.

However, if there was metabolic acidosis then the curve representing

the relationship between ventilation ratio and metabolic rate ratio

should have its concavity upward, because the degree of metabolic

acidosis should increase with the intensity of work, thus resulting

in an increase in the ventilation equivalent for oxygen. Hence, it is

unlikely that there was significant metabolic acidosis in the humoral

dog.

Our next step is to inquire into the responses of the neural

dog, if an abnormal stimulus were present. In order to make the

situation simple, let us assume that under our experimental situation

the exercise stimulus was in direct proportion to the metabolic rate

as in normal exercise. If this assumption were true, it is, then

possible that In the neural dog there was an abnormal stimulus,

because the ventilation was high in relation to metabolic rate. If

the parametric forcing was not operating at all, the actually observed

ventilation should be the same as that predicted in Figure 45 > curve B.

However, if the sensitivity of ventilatory response to carbon dioxide

in the animal decreases under anesthesia, curve B in Figure 45 will

elevate, approaching curve N as the limit, In which case the sensitivity

of the animal to carbon dioxide inhibition would be zero.

Under normal conditions in anesthetized dogs, the relationship

between ventilation and metabolic rate during moderate exercise is

rectilinear. This is also true in man. Must this be true in the

 -211-
10

t
3
c+
H*
H
PJ
c+-
P*
O
o
&
c*-
S*
normal (N)
<1
&
feedback mechanism

(inhibition)

(B) observed response without parametric forcing

0 2 k 6

metabolic rate ratio (MRR)

Figure u$* The relationship between ventilation ratio and the

metabolic rate ratio dn normal condition and in

that when the parametric forcing is absent.

 -212-
neural dog? In other words, is there any dissociation of the actual

normal exercise stimulus and the metabolic rate? First, let us examine

the rationale that the metabolic rate is the normal exercise stimulus.

Since, in normal moderate exercise, ventilation is adjusted directly

proportionally to metabolic rate, it is considered that whatever the

exercise stimulus is, it must be in direct proportion to the metabolic

rate. This statement is purely an assumption and there is no evidence

that they are not Incidentally related, nor is there evidence that they

must be related. If dissociation of the exercise stimulus and

metabolic rate occurs, then the metabolic rate would not be an accurate

index of the intensity of the exercise stimulus. It is then likely

that the increase in metabolic rate in the humoral animal is lower than

the exercise stimulus in the neural dog, and therefore there may be

poor correlation between the ventilatory response in the neural dog

and the increase in metabolic rate in the humoral dog, and the slope

for VR = f (MRR) may be high.

C. The Nature of the nErgoreceptor.n

It has been shown that our results are incompatible with the

humoral-humoral hypothesis, but compatible with the reflex-humoral

hypothesis. If the reflex-humoral mechanism is actually utilized in

the regulation of breathing during exercise, It necessitates a local

peripheral receptor for its operation. Me have named this receptor

,,ergoreceptor,t as a non-committal term and also mentioned that this

receptor may be chemo-, motio-, thermo-, tensio-, or any other type

of receptor. From the literature dealing with passive exercise, it

has been discovered that probably the so-called motioreceptor does not
 -213-
exisi*. Since there are known central chemoreceptors, the first step in

identifying the peripheral ergoreceptors is to investigate the

possibility of the existence of peripheral chemorecentors.

During rebreathing, the arterial blood of the animal becomes

anoxic, hypercapnial, and acidic (62)* If this blood is perfused

to an extremity of another animal whose circulation (neural dog) is

not connected to its perfused extremity, and if there are peripheral

chemoreceptors responsive to the blood changes,'there must be some

increase In breathing in the neural dog* This experiment lias been

carried out and according to our results, there are no such chemo­

receptors in the extremities comparable with those in the carotid

sinus, aortic arch, and in the brain.

Literature dealing with identification of peripheral chemo­

receptors is extremely meager and inadequate. Comroe and Schmidt

(11, 59) concluded that there are no "peripheral chemoreceptors11 but

provided no evidence* However, from the present experiment one csn

infer that the possibility of a peripheral chemoreceptor being-

responsible for the regulation of breathing is excluded.

It is known that temperature causes an Increase In breathing

and that temperature Increases in the bod3^ during exercise (5, 51)*

Therefore, temperature must be at least partially responsible for the

regulation of breathing during exercise. Further evidence has been

found that in anesthetized dogs during exercise the muscle temperature

rather than the carotid temperature Is well correlated with the

increase in ventilation in both the steady and the unsteady states (51),

implying the presence of a peripheral thermoreceptor In the tissues of

 -214-
bhe working extremities# Histologically it has long been known that

in the connective tissue of the extremities as well as elsewhere there

are thermo-sensitive receptors. It has also been demonstrated (63) that

in anesthetized dogs during diathermy heating, the ventilation increased,

but when the nerves supplying the heated area were cun, there was a

considerable decrease in ventilation. It is possible that in this type

of experiment, an abnormal stimulus (e.g. pain) was generated, never­

theless, it implies that there are peripheral receptors which when

stimulated cause an increase in breathing.

♦
It would be profitable to reinvestigate the role of temperature

in the regulation of breathing, employing the vascular anastomosis

technique. A response in the neural dog implies that a peripheral

thermoreceptor is present. The abnormal stimulus incident to the

heat production should be evaluated. Histologically, there has been

located In the muscle and tendon (64) some sensory neuron apparatus

which may be sensitive to tension and pain. During exercise, the

tension in the muscle and tendon must be increased. Hence, it is

reasonable to postulate that tension might be involved in the regula­

tion of breathing during exercise. However, no experiments have been

performed in this regard.

