Regulating the Ventilatory Pump
A Splendid Control System Prone to Fail During Sleep

JOHN E. REMMERS and SUKHAMAY LAHIRI

Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; and Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

	INTRODUCTION

TOP INTRODUCTION REFERENCES

A half century ago, ideas about the control of breathing were in their infancy, and serious investigation into the area had just begun. Nevertheless, it was clearly realized that the respiratory control system presented a host of fascinating research opportunities and challenges. Two key concepts had been established that have persisted as dominant research themes throughout the next 50 years. The first was that the respiratory control system is a chimera; on the one hand, it is an automatically driven negative feedback control system that regulates arterial PCO₂ and PO₂; on the other hand, its output involves the voluntary musculoskeletal system that is frequently utilized for nonrespiratory behavioral acts. The other fundamental concept was that the system exhibits autorhythmicity derived from a brainstem oscillator that produces a rhythmic output when appropriately excited by chemoreceptor input. This input is projected to a diverse array of output nerves in the cranium and spinal cord. These themes have continued to be explored over the past half century, and the insights developed have provided important clinical advances.

	RESPIRATORY PATTERN

The linkage of tidal volume, duration of inspiration, and duration of expiration became a key focus of investigation from 1960 to 1980. This interest evolved from fundamental considerations of the importance of phasic volume feedback in the regulation of respiratory pattern. Neuronal activity and feedback occurring during inspiration and expiration were found to differ fundamentally; during inspiration, the intensity of chemostimulation of the respiratory controller was shown to determine uniquely the rate of rise of inspiratory muscle activation and, hence, inspiratory airflow (1). Feedback from slowly adapting receptors in the lung provides the controller with information related to instantaneous lung volume, and the intensity of afferent traffic from these receptors in the vagus nerve increase progressively during inspiration until a critical load is reached and inspiration is switched off. The tidal volume and duration of inspiration were found to be linked and described by an off-switch threshold curve such that the tidal volume required to terminate inspiration declined curvilinearly from the beginning of inspiration (2). Inspiratory off-switching is not a simple all-or-nothing step. Rather, the phenomenon of terminating inspiratory neuronal activity is a two-stage process, the first stage of which consists of graded reversible inhibition of inspiratory activity followed by the sudden irreversible termination of inspiratory activity (3). In contrast to the termination of inspiration, expiration was found to be a continuously regulated process wherein post-inspiratory activity of inspiratory muscles and laryngeal resistance were regulated actively throughout expiration to achieve expiratory braking and produce a dynamic end-expiratory volume that often exceeded the passive relaxation volume of the system (4). These vagally mediated reflexes were found to be processed in the brainstem and linked clearly to a central oscillator, which underwent graded and then irreversible phase switching. Afferent impulses from the lung were found to be processed in an integrative fashion, suggesting a fundamental interaction of the phasic volume feedback derived from slowly adapting receptors with the neuronal oscillator itself (5, 6). Rapidly adapting receptors were shown to provide information related to epithelial chemical and mechanical processes and unmyelinated afferent nerves in the lung were found to be sensitive to pain and pulmonary vascular congestion (7). The transduction of these last two stimuli is responsible for rapid shallow breathing and augmented expiratory braking in pulmonary vascular congestion and edema (8).

	RESPIRATORY RHYTHMOGENESIS

The bulbopontine "respiratory centers" became a focus for investigation of the neural processes controlling the automatic or metabolic ventilatory regulation. Clusters of inspiratory and expiratory neurons were found to be located in the pons and medulla (9). It became apparent that inspiratory and expiratory neurons provided mutually inhibitory interactions and that phase-switching of the central pattern generator could be initiated via internal feedback that involved neurons of the rostral pons (10). The so-called respiratory centers were given anatomic definition by grouping neurons into two major clusters; the dorsal respiratory group in the vicinity of the nucleus of the tractus solitarius, and the ventral respiratory group near the ambiguus nucleus (11). The latter was found to lie in a prolonged column stretching from the caudal pons to the facial nucleus and exhibited topographical clustering of expiratory and inspiratory neurons at discrete points throughout this nucleus (12). Pontine neurons were found to lie in the nucleus parabrachialis medialis and in the Kölliker-Fuse nucleus (13). The latter was found to be particularly responsive to vagal feedback; which lead to the notion that phase switching occurred in the rostral pons (14).

