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Integration of Central and Peripheral Respiratory Chemoreflexes

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ABSTRACT

A debate has raged since the discovery of central and peripheral respiratory chemoreceptors as to whether the reflexes they mediate combine in an additive (i.e., no interaction), hypoadditive or hyperadditive manner. Here we critically review pertinent literature related to O2 and CO2 sensing from the perspective of system integration and summarize many of the studies on which these seemingly opposing views are based. Despite the intensity and quality of this debate, we have yet to reach consensus, either within or between species. In reviewing this literature, we are struck by the merits of the approaches and preparations that have been brought to bear on this question. This suggests that either the nature of combination is not important to system responses, contrary to what has long been supposed, or that the nature of the combination is more malleable than previously assumed, changing depending on physiological state and/or respiratory requirement. © 2016 American Physiological Society. Compr Physiol 6:1005‐1041, 2016.

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Figure 1. Figure 1. Types of chemoreceptor integration. Integration of chemoreflexes has long been a source of controversy and has yet to be resolved. Three forms of integration are traditionally considered: additive (no interaction; (A)); hypoadditive (B); and hyperadditive (C). Recently, a hybrid system has been proposed in which the type of interaction depends critically on physiological state (D). Blue and Red bars representing one chemoreflex with the other inactive, and vice versa; green bars represent concurrent activation of both chemoreflexes. In upper panels, size of bars shows response of a ventilatory parameter (e.g., V T, frequency of V E). In lower panels, ventilatory activity is plotted versus variable activation of one chemoreflex with the other at two fixed levels of activation (high green, low blue).
Figure 2. Figure 2. Recent preparations used to tease apart the nature of central and peripheral chemoreflex interaction. (A) Dog donor‐perfused, bilateral carotid sinus preparation; both carotid bodies intact and perfused independently of systemic circulation. Donor dog breathed hypoxic mixtures; the recipient received hypercapnic mixtures (from Adams et al. 1978). (B) Extracorporeal‐perfused carotid body in conscious dogs; one carotid body resected, CBX, the other carotid bodies perfused independently of systemic circulation (from Blain et al. 2010). (C) Decerebrate rat, dual perfused preparation; both carotid bodies intact and perfused independently of brainstem with artificial saline (from Day and Wilson, 2005).
Figure 3. Figure 3. Data from conscious dogs with an extracorporeal perfused carotid body suggesting hyperadditive inter‐action in v e between central and peripheral chemoreflexes. Each graph shows data from a different conscious dog with one carotid body extracorporeally perfused and the other denervated. Systemic (inspired) CO2 was varied against three different backgrounds of carotid body stimulation: normoxic‐normocapnia (filled squares), hyperoxic‐hypocapnia (“inhibited”; open squares), and hypoxic‐normocapnia blood (“stimulated”; shaded triangles). Note how the lines splay apart, indicative of a hyperadditive interaction. From Blain et al. 2010.
Figure 4. Figure 4. Additive interactions in one respiratory variable requires hypoadditivity in another. Primary respiratory variables are plotted against variable activation of one chemoreflex with the other at two fixed levels of activation (high green, low blue). In (A), addition (no interaction) between chemoreflexes in V T and frequency results in a hyperadditive interaction in V E. In (B), a hypoadditive interaction in either freq or V T (shown) results in a hypoadditive interaction in V E, or stated in another way, an additive interaction in V E necessitates a hypoadditive interaction in either freq or V T (). Adapted from ().
Figure 5. Figure 5. Order of stimuli has no effect on nature of interaction in dog extracorporeal‐perfused carotid body preparation. Ventilatory response to carotid body stimulation and systemic CO2 challenges in an extracorporeally perfused carotid body preparation. Animals were anesthetized with pentobarbital. Top panels, tidal volume (V T); bottom panels, frequency (f). Left panels show response to changes in inspired PO2 against a background in which the carotid body was perfused with normoxia or constantly stimulated with hypoxic‐hypercapnia. Right panels show the reverse order; carotid bodies either normoxic or stimulated against a constant background of different inspired PCO2. Regardless of the order in which brainstem and carotid bodies where stimulated, the magnitude of responses were the same. Data from this preparation supports a hypoadditive interaction. From Adams and Severns, 1982.
Figure 6. Figure 6. Data from dual perfused in situ rat preparation suggesting a hypoadditive interaction in v e between central and peripheral chemoreflexes. The dual perfused preparation allows the carotid bodies and brainstem to be perfused independently with defined medium. In this preparation, there are no descending inputs to the brainstem; vagotomy removes possible influences of lung stretch, irritant and neuroepithelial body activation; and hormonal or sympathetic influences on the carotid body are eliminated. The brainstem was held constant at one of three levels of PCO2 (25, 35, and 50 Torr; circles, triangle, and square symbols, respectively) while the response of the preparation to changes in PO2 at the carotid body was changed. Phrenic activity was used as a surrogate measure of ventilation; phrenic burst amplitude, nVT, was assumed to be proportional to tidal volume and multiplied by burst frequency to yield neural minute ventilation, nV E). Note how the lines converge indicative of a hypoadditive interaction. From Day and Wilson, 2009.
Figure 7. Figure 7. Data from humans suggesting a hyperadditive interaction between central and peripheral chemoreflexes. Effect of bicarbonate infusion (open symbols) on the ventilatory O2 ‐[H+] response relationship. A bicarbonate infusion reduces arterial [H+] and shifts the ventilatory O2 ‐[H+] response relationship to the left, whether pre‐treated with placebo or acetazolamide. Defining hypoxic sensitivity as the ratio of delta ventilation over delta log PaO2, for placebo the hypoxic sensitivity = 8.73 × [H+] − 304 and 9.06 × [H+] − 316 before and after bicarbonate, respectively. For acetazolamide, hypoxic sensitivity = 9.05 × [H+] − 432 and 6.07 × [H+] − 235 before and after bicarbonate, respectively. Numbers added to data points are mean arterial PCO2 values in Torr. At points d' and f, arterial [H +] is about equal, but at d' with a PaCO2. 7.1 Torr higher than at D, hypoxic sensitivity is doubled. Data are means ± SE from eight subjects. From: Teppema et al. 2010.
Figure 8. Figure 8. The hybrid model. Day and Wilson propose a hybrid model to reconcile their observation of a strong hypoadditive interaction in rats with observations of a hyperadditive interaction in the Smith‐Dempsey dog model (). Carotid body activation can maintain breathing when the brainstem is extremely hypocapnic as shown in cats and rats () suggesting ventilatory responses to increasing chemoreceptor activity converge below eupnea (red dotted lines), indicative of a hypoadditive interaction. Above eupnea in wake dogs, ventilatory response slopes diverge (blue dashed line) indicative of a hyperadditive interaction. Transition between hypoadditive and hyperadditive interaction (i.e., the hybrid transition point; yellow star) may occur at a single point of convergence (right panel) or multiple points (left panel), and depend on metabolism and/or other factors determining physiological state. Left panel adapted from Wilson and Day, 2013.


Figure 1. Types of chemoreceptor integration. Integration of chemoreflexes has long been a source of controversy and has yet to be resolved. Three forms of integration are traditionally considered: additive (no interaction; (A)); hypoadditive (B); and hyperadditive (C). Recently, a hybrid system has been proposed in which the type of interaction depends critically on physiological state (D). Blue and Red bars representing one chemoreflex with the other inactive, and vice versa; green bars represent concurrent activation of both chemoreflexes. In upper panels, size of bars shows response of a ventilatory parameter (e.g., V T, frequency of V E). In lower panels, ventilatory activity is plotted versus variable activation of one chemoreflex with the other at two fixed levels of activation (high green, low blue).


Figure 2. Recent preparations used to tease apart the nature of central and peripheral chemoreflex interaction. (A) Dog donor‐perfused, bilateral carotid sinus preparation; both carotid bodies intact and perfused independently of systemic circulation. Donor dog breathed hypoxic mixtures; the recipient received hypercapnic mixtures (from Adams et al. 1978). (B) Extracorporeal‐perfused carotid body in conscious dogs; one carotid body resected, CBX, the other carotid bodies perfused independently of systemic circulation (from Blain et al. 2010). (C) Decerebrate rat, dual perfused preparation; both carotid bodies intact and perfused independently of brainstem with artificial saline (from Day and Wilson, 2005).


Figure 3. Data from conscious dogs with an extracorporeal perfused carotid body suggesting hyperadditive inter‐action in v e between central and peripheral chemoreflexes. Each graph shows data from a different conscious dog with one carotid body extracorporeally perfused and the other denervated. Systemic (inspired) CO2 was varied against three different backgrounds of carotid body stimulation: normoxic‐normocapnia (filled squares), hyperoxic‐hypocapnia (“inhibited”; open squares), and hypoxic‐normocapnia blood (“stimulated”; shaded triangles). Note how the lines splay apart, indicative of a hyperadditive interaction. From Blain et al. 2010.


Figure 4. Additive interactions in one respiratory variable requires hypoadditivity in another. Primary respiratory variables are plotted against variable activation of one chemoreflex with the other at two fixed levels of activation (high green, low blue). In (A), addition (no interaction) between chemoreflexes in V T and frequency results in a hyperadditive interaction in V E. In (B), a hypoadditive interaction in either freq or V T (shown) results in a hypoadditive interaction in V E, or stated in another way, an additive interaction in V E necessitates a hypoadditive interaction in either freq or V T (). Adapted from ().