The actual identification of the peripheral receptors (may be one

or more types) in relation to the regulation of breathing necessitates

at least two steps: l) to produce a single stimulus and observe the

quantitative potency of it to ventilation, 2) identify this stimulus

and its magnitude of alteration in exercise. The vascular-anasuomosis

procedure of the present study may be helpful in setting up an

 -215-

experiment to identify the exercise stimuli and to determine their

contributions to stimulation of ventilation both during exercise and

at rest.
 -216-

VIII. SUlliARY AiiD CONCLUSIONS

The kncnm principles of the simple respiratory chemostat were

found inadequate to explain the regulation of breathing during exercise.

However, modification of the simple chemostat with the addition of a

direct forcing exercise stimulus can account for the ventilatory

behaviors during normal exercise. Hence, during exercise, it is

necessary to take into consideration both the direct and the para­

metric forces that affect the responses. Accordingly, two alternative

dual hypotheses were postulated for the mechanism involved in the

regulation of breathing during exercise: 1) a humoral-humoral

mechanism, both the direct forcing and the parametric forcing being

humoral, and 2) a reflex-humoral mechanism, the direct forcing being

reflex and the parametric forcing being humoral. The ventilatory

behavioisunder different types of experimental procedures were pre­

dicted on the basis of these hypotheses.

The literature was reviewed in order to obtain information to

test these hypotheses. It was found that the observations from

denervation experiments are compatible with the reflex-humoral

hypothesis, but the confidence in this agreement is reduced because

of the experimental complications. Passive exercise experiments

have shown that motion is probably not concerned in the direct forcing

of the respiratory chemostat during exercise, but these experiments

provide no other information with regard to the mechanism involved.

Ischemia experiments are unreliable because ischemia causes an

accumulation of the normal and the production of abnormal exercise

 -217-

stimuli. Hence, the observations neither deny nor confirm either

hypothesis* 'The ideal method of testing the hypotheses would appear

bo be by means of vascular anastomosis experiments, since ischemia and

the complications arising from chordotomy may be avoided and the

humoral-reflex pathways may be completely dissociated^ yet a review

of the literature revealed that such experiments have thus far not

been properly performed* Therefore, more satisfactory experimental

procedures were designed using cross-circulation techniques to study

the mechanism of exercise hyperpnea. Since exercise was induced

electrically, the abnormal sensory stimulation caused by the electric

current had to be evaluated. In addition, experiments were carried

out in an attempt to identify peripheral chemoreceptors.

With regard to the evaluation of the abnormal sensory stimula­

tion in electrically induced exercise, experiments were carried out

in five animals in which exercise was induced by peripheral and

spinal motor root stimulation* It was found that in the transient

state of induced exercise by either procedure that l) ventilation

increased with the first breath (no less than three seconds after the

stimulation was started), 2) oxygen consumption and the ventilation

equivalent for oxygen increased, 3) both oxygen consumption and

ventilation attained a steady state well within the period of observa­

tion, and 4) "bhe ventilation equivalent for oxygen increased to a

higher value in peripheral stimulation than in spinal motor root

stimulation. In the steady state, the relationship between ventila­

tion and oxygen consumption observed in peripheral stimulation is not

significantly different from that in spinal motor root stimulation.

 -218-

iherefore, ib is 00110111(16(1 that in the transient state the ventilatory

responses observed in the animals with peripheral stimulation is

qualitatively the same as that with spinal motor root stimulation,

ihe increase in ventilation with the first breath during exercise

produced by spinal motor root stimulation implies that there is a

neural mechanism involved in the stimulation of breathing during

exercise, at least in the transient state. In the steady state there

is no significant abnormal sensory stimulation in peripherally

induced exercise.

With regard to the mechanism involved in the regulation of

breathing during exercise, experiments were carried out on five pairs

of vascular-anastomosed dogs. It was found that the ventilatory

behavior of the humoral dog is qualitatively the same as predicted

for the behavior during parametric forcing and that of the neural

dog is qualitatively the same as predicted for that during direct

forcing. Therefore, it is concluded that the humoral-humoral

hypothesis must be rejected, and that before the reflex-humoral

hypothesis can be considered to be finally established, quantitative

experiments must be performed.

With regard to the existence of peripheral chemoreceptors, experi­

ments were carried out in three pairs of vascular-anastomosed dogs.

The ventilatory responses were determined, in both the humoral and the

neural dog while the humoral dog rebreathed in a closed circuit. It

was found that there was no significant change of breathing in the

neural dog while the humoral dog showed a marked increase in ventila­

tion during the eight minutes of rebreathing. Therefore, it is

 -219-

concluded that no evidence was found in the present study to support

the existence of peripheral ehemoreceptors.

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Master Thesis, Department of Physiology, Northwestern University
Medical School, 1950.

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 VITA

Born: Jan. 29, 1919, Peking, China

Education:

Jefferson Acadenjy, Tunghsien,Hopei,China

Yenching University,Peking, China.

B.So, 191*3.

West China Union University, College of Medical Sciences,

Chengtu,China„
M.D. ,191*7.

Intemeship: University Hospitals,W. C. U. U. ,191*6-191*7°

Residencies: Pathology, University Hospitals,W. C.U.U.,

19U7-19i*8o

Internal Medicine, Wesley Memorial Hospital,

Chicago,111., 191*8-19l*9o

Northwestern University Medical School, Chicago,111.

Research Fellow, Department of Physiology,19l*9-195CL
M.So degree in Physiology, June, 1950o

Academic Appointments:

Teaching Assistant, Department of Pathology,W. C. U.U.

19l*7-19l*8o

Teaching Assistant, Department of Physiology, N.U.M.S.

1950-1951.

Instructor of Physiology, Department of Physiology,N. Q.M.S0

1951-

Honoraries:

Morse Medal (W. C.U.U.), 191*7•

Sigma Xi ( Northwestern Chapter), 1951.