A major breakthrough in the investigation of central neural control of breathing occurred when Richter perfected techniques for the intracellular recording of bulbar respiratory neurons (15, 16). Although extracellular recordings could provide a "digital" analysis of the respiratory network, intracellular recording of membrane potential of the bulbar respiratory neurons provided an "insider's view" of the dynamic interaction among respiratory neurons. Essentially, respiratory fluctuations of membrane potential reveal the sequential arrival of excitatory and inhibitory post-synaptic potentials whereby respiratory neurons "communicate" with one another. In addition, these recordings allowed systematic identification of various respiratory neurons synaptically interconnected principally by inhibitory mechanisms (17). Further, these techniques led to the understanding that the neurorespiratory cycle consisted of three, not two, phases: inspiration, post-inspiration, and neural expiration (18, 19). These findings reveal that the expiratory component of the neural-respiratory cycle has two phases: an early-expiratory (post-inspiratory) and a late expiratory phase (20, 21). This division of expiration into two phases is in accord with neuromechanical observations in unanesthetized mammals showing that during the first phase of expiration airflow is retarded, whereas during the second phase it is accelerated (4). In addition, this three-phase respiratory cycle appears to derive evolutionarily from a three-phase neuromechanical ventilatory cycle that may be observed in amphibians and reptiles.

The development of a fictitiously breathing in vitro brainstem model by Feldman and coworkers allowed another major step in understanding the basic features of neural control of breathing (21, 23). Recently, this approach has been further advanced by the development of techniques for studying respiratory rhythmogenesis in an isolated slice of the medulla (24). The results of these experiments reveal that pacemaker neurons in the rostral ventrolateral pons interact with excitatory synaptic interconnections to produce the bursting rhythm that underlies breathing. One caveat associated with this discovery is that the respiratory rhythm studied under these conditions may represent "gasping" rather than eupnea, inasmuch as the preparation is substantially hypoxic.

Understanding the control of breathing during exercise- induced hyperpnea has been a major challenge for investigators in this field. Results of a variety of investigations indicate that both central and peripheral neural mechanisms are at play (25). An example of the latter is respiratory stimulation derived from muscular afferents activated during muscle contraction; an example of the former is central excitatory processes that are co-activated during the motor act of locomotion (25, 26).

	CENTRAL RESPIRATORY CHEMORECEPTION

There has been substantial progress in the understanding of central respiratory chemoreception during the last 50 years. Considerable progress was achieved in two seminal studies performed in the mid-1960s. One was the work of Loesche and colleagues, who located central respiratory chemoreceptors sensitive to CO₂ and pH on the ventral surface of the medulla (27). The other was the landmark experiments by Pappenheimer and associates illustrating that brain extracellular fluid pH and PCO₂ regulate pulmonary ventilation (28) and that the receptors to pH and PCO₂ could be theoretically localized along a diffusion gradient between the blood and the CSF (29). More recent studies by Nattie and colleagues have demonstrated that central respiratory chemoreception is located at a variety of sites within the brainstem, and probably are located in the same areas that are important for respiratory rhythmogenesis and pattern control (30). Major unresolved questions currently under investigation include: are respiratory neurons chemosensitive? Is chemoreception related to intra- or extracellular pH? What is the membrane biophysical mechanism responsible for transduction of the H⁺ signal? Answers to these questions are on the horizon, suggesting that investigation of cellular and molecular basis for central respiratory chemoreception will yield major insights in the next decade.

	PERIPHERAL RESPIRATORY CHEMORECEPTION

Discovery of Peripheral Chemoreceptors and the Nobel Prize

In their article on the history of chemoreception, Fitzgerald and Lahiri (31) have given an account of peripheral chemoreceptors and chemoreception. The existence of peripheral chemoreceptors was known in the eighteenth century, but precise location of the chemoreceptors was not known until Fernando De Castro gave the first histological description in 1926. In 1928, he hinted at its functional significance as "tasting blood" chemistry. Soon afterwards, Corneille Heymans discovered by means of an "unplanned" experiment that when the carotid sinus areas of an anesthetized dog were cross-circulated with blood containing acetylcholine, the dog increased its breathing. From then onwards, many planned experiments were performed, and chemoreflex due to carotid bodies and baroreflex due to baroreceptors in the carotid sinus areas were identified and separated. For these studies, Corneille Heymans was awarded the Nobel Prize in 1938.

Peripheral Chemoreceptors and Chemoreflexes

Control of breathing is an important function of peripheral chemoreception. Without this function, oxygen sensing by itself is of no use to the organism.

