Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Historical Perspectives on the Control of Breathing

Robert S. Fitzgerald, Neil S. Cherniack

10.1002/cphy.c100007

Source: Volume 2, Issue 2, April 2012

Published online: April 2012

Full Article on Wiley Online Library



Abstract

Among the several topics included in respiratory studies investigators have focused on the control of breathing for a relatively few number of years, perhaps only the last 75 to 80. For a very long time, the phenomenon of respiration presented a great mystery. The Chinese had suggestions for proper breathing, and later the Egyptians sought to understand its purpose. But in the western world, the early Greeks made the more significant observations. Centuries passed before the anatomical structures pertinent to respiration were properly visualized and located. There followed efforts to understand if lung movement was necessary for life and what happened in the lung. The rise of chemistry in the 18th century eventually clarified the roles of the gases significant in respiratory behavior. More time was needed to understand what gases provoked increases in breathing and where those gases worked. At this point, control of breathing became a significant focus of respiratory investigators. Studies included identifying the structures and functions of central and peripheral chemoreceptors, and airway receptors, sources of respiratory rhythm and pattern generation, the impact of the organism's status on its breathing including environment and disease/trauma. At this same time, mid‐ to late‐20th century, efforts to mathematicize the variables in the control of breathing appeared. So though wonderment about the mysterious phenomenon of respiration began over two millennia ago, serious physiological investigation into its control is by comparison very young. © 2012 American Physiological Society. Compr Physiol 2:915‐932, 2012.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

A recent search of PubMed by Zapata and Larrain for the International Society for Arterial Chemoreception using carotid body‐related terms produced more than 5,000 citations of which most of the early ones treated carotid body tumors. Presented here are carotid body publications in 5‐year intervals starting in 1945 which are focused more on anatomy, cytology, neurophysiology, neurochemistry, resulting reflex responses to stimulation.
Figure 2. Figure 2.

Galen (130‐199 A.D.) of Pergamum was a prominent Roman physician (indeed, to the Emperor Marcus Aurelius) and philosopher of Greek origin. His anatomical views of the cardiovascular system were based on studies in the monkey since dissection was not allowed at that time; these views were taught for 1,300 years. The “spirits” added to the blood in Galen's view came from the left ventricle (vital spirit) as the blood coursed through the invisible pores of the interventricular septum between right and left ventricles. The “animal spirit” came from the brain.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.
Figure 3. Figure 3.

Ibn Sina (980‐1037 A.D.), known in the West as Avicenna, was the foremost philosopher and physician of his day. He was greatly influenced by Aristotle, and, in turn, greatly influenced Thomas Aquinas, Galileo, Harvey, and several others. Avicenna wrote over 400 treatises of which about half have survived. Most focus on philosophy (for which he was criticized); about 40 deal with medicine. His encyclopedic Canon of Medicine (completed before Avicenna was 21 years old) was a commonly used source in many medieval universities, and was a textbook at the Universities of Louvain and Montpelier as late as 1650 A.D. Avicenna's medical system combined his own extensive experience with Islamic medicine, a system used by Galen.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.
Figure 4. Figure 4.

Andreas Vesalius (1514‐1564A.D.), born in Brussels, Belgium with the non‐Latinized name of Andreas van Wesel into a family of physicians, a grandfather being Royal Physician of Emperor Maximilian. While pursuing his medical education in Paris he became interested in anatomy. He is often called the Father of Modern Anatomy. He was among the first to experiment in the area of respiratory physiology. He corrected many of Galen's errors. This plate and several others from his De Humani Corporis Fabrica confirmed that anatomy had switched from Galenic to Vesalian.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.
Figure 5. Figure 5.

Marcello Malpighi (1628‐1694 A.D.), an Italian physician, greatly clarified the microscopic anatomy of the lung, especially the “orbicular” shape of the alveoli and the role of the tortuous pathways of the capillaries across the alveoli from larger arterioles to the venous side. His drawings really provided the first correct anatomical basis for understanding the role of the alveoli and their relation to the pulmonary circulation.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.
Figure 6. Figure 6.

Antoine Laurent Lavoisier (1743‐1794 A.D.) was truly the Father of Modern Chemistry. Discovered the similarity between respiration and combustion, involving the uptake of oxygen from the air and the production of carbon dioxide. But he thought, incorrectly, that all the heat produced by the combination of oxygen with combustible substrates took place in the lung. This notion was later corrected by Spallanzani. Probably should be credited as the investigator who most solidly disproved the then currently popular phlogiston theory.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.
Figure 7. Figure 7.

John Scott Haldane (1860‐1936 A.D.) was a Fellow of New College at Oxford where he had his laboratory. But he was also an honorary Professor at Birmingham University. He is credited with opening a new phase of physiology with his experiments using human subjects. With J.G. Priestley he first clearly demonstrated that resting ventilation was more under the control of carbon dioxide than under the control of oxygen. Dyspnea in his subjects occurred if the former rose to only 3% in an enclosed chamber, whereas oxygen had to drop to 14% to generate the same level of dyspnea. His many other experiments had significant practical applications

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.
Figure 8. Figure 8.

