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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
ProQuest Number: 10101571
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TABLE OF CONTENTS
Page
I* Introduction. 1
II. Theoretical Analysis of Respiratory Responses toE xercise. 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 anastomosise xperiments. 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 TheirA nalysis. 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