Carotid and aortic bodies are generally known as peripheral arterial chemoreceptors; arterial because of the assumption that they "taste" arterial and not venous blood PO₂. The concept still is valid. These are very small organs. There are only a few small organs, such as the pituitary, on which the entire organism depends so much.

Structurally, carotid and aortic bodies are similar. Situated in the carotid sinus area in which baroreceptors originate, the carotid chemoreceptors are poised for integration of the cardiorespiratory systems. The consensus is that sensing of PO₂ and PCO₂ is done by the glomus cells, and they are the only cells that are innervated by the processes of the pertrosal ganglion cells, which then project in the central nervous system, specifically the respiratory nuclei in brain stem.

Like all organs, peripheral chemoreceptors also undergo development as the organism matures. Their rate of development is determined by the genetic constitution of the cell. Superimposed on this, another determinant is the environment in which the organism lives.

Life for mammals begins with hypoxia, which presumably offers optimal conditions for controlled embryonic and fetal development. At fetal arterial PO₂ of 25-30 mm Hg and slightly acidic pH at sea level, the peripheral chemoreceptors would be maximally active by the adult standard, and the consequent reflex drive, particularly respiratory, would be strong but wasteful. Thus, although the genetically coded development must follow its course during gestation, the hypoxic environment favors delayed maturity of the peripheral chemoreceptors. The blunted chemoreflex response in subjects born in hypoxic environments supports this concept. Kittens born and raised in a hypoxic environment showed a delayed development of hypoxic chemoreflex drive (32). Similarly, people born at high altitude develop their hypoxic drive at a slower pace.

The major hypotheses regarding the mechanism of O₂ chemoreception are "respiratory" and "non-respiratory." The respiratory hypothesis involves an effect of O₂ on mitochondrial respiratory chain, and the nonrespiratory hypothesis involves an action of O₂ on the glomus cell membrane (33). Both hypotheses incorporate [Ca²⁺]I increases, neurosecretion and neural discharge followed by chemoreflex.

Neurosecretion in the carotid body (CB) has also been linked with development. Tyrosine hydroxylase is O₂-sensitive and is responsible for dopamine and norepinephrine turnover rates in the CB. Dopamine and norepinephrine are constituent parts of carotid body metabolism, and influence chemosensory discharge. However, the linkage of hypoxic response to dopamine is questionable (34). Marchal and coworkers (35) reported that exogenous dopamine exerted both inhibitory and excitatory effects on the chemosensory responses in the newborn kittens, and required more than two weeks to develop a fully mature response that was inhibitory. They also found that dopamine D2 receptors already were developed in these kittens. Hypoxia increases dopamine secretion associated with chemosensory discharge; because of this correlation, it is thought to be excitatory (36). On the other hand, hypercapnia also causes carotid chemosensory discharge but inhibits dopamine release (37). Chronic hypoxia increases dopamine concentration several fold and is accompanied by hypertrophy of the CB (38, 39). Thus, hypoxia is associated with carotid body dopamine metabolism; however, the role it plays during hypoxic stimulation is currently debated.

Acute chemoreceptor stimulation is known to cause corresponding changes in ventilation (40). This increase in ventilation, however, is dependent on the cycle of ventilation. During the early part of the cycle the ventilatory increase is the largest. This is true of slowly breathing large animals as well as the fast breathing small animals.

Altitude Acclimatization

Short term. During exposure to hypoxia over several hours, ventilation continues to increase despite a decrease in arterial PCO₂. Despite this decrease in Pa_CO2, alkolosis, and decreased stimulus to chemoreceptor stimulation, ventilation continues to increase. This means that drive to ventilation must arise from peripheral and/or central chemoreceptors. During the acclimatization period, peripheral drive to ventilation increases (41), and direct measurement of carotid chemoreceptors cause increased sensitivity to hypoxia (42). This increase may explain the enormous amount of ventilation experienced by climbers on Mount Everest, which drives down alveolar PCO₂ to about 10 mm Hg (alkaline blood), which in turn decreases the drive from the CB almost entirely, as if at sea level (43). This raises the questions: what is responsible for the hyperventilation seen in individuals on Mount Everest?

Long term. Adult highlanders who are exposed to hypoxia over a prolonged period showed a significantly reduced ventilatory drive to acute hypoxia (44). Adult Tibetans who reside at altitudes up to 3,650 m showed a normal response; however, exposed to an altitude of 4,400 m they showed blunted response (45). The degree of blunting is correlated with years in residence at high altitude but is also proportional to altitude. This characteristic was found to be reversible (41). There is no change in ventilatory response to hypercapnia. This is consistent with the finding that goat CB exposed to hypercapnia does not cause ventilatory acclimatization (46). It is only to hypoxia that CB showed adaptation.