Isidoor Leusen, pursuing chemosensitive structures in the CNS, perfused the lateral ventricles of anesthetized dogs with CO2‐rich fluid (while collecting from the cisterna) and saw an increase in ventilation; this altered the level of CO2 in the cerebrospinal fluid. CO2‐poor fluid provoked a decrease in ventilation. Data was highly suggestive of where hypercapnia exerted its effects on ventilation. But at the time the changes in ventilation were thought to be due to the direct action on the respiratory centers.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 294
Figure 9. Figure 9.

Robert Mitchell (left) and John Severinghaus in collaboration with Hans Loeschcke soaked cotton pledgets in CO2‐rich or H+‐rich solutions and applied them to selected, discreet areas on the ventral lateral surfaces of the medulla in the anesthetized cat. Hyperpnea was the result. They concluded that an area sensitive to CSF H+ (a “central chemoreceptor”) was at or near the surface—within or just beneath the pia.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 296
Figure 10. Figure 10.

John Pappenheimer (right) and Vladimir Fencl used a ventriculo‐cisternal perfusion technique in unanesthetized goats. They concluded from their results that the acid‐sensitive zone (i.e., a “central chemoreceptor”) was not superficial but rather two‐thirds to three‐fourths of the distance along a bicarbonate concentration gradient between blood and CSF in the brainstem.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 297
Figure 11. Figure 11.

Sagittal view of rat brainstem showing location of superior olive (SO), trigeminal nerve 5, facial nerve 7, Bötzinger complex (BötC), pre‐Bötzinger complex (pre‐BötC), retrotrapazoid nucleus (RTN), and parafacial respiratory group (pFRG). pre‐BötC and BötC are thought responsible for inspiratory rhythm; RTN/pFRG more involved with expiratory efforts.
Figure 12. Figure 12.

Plot of the ventilatory response to CO2 in unanesthetized, unsedated lamb. The animal was fitted with an extracorporeal carbon dioxide membrane lung (CDML) through which subclavian arterial blood was passed, and returned to the jugular vein. Functioning like a kidney dialyzer, the CDML gradually removed as much CO2 as the animal was producing. Total CDML removal of CO2 produced a 100% decrease in ventilation. The data supported the notion that peripheral input is needed for the central pattern generator and other central neural mechanisms to operate.

with permission from Anesthesiology 46: 138‐141, 1977
Figure 13. Figure 13.

Diagram illustrating the principal features of the existential organization of the neural factors controlling breathing, revealing the pathway for suprapontine/medullary input. Output is not just to striated muscles to expand the lungs but also to muscles of the airways via the premotor and motor neurons. Hypothal, hypothalamus; pulm, pulmonary; extern. Intercost, external intercostal; intern. Intercost, internal intercostal; MN, motor neuron; preMN, premotor neuron.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 256
Figure 14. Figure 14.

Corneille Heymans (left) and Fernando DeCastro were pioneers of carotid body physiology. DeCastro provided superb drawings of the carotid sinus area and the carotid body. As early as 1928, he correctly distinguished the function of each structure. Heymans using anesthetized dogs reported the reflex responses resulting from stimulation in the area for which he was awarded the Nobel Prize in Physiology or Medicine for 1938. After winning the prize he was asked by the press corps if he thought people could live without their carotid bodies. He replied that he thought they could, but thought his own career certainly would have suffered terribly.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 303
Figure 15. Figure 15.

Carlos Eyzaguirre was the patriarch of carotid body studies in the U.S. He with his many colleagues investigated virtually every aspect of chemoreception, and advanced the field in a unique and major way. It is unlikely that any mentor active today has trained more investigators (with permission from Respiratory Physiology People and Ideas, edited by John West, p. 306).
Figure 16. Figure 16.

Location and neural connections of one of the most important peripheral interoreceptors for ventilatory control, the carotid body (CB). Selective stimulation of the CB with hypoxia, hypercapnia, acidosis, or hypoglycemia can precipitate increases in tidal volume, respiratory frequency, functional residual capacity (FRC), airways resistance, airway secretions, and decreases in pulmonary vascular resistance.
Figure 17. Figure 17.

Jerome Dempsey (center), Hubert Forster (left), and Gerald Bisgard were leaders in the “Wisconsin Group” which spearheaded studies elucidating the importance of carotid bodies to control eupneic breathing and the response to hyperoxic hypercapnia. They also studied ventilatory acclimatization to hypoxia in several animal species and in humans. They concluded that changes in cerebral spinal fluid bicarbonate was not the critical factor in the process of acclimatization, and not nearly as important as previously believed; rearrangement of carotid body sensing mechanisms during hypoxia seemed to be more responsible (with permission from Respiratory Physiology People and Ideas, edited by John West, p. 298).
Figure 18. Figure 18.