Figure 5. Order of stimuli has no effect on nature of interaction in dog extracorporeal‐perfused carotid body preparation. Ventilatory response to carotid body stimulation and systemic CO2 challenges in an extracorporeally perfused carotid body preparation. Animals were anesthetized with pentobarbital. Top panels, tidal volume (V T); bottom panels, frequency (f). Left panels show response to changes in inspired PO2 against a background in which the carotid body was perfused with normoxia or constantly stimulated with hypoxic‐hypercapnia. Right panels show the reverse order; carotid bodies either normoxic or stimulated against a constant background of different inspired PCO2. Regardless of the order in which brainstem and carotid bodies where stimulated, the magnitude of responses were the same. Data from this preparation supports a hypoadditive interaction. From Adams and Severns, 1982.


Figure 6. Data from dual perfused in situ rat preparation suggesting a hypoadditive interaction in v e between central and peripheral chemoreflexes. The dual perfused preparation allows the carotid bodies and brainstem to be perfused independently with defined medium. In this preparation, there are no descending inputs to the brainstem; vagotomy removes possible influences of lung stretch, irritant and neuroepithelial body activation; and hormonal or sympathetic influences on the carotid body are eliminated. The brainstem was held constant at one of three levels of PCO2 (25, 35, and 50 Torr; circles, triangle, and square symbols, respectively) while the response of the preparation to changes in PO2 at the carotid body was changed. Phrenic activity was used as a surrogate measure of ventilation; phrenic burst amplitude, nVT, was assumed to be proportional to tidal volume and multiplied by burst frequency to yield neural minute ventilation, nV E). Note how the lines converge indicative of a hypoadditive interaction. From Day and Wilson, 2009.


Figure 7. Data from humans suggesting a hyperadditive interaction between central and peripheral chemoreflexes. Effect of bicarbonate infusion (open symbols) on the ventilatory O2 ‐[H+] response relationship. A bicarbonate infusion reduces arterial [H+] and shifts the ventilatory O2 ‐[H+] response relationship to the left, whether pre‐treated with placebo or acetazolamide. Defining hypoxic sensitivity as the ratio of delta ventilation over delta log PaO2, for placebo the hypoxic sensitivity = 8.73 × [H+] − 304 and 9.06 × [H+] − 316 before and after bicarbonate, respectively. For acetazolamide, hypoxic sensitivity = 9.05 × [H+] − 432 and 6.07 × [H+] − 235 before and after bicarbonate, respectively. Numbers added to data points are mean arterial PCO2 values in Torr. At points d' and f, arterial [H +] is about equal, but at d' with a PaCO2. 7.1 Torr higher than at D, hypoxic sensitivity is doubled. Data are means ± SE from eight subjects. From: Teppema et al. 2010.


Figure 8. The hybrid model. Day and Wilson propose a hybrid model to reconcile their observation of a strong hypoadditive interaction in rats with observations of a hyperadditive interaction in the Smith‐Dempsey dog model (). Carotid body activation can maintain breathing when the brainstem is extremely hypocapnic as shown in cats and rats () suggesting ventilatory responses to increasing chemoreceptor activity converge below eupnea (red dotted lines), indicative of a hypoadditive interaction. Above eupnea in wake dogs, ventilatory response slopes diverge (blue dashed line) indicative of a hyperadditive interaction. Transition between hypoadditive and hyperadditive interaction (i.e., the hybrid transition point; yellow star) may occur at a single point of convergence (right panel) or multiple points (left panel), and depend on metabolism and/or other factors determining physiological state. Left panel adapted from Wilson and Day, 2013.
References
 1. Abbott SB , Stornetta RL , Fortuna MG , Depuy SD , West GH , Harris TE , Guyenet PG . Photostimulation of retrotrapezoid nucleus phox2b‐expressing neurons in vivo produces long‐lasting activation of breathing in rats. J Neurosci 29: 5806‐5819, 2009.
 2. Adams JM , Attinger FM , Attinger EO . Medullary and carotid chemoreceptor interaction for mild stimuli. Pflugers Arch 374: 39‐45, 1978.
 3. Adams JM , Severns ML . Interaction of chemoreceptor effects and its dependence on the intensity of stimuli. J Appl Physiol 52: 602‐606, 1982.
 4. Bayliss DA , Talley EM , Sirois JE , Lei Q . TASK‐1 is a highly modulated pH‐sensitive “leak” K(+) channel expressed in brainstem respiratory neurons. Respir Physiol 129: 159‐174, 2001.
 5. van Beek JH , Berkenbosch A , De Goede J , Olievier CN . Influence of peripheral O2 tension on the ventilatory response to CO2 in cats. Respir Physiol 51: 379‐390, 1983.
 6. van Beek JH , Berkenbosch A , De Goede J , Olievier CN . Effects of brain stem hypoxaemia on the regulation of breathing. Respir Physiol 57: 171‐188, 1984.
 7. Bellville JW , Whipp BJ , Kaufman RD , Swanson GD , Aqleh KA , Wiberg DM . Central and peripheral chemoreflex loop gain in normal and carotid body‐resected subjects. J Appl Physiol 46: 843‐853, 1979.
 8. Berger W , Berger K , Berndt J , Giese K . Interaction of peripheral and central respiratory drives in cats. I. Effects of sodium cyanide as a peripheral chemoreceptor stimulus at different levels of CSF pH. Pflugers Arch 374: 205‐210, 1978.
 9. Berkenbosch A , van Beek JH , Olievier CN , De Goede J , Quanjer PH . Central respiratory CO2 sensitivity at extreme hypocapnia. Respir Physiol 55: 95‐102, 1984.
 10. Berkenbosch A , DeGoede J , Ward DS , Olievier CN , VanHartevelt J . Dynamic response of peripheral chemoreflex loop to changes in end‐tidal CO2 . J Appl Physiol 64: 1779‐1785, 1988.
 11. Berkenbosch A , DeGoede J , Ward DS , Olievier CN , VanHartevelt J . Dynamic response of the peripheral chemoreflex loop to changes in end‐tidal O2. J Appl Physiol 71: 1123‐1128, 1991.
 12. Berkenbosch A , Heeringa J , Olievier CN , Kruyt EW . Artificial perfusion of the ponto‐medullary region of cats. A method for separation of central and peripheral effects of chemical stimulation of ventilation. Respir Physiol 37: 347‐364, 1979.
 13. Berndt J , Berger W , Berger K , Schmidt M . Untersuchungen zum zentralen chemosensiblen Mechanismus der Atmung III. Die Wirkung starker J∼nderungen des Liquor‐pH (pH 5,4–7,7). Pfliigers Arch 332: 171‐183, 1972.
 14. Biancardi V , Bicego KC , Almeida MC , Gargaglioni LH . Locus coeruleus noradrenergic neurons and CO2 drive to breathing. Pflugers Arch 455: 1119‐1128, 2008.
 15. Biancardi V , da Silva LT , Bicego KC , Gargaglioni LH . Role of locus coeruleus noradrenergic neurons in cardiorespiratory and thermal control during hypoxia. Respir Physiol Neurobiol 170: 150‐156, 2010.
 16. Biscoe TJ , Lall A , Sampson SR . Electron microscopic and electrophysiological studies on the carotid body following intracranial section of the glossopharyngeal nerve. J Physiol 208: 133‐152, 1970.
 17. Biscoe TJ , Purves MJ . Observations on the rhythmic variation in the cat carotid body chemoreceptor activity which has the same period as respiration. J Physiol 190: 389‐412, 1967.
 18. Biscoe TJ , Purves MJ , Sampson SR . The frequency of nerve impulses in single carotid body chemoreceptor afferent fibres recorded in vivo with intact circulation. J Physiol 208: 121‐131, 1970.
 19. Bisgard GE , Busch MA , Daristotle L , Berssenbrugge AD , Forster HV . Carotid body hypercapnia does not elicit ventilatory acclimatization in goats. Respir Physiol 65: 113‐125, 1986.
 20. Bisgard GE , Forster HV , Orr JA , Buss DD , Rawlings CA , Rasmussen B . Hypoventilation in ponies after carotid body denervation. J Appl Physiol 40: 184‐190, 1976.
 21. Black AM , McCloskey DI , Torrance RW . The responses of carotid body chemoreceptors in the cat to sudden changes of hypercapnic and hypoxic stimuli. Respir Physiol 13: 36‐49, 1971.
 22. Black AM , Torrance RW . Respiratory oscillations in chemoreceptor discharge in the control of breathing. Respir Physiol 13: 221‐237, 1971.
 23. Blain GM , Smith CA , Henderson KS , Dempsey JA . Contribution of the carotid body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog. J Appl Physiol 106: 1564‐1573, 2009.
 24. Blain GM , Smith CA , Henderson KS , Dempsey JA . Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO(2). J Physiol 588: 2455‐2471, 2010.
 25. Bradley SR , Pieribone VA , Wang W , Severson CA , Jacobs RA , Richerson GB . Chemosensitive serotonergic neurons are closely associated with large medullary arteries. Nat Neurosci 5: 401‐402, 2002.
 26. Brunner MJ , Sussman MS , Greene AS , Kallman CH , Shoukas AA . Carotid sinus baroreceptor reflex control of respiration. Circ Res 51: 624‐636, 1982.