Mechanisms of Chemoreception

The carotid body is structurally complex, and the afferent chemosensory fibers, which synaptically contact only with one type of cells in cluster, the glomus, or type I cells, together constitute the chemoreceptor unit. These cells, approximately 10 µm in diameter, are the only cells that primarily contain neurotransmitter vesicles. Neurosecretion from these sources produces neural discharge chemoreflexes (Figure 1).

View larger version (22K): [in this window] [in a new window]   Figure 1.   Schematic showing how glomus cells would respond to hypoxia and PCO2 (H+) by metabolic and non-metabolic means, and how PCO2 (H+) could also respond by Na+/Ca2+ exchanger.

The consensus model, the membrane hypothesis, is that O₂ binds with heme-membrane and keeps it inactivated (49). Only bits and pieces of the mechanisms of the steps are known. For example, how hypoxia activates and depolarizes glomus cells is not known because the activation threshold (30 to 40 mV) due to current injection is higher than resting membrane potential (55 mV); how hypoxia can influence the resting membrane depolarization remains uncertain; the graded effects of hypoxia on the membrane remain controversial (50); only the graded effects of hypoxia on [Ca²⁺]I are known (51, 52). The effects of CO₂, at high PCO₂ only (mostly around 140 mm Hg), are known (53). Hypoxia directly suppresses the K⁺ channel activity (54), but a link between suppression of K⁺ and chemosensory discharge has not been established (57). The nature of the neurotransmitter is also uncertain. On the other hand, the metabolic hypothesis (58) states that hypoxia acts intracellularly on calcium stores and contributes to [Ca²⁺]I (see Figure 1).

Investigative tasks that remain include: (1) to test the hypothesis that glomus cells are the site of chemoreception and that O₂ and CO₂-H+ interaction with the receptor (62) takes place at the cellular site; (2) to verify the validity of the membrane hypothesis of chemoreception, by use of K⁺ current suppressants (see 57); (3) to pursue the hypothesis that hypoxic and CO₂-H+ chemoreception are caused by different mechanisms; (4) to discriminate between extra- and intracellular Ca²⁺; (5) to test the hypothesis that CO₂-HCO is "essential" for O₂ chemoreception; and (6) to test the hypothesis that H₂O₂ and O₂-generation by the mediation of NADPH oxidase. These studies, among others, will be done to unravel the mystery of chemoreception in the carotid body.

	DISORDERS OF CONTROL OF BREATHING

As recently as thirty years ago, the understanding of the respiratory control system seemed to have little relevance to clinical respiratory disorders. Other than clinical problems associated with overt CNS abnormalities or respiratory depressants, the respiratory control system appeared to regulate so well that abnormalities of the control system were simply not clinically important. This view has changed radically. While the system functions very well during wakefulness, the control of breathing commonly is disrupted during sleep. Over the past 20 years, investigators came to appreciate that the control of breathing changes drastically during sleep, largely because a loss of the "higher nervous system" influence on control of breathing. The principal alteration in control of breathing during non-rapid eye movement sleep entails a loss of a wakefulness factor which promotes stable breathing and thus ensuring a patent upper airway. During rapid eye movement sleep, chemoreflex control is attenuated and motor output to upper airway and nondiaphragmatic respiratory muscles is suppressed (63).

Initial investigations revealed that obese patients with daytime sleepiness and respiratory failure exhibited obstructive sleep apnea, results that led to a re-evaluation of the pathogenic theories regarding pickwickian syndrome. Remmers and colleagues established that the pharynx was the site of occlusion in this disorder and that the patency of the pharynx depended on the balance of two factors, an inward collapsing action of subatmospheric intrapharyngeal pressure during inspiration, and a dilating action exerted by the phasic activity of the genioglossus muscle (64). Whereas initial studies focused on obstructive sleep apnea in several obese patients, the prospective studies of Young and coworkers revealed that obstructive sleep apnea is a prevalent disorder effecting 4-9% of the adult population (65). Subsequent studies have established the existence of a structural abnormality in patients with obstructive sleep apnea, whereby the maximum area of the passive pharynx is reduced and its closing pressure is increased (66). During wakefulness the genioglossal activity of patients with obstructive sleep apneas is increased, compensating for the anatomic narrowing of the pharyngeal airway. During sleep, this compensation is lost, and severe pharyngeal narrowing or occlusion occurs.