Abbreviated dorsal view in rat of peripheral input into pontine‐medullary region of information important/essential for the genesis of respiratory rhythm. Proceding via the glossopharyngeal (IX) nerve is the critically important information from arguably the most important peripheral interoreceptor in the organism, the carotid body (CB). Carotid sinus baroreceptor information also proceeds along IX and solitary tract to the nucleus tractus solitarii (NTS). Information via the vagus (X) comes from the slowly adapting receptors in airway smooth muscle (SARs), from the rapidly adapting receptors in the airway epithelium (RARs), and from the C‐fibers in the parenchyma of the lung. Facial nerve nuclei (geniculate and facial motor nerve), located in the pontine area, seem to have little direct impact per se on ventilatory control. The ventral respiratory group has several different important loci: nucleus ambiguus sends efferent fibers to control airway smooth muscle, as well as cardiac performance. Excitatory inspiratory neurons innervating the phrenic nucleus are also found in the ventral respiratory group. AP, area postrema also called the calamus scriptorius (medullary landmarks); PBr/KF region, parabrachialis/Kölliker‐Fuse nucleus—components of the pontine respiratory group.


Figure 1.

A recent search of PubMed by Zapata and Larrain for the International Society for Arterial Chemoreception using carotid body‐related terms produced more than 5,000 citations of which most of the early ones treated carotid body tumors. Presented here are carotid body publications in 5‐year intervals starting in 1945 which are focused more on anatomy, cytology, neurophysiology, neurochemistry, resulting reflex responses to stimulation.



Figure 2.

Galen (130‐199 A.D.) of Pergamum was a prominent Roman physician (indeed, to the Emperor Marcus Aurelius) and philosopher of Greek origin. His anatomical views of the cardiovascular system were based on studies in the monkey since dissection was not allowed at that time; these views were taught for 1,300 years. The “spirits” added to the blood in Galen's view came from the left ventricle (vital spirit) as the blood coursed through the invisible pores of the interventricular septum between right and left ventricles. The “animal spirit” came from the brain.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.


Figure 3.

Ibn Sina (980‐1037 A.D.), known in the West as Avicenna, was the foremost philosopher and physician of his day. He was greatly influenced by Aristotle, and, in turn, greatly influenced Thomas Aquinas, Galileo, Harvey, and several others. Avicenna wrote over 400 treatises of which about half have survived. Most focus on philosophy (for which he was criticized); about 40 deal with medicine. His encyclopedic Canon of Medicine (completed before Avicenna was 21 years old) was a commonly used source in many medieval universities, and was a textbook at the Universities of Louvain and Montpelier as late as 1650 A.D. Avicenna's medical system combined his own extensive experience with Islamic medicine, a system used by Galen.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.


Figure 4.

Andreas Vesalius (1514‐1564A.D.), born in Brussels, Belgium with the non‐Latinized name of Andreas van Wesel into a family of physicians, a grandfather being Royal Physician of Emperor Maximilian. While pursuing his medical education in Paris he became interested in anatomy. He is often called the Father of Modern Anatomy. He was among the first to experiment in the area of respiratory physiology. He corrected many of Galen's errors. This plate and several others from his De Humani Corporis Fabrica confirmed that anatomy had switched from Galenic to Vesalian.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.


Figure 5.

Marcello Malpighi (1628‐1694 A.D.), an Italian physician, greatly clarified the microscopic anatomy of the lung, especially the “orbicular” shape of the alveoli and the role of the tortuous pathways of the capillaries across the alveoli from larger arterioles to the venous side. His drawings really provided the first correct anatomical basis for understanding the role of the alveoli and their relation to the pulmonary circulation.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.


Figure 6.

Antoine Laurent Lavoisier (1743‐1794 A.D.) was truly the Father of Modern Chemistry. Discovered the similarity between respiration and combustion, involving the uptake of oxygen from the air and the production of carbon dioxide. But he thought, incorrectly, that all the heat produced by the combination of oxygen with combustible substrates took place in the lung. This notion was later corrected by Spallanzani. Probably should be credited as the investigator who most solidly disproved the then currently popular phlogiston theory.

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.


Figure 7.

John Scott Haldane (1860‐1936 A.D.) was a Fellow of New College at Oxford where he had his laboratory. But he was also an honorary Professor at Birmingham University. He is credited with opening a new phase of physiology with his experiments using human subjects. With J.G. Priestley he first clearly demonstrated that resting ventilation was more under the control of carbon dioxide than under the control of oxygen. Dyspnea in his subjects occurred if the former rose to only 3% in an enclosed chamber, whereas oxygen had to drop to 14% to generate the same level of dyspnea. His many other experiments had significant practical applications

Courtesy of the Institute of the History of Medicine, The Johns Hopkins University.


Figure 8.

Isidoor Leusen, pursuing chemosensitive structures in the CNS, perfused the lateral ventricles of anesthetized dogs with CO2‐rich fluid (while collecting from the cisterna) and saw an increase in ventilation; this altered the level of CO2 in the cerebrospinal fluid. CO2‐poor fluid provoked a decrease in ventilation. Data was highly suggestive of where hypercapnia exerted its effects on ventilation. But at the time the changes in ventilation were thought to be due to the direct action on the respiratory centers.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 294


Figure 9.