 27. Buckler KJ . A novel oxygen‐sensitive potassium current in rat carotid body type I cells. J Physiol 498(Pt 3): 649‐662, 1997.
 28. Buckler KJ . TASK‐like potassium channels and oxygen sensing in the carotid body. Respir Physiol Neurobiol 157: 55‐64, 2007.
 29. Buckler KJ . Responses of glomus cells to hypoxia and acidosis. J Physiol 591: 3667, 2013.
 30. Buckler KJ . TASK channels in arterial chemoreceptors and their role in oxygen and acid sensing. Pflüg Arch Eur J Physiol 467: 1013‐1025, 2015.
 31. Buckler KJ , Vaughan‐Jones RD , Peers C , Lagadic‐Gossmann D , Nye PC . Effects of extracellular pH, PCO2 and HCO3‐ on intracellular pH in type I cells of the neonatal rat carotid body. J Physiol 444: 703‐721, 1991.
 32. Buckler KJ , Vaughan‐Jones RD , Peers C , Nye PC . Intracellular pH and its regulation in isolated type I carotid body cells of the neonatal rat. J Physiol 436: 107‐129, 1991.
 33. Buckler KJ , Williams BA , Honore E . An oxygen‐, acid‐ and anaesthetic‐sensitive TASK‐like background potassium channel in rat arterial chemoreceptor cells. J Physiol 525(Pt 1): 135‐142, 2000.
 34. Buckler KJ , Williams BA , Orozco RV , Wyatt CN . The role of TASK‐like K+ channels in oxygen sensing in the carotid body. Novartis Found Symp 272: 73‐85, 2006.
 35. Buerk DG , Osanai S , Mokashi A , Lahiri S . Dopamine, sensory discharge, and stimulus interaction with CO2 and O2 in cat carotid body. J Appl Physiol 85: 1719‐1726, 1998.
 36. Busch MA , Bisgard GE , Forster HV . Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia. J Appl Physiol 58: 1874‐1880, 1985.
 37. Busch MA , Bisgard GE , Mesina JE , Forster HV . The effects of unilateral carotid body excision on ventilatory control in goats. Respir Physiol 54: 353‐361, 1983.
 38. Campanucci VA , Dookhoo L , Vollmer C , Nurse CA . Modulation of the carotid body sensory discharge by NO: An up‐dated hypothesis. Respir Physiol Neurobiol 184: 149‐157, 2012.
 39. Carroll JL , Bamford OS , Fitzgerald RS . Postnatal maturation of carotid chemoreceptor responses to O2 and CO2 in the cat. J Appl Physiol 75: 2383‐2391, 1993.
 40. Carroll JL , Bureau MA . Peripheral chemoreceptor CO2 response during hyperoxia in the 14‐day‐old awake lamb. Respir Physiol 73: 339‐349, 1988.
 41. Carroll JL , Canet E , Bureau MA . Dynamic ventilatory responses to CO2 in the awake lamb: Role of the carotid chemoreceptors. J Appl Physiol 71: 2198‐2205, 1991.
 42. Carroll MS , Patwari PP , Kenny AS , Brogadir CD , Stewart TM , Weese‐Mayer DE . Residual chemosensitivity to ventilatory challenges in genotyped congenital central hypoventilation syndrome. J Appl Physiol 116: 439‐450, 2014.
 43. Chernov MM , Daubenspeck JA , Denton JS , Pfeiffer JR , Putnam RW , Leiter JC . A computational analysis of central CO2 chemosensitivity in Helix aspersa. Am J Physiol Cell Physiol 292: C278‐C291, 2007.
 44. Chitravanshi VC , Sapru HN . Chemoreceptor‐sensitive neurons in commissural subnucleus of nucleus tractus solitarius of the rat. AmJ Physiol 268: R851‐R858, 1995.
 45. Clement ID , Bascom DA , Conway J , Dorrington KL , O'Connor DF , Painter R , Paterson DJ , Robbins PA . An assessment of central‐peripheral ventilatory chemoreflex interaction in humans. Respir Physiol 88: 87‐100, 1992.
 46. Clement ID , Pandit JJ , Bascom DA , Dorrington KL , O'Connor DF , Robbins PA . An assessment of central‐peripheral ventilatory chemoreflex interaction using acid and bicarbonate infusions in humans. J Physiol 485(Pt 2): 561‐570, 1995.
 47. Coates EL , Li A , Nattie EE . Widespread sites of brain stem ventilatory chemoreceptors. J Appl Physiol 75: 5‐14, 1993.
 48. Corcoran AE , Hodges MR , Wu Y , Wang W , Wylie CJ , Deneris ES , Richerson GB . Medullary serotonin neurons and central CO2 chemoreception. Respir Physiol Neurobiol 168: 49‐58, 2009.
 49. Corne S , Webster K , Younes M . Hypoxic respiratory response during acute stable hypocapnia. Am J Respir Crit Care Med 167: 1193‐1199, 2003.
 50. Cragg PA , Drysdale DB . Interaction of hypoxia and hypercapnia on ventilation, tidal volume and respiratory frequency in the anaesthetized rat. J Physiol 341: 477‐493, 1983.
 51. Crosby A , Talbot NP , Balanos GM , Donoghue S , Fatemian M , Robbins PA . Respiratory effects in humans of a 5‐day elevation of end‐tidal PCO2 by 8 Torr. J Appl Physiol 95: 1947‐1954, 2003.
 52. Cross BA , Grant BJ , Guz A , Jones PW , Semple SJ , Stidwill RP . Dependence of phrenic motoneurone output on the oscillatory component of arterial blood gas composition. J Physiol 290: 163‐184, 1979.
 53. Cui Z , Fisher JA , Duffin J . Central‐peripheral respiratory chemoreflex interaction in humans. Respir Physiol Neurobiol 180: 126‐131, 2012.
 54. Cummings KJ . Interaction of central and peripheral chemoreflexes in neonatal mice: evidence for hypo‐addition. Respir Physiol Neurobiol 203: 75‐81, 2014.
 55. Cummings KJ , Wilson RJ . Time‐dependent modulation of carotid body afferent activity during and after intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 288: R1571‐R1580, 2005.
 56. Cunningham DJC , Robbins PA , Wolff CB . Integration of respiratory response to changes in alveolar partial pressures in CO1034;2 and O2 and in arterial pH. 1034. In: Cherniack NS , Widdicombe JG , editors. Handbook of Physiology: The Respiratory System. Bethesda MD, U.S.A.: American Physiological Society, 1986, pp. 475‐528.
 57. Cunningham ET Jr , Sawchenko PE . A circumscribed projection from the nucleus of the solitary tract to the nucleus ambiguus in the rat: Anatomical evidence for somatostatin‐28‐immunoreactive interneurons subserving reflex control of esophageal motility. J Neurosci 9: 1668‐1682, 1989.
 58. Curran AK , Rodman JR , Eastwood PR , Henderson KS , Dempsey JA , Smith CA . Ventilatory responses to specific CNS hypoxia in sleeping dogs. J Appl Physiol 88: 1840‐1852, 2000.
 59. Cutz E , Pan J , Yeger H , Domnik NJ , Fisher JT . Recent advances and controversies on the role of pulmonary neuroepithelial bodies as airway sensors. Semin Cell Dev Biol 24: 40‐50, 2013.
 60. Dahan A , DeGoede J , Berkenbosch A , Olievier IC . The influence of oxygen on the ventilatory response to carbon dioxide in man. J Physiol 428: 485‐499, 1990.
 61. Dahan A , Nieuwenhuijs D , Teppema L . Plasticity of central chemoreceptors: Effect of bilateral carotid body resection on central CO2 sensitivity. PLoS Med 4: e239, 2007.
 62. Daristotle L , Berssenbrugge AD , Engwall MJ , Bisgard GE . The effects of carotid body hypocapnia on ventilation in goats. Respir Physiol 79: 123‐135, 1990.
 63. Daristotle L , Bisgard GE . Central‐peripheral chemoreceptor ventilatory interaction in awake goats. Respir Physiol 76: 383‐391, 1989.
 64. Daristotle L , Engwall MJ , Niu WZ , Bisgard GE . Ventilatory effects and interactions with change in PaO2 in awake goats. J Appl Physiol 71: 1254‐1260, 1991.
 65. Dasso LL , Buckler KJ , Vaughan‐Jones RD . Interactions between hypoxia and hypercapnic acidosis on calcium signaling in carotid body type I cells. Am J Physiol Lung Cell Mol Physiol 279: L36‐L42, 2000.
 66. Dauger S , Pattyn A , Lofaso F , Gaultier C , Goridis C , Gallego J , Brunet JF . Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways. Development 130: 6635‐6642, 2003.
 67. Day TA , Wilson RJA. Specific carotid body chemostimulation is sufficient to elicit phrenic poststimulus frequency decline in a novel in situ dual‐perfused rat preparation. Am J Physiol Regul Integr Comp Physiol 289: R532‐R544, 2005.
 68. Day TA , Wilson RJA . Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation. J Physiol 578: 843‐857, 2007.
 69. Day TA , Wilson RJA . A negative interaction between central and peripheral respiratory chemoreceptors may underlie sleep‐induced respiratory instability: A novel hypothesis. Adv Exp Med Biol 605: 447‐451, 2008.
 70. Day TA , Wilson RJA . A negative interaction between brainstem and peripheral respiratory chemoreceptors modulates peripheral chemoreflex magnitude. J Physiol 587: 883‐896, 2009.