A major breakthrough was provided by Sullivan and colleagues with the demonstration that nasal continuous positive airway pressure (CPAP) eliminates apnea in patients with obstructive sleep apnea (67). This monumental discovery had two implications. First, it established that pharyngeal transmural pressure was a pivotal factor in determining airway patency. Secondly, it provided a badly needed means of therapy for patients with obstructive sleep apnea. The therapy proved to be remarkably effective and lacking in significant side effects. Nasal CPAP has become standard therapy for obstructive sleep apnea, and the multidisciplinary sleep center, with the prominent participation of pulmonologists, has become an important feature of modern medical care. Current investigations into alternative types of therapy for obstructive sleep apnea for use in cases of mild to moderate severity focus on dental appliances that protrude the mandible and neuromodulators, such as serotonin agonists, which may activate hypoglossal motoneurons.

The past thirty years has witnessed a phenomenal explosion of new knowledge related to control of breathing and abnormalities resulting from disorders of this control system. Overall, the splendid performance of the control system is readily apparent; the nervous system integrates chemical, proprioceptive, and behavioral influences, translates them to a rhythm generator that, in turn, executes the highly complex, coordinated motor act we refer to as breathing. This control is extraordinarily complex and interfaces with postural and vocalization needs of the organism. Not surprisingly, such complicated and sophisticated control depends heavily on the higher nervous system, and loss of such supervisory function during sleep presumably accounts for the propensity of the system to be compromised in this state. Such compromise is manifested by the high prevalence of sleep-disordered breathing in humans. Although we have made enormous progress in understanding basic normal and abnormal functions, the cellular molecular and integrative aspects of this control system largely remain to be elucidated.

	Footnotes

Correspondence and requests for reprints should be addressed to Dr. John E. Remmers, Faculty of Medicine, University of Calgary, 3300 Hospital Dr. NW, Calgary, AB, T2N 4N1 Canada.

Acknowledgments: Supported in part by Grant #HL-43413-08 and #HL-50180-3, and Medical Research Council of Canada Grant #MA9719.

	References

TOP INTRODUCTION REFERENCES

1. von Euler, C. 1986. Brain stem mechanisms for generation and control of breathing pattern. In A. P. Fishman, N. S. Cherniack, and J. G. Widdicombe, editors. Handbook of Physiology. The Respiratory System. Control of Breathing, Sect. 3, Vol. 2, Chap. 1. American Physiological Society, Washington, DC. 1-67.

2. Clark, F. J., and C. von Euler. 1972. On the regulation of depth and rate of breathing. J. Physiol. London 222: 267-295 [Abstract/Free Full Text].

3. Younes, M. K., J. E. Remmers, and J. Baker Jr.. 1978. Characteristics of inspiratory inhibition by phasic volume feedback in cats. J. Appl. Physiol 45: 80-86 [Abstract/Free Full Text].

4. Remmers, J. E., and D. Bartlett Jr.. 1977. Reflex control of expiratory airflow and duration. J. Appl. Physiol. 42: 80-87 [Abstract/Free Full Text].

5. Younes, M., and J. Polacheck. 1981. Temporal changes in effectiveness of a constant inspiratory-terminating vagal stimulus. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 50:1183-1192.

6. Zuperku, E. J., F. A. Hopp, and J. P. Kampine. 1982. Central integration of pulmonary stretch receptor input in the control of expiration. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 52:1296-1315.

7. Coleridge, H. M., and J. C. G. Coleridge. 1986. Reflexes evoked for the tracheobronchial tree and lungs. In A. P. Fishman, N. S. Cherniack, and J. G. Widdicombe, editors. Handbook of Physiology. The Respiratory System. Control of Breathing, Sect. 3, Vol. 2, Chap. 12. American Physiological Society, Washington, DC. 395-429.

8. Hatridge, J., A. Haji, J. E. Perez-Padilla, and J. E. Remmers. 1989. Rapid shallow breathing caused by pulmonary vascular congestion in cats. J. Appl. Physiol 67: 2257-2264 [Abstract/Free Full Text].

9. Cohen, M. I. 1979. Neurogenesis of respiratory rhythm in the mammal. Physiol. Rev. 1105-1173.

10. Cohen, M. I., and S. C. Wang. 1959. Respiratory neuronal activity in the pons of cat. J. Neurophysiol 22: 33-50 [Free Full Text].