Robert Mitchell (left) and John Severinghaus in collaboration with Hans Loeschcke soaked cotton pledgets in CO2‐rich or H+‐rich solutions and applied them to selected, discreet areas on the ventral lateral surfaces of the medulla in the anesthetized cat. Hyperpnea was the result. They concluded that an area sensitive to CSF H+ (a “central chemoreceptor”) was at or near the surface—within or just beneath the pia.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 296


Figure 10.

John Pappenheimer (right) and Vladimir Fencl used a ventriculo‐cisternal perfusion technique in unanesthetized goats. They concluded from their results that the acid‐sensitive zone (i.e., a “central chemoreceptor”) was not superficial but rather two‐thirds to three‐fourths of the distance along a bicarbonate concentration gradient between blood and CSF in the brainstem.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 297


Figure 11.

Sagittal view of rat brainstem showing location of superior olive (SO), trigeminal nerve 5, facial nerve 7, Bötzinger complex (BötC), pre‐Bötzinger complex (pre‐BötC), retrotrapazoid nucleus (RTN), and parafacial respiratory group (pFRG). pre‐BötC and BötC are thought responsible for inspiratory rhythm; RTN/pFRG more involved with expiratory efforts.



Figure 12.

Plot of the ventilatory response to CO2 in unanesthetized, unsedated lamb. The animal was fitted with an extracorporeal carbon dioxide membrane lung (CDML) through which subclavian arterial blood was passed, and returned to the jugular vein. Functioning like a kidney dialyzer, the CDML gradually removed as much CO2 as the animal was producing. Total CDML removal of CO2 produced a 100% decrease in ventilation. The data supported the notion that peripheral input is needed for the central pattern generator and other central neural mechanisms to operate.

with permission from Anesthesiology 46: 138‐141, 1977


Figure 13.

Diagram illustrating the principal features of the existential organization of the neural factors controlling breathing, revealing the pathway for suprapontine/medullary input. Output is not just to striated muscles to expand the lungs but also to muscles of the airways via the premotor and motor neurons. Hypothal, hypothalamus; pulm, pulmonary; extern. Intercost, external intercostal; intern. Intercost, internal intercostal; MN, motor neuron; preMN, premotor neuron.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 256


Figure 14.

Corneille Heymans (left) and Fernando DeCastro were pioneers of carotid body physiology. DeCastro provided superb drawings of the carotid sinus area and the carotid body. As early as 1928, he correctly distinguished the function of each structure. Heymans using anesthetized dogs reported the reflex responses resulting from stimulation in the area for which he was awarded the Nobel Prize in Physiology or Medicine for 1938. After winning the prize he was asked by the press corps if he thought people could live without their carotid bodies. He replied that he thought they could, but thought his own career certainly would have suffered terribly.

with permission from Respiratory Physiology People and Ideas, edited by John West, p. 303


Figure 15.

Carlos Eyzaguirre was the patriarch of carotid body studies in the U.S. He with his many colleagues investigated virtually every aspect of chemoreception, and advanced the field in a unique and major way. It is unlikely that any mentor active today has trained more investigators (with permission from Respiratory Physiology People and Ideas, edited by John West, p. 306).



Figure 16.

Location and neural connections of one of the most important peripheral interoreceptors for ventilatory control, the carotid body (CB). Selective stimulation of the CB with hypoxia, hypercapnia, acidosis, or hypoglycemia can precipitate increases in tidal volume, respiratory frequency, functional residual capacity (FRC), airways resistance, airway secretions, and decreases in pulmonary vascular resistance.



Figure 17.

Jerome Dempsey (center), Hubert Forster (left), and Gerald Bisgard were leaders in the “Wisconsin Group” which spearheaded studies elucidating the importance of carotid bodies to control eupneic breathing and the response to hyperoxic hypercapnia. They also studied ventilatory acclimatization to hypoxia in several animal species and in humans. They concluded that changes in cerebral spinal fluid bicarbonate was not the critical factor in the process of acclimatization, and not nearly as important as previously believed; rearrangement of carotid body sensing mechanisms during hypoxia seemed to be more responsible (with permission from Respiratory Physiology People and Ideas, edited by John West, p. 298).



Figure 18.

Abbreviated dorsal view in rat of peripheral input into pontine‐medullary region of information important/essential for the genesis of respiratory rhythm. Proceding via the glossopharyngeal (IX) nerve is the critically important information from arguably the most important peripheral interoreceptor in the organism, the carotid body (CB). Carotid sinus baroreceptor information also proceeds along IX and solitary tract to the nucleus tractus solitarii (NTS). Information via the vagus (X) comes from the slowly adapting receptors in airway smooth muscle (SARs), from the rapidly adapting receptors in the airway epithelium (RARs), and from the C‐fibers in the parenchyma of the lung. Facial nerve nuclei (geniculate and facial motor nerve), located in the pontine area, seem to have little direct impact per se on ventilatory control. The ventral respiratory group has several different important loci: nucleus ambiguus sends efferent fibers to control airway smooth muscle, as well as cardiac performance. Excitatory inspiratory neurons innervating the phrenic nucleus are also found in the ventral respiratory group. AP, area postrema also called the calamus scriptorius (medullary landmarks); PBr/KF region, parabrachialis/Kölliker‐Fuse nucleus—components of the pontine respiratory group.

