NORTHWESTERN UNIVERSITY LIBRARY Manuscript Theses Unpublished theses submitted for the Master's and Doctor*s degrees and deposited in the Northwestern University Library are open for inspect!on, but are to be used only with due regard to the rights of the authors* Bibliographical references may be noted, but passages may be copied only with the permission of the authors, and proper credit must be given in subsequent written or published work* Extensive copying or publication of the thesis in whole or in part requires also the consent of the Dean of the Graduate School of Northwestern University. Theses may be reproduced on microfilm for use in place of the manuscript itself provided the rules listed above are strictly adhered to and the rights of the author are in no way Jeopardized. This thesis by . has been used by the following persons, whose signatures attest their acceptance of the above restrictions* A Library which borrows this thesis for use by its patrons is expected to secure the signature of each user. NAME AND ADDRESS DATE * A CKNCV/LKJGEMENTS The author wishes to express his gratitude to Drs, John S0 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 ProQuest Number: 10101571 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest, ProQuest 10101571 Published by ProQuest LLC (2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346 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