 71. Dean JB , Bayliss DA , Erickson JT , Lawing WL , Millhorn DE . Depolarization and stimulation of neurons in nucleus tractus solitarii by carbon dioxide does not require chemical synaptic input. Neuroscience 36: 207‐216, 1990.
 72. Dean JB , Lawing WL , Millhorn DE . CO2 decreases membrane conductance and depolarizes neurons in the nucleus tractus solitarii. Exp Brain Res 76: 656‐661, 1989.
 73. DeGoede J , Berkenbosch A , Ward DS , Bellville JW , Olievier CN . Comparison of chemoreflex gains obtained with two different methods in cats. J Appl Physiol 1985 59: 170‐179, 1985.
 74. Deng BS , Nakamura A , Zhang W , Yanagisawa M , Fukuda Y , Kuwaki T . Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice. J Appl Physiol 103: 1772‐1779, 2007.
 75. Depuy SD , Kanbar R , Coates MB , Stornetta RL , Guyenet PG . Control of breathing by raphe obscurus serotonergic neurons in mice. J Neurosci 31: 1981‐1990, 2011.
 76. Dias MB , Li A , Nattie E . The orexin receptor 1 (OX1R) in the rostral medullary raphe contributes to the hypercapnic chemoreflex in wakefulness, during the active period of the diurnal cycle. Respir Physiol Neurobiol 170: 96‐102, 2010.
 77. Dias MB , Li A , Nattie EE . Antagonism of orexin receptor‐1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness. J Physiol 587: 2059‐2067, 2009.
 78. DiGiulio C , Huang W , Mokashi A , Lahiri S . Further characterization of stimulus interaction of cat carotid chemoreceptors. J Auton Nerv Syst 71: 196‐200, 1998.
 79. Dobbins EG , Feldman JL . Brainstem network controlling descending drive to phrenic motoneurons in rat. J Comp Neurol 347: 64‐86, 1994.
 80. Donnelly DF , Smith E , Dutton RE . Carbon dioxide versus H ion as a chemoreceptor stimulus. Brain Res 245: 136‐138, 1982.
 81. Dubreuil V , Ramanantsoa N , Trochet D , Vaubourg V , Amiel J , Gallego J , Brunet JF , Goridis C . A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons. Proc Natl Acad Sci U S A 105: 1067‐1072, 2008.
 82. Duffin J , Mateika JH . Cross‐Talk: The peripheral and central chemoreflexes have additive effects on ventilation in humans. J Physiol 591(Pt 18): 4351‐4353, 2013.
 83. Duffin J , Mohan RM , Vasiliou P , Stephenson R , Mahamed S . A model of the chemoreflex control of breathing in humans: Model parameters measurement. Respir Physiol 120: 13‐26, 2000.
 84. Duprat F , Lauritzen I , Patel A , Honore E . The TASK background K(2P) channels: Chemo‐ and nutrient sensors. Trends Neurosci 30: 573‐580, 2007.
 85. Dutton RE , Fitzgerald RS , Gross N . Ventilatory response to square‐wave forcing of carbon dioxide at the carotid bodies. Respir Physiol 4: 101‐108, 1968.
 86. Easton PA , Slykerman LJ , Anthonisen NR . Recovery of the ventilatory response to hypoxia in normal adults. J Appl Physiol 64: 521‐528, 1988.
 87. Edelman NH , Epstein PE , Lahiri S , Cherniack NS . Ventilatory responses to transient hypoxia and hypercapnia in man. Respir Physiol 17: 302‐314, 1973.
 88. Edwards BA , Sands SA , Skuza EM , Brodecky V , Stockx EM , Wilkinson MH , Berger PJ . Maturation of respiratory control and the propensity for breathing instability in a sheep model. J Appl Physiol 107: 1463‐1471, 2009.
 89. Elam M , Yao T , Thoren P , Svensson TH . Hypercapnia and hypoxia: Chemoreceptor‐mediated control of locus coeruleus neurons and splanchnic, sympathetic nerves. Brain Res 222: 373‐381, 1981.
 90. Eldridge FL , Gill‐Kumar P , Millhorn DE . Input‐output relationships of central neural circuits involved in respiration in cats. J Physiol 311: 81‐95, 1981.
 91. Erlichman JS , Leiter JC . Glia modulation of the extracellular milieu as a factor in central CO2 chemosensitivity and respiratory control. J Appl Physiol 108: 1803‐1811, 2010.
 92. Erlichman JS , Li A , Nattie EE . Ventilatory effects of glial dysfunction in a rat brain stem chemoreceptor region. J Appl Physiol 85: 1599‐1604, 1998.
 93. Eyzaguirre C , Koyano H . Effects of hypoxia, hypercapnia, and pH on the chemoreceptor activity of the carotid body in vitro. J Physiol 178: 385‐409, 1965.
 94. Eyzaguirre C , Lewin J . Chemoreceptor activity of the carotid body of the cat. J Physiol 159: 222‐237, 1961.
 95. Eyzaguirre C , Lewin J . The effect of sympathetic stimulation on carotid nerve activity. J Physiol 159: 251‐267, 1961.
 96. Fagerlund MJ , Kahlin J , Ebberyd A , Schulte G , Mkrtchian S , Eriksson LI . The human carotid body: expression of oxygen sensing and signaling genes of relevance for anesthesia. Anesthesiology 113: 1270‐1279, 2010.
 97. Fatemian M , Gamboa A , Leon‐Velarde F , Rivera‐Ch M , Palacios JA , Robbins PA . Selected contribution: Ventilatory response to CO2 in high‐altitude natives and patients with chronic mountain sickness. J Appl Physiol 94: 1279‐1287, 2003.
 98. Fatemian M , Nieuwenhuijs DJ , Teppema LJ , Meinesz S , van der Mey AG , Dahan A , Robbins PA . The respiratory response to carbon dioxide in humans with unilateral and bilateral resections of the carotid bodies. J Physiol 549: 965‐973, 2003.
 99. Fiamma M‐N , O'Connor ET , Roy A , Zuna I , Wilson RJA . The essential role of peripheral respiratory chemoreceptor inputs in maintaining breathing revealed when CO2 stimulation of central chemoreceptors is diminished. J Physiol 591: 1507‐1521, 2013.
 100. Fidone SJ , Sato A . A study of chemoreceptor and baroreceptor A and C‐fibres in the cat carotid nerve. J Physiol 205: 527‐548, 1969.
 101. Filosa JA , Dean JB , Putnam RW . Role of intracellular and extracellular pH in the chemosensitive response of rat locus coeruleus neurones. J Physiol 541: 493‐509, 2002.
 102. Filosa JA , Putnam RW . Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K+ and Ca2+ channels. Am J Physiol Cell Physiol 284: C145‐C155, 2003.
 103. Finley JC , Katz DM . The central organization of carotid body afferent projections to the brainstem of the rat. Brain Res 572: 108‐116, 1992.
 104. Fitzgerald R . Single fiber chemoreceptor response of carotid and aortic bodies. In: Paintal A , editor. Morphology and Mechanisms of Chemoreceptors. Vallabhbai Patel Chest Institute, Delhi, 1976, pp. 27‐36.
 105. Fitzgerald RS , Lahiri S . Reflex responses to chemoreceptors stimulation. In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD USA: American Physiological Society, 1986, pp. 313‐362.
 106. Fitzgerald RS , Leitner LM , Liaubet MJ . Carotid chemoreceptor response to intermittent or sustained stimulation in the cat. Respir Physiol 6: 395‐402, 1969.
 107. Fitzgerald RS , Parks DC . Effect of hypoxia on carotid chemoreceptor response to carbon dioxide in cats. Respir Physiol 12: 218‐229, 1971.
 108. Fitzgerald RS , Shirahata M , Chang I . The impact of PCO2 and H+ on the release of acetylcholine from the cat carotid body. Neurosci Lett 397: 205‐209, 2006.
 109. Forster HV , Martino P , Hodges M , Krause K , Bonis J , Davis S , Pan L . The carotid chemoreceptors are a major determinant of ventilatory CO2 sensitivity and of PaCO2 during eupneic breathing. Adv Exp Med Biol 605: 322‐326, 2008.
 110. Forster HV , Pan LG , Lowry TF , Serra A , Wenninger J , Martino P . Important role of carotid chemoreceptor afferents in control of breathing of adult and neonatal mammals. Respir Physiol 119: 199‐208, 2000.
 111. Forster HV , Smith CA . Contributions of central and peripheral chemoreceptors to the ventilatory response to CO2/H+. J Appl Physiol Bethesda Md 1985 108: 989‐994, 2010.
 112. Gallego J . Genetic diseases: Congenital central hypoventilation, Rett, and Prader‐Willi syndromes. Compr Physiol 2: 2255‐2279, 2012.
 113. Garcia AJ III , Zanella S , Koch H , Doi A , Ramirez JM . Chapter 3–networks within networks: The neuronal control of breathing. Prog Brain Res 188: 31‐50, 2011.
 114. Gargaglioni LH , Hartzler LK , Putnam RW . The locus coeruleus and central chemosensitivity. Respir Physiol Neurobiol 173: 264‐273, 2010.
 115. Gautier H , Bonora M . Possible alterations in brain monoamine metabolism during hypoxia‐induced tachypnea in cats. J Appl Physiol 49: 769‐777, 1980.