References
 1. Balbir A, Lee H, Okumura M, Biswal S, Fitzgerald RS, Shirahata M. A search for genes that may confer divergent morphology and function in the carotid body between two strains of mice. Am J Physiol Lung Cell Mol Physiol 292: L704‐L715, 2007.
 2. Campbell EJM, Howell JBL. The sensation of breathlessness. Br Med Bull 19: 36‐40, 1963.
 3. Cherniack NS, Altose MD. Respiratory responses to ventilatory loading. In: Hornbein TF, editor Regulation of Breathing. Lung Biology in Health and Disease vol. 17. New York: Marcel Dekker, 1981, chap. 14, p. 905‐964.
 4. Cherniack NS, Longobardo GS. Oxygen and carbon dioxide gas stores of the body. Physiol Rev 50: 196‐243, 1970.
 5. Cherniack NS, Longobardo GS. Cheyne‐Stokes breathing, an instability in physiological control. NEJM 288: 952‐957, 1973.
 6. Cherniack NS, Longobardo GS. Mathematical models of periodic breathing and their usefulness in understanding cardiovascular and respiratory disorders. Exp Physiol 91: 295‐305, 2006.
 7. Cherniack NS, Longobardo GS, Evangelista CJ. Causes of Cheyne‐Stokes respiration. Neurocrit Care 3: 271‐279, 2006.
 8. Chonan T, Mulholland MB, Leitner J, Altose MD, Cherniack NS. Sensation of dyspnea during hypercapnia, exercise, and voluntary hyperventilation. J Appl Physiol 68: 2100‐2106, 1990.
 9. Clendening L. Source Book of Medical History. New York: Dover, 1960.
 10. Crowell JW, Guyton AC, Moore JW. Basic oscillating mechanism of Cheyne‐Stokes breathing. Am J Physiol 187: 395‐398, 1956.
 11. De Castro T. Sur la structure et l'innervation de la glande intercarotidienne (glomus caroticum) de l'homme et des mammiferes, et sur un noveau système d'innervation autonome du nerf glossopharyngien. Trav Lab Rech Biol Univ Madrid 24: 365‐432, 1926.
 12. De Castro T. Sur la structure et l'innervation du sinus carotidien de l'homme et des mammiferes. Nouveaux faites sur l'innervation et la fonction du Glomus caroticum. Trav Lab Rech Biol Univ Madrid 25: 331‐380, 1928.
 13. Defares JG, Derksen HE, Duyff JW. Cerebral blood flow in the regulation of respiration. Acta Physiol Pharmacol Neerl 9: 327‐360, 1953
 14. Dement WC. Recent studies on the biological role of rapid eye movement sleep. Am J Psychiatry 122: 404‐408, 1965.
 15. Euler von C. Introduction: Forebrain control of breathing behavior. In: von Euler C, Katz‐Salaman M, editors Respiratory Psychophysiology. Wenner‐Gren International Symposium Series, Vol.50. K Basingstoke: The Macmillan Press, 1988, p. 1‐14.
 16. Farhi LE, Rahn H. Gas stores of the body and the unsteady state. J Appl Physiol 7: 472‐484, 1955.
 17. Fitzgerald RS, Hauer MC, Bierkamper GG, Raff H. Responses of the in vitro rat diaphragm to changes in acid‐base environment. J Appl Physiol 57: 1202‐1210, 1984.
 18. Fitzgerald RS, Howell S, Jacobus WE. 31P‐NMR study of the resting in vitro rat diaphragm exposed to hypercapnia. J Appl Physiol 65: 2270‐2277, 1988.
 19. Fitzgerald RS, Howell S, Pike MM, Jacobus WE. NMR study of rat diaphragm exposed to metabolic and compensated metabolic acidosis. J Appl Physiol 65: 2278‐2284, 1988.
 20. Franklin KJ. A Short History of Physiology (2nd ed). London: Staples, 1949.
 21. Fredericq L. Sur la cause de l'apnée. Archiv Biol Liége 17: 561‐576, 1900.
 22. Garrison FH. An Introduction to the History of Medicine (4th ed). Phildelphia: Saunders, 1929.
 23. Gray JS. The Multiple Factor Theory of the control of respiratory ventilation. Science 103: 739‐744, 1946.
 24. Grocott MPW, Martin DS, Levett DZH, McMorrow R, Windsor J, Montgomery HE. Arterial blood gases and oxygen content in climbers on Mount Everest. NEJM 360: 140‐149, 2009.
 25. Grodins FS. Control Theory and Biological Systems. New York: Columbia University Press, 1963.
 26. Grodins FS, Buell J, Bart AJ. Mathematical analysis and digital simulation of the respiratory control system. J Appl Physiol 22: 260‐276, 1967.
 27. Grodins FS, Gray JS, Schroeder KR, Norins AL, Jones RW. Respiratory responses to CO2 inhalation: A theoretical study of a nonlinear biological regulator. J Appl Physiol 7: 283‐308, 1954.