11. Merrill, E. G.. 1981. Where are the real respiratory neurons? Federation Proc 40: 2389-2394 [Medline].

12. Merrill, E. G.. 1970. The lateral respiratory neurons of the medulla: their association with nucleus ambiguus, nucleus retroambigualis, the spinal accessory nucleus and the spinal cord. Brain Res 24: 11-28 [Medline].

13. Dick, T. E., M. C. Bellingham, and D. W. Richter. 1994. Pontine respiratory neurons in anesthetized cats. Brain Res 636: 259-269 [Medline].

14. Feldman, J. L., M. I. Cohen, and P. Wolotsky. 1976. Powerful inhibition of pontine respiratory neurons by pulmonary afferent activity. Brain Res. 104: 341-346 [Medline].

15. Richter, D. W., F. Heyde, and M. Gabriel. 1975. Intracellular recordings from different types of medullary respiratory neurons of the cat. J. Neurophysiol 38: 1162-1181 [Abstract/Free Full Text].

16. Richter, D. W., F. Heyde, and M. Gabriel. 1975. Accommodative reactions of medullary respiratory neurons of the cat. J. Neurophysiol 38: 1182-1190 .

17. Bianchi, A., M. Denavit-Saubié, and J. Champagnat. 1995. Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiol. Rev 75: 1-45 [Free Full Text].

18. Ballantyne, D., and D. W. Richter. 1984. Post-synaptic inhibition of bulbar inspiratory neurones in the cat. J. Physiol. Lond 348: 67-87 [Abstract/Free Full Text].

19. Ballantyne, D., and D. W. Richter. 1986. The non-uniform character of expiratory synaptic activity in expiratory bulbospinal neurones of the cat. J. Physiol. Lond 370: 433-456 [Abstract/Free Full Text].

20. Remmers, J. E., D. W. Richter, D. Ballantyne, C. Bainton, and J. Klein. 1986. Reflex prolongation of stage I of expiration. Pfluegers Arch 407: 190-198 [Medline].

21. Richter, D. W., D. Ballantyne, and J. E. Remmers. 1987. The differential organization of medullary post-inspiratory activities. Pfluegers Arch 410: 420-427 [Medline].

22. Smith, J. C., J. J. Greer, G. Liu, and J. L. Feldman. 1990. Neural mechanisms generating respiratory pattern in mammalian brain stem-spinal cord in vitro: I. Spatiotemporal patterns of motor and medullary neuron activity. J. Neurophysiol 64: 1149-1169 [Abstract/Free Full Text].

23. Feldman, J. L., and J. C. Smith. 1989. Cellular mechanisms underlying modulation of breathing pattern in mammals. Annals of the New York Academy of Sciences 563: 114-130 [Medline].

24. Smith, J. C., H. H. Ellenberger, K. Ballanyi, D. W. Richter, and J. L. Feldman. 1991. Pre-Bötzinger complex: a brain stem region that may generate respiratory rhythm in mammals. Science 254: 726-729 [Abstract/Free Full Text].

25. Dempsey, J. A., H. V. Forster, and D. M. Ainsworth. 1995. Regulation of hyperpnea, hyperventilation and respiratory muscle recruitment during exercise. In J. A. Dempsey and A. I. Pack, editors. Lung Biology in Health and Disease, Vol. 79. Regulation of Breathing. Marcel Dekker, New York. 1065-1034.

26. Kaufman, M. P. 1995. Afferents from limb skeletal muscle. In J. A. Dempsey and A. I. Pack, editors. Lung Biology in Health and Disease, Vol. 79. Regulation of Breathing. Marcel Dekker, New York. 583-616.

27. Mitchell, R. A., H. H. Loeschcke, W. H. Massion, and J. W. Severinghaus. 1963. Respiratory responses mediated through superficial chemosensitive areas on the medulla. J. Appl. Physiol 18: 523-533 [Abstract/Free Full Text].

28. Pappenheimer, J. R., V. Fencl, S. R. Heisey, and D. Held. 1965. Role of cerebral fluids in control of respiration as studied in unanesthetized goats. Am. J. Physiol 208: 436-450 .

29. Fencl, V., T. B. Miller, and J. Pappenheimer. 1966. Studies on the respiratory response to disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. Am. J. Physiol 210: 459-472 .