 116. Gelfand R , Lambertsen CJ . Dynamic respiratory response to abrupt change of inspired CO2 at normal and high PO2 . J Appl Physiol 35: 903‐913, 1973.
 117. Gesell R , Lapides J , Levin M . The interaction of central and peripheral chemical control of breathing. Am J Physiol – Legacy Content 130: 155‐170, 1940.
 118. Gestreau C , Heitzmann D , Thomas J , Dubreuil V , Bandulik S , Reichold M , Bendahhou S , Pierson P , Sterner C , Peyronnet‐Roux J , Benfriha C , Tegtmeier I , Ehnes H , Georgieff M , Lesage F , Brunet J‐F , Goridis C , Warth R , Barhanin J . Task2 potassium channels set central respiratory CO2 and O2 sensitivity. Proc Natl Acad Sci U S A 107: 2325‐2330, 2010.
 119. Gheshmy A , Anari A , Besada D , Reid SG . Afferent input modulates the chronic hypercapnia‐induced increase in respiratory‐related central pH/CO2 chemosensitivity in the cane toad (Bufo marinus). J Exp Biol 210: 227‐237, 2007.
 120. Giese K , Berndt J , Berger W . Interaction of central and peripheral respiratory drives in cats II. Peripheral and central interaction of hypoxia and hypercapnia. Pflugers Arch 374: 211‐217, 1978.
 121. De Goede J , Berkenbosch A , Olievier CN , Quanjer PH . Ventilatory response to carbon dioxide and apnoeic thresholds. Respir Physiol 45: 185‐199, 1981.
 122. Gonzalez C , Almaraz L , Obeso A , Rigual R . Carotid body chemoreceptors: From natural stimuli to sensory discharges. Physiol Rev 74: 829‐898, 1994.
 123. Goodman NW , Nail BS , Torrance RW . Oscillations in the discharge of single carotid chemorecptor fibers of the cat. Respir Physiol 20: 251‐269, 1974.
 124. Gourine AV , Kasymov V , Marina N , Tang F , Figueiredo MF , Lane S , Teschemacher AG , Spyer KM , Deisseroth K , Kasparov S . Astrocytes control breathing through pH‐dependent release of ATP. Science 329: 571‐575, 2010.
 125. Gray BA . Response of the perfused carotid body to changes in pH and PCO2. Respir Physiol 4: 229‐245, 1968.
 126. Grodins FS , Buell J , Bart AJ . Mathematical analysis and digital simulation of the respiratory control system. J Appl Physiol 22: 260‐276, 1967.
 127. Grunstein MM , Derenne JP , Milic‐Emili J . Control of depth and frequency of breathing during baroreceptor stimulation in cats. J Appl Physiol 39: 395‐404, 1975.
 128. Guenther MA , Bruder ED , Raff H . Effects of body temperature maintenance on glucose, insulin, and corticosterone responses to acute hypoxia in the neonatal rat. Am J Physiol Regul Integr Comp Physiol 302: R627‐R633, 2012.
 129. Guyenet PG . Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol 4: 1511‐1562, 2014.
 130. Guyenet PG , Abbott SB , Stornetta RL . The respiratory chemoreception conundrum: Light at the end of the tunnel? Brain Res 1511: 126‐137, 2013.
 131. Guyenet PG , Mulkey DK . Retrotrapezoid nucleus and parafacial respiratory group. Respir Physiol Neurobiol 173: 244‐255, 2010.
 132. Guyenet PG , Stornetta RL , Bayliss DA . Central respiratory chemoreception. J Comp Neurol 518: 3883‐3906, 2010.
 133. Guz A , Noble MI , Widdicombe JG , Trenchard D , Mushin WW . The effect of bilateral block of vagus and glossopharyngeal nerves on the ventilatory response to CO2 of conscious man. Respir Physiol 1: 206‐210, 1966.
 134. Hancock MB . Evidence for direct projections from the nucleus of the solitary tract onto medullary adrenaline cells. J Comp Neurol 276: 460‐467, 1988.
 135. Heeringa J , Berkenbosch A , De Goede J , Olievier CN . Relative contribution of central and peripheral chemoreceptors to the ventilatory response to CO2 during hyperoxia. Respir Physiol 37: 365‐379, 1979.
 136. Hellstrom S . Morphometric studies of dense‐cored vesicles in type I cells of rat carotid body. J Neurocytol 4: 77‐86, 1975.
 137. Herbert H , Moga MM , Saper CB . Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat. J Comp Neurol 293: 540‐580, 1990.
 138. Hernandez‐Miranda LR , Birchmeier C . CO2 in the spotlight. eLife 4, e08086, 2015.
 139. He SF , Wei JY , Eyzaguirre C . Intracellular pH and some membrane characteristics of cultured carotid body glomus cells. Brain Res 547: 258‐266, 1991.
 140. Heymans C , Neil E . Reflexogenic Areas of the Cardiovascular System. London: Churchill, 1958.
 141. Hodges MR , Forster HV . Respiratory neuroplasticity following carotid body denervation: Central and peripheral adaptations. Neural Regen Res 7: 1073‐1079, 2012.
 142. Hodges MR , Martino P , Davis S , Opansky C , Pan LG , Forster HV . Effects on breathing of focal acidosis at multiple medullary raphe sites in awake goats. J Appl Physiol 97: 2303‐2309, 2004.
 143. Holleran J , Babbie M , Erlichman JS . Ventilatory effects of impaired glial function in a brain stem chemoreceptor region in the conscious rat. J Appl Physiol 90: 1539‐1547, 2001.
 144. Honda Y . Respiratory and circulatory activities in carotid body‐resected humans. J Appl Physiol 73: 1‐8, 1992.
 145. Honda Y , Hata N , Sakakibara Y , Nishino T , Satomura Y . Central hypoxic‐hypercapnic interaction in mild hypoxia in man. Pflugers Arch 391: 289‐295, 1981.
 146. Honda Y , Watanabe S , Hashizume I , Satomura Y , Hata N , Sakakibara Y , Severinghaus JW . Hypoxic chemosensitivity in asthmatic patients two decades after carotid body resection. J Appl Physiol 46: 632‐638, 1979.
 147. Hornbein T . The relation between stimulus to chemoreceptors and their response. In: Torrance RW , editor. Arterial Chemoreceptors. Oxford: Blackwell Scientific Publications, 1968, pp. 65‐76.
 148. Hornbein TF , Griffo ZJ , Roos A . Quantitation of chemoreceptor activity: Interrelation of hypoxia and hypercapnia. J Neurophysiol 24: 561‐568, 1961.
 149. Hornbein TF , Roos A . Specificity of H ion concentration as a carotid chemoreceptor stimulus. J Appl Physiol 18: 580‐584, 1963.
 150. Housley GD , Martin‐Body RL , Dawson NJ , Sinclair JD . Brain stem projections of the glossopharyngeal nerve and its carotid sinus branch in the rat. Neuroscience 22: 237‐250, 1987.
 151. Iceman KE , Harris MB . A group of non‐serotonergic cells is CO2‐stimulated in the medullary raphé. Neuroscience 259: 203‐213, 2014.
 152. Iceman KE , Richerson GB , Harris MB . Medullary serotonin neurons are CO2 sensitive in situ. J Neurophysiol 110: 2536‐2544, 2013.
 153. Ichikawa H . Innervation of the carotid body: Immunohistochemical, denervation, and retrograde tracing studies. Microsc Res Tech 59: 188‐195, 2002.
 154. Iturriaga R . Carotid body chemoreception: The importance of CO2 . Biol Res 26: 319‐329, 1993.
 155. Iturriaga R , Lahiri S . Carotid body chemoreception in the absence and presence of CO2‐HCO3‐. Brain Res 568: 253‐260, 1991.
 156. Iturriaga R , Lahiri S , Mokashi A . Carbonic anhydrase and chemoreception in the cat carotid body 1. Am J Physiol 261: C565‐C573, 1991.
 157. Iturriaga R , Mokashi A , Lahiri S . Anion exchanger and chloride channel in cat carotid body chemotransduction. J Auton Nerv Syst 70: 23‐31, 1998.
 158. Jiang C , Xu H , Cui N , Wu J . An alternative approach to the identification of respiratory central chemoreceptors in the brainstem. Respir Physiol 129: 141‐157, 2001.
 159. Jones JFX . Retrospective view of the carotid body research of Ronan G. O'Regan. Exp Physiol 89: 39‐43, 2004.
 160. Jounieaux V , Parreira VF , Aubert G , Dury M , Delguste P , Rodenstein DO . Effects of hypocapnic hyperventilation on the response to hypoxia in normal subjects receiving intermittent positive‐pressure ventilation. Chest 121: 1141‐1148, 2002.
 161. Jun JC , Shin M‐K , Yao Q , Bevans‐Fonti S , Poole J , Drager LF , Polotsky VY . Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice. Am J Physiol Endocrinol Metab 303: E377‐E388, 2012.
 162. Kang D , Wang J , Hogan JO , Vennekens R , Freichel M , White C , Kim D . Increase in cytosolic Ca2+produced by hypoxia and other depolarizing stimuli activates a non‐selective cation channel in chemoreceptor cells of rat carotid body. J Physiol 592: 1975‐1992, 2014.
 163. Kawai A , Ballantyne D , Muckenhoff K , Scheid P . Chemosensitive medullary neurones in the brainstem–spinal cord preparation of the neonatal rat. J Physiol 492(Pt 1): 277‐292, 1996.