 28. Grodins FS, Yamashiro SM. Optimization of the mammalian respiratory gas transport system. Annu Rev Biophys Bioeng 2: 115‐130, 1973.
 29. Guthrie D. A History of Medicine. London: Nelson, 1946.
 30. Guz A. Brain, breathing and breathlessness. Respir Physiol 109: 197‐204, 1997.
 31. Haldane JS, Priestley JG. The regulation of lung ventilation. J Physiol London 32: 225‐266, 1905.
 32. Heymans C, Bouckaert J‐J, Dautrebande L. Rôle réflexogène respiratoire des zones vaso‐sensible cardio‐aortique et sino‐carotidiennes. Ion Hydrogène, CO2, sinus carotidiens et réflexes respiratoires. C R Soc Biol 105: 881‐884, 1930.
 33. Heymans J‐F, Heymans C. Sur les modifications directes et indirectes et sur la regulation réflexe de l'activité du centre respiratoire de la tête isolée du chien. Arch Int Pharmacodyn Ther 33: 273‐372, 1927.
 34. Hooke R. An account of an experiment made by M. Hooke of preserving animals alive by blowing through their lungs with bellows. Phil Trans Roy Soc London 28: 539‐550, 1667.
 35. Houston CS, Riley RL. Respiratory and circulatory changes during acclimatization to high altitude. Amer J Physiol 140: 565‐588, 1947.
 36. Houston CS, Sutton JR, Cymerman A, Reeves JT. Operation Everest II: Man at extreme altitude. J Appl Physiol 63: 877‐882, 1987.
 37. Howell JBL, Campbell EJM, editors. Breathlessness. Philadelphia: F.A. Davis Co., 1966, p. 233‐238.
 38. Howell S, Fitzgerald RS, Roussos Ch. Effects of aminophylline, isoproterenol, and neostigmine on hypercapnic depression of diaphragmatic contractility. Am Rev Resp Dis 132: 241‐247, 1985.
 39. Howell S, Fitzgerald RS, Roussos Ch. Effects of uncompensated and compensated metabolic acidosis on canine diaphragm. J Appl Physiol 59: 1376‐1382, 1985.
 40. Jacobs MH. The production of intracellular acidity by neutral and alkaline solutions containing carbon dioxide. Amer J Physiol 53: 457‐463, 1920.
 41. Khoo MCK, Gottschalk A, Pack AI. Sleep‐induced periodic breathing and apnea: A theoretical study. J Appl Physiol 70: 2014‐2024, 1991.
 42. Kikuchi Y, Okabe S, Tamura G, Hida W, Homma M, Shirato K, Takishima T. Chemosensitivity and perception of dyspnea in patients with a history of near‐fatal asthma. NEJM 330: 1329‐1334, 1994.
 43. Kolobow T, Gattinoni L, Tomlinson TA, Pierce JE. Control of breathing using an extracorporeal membrane lung. Anesthesiol 46: 138‐141, 1977.
 44. Lavoisier AL. Expériences sur la respiration des animaux et sur les changements qui arrivent a l'air en passant par leur poumon. In: Oeuvres de Lavoisier, Vol II. Paris: Imprimerie Imperiale, 1862‐1893, p. 174‐183.
 45. LeGallois C. Expériences Sur le Principe de La Vie. Paris: d'Hautel, 1812.
 46. Leusen I. Influence du pH du liquide céphalorachidien sur la respiration. Experientia 6: 272, 1950.
 47. Leusen I. Chemosensitivity of the respiratory center. Influence of CO2 in the cerebral ventricles on respiration. Amer J Physiol 176: 39‐44, 1954.
 48. Li YL, Ding Y, Agnew C, Schultz HD. Exercise training improves peripheral chemoreflex function in heart failure rabbits. J Appl Physiol 105: 782‐790, 2008.
 49. Li YL, Xia XH, Zheng H, Gao L, Li YF, Liu D, Patel KP, Wang W, Schultz HD. Angiotensin II enhances carotid body chemoreflex control of sympathetic outflow in chronic heart failure rabbits. Card Res 71: 129‐138, 2006.
 50. Lloyd BB, Jukes MG, Cunningham DJ. The relation between alveolar oxygen pressure and the respiratory response to carbon dioxide in man. Q J Exp Physiol Cogn Med Sci 43: 214‐227, 1958.
 51. Longobardo GS, Evangelista CJ, Cherniack NS. Analysis of the interplay between neurochemical control of respiration and upper airway mechanics producing upper airway obstruction during sleep in humans. Exp Physiol 93: 271‐287, 2008.
 52. Longobardo GS, Gothe B, Goldman MD, Cherniack NS. Sleep apnea considered as a control system instability. Respir Physiol 50: 311‐333, 1982.
 53. Lugaresi E, Coccagna G, Mantovani M, Brignani F. Effects of tracheotomy in hypersomnia with periodic respiration. Rev Neurol (Paris) 123: 267‐268, 1970.