30. Nattie, E. E. 1995. Central chemoreception. In J. A. Dempsey and A. I. Pack, editors. Lung Biology in Health and Disease, Vol. 79. Regulation of Breathing. Marcel Dekker, New York. 473-510.

31. Fitzgerald, R. S., and S. Lahiri. 1996. The history of chemoreception. In J. B. West, editor. Respiratory Physiology: People and Ideas. Oxford University Press, New York. 289-318.

32. Hanson, M. A., P. Kumer, and B. A. Williams. 1989. The effect of chronic hypoxia on the development of respiratory chemoreflexes in the newborn kitten. J. Physiol 411: 563-574 [Abstract/Free Full Text].

33. Lahiri, S.. 1995. Carotid body O₂ chemoreception: respiratory and non-respiratory aspects. Biol. Signals 4: 257-262 [Medline].

34. Kholwadwala, D., and D. F. Donnelly. 1992. Maturation of carotid chemoreceptor sensitivity in hypoxia: in vitro studies in the newborn rat. J. Physiol 453: 461-473 [Abstract/Free Full Text].

35. Marchal, F., A. Bairam, P. Hougi, J. M. Hassock, J. P. Crance, P. Vert, and S. Lahiri. 1972. Dual responses of carotid chemosensory afferents to dopamine in the newborn kittens. Respir. Physiol 90: 173-183 .

36. Buerk, D. G., S. Lahiri, D. Chugh, and A. Mokashi. 1995. Electrochemical detection of rapid dopamine release kinetics during hypoxia in perfused/superfused cat carotid bodies. J. Appl. Physiol 78: 830-837 [Abstract/Free Full Text].

37. Buerk, D. G., S. Osanai, A. Mokashi, and S. Lahiri. 1998. Dopamine and sensory discharge CO₂-O₂ stimulus-interaction in cat carotid body. J. Appl. Physiol. (In press)

38. Hanbauer, I., F. Karoum, S. Hellstrom, and S. Lahiri. 1981. Effects of long-term hypoxia on the catecholamine content in rat carotid body. Neuroscience 6: 81-86 [Medline].

39. McGregor, K. H., J. Gil, and S. Lahiri. 1984. A morphometric study of the carotid body in chronically hypoxic rats. J. Appl. Physiol 57: 1430-1438 [Abstract/Free Full Text].

40. Eldridge, F. L.. 1972. The importance of timing on the respiration effects of intermittent carotid sinus nerve stimulation. J. Physiol 222: 279-318 .

41. Lahiri, S., R. G. Delaney, J. S. Brody, M. Seinpeer, T. Velasquez, E. K. Motayama, and G. Polgar. 1978. Relative role of environmental and genetic factors in respiratory adaptation to high altitude. Nature 261: 133-135 .

42. Barnard, P. S., S. Andronikou, M. Pokorski, N. J. Smatresk, A. Mokashi, and S. Lahiri. 1987. Time dependent effect of hypoxia on carotid body chemosensory function. J. Appl. Physiol 63: 685 [Abstract/Free Full Text].

43. Lahiri, S., A. Mokashi, R. G. Delaney, and A. P. Fishman. 1978. Arterial PO₂ and PCO₂ stimulus threshold for carotid chemoreceptors and breathing. Respir. Physiol 34: 359-375 [Medline].

44. Lahiri, S., and J. S. Milledge. 1965. Sherpa physiology. Nature 207: 610-612 [Medline].

45. Curran, L. S., J. Zhung, T. Droma, L. Land, and L. G. Moore. 1995. Hypoxic ventilatory response in Tibetan residents of 4400 m compared with 3658 m. Respir. Physiol 100: 223-230 [Medline].

46. Bisgard, G. E., and H. V. Forster. 1996. Ventilatory responses to acute and chronic hypoxia. In M. J. Fregly and C. M. Blakis, editors. Environmental Physiology. Oxford University Press, New York. 1207- 1239.

47. Weil, J. V., E. Bryne-Quinn, I. E. Sodal, G. F. Filley, and R. F. Grover. 1971. Acquired attenuation of chemoreceptor function in chronically hypoxic man at high altitude. J. Clin. Invest 50: 186-195 .

48. Lahiri, S., J. S. Brody, E. K. Motoyama, and T. Velasquez. 1978. Regulation of breathing in newborns at high altitude. J. Appl. Physiol 44: 673-678 [Abstract/Free Full Text].

49. Peers, C., and K. J. Buckler. 1995. Transduction of chemostimuli by type I carotid body cell. Membrane Biol 144: 1-9 .