 164. Khamnei S , Robbins PA . Hypoxic depression of ventilation in humans: Alternative models for the chemoreflexes. Respir Physiol 81: 117‐134, 1990.
 165. Kim D , Cavanaugh EJ , Kim I , Carroll JL . Heteromeric TASK‐1/TASK‐3 is the major oxygen‐sensitive background K+ channel in rat carotid body glomus cells. J Physiol 587: 2963‐2975, 2009.
 166. Kim DK , Prabhakar NR , Kumar GK . Acetylcholine release from the carotid body by hypoxia: evidence for the involvement of autoinhibitory receptors. J Appl Physiol 96: 376‐383, 2004.
 167. Kimura H , Tanaka M , Nagao K , Niijima M , Masuyama S , Mizoo A , Uruma T , Tatsumi K , Kuriyama T , Masuda A , Kobayashi T , Honda Y . A new aspect of the carotid body function controlling hypoxic ventilatory decline in humans. Appl Human Sci 17: 131‐137, 1998.
 168. Kinkead R , Filmyer WG , Mitchell GS , Milsom WK . Vagal input enhances responsiveness of respiratory discharge to central changes in pH/CO2 in bullfrogs. J Appl Physiol 77: 2048‐2051, 1994.
 169. Kirby GC , McQueen DS . Characterization of opioid receptors in the cat carotid body involved in chemosensory depression in vivo. BrJ Pharmacol 88: 889‐898, 1986.
 170. Kiwull P , Kiwull‐Schone H , Klatt W . Interaction of central and peripheral respiratory drives: Differentiation between the role of stimuli and afferents. In: HH Loeschcke, editor. Acid‐Base Homeostasis of the Brain Extracellular Fluid and the Respiratory Control System. Stuttgart: Thieme, 1976, pp. 146‐156.
 171. Kiwull‐Schöne H , Kiwull P . The role of the vagus nerves in the ventilatory response to lowered PaO2 with intact and eliminated carotid chemoreflexes. Pflüg Arch Eur J Physiol 381: 1‐9, 1979.
 172. Kiwull‐Schone H , Kiwull P , Muckenhoff K , Both W . The role of carotid chemoreceptors in the regulation of arterial oxygen transport under hypoxia with and without hypercapnia. Adv Exp Med Biol 75: 469‐476, 1976.
 173. Klein JP , Forster HV , Bisgard GE , Kaminski RP , Pan LG , Hamilton LH . Ventilatory response to inspired CO2 in normal and carotid body‐denervated ponies. J Appl Physiol 52: 1614‐1622, 1982.
 174. Kobayashi S . Fine structure of the carotid body of the dog. Arch Histol Jpn 30: 95‐120, 1968.
 175. Kuhlmann WD , Fedde MR . Intrapulmonary receptors in the bullfrog: Sensitivity to CO2 . J Comp Physiol 132: 69‐75, 1979.
 176. Kumar NN , Velic A , Soliz J , Shi Y , Li K , Wang S , Weaver JL , Sen J , Abbott SBG , Lazarenko RM , Ludwig M‐G , Perez‐Reyes E , Mohebbi N , Bettoni C , Gassmann M , Suply T , Seuwen K , Guyenet PG , Wagner CA , Bayliss DA . PHYSIOLOGY. Regulation of breathing by CO2 requires the proton‐activated receptor GPR4 in retrotrapezoid nucleus neurons. Science 348: 1255‐1260, 2015.
 177. Kumar P , Nye PC , Torrance RW . Do oxygen tension variations contribute to the respiratory oscillations of chemoreceptor discharge in the cat? J Physiol 395: 531‐552, 1988.
 178. Kumar P , Prabhakar NR . Peripheral chemoreceptors: Function and plasticity of the carotid body. Compr Physiol 2: 141‐219, 2012.
 179. Kummer W . Three types of neurochemically defined autonomic fibres innervate the carotid baroreceptor and chemoreceptor regions in the guinea‐pig. Anat Embryol (Berl) 181: 477‐489, 1990.
 180. Kuwaki T . Orexinergic modulation of breathing across vigilance states. Respir Physiol Neurobiol 164: 204‐212, 2008.
 181. Läderach H , Straub W . Effects of voluntary hyperventilation on glucose, free fatty acids and several glycostatic hormones. Swiss Med Wkly 131: 19‐22, 2001.
 182. Lahiri S , DeLaney RG . Relationship between carotid chemoreceptor activity and ventilation in the cat. Respir Physiol 24: 267‐286, 1975.
 183. Lahiri S , DeLaney RG . Stimulus interaction in the responses of carotid body chemoreceptor single afferent fibers. Respir Physiol 24: 249‐266, 1975.
 184. Lahiri S , Mokashi A , DeLaney RG , Fishman AP . Arterial PO2 and PCO2 stimulus threshold for carotid chemoreceptors and breathing. Respir Physiol 34: 359‐375, 1978.
 185. Lahiri S , Mulligan E , Mokashi A . Adaptive response of carotid body chemoreceptors to CO2. Brain Res 234: 137‐147, 1982.
 186. LaManna JC , Haxhiu MA , Kutina‐Nelson KL , Pundik S , Erokwu B , Yeh ER , Lust WD , Cherniack NS . Decreased energy metabolism in brain stem during central respiratory depression in response to hypoxia. J Appl Physiol 81: 1772‐1777, 1996.
 187. Lee LY , Milhorn HT . Central ventilatory responses to O2, and CO2 At three levels of carotid chemoreceptor stimulation. Respir Physiol 25: 319‐333, 1975.
 188. Lele EE , Hantos Z , Bitay M , Szívós B , Bogáts G , Peták F , Babik B . Bronchoconstriction during alveolar hypocapnia and systemic hypercapnia in dogs with a cardiopulmonary bypass. Respir Physiol Neurobiol 175: 140‐145, 2011.
 189. Li A , Nattie E . Catecholamine neurones in rats modulate sleep, breathing, central chemoreception and breathing variability. J Physiol 570: 385‐396, 2006.
 190. Limberg JK , Taylor JL , Dube S , Basu R , Basu A , Joyner MJ , Wehrwein EA . Role of the carotid body chemoreceptors in baroreflex control of blood pressure during hypoglycaemia in humans. Exp Physiol 99(4):640‐50, 2014.
 191. Long WQ , Giesbrecht GG , Anthonisen NR . Ventilatory response to moderate hypoxia in awake chemodenervated cats. J Appl Physiol 74: 805‐810, 1993.
 192. Lopez‐Lopez JR , Perez‐Garcia MT . Oxygen sensitive Kv channels in the carotid body. Respir Physiol Neurobiol 157: 65‐74, 2007.
 193. Lopez‐Lopez JR , Perez‐Garcia MT . An ASIC channel for acid chemotransduction. Circ Res 101: 965‐967, 2007.
 194. Lu Y , Whiteis CA , Sluka KA , Chapleau MW , Abboud FM . Responses of glomus cells to hypoxia and acidosis are uncoupled, reciprocal and linked to ASIC3 expression: selectivity of chemosensory transduction. J Physiol 591: 919‐32, 2013.
 195. Marek W , Muckenhoff K , Prabhakar NR . Significance of pulmonary vagal afferents for respiratory muscle activity in the cat. J Physiol Pharmacol Off J Pol Physiol Soc 59(Suppl 6): 407‐420, 2008.
 196. Marshall JM . Interaction between the responses to stimulation of peripheral chemoreceptors and baroreceptors: The importance of chemoreceptor activation of the defence areas. J Auton Nerv Syst 3: 389‐400, 1981.
 197. Martin‐Body RL , Robson GJ , Sinclair JD . Restoration of hypoxic respiratory responses in the awake rat after carotid body denervation by sinus nerve section. J Physiol 380: 61‐73, 1986.
 198. Meuret AE , Ritz T , Wilhelm FH , Roth WT . Voluntary hyperventilation in the treatment of panic disorder–functions of hyperventilation, their implications for breathing training, and recommendations for standardization. Clin Psychol Rev 25: 285‐306, 2005.
 199. Milic‐Emili J , Grunstein MM . Drive and timing components of ventilation. Chest 70: 131‐133, 1976.
 200. Miller JR , Neumueller S , Muere C , Olesiak S , Pan L , Hodges MR , Forster HV . Changes in neurochemicals within the ventrolateral medullary respiratory column in awake goats after carotid body denervation. J Appl Physiol 115: 1088‐1098, 2013.
 201. Miller MJ , Tenney SM . Hypoxia‐induced tachypnea in carotid‐deafferented cats. Respir Physiol 23: 31‐39, 1975.
 202. Milsom WK , Jones DR . Carbon dioxide sensitivity of pulmonary receptors in the frog. Experientia 33: 1167‐1168, 1977.
 203. Milsom WK , Sadig T . Interaction between norepinephrine and hypoxia on carotid body chemoreception in rabbits. J Appl Physiol 55: 1893‐1898, 1983.
 204. Mitchell GS , Cross BA , Hiramoto T , Scheid P . Interactions between lung stretch and PaCO2 in modulating ventilatory activity in dogs. J Appl Physiol 53: 185‐191, 1982.
 205. Mitchell GS , Douse MA , Foley KT . Receptor interactions in modulating ventilatory activity. Am J Physiol 259: R911‐R920, 1990.