 54. Lugaresi E, Coccagna G, Petrella A, Berti Ceroni G, Pazzaglia P. The disorder of sleep and respiration in the Pickwick syndrome. Sist Nerv 20: 38‐50, 1968.
 55. Lumsden T. The regulation of respiration; Pt. II, normal type. J Physiol London 58: 111‐126, 1923‐24.
 56. Lyons HA, Burno F, Stone RW. Pulmonary compliance in patients with periodic breathing. Circulation 17: 1056‐1061, 1958.
 57. Marckwald M. Die Athembewegungen und deren Innervation beim Kaninchen. Z Biol 23: 149‐283, 1887.
 58. Mayow J. Opera Omnia Medico‐Physica Tractatibus Quinque Comprehensa. The Hague, 1681. In: English translation, Medico‐Physical Works. Edinburgh, Alembic Club Reprints, No.17, 1907, p. 8.
 59. Merrill EG. The lateral respiratory neurons of the medulla: Their associations with nucleus ambiguus, nucleus retroambigualis, the spinal accessory nucleus and the spinal cord. Brain Res 24: 11‐28, 1970.
 60. Miescher‐Rusch F. Bermerkungen zur Lehre von den Atembewegungen. Arch Anat u Physiol Leipzig 6: 355‐380, 1885.
 61. Mitchell RA, Loeschcke HH, Severinghaus JL, Richardson BW, Massion WH. Regions of respirtory chemosensitivity on the surface of the medulla. Ann NY Acad Sci 109: 661‐681, 1963.
 62. Morse WR. Chinese Medicine, Vol. XI Clio Medica Ser. New York: Hoeber, 1934.
 63. Nielsen M, Smith H. Studies in the regulation of ventilation in acute hypoxia. Acta Physiol Scand 24: 293‐313, 1953.
 64. Oku Y, Saidel GM, Altose MD Cherniack NS. Perceptual contributions to optimization of breathing. Ann Biomed Eng 21: 509‐515, 1993.
 65. Oku Y, Saidel GM, Cherniack NS, Altose MD. Model of respiratory sensation and wilful control of ventilation. Med Biol Eng Comput 33: 252‐256, 1995.
 66. Pappenheimer J, Fencl V, Heisey S, Held D. Role of cerebral fluids in control of respiration as studied in unanesthetized goats. Amer J Physiol 208: 436‐450, 1967.
 67. Phillipson EA. Control of breathing during sleep. Am Rev Respir Dis 118: 909‐939, 1978.
 68. Phillipson EA, Duffin J, Cooper JD. Critical dependence of respiratory rhythmicity on metabolic CO2 load. J Appl Physiol 50: 45‐54, 1981.
 69. Plum F, Brown WH. The neurological bases of Cheyne‐Stokes respiration. Am J Med 30: 849‐860, 1961.
 70. Plum F, Brown WH. The effect on respiration of central nervous system disease. Ann NY Acad Sci 109: 915‐931, 1963.
 71. Poon CS. Ventilatory control in hypercapnia and exercise: Optimization hypothesis. J Appl Physiol 62: 2447‐2459, 1987.
 72. Rechtschaffen A, Roth B. A polygraphic study of night sleep in patients with hypersomnia. Electroencephalogr Clin Neurophysiol 26: 230‐237, 1969.
 73. Richalet J‐P, Donoso MV, Jimenez D, Antezana A‐M, Hudson C, Cortes G, Osoria J, Leon A. Chilean miners commuting from sea level to 4500 m: a prospective study. High Alt Med Biol 3: 159‐166, 2002.
 74. Richter DE, Heyde F, Gabriel M. Intracellular recordings from different types of medullary respiratory neurons of the cat. J Neurophysiol 38: 1182‐1190, 1975.
 75. Smith JC, Ellenberger HH, Ballanyi K, Richter DW, Feldman JL. Pre‐Botzinger complex: A brainstem region that may generate respiratory rhythm in mammals. Science 254: 726‐729, 1991.
 76. Rodman JR, Curran AK, Henderson KS, Dempsey JA, Smith CA. Carotid body denervation in dogs: Eupnea and the ventilatory response to hyperoxic hypercapnia. J Appl Physiol 91: 328‐335, 2001.
 77. Sackner MA, Landa J, Forrest T, Greeneltch D. Periodic sleep apnea: Chronic sleep deprivation related to intermittent upper airway obstruction and central nervous system disturbance. Chest 67: 164‐171, 1975.
 78. Schaefer KE, Hastings BJ, Carey CR, Nichols G Jr. Respiratory acclimatization to carbon dioxide. J Appl Physiol 18: 1071‐1078, 1963.
 79. Schnader J, Howell S, Fitzgerald RS, Roussos Ch. Interaction of fatigue and hypercapnia in the canine diaphragm. J Appl Physiol 64: 1636‐1643, 1988.
 80. Schnader JY, Juan G, Howell S, Fitzgerald RS, Roussos Ch. Arterial CO2 partial pressure affects diaphragmatic function. J Appl Physiol 58: 823‐829, 1985.