50. Lahiri, S.. 1994. Chromophores in O₂ chemoreception: the carotid body model. News Physiol. Sci. 9: 161-164 . [Abstract/Free Full Text]

51. Buckler, K. J., and R. D. Vaughan-Jones. 1994. Effects of hypoxia on membrane potential and intracellular calcium in rat neonatal carotid body type I cells. J. Physiol 476: 423-428 [Abstract/Free Full Text].

52. Montoro, R. J., J. Urena, R. Fernandez-Chaion, G. Alverez de Toledo, and J. Lopez-Barneo. 1996. Oxygen sensing by ion channels and chemotransduction in single glomus cell. J. Gen. Physiol 107: 133-143 [Abstract/Free Full Text].

53. Buckler, K. J., and R. D. Vaughan-Jones. 1994. Effects of hypercapnia on membrane potential and intracellular calcium in rat carotid body type I cells. J. Physiol 478: 157-171 [Abstract/Free Full Text].

54. Lopez-Barneo, J. R., J. R. Lopez-Lopez, J. Urena, and C. Gonzalez. 1988. Chemotransduction in carotid body K+ current modulated by PO₂ in type I chemoreceptor cells. Science 241: 580-582 [Abstract/Free Full Text].

55. Lopez-Lopez, J. R., D. A. de Luis, and C. Gonzalez. 1993. Properties of transient K+ current in chemoreceptor cell of rabbit carotid body. J. Physiol 460: 15-32 [Abstract/Free Full Text].

56. Peers, C.. 1990. Hypoxic suppression of K+ currents in type I carotid body cells: selective effect on the Ca2+-activated K+ current. Neurosci. Letts 119: 253-256 [Medline].

57. Roy, A., C. Rozanov, D. G. Buerk, A. Mokashi, and S. Lahiri. 1998. 4-aminopyridine is not related to [Ca²⁺]i, dopamine release and chemosensory discharge from cat carotid body. Brain Res. (In press)

58. Mulligan, E., S. Lahiri, and B. T. Storey. 1981. Carotid body O₂ chemoreception and mitochondrial oxidative phosphorylation. J. Appl. Physiol 51: 438-446 [Abstract/Free Full Text].

59. Biscoe, T. J., and D. R. Duchen. 1990. Responses of type I cells dissociated from the rabbit carotid body to hypoxia. J. Physiol 425: 39-59 .

60. Wilson, D. F., A. Mokashi, D. Chugh, S. Vinogradov, S. Osanai, and S. Lahiri. 1994. The primary oxygen sensor of the carotid body is cytochrome a3 of the mitochondrial respiratory chain. FEBS Letts 351: 370-374 [Medline].

61. Lahiri, S., D. G. Buerk, S. Osanai, A. Mokashi, and D. K. Chugh. 1997. Effect of CO on O₂ of carotid body and chemoreception. J. Autonom. Nerv. Syst 66: 1-6 [Medline].

62. Lahiri, S., and R. G. DeLaney. 1975. Stimulus interaction in the responses of the carotid body chemoreceptor single afferent fibers. Respir. Physiol 24: 249-266 [Medline].

63. Pack, A. I. 1995. Changes in respiratory motor activity during rapid eye movement sleep. In J. A. Dempsey and A. I. Pack, editors. Lung Biology in Health and Disease, Vol. 79. Regulation of Breathing. Marcel Dekker, New York. 983-1010.

64. Remmers, J. E., W. J. deGroot, E. K. Sauerland, and A. M. Anch. 1978. Pathogenesis of upper airway occlusion during sleep. J. Appl. Physiol 44: 931-938 [Free Full Text].

65. Young, T., M. Palta, J. Dempsey, J. Skatrud, S. Weber, and S. Badr. 1993. The occurrence of sleep-disordered breathing among middle-aged adults. N. Engl. J. Med. 328: 1230-1235 [Abstract/Free Full Text].

66. Isono, S., J. E. Remmers, A. Tanaka, Y. Sho, J. Sato, and T. Nishino. 1997. Anatomy of the pharynx in patients with obstructive sleep apnea and normal subjects. J. Appl. Physiol 82: 1319-1326 [Abstract/Free Full Text].

67. Mezzanotte, W. S., D. J. Tangel, and D. P. White. 1992. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J. Clin. Invest 89: 1571-1579 .

68. Sullivan, C. E., F. G. Issa, M. Berthon-Jones, and L. Eves. 1981. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1: 862-865 [Medline].