 206. Mitchell GS , Smith CA , Vidruk EH , Jameson LC , Dempsey JA . Effects of p‐chlorophenylalanine on ventilatory control in goats. J Appl Physiol 54: 277‐283, 1983.
 207. Mkrtchian S , Kåhlin J, Ebberyd A , Gonzalez C , Sanchez D , Balbir A , Kostuk EW , Shirahata M , Fagerlund MJ , Eriksson LI . The human carotid body transcriptome with focus on oxygen sensing and inflammation – a comparative analysis. J Physiol 590: 3807‐3819, 2012.
 208. Mokashi A , Ray D , Botre F , Katayama M , Osanai S , Lahiri S . Effect of hypoxia on intracellular pH of glomus cells cultured from cat and rat carotid bodies. J Appl Physiol 78: 1875‐1881, 1995.
 209. Morita E , Chiocchio SR , Tramezzani JH . Four types of main cells in the carotid body of the cat. J Ultrastruct Res 28: 399‐410, 1969.
 210. Moss IR . Canadian Association of Neuroscience Review: Respiratory control and behavior in humans: lessons from imaging and experiments of nature. Can J Neurol Sci J Can Sci Neurol 32: 287‐297, 2005.
 211. Mouradian GC , Forster HV , Hodges MR . Acute and chronic effects of carotid body denervation (CBD) on ventilation and chemoreflexes in three rat strains. J Physiol 590(Pt 14):3335‐47, 2012.
 212. Mulkey DK , Stornetta RL , Weston MC , Simmons JR , Parker A , Bayliss DA , Guyenet PG . Respiratory control by ventral surface chemoreceptor neurons in rats. Nat Neurosci 7: 1360‐1369, 2004.
 213. Mulkey DK , Talley EM , Stornetta RL , Siegel AR , West GH , Chen X , Sen N , Mistry AM , Guyenet PG , Bayliss DA . TASK channels determine pH sensitivity in select respiratory neurons but do not contribute to central respiratory chemosensitivity. J Neurosci 27: 14049‐14058, 2007.
 214. Mulligan E , Lahiri S . Separation of carotid body chemoreceptor responses to O2 and CO2 by oligomycin and by antimycin A. Am J Physiol 242: C200‐C206, 1982.
 215. Musch TI , Pelligrino A , Dempsey JA . Effects of prolonged N2O and barbiturate anesthesia on brain metabolism and pH in the dog. Respir Physiol 39: 121‐131, 1980.
 216. Nakamura A , Zhang W , Yanagisawa M , Fukuda Y , Kuwaki T . Vigilance state‐dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 102: 241‐248, 2007.
 217. Nakayama H , Smith CA , Rodman JR , Skatrud JB , Dempsey JA . Carotid body denervation eliminates apnea in response to transient hypocapnia. J Appl Physiol 94: 155‐164, 2003.
 218. Nattie EE , Li A . CO2 dialysis in the medullary raphe of the rat increases ventilation in sleep. J Appl Physiol 90: 1247‐1257, 2001.
 219. Nattie EE , Li A . CO2 dialysis in nucleus tractus solitarius region of rat increases ventilation in sleep and wakefulness. J Appl Physiol 92: 2119‐2130, 2002.
 220. Nattie E , Li A . Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol 106: 1464‐1466, 2009.
 221. Nattie E , Li A . Central chemoreceptors: Locations and functions. Compr Physiol 2: 221‐254, 2012.
 222. Nichols NL , Hartzler LK , Conrad SC , Dean JB , Putnam RW . Intrinsic chemosensitivity of individual nucleus tractus solitarius (NTS) and locus coeruleus (LC) neurons from neonatal rats. Adv Exp Med Biol 605: 348‐352, 2008.
 223. Nichols NL , Mulkey DK , Wilkinson KA , Powell FL , Dean JB , Putnam RW . Characterization of the chemosensitive response of individual solitary complex neurons from adult rats. Am J Physiol Regul Integr Comp Physiol 296: R763‐R773, 2009.
 224. Nielsen M , Smith H . Studies on the regulation of respiration in acute hypoxia; with a appendix on respiratory control during prolonged hypoxia. Acta Physiol Scand 24: 293‐313, 1952.
 225. Niu WZ , Engwall MJ , Bisgard GE . Two discharge patterns of carotid body chemoreceptors in the goat. J Appl Physiol 69: 734‐739, 1990.
 226. Nuding SC , Segers LS , Shannon R , O'Connor R , Morris KF , Lindsey BG . Central and peripheral chemoreceptors evoke distinct responses in simultaneously recorded neurons of the raphe‐pontomedullary respiratory network. Philos Trans R Soc Lond B Biol Sci 364: 2501‐2516, 2009.
 227. Nunes AR , Holmes AP , Sample V , Kumar P , Cann MJ , Monteiro EC , Zhang J , Gauda EB . Bicarbonate‐sensitive soluble and transmembrane adenylyl cyclases in peripheral chemoreceptors. Respir Physiol Neurobiol 188(2):83‐93, 2013.
 228. Nurse C . Carbonic anhydrase and neuronal enzymes in cultured glomus cells of the carotid body of the rat. Cell Tissue Res 261: 65‐71, 1990.
 229. Nurse CA . Neurotransmission and neuromodulation in the chemosensory carotid body. Auton Neurosci 120: 1‐9, 2005.
 230. Nurse CA . Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptors. Exp Physiol 95: 657‐667, 2010.
 231. Onimaru H , Ikeda K , Kawakami K . CO2‐sensitive preinspiratory neurons of the parafacial respiratory group express Phox2b in the neonatal rat. J Neurosci 28: 12845‐12850, 2008.
 232. O'Regan RG , Majcherczyk S . Role of peripheral chemoreceptors and central chemosensitivity in the regulation of respiration and circulation. J Exp Biol 100: 23‐40, 1982.
 233. Ortega‐Saenz P , Levitsky KL , Marcos‐Almaraz MT , Bonilla‐Henao V , Pascual A , Lopez‐Barneo J . Carotid body chemosensory responses in mice deficient of TASK channels. J Gen Physiol 135: 379‐392, 2010.
 234. Ortega‐Sáenz P , Pardal R , Levitsky K , Villadiego J , Muñoz‐Manchado AB , Durán R , Bonilla‐Henao V , Arias‐Mayenco I , Sobrino V , Ordóñez A , Oliver M , Toledo‐Aral JJ , López‐Barneo J . Cellular properties and chemosensory responses of the human carotid body. J Physiol 591: 6157‐6173, 2013.
 235. Ou LC , Tenney SM . The role of brief hypocapnia in the ventilatory response to CO2 with hypoxia. Respir Physiol 28: 333‐346, 1976.
 236. Painter R , Khamnei S , Robbins P . A mathematical model of the human ventilatory response to isocapnic hypoxia. J Appl Physiol 74: 2007‐2015, 1993.
 237. Pan LG , Forster HV , Martino P , Strecker PJ , Beales J , Serra A , Lowry TF , Forster MM , Forster AL . Important role of carotid afferents in control of breathing. J Appl Physiol 85: 1299‐1306, 1998.
 238. Pardal R , Ortega‐Saenz P , Duran R , Lopez‐Barneo J . Glia‐like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body. Cell 131: 364‐377, 2007.
 239. Patel AJ , Honore E . Anesthetic‐sensitive 2P domain K+ channels. Anesthesiology 95: 1013‐1021, 2001.
 240. Pedersen ME , Dorrington KL , Robbins PA . Effects of dopamine and domperidone on ventilatory sensitivity to hypoxia after 8 h of isocapnic hypoxia. J Appl Physiol 86: 222‐229, 1999.
 241. Pedersen ME , Fatemian M , Robbins PA . Identification of fast and slow ventilatory responses to carbon dioxide under hypoxic and hyperoxic conditions in humans. J Physiol 521: 273‐287, 1999.
 242. Peers C . Effect of lowered extracellular pH on Ca2(+)‐dependent K+ currents in type I cells from the neonatal rat carotid body. J Physiol 422: 381‐395, 1990.
 243. Peers C . Interactions of chemostimuli at the single cell level: Studies in a model system. Exp Physiol 89: 60‐65, 2004.
 244. Peers C , Green FK . Inhibition of Ca(2+)‐activated K+ currents by intracellular acidosis in isolated type I cells of the neonatal rat carotid body. J Physiol 437: 589‐602, 1991.
 245. Peers C , Wyatt CN . The role of maxiK channels in carotid body chemotransduction. Respir Physiol Neurobiol 157: 75‐82, 2007.
 246. Pepper DR , Kumar P . Inhibition of adult rat carotid body type I cell K+ currents by combined hypoxic and acidotic stimuli. J Physiol 487: 177P‐178P, 1997.
 247. Pepper DR , Landauer RC , Kumar P . Postnatal development of CO2‐O2 interaction in the rat carotid body in vitro. JPhysiol 485: 531‐541, 1995.
 248. Perez H , Ruiz S . Medullary responses to chemoreceptor activation are inhibited by locus coeruleus and nucleus raphe magnus. Neuroreport 6: 1373‐1376, 1995.
 249. Petheo GL , Molnár Z , Róka A , Makara JK , Spät A . A pH‐sensitive chloride current in the chemoreceptor cell of rat carotid body. J Physiol 535: 95‐106, 2001.
 250. Phillipson EA , Hickey RF , Bainton CR , Nadel JA . Effect of vagal blockade on regulation of breathing in conscious dogs. J Appl Physiol 29: 475‐479, 1970.