 81. Serebrovskaya T. Intermittent hypoxia research in the former soviet union and the commonwealth of independent states: History and review of the concept and selected applications. High Alt Med Biol 3: 205‐221, 2002.
 82. Severinghaus JW. History of measuring O2 and CO2 responses. Adv Exp Med Biol 605: 3‐8, 2008.
 83. Singer C. A Short History of Anatomy and Physiology from the Greeks to Harvey. New York: Dover, 1957.
 84. Singer C. A Short History of Scientific Ideas to 1900. London: Oxford, 1959.
 85. Sullivan CE, Kozar LF, Murphy E, Phillipson EA. Primary role of respiratory afferents in sustaining breathing rhythm. J Appl Physiol: Respirat Environ Exercise Physiol 45: 11‐17, 1978.
 86. Tankersley CG, Fitzgerald RS, Kleeberger SR. Differential control of ventilation among inbred strains of mice. Am J Physiol 267: R1371‐R1377, 1994.
 87. Tankersley CG, Fitzgerald RS, Levitt RC, Mitzner WA, Ewart SL, Kleeberger SR. Genetic control of differential baseline breathing pattern. J Appl Physiol 82: 874‐881, 1997.
 88. Takala J, Askanazi J, Weissman C, LaSala PA. Breathing during sleep in patients with obstructive lung disease. Am Rev Respir Dis 141: 1055–1070, 1990.
 89. Taylor FS. A Short History of Science and Scientific Thought. New York: Norton, 1949.
 90. Vinci da L. Notebooks of Leonardo da Vinci. [in L. Clendening; op.cit. (9), p. 124].
 91. Wang SC, Ngai SH, Frumin MJ. Organization of central respiratory mechanisms in the brain stem of the cat: Genesis of normal respiratory rhythmicity. Am J Physiol 190: 333‐342, 1957.
 92. West JB. The physiologic basis of high‐altitude diseases. Ann Intern Med 14: 789‐800, 2004.
 93. Whitehead AN. The origins of modern science. In: Science and the Modern World. New York: Macmillan, 1925, p. 9‐25.
 94. Widdicombe J. Airway receptors. Respir Physiol 125: 3‐15, 2001.
 95. Wilson LG. Erasistratus, Galen, and the pneuma. Bull Hist Med 33: 293‐314, 1959.
 96. Wilson LG. The transformation of ancient concepts of respiration. Isis 51(3): 161‐172, 1960.
 97. Wilson LG. The problem of the discovery of the pulmonary circulation. J Hist Med 16: 229‐244, 1962.
 98. Winterstein H. Die Regulierung der Atmng durch das Blut. Zentr Physiol 24: 811, 1910.
 99. Winterstein H. Die regulierung der atmung durch das blut. Arch Ges Physiol 38: 167‐184, 1911.
 100. Winterstein H. Die raktionstheorie der atmungsregulation. Arch Ges Physiol 189: 293‐298, 1921.
 101. Wu TY, Ding SQ, Liu JL, Yu MT, Jia JH, Duan JQ, Chai ZC, Dai RC, Zhang SL, Liang BZ, Shao JS, Qi DT, Sun YF, Kayser B. Reduced incidence and severity of acute mountain sickness in Qinghai‐Tibet railroad construction workers after repeated 7‐month exposures despite 5‐month low altitude periods. High Alt Med Biol 10: 221‐232, 2009.
 102. Yamaguchi S, Balbir A, Schofield B, Coram J, Tankersley CG, Fitzgerald RS, O'Donnell CP, Shirahata M. Structural and functional differences of the carotid body between DBA/2J and A/J strains of mice. J Appl Physiol 94: 1536‐1542, 2003.
 103. Yamamoto WS. Computer simulation of experiments in responses to intravenous and inhaled CO2. J Appl Physiol 50: 835‐843, 1981.

Further Reading

Respiratory Physiology People and Ideas edited by John B. West. New York, Oxford.  Published for the American Physiological Society by Oxford University Press, 1996.

A History of Breathing Physiology edited by Donald F. Proctor. New York, Marcel Dekker, Inc., 1995.  Volume 83 of the Lung Biology in Health and Disease series.  Executive Editor: Claude Lenfant.

John F. Perkins, Jr. “Historical development of respiratory physiology” In: Handbook of Physiology.  Section 3: Respiration Volume I.  Section Editors: Wallace O. Fenn and Hermann Rahn.  Washington, DC, American Physiological Society, 1964.

John E. Remmers.  A century of control of breathing.  Amer. J. Resp. Crit. Care Med. 172: 6-11, 2005.


Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Historical Perspectives on the Control of Breathing
 

How to Cite

Robert S. Fitzgerald, Neil S. Cherniack. Historical Perspectives on the Control of Breathing. Compr Physiol 2012, 2: 915-932. doi: 10.1002/cphy.c100007