 251. Plum F , Brown HW . Hypoxic‐hypercapnic interaction in subjects with bilateral cerebral dysfunction. J Appl Physiol 18: 1139‐1145, 1963.
 252. Pokorski M , Lahiri S . Relative peripheral and central chemosensory responses to metabolic alkalosis. AmJ Physiol 245: R873‐R880, 1983.
 253. Pokorski M , Takeda K , Sato Y , Okada Y . The hypoxic ventilatory response and TRPA1 antagonism in conscious mice. Acta Physiol Oxf Engl 210: 928‐938, 2014.
 254. Prabhakar NR . O2 sensing at the mammalian carotid body: Why multiple O2 sensors and multiple transmitters? Exp Physiol 91: 17‐23, 2006.
 255. Prabhakar NR , Peng Y‐J , Kumar GK , Nanduri J . Peripheral chemoreception and arterial pressure responses to intermittent hypoxia. Compr Physiol 5: 561‐577, 2015.
 256. Reid SG . Chemoreceptor and pulmonary stretch receptor interactions within amphibian respiratory control systems. Respir Physiol Neurobiol 154: 153‐164, 2006.
 257. Reid SG , Milsom WK , Meier JT , Munns S , West NH . Pulmonary vagal modulation of ventilation in toads (Bufo marinus). Respir Physiol 120: 213‐230, 2000.
 258. Richardson PS , Widdicombe JG . The role of the vagus nerves in the ventilatory responses to hypercapnia and hypoxia in anaesthetized and unanaesthetized rabbits. Respir Physiol 7: 122‐135, 1969.
 259. Richerson GB . Response to CO2 of neurons in the rostral ventral medulla in vitro. J Neurophysiol 73: 933‐944, 1995.
 260. Richerson GB . Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 5: 449‐461, 2004.
 261. Ridderstrale Y , Hanson MA . Histochemical localization of carbonic anhydrase in the cat carotid body. Ann NY Acad Sci 429: 398‐400, 1984.
 262. Rigual R , Lopez‐Lopez JR , Gonzalez C . Release of dopamine and chemoreceptor discharge induced by low pH and high PCO2 stimulation of the cat carotid body. J Physiol 433: 519‐531, 1991.
 263. Ritthaler T , Schricker K , Kees F , Krämer B , Kurtz A . Acute hypoxia stimulates renin secretion and renin gene expression in vivo but not in vitro. Am J Physiol 272: R1105‐R1111, 1997.
 264. Robbins PA . Evidence for interaction between the contributions to ventilation from the central and peripheral chemoreceptors in man. J Physiol 401: 503‐518, 1988.
 265. Roberts CA , Corfield DR , Murphy K , Calder NA , Hanson MA , Adams L , Guz A . Modulation by “central” PCO2 of the response to carotid body stimulation in man. Respir Physiol 102: 149‐161, 1995.
 266. 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.
 267. Rosin DL , Chang DA , Guyenet PG . Afferent and efferent connections of the rat retrotrapezoid nucleus. J Comp Neurol 499: 64‐89, 2006.
 268. Ross CA , Ruggiero DA , Reis DJ . Projections from the nucleus tractus solitarii to the rostral ventrolateral medulla. J Comp Neurol 242: 511‐534, 1985.
 269. Roux JC , Pequignot JM , Dumas S , Pascual O , Ghilini G , Pequignot J , Mallet J , Denavit‐Saubi M . O2‐sensing after carotid chemodenervation: Hypoxic ventilatory responsiveness and upregulation of tyrosine hydroxylase mRNA in brainstem catecholaminergic cells. Eur J Neurosci 12: 3181‐3190, 2000.
 270. Roy A , Mandadi S , Fiamma M‐N , Rodikova E , Ferguson EV , Whelan PJ , Wilson RJA . Anandamide modulates carotid sinus nerve afferent activity via TRPV1 receptors increasing responses to heat. J Appl Physiol 112: 212‐224, 2012.
 271. Roy A , Rozanov C , Mokashi A , Lahiri S . P(O(2))‐P(CO(2)) stimulus interaction in [Ca(2+)](i) and CSN activity in the adult rat carotid body. Respir Physiol 122: 15‐26, 2000.
 272. Ruffault P‐L , D'Autréaux F , Hayes JA , Nomaksteinsky M , Autran S , Fujiyama T , Hoshino M , Hägglund M , Kiehn O , Brunet J‐F , Fortin G , Goridis C . The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO2 . eLife 4, e07051, 2015.
 273. Ryan ML , Hedrick MS , Pizarro J , Bisgard GE . Effects of carotid body sympathetic denervation on ventilatory acclimatization to hypoxia in the goat. Respir Physiol 99: 215‐224, 1995.
 274. Salman S , Buttigieg J , Zhang M , Nurse CA . Chronic exposure of neonatal rat adrenomedullary chromaffin cells to opioids in vitro blunts both hypoxia and hypercapnia chemosensitivity. J Physiol 591: 515‐529, 2013.
 275. Santin JM , Watters KC , Putnam RW , Hartzler LK . Temperature influences neuronal activity and CO2/pH sensitivity of locus coeruleus neurons in the bullfrog, Lithobates catesbeianus. Am J Physiol Regul Integr Comp Physiol 305: R1451‐R1464, 2013.
 276. Schuitmaker JJ , Berkenbosch A , De Goede J , Olievier CN . Effects of CO2 and H+ on the ventilatory response to peripheral chemoreceptor stimulation. Respir Physiol 64: 69‐79, 1986.
 277. Sears RM , Fink AE , Wigestrand MB , Farb CR , de Lecea L , Ledoux JE . Orexin/hypocretin system modulates amygdala‐dependent threat learning through the locus coeruleus. Proc Natl Acad Sci U S A 110: 20260‐20265, 2013.
 278. Serra A , Brozoski D , Hedin N , Franciosi R , Forster HV . Mortality after carotid body denervation in rats. J Appl Physiol 91: 1298‐1306, 2001.
 279. Shirahata M , Fitzgerald RS . The presence of CO2/HCO3‐ is essential for hypoxic chemotransduction in the in vivo perfused carotid body. Brain Res 545: 297‐300, 1991.
 280. Smith CA , Bisgard GE , Nielsen AM , Daristotle L , Kressin NA , Forster HV , Dempsey JA . Carotid bodies are required for ventilatory acclimatization to chronic hypoxia. J Appl Physiol 60: 1003‐1010, 1986.
 281. Smith CA , Blain GM , Henderson KS , Dempsey JA . Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2: Role of carotid body CO2 . J. Physiol. 593(18):4225‐4243, 2015.
 282. Smith CA , Forster HV , Blain GM , Dempsey JA . An interdependent model of central/peripheral chemoreception: Evidence and implications for ventilatory control. Respir Physiol Neurobiol 173: 288‐297, 2010.
 283. Smith CA , Harms CA , Henderson KS , Dempsey JA . Ventilatory effects of specific carotid body hypocapnia and hypoxia in awake dogs. J Appl Physiol 82: 791‐798, 1997.
 284. Smith CA , Jameson LC , Mitchell GS , Musch TI , Dempsey JA . Central‐peripheral chemoreceptor interaction in awake cerebrospinal fluid‐perfused goats. J Appl Physiol 56: 1541‐1549, 1984.
 285. Smith CA , Nakayama H , Dempsey JA . The essential role of carotid body chemoreceptors in sleep apnea. Can J Physiol Pharmacol 81: 774‐779, 2003.
 286. Smith CA , Rodman JR , Chenuel BJ , Henderson KS , Dempsey JA . Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: Central vs. peripheral chemoreceptors. J Appl Physiol 100: 13‐19, 2006.
 287. Smith CA , Saupe KW , Henderson KS , Dempsey JA . Ventilatory effects of specific carotid body hypocapnia in dogs during wakefulness and sleep. J Appl Physiol 79: 689‐699, 1995.
 288. Smith JC , Abdala AP , Rybak IA , Paton JF . Structural and functional architecture of respiratory networks in the mammalian brainstem. Philos Trans R Soc Lond B Biol Sci 364: 2577‐2587, 2009.
 289. Smith PG , Mills E . Restoration of reflex ventilatory response to hypoxia after removal of carotid bodies in the cat. Neuroscience 5: 573‐580, 1980.
 290. St Croix CM , Cunningham DA , Paterson DH . Nature of the interaction between central and peripheral chemoreceptor drives in human subjects. CanJ Physiol Pharmacol 74: 640‐646, 1996.
 291. Summers BA , Overholt JL , Prabhakar NR . CO(2) and pH independently modulate L‐type Ca(2+) current in rabbit carotid body glomus cells. J Neurophysiol 88: 604‐612, 2002.
 292. Swanson GD , Bellville JW . Hypoxic‐hypercapnic interaction in human respiratory control. J Appl Physiol 36: 480‐487, 1974.
 293. Takakura AC , Moreira TS , Colombari E , West GH , Stornetta RL , Guyenet PG . Peripheral chemoreceptor inputs to retrotrapezoid nucleus (RTN) CO2‐sensitive neurons in rats. J Physiol 572: 503‐523, 2006.
 294. Talley EM , Bayliss DA . Modulation of TASK‐1 (Kcnk3) and TASK‐3 (Kcnk9) potassium channels: Volatile anesthetics and neurotransmitters share a molecular site of action. J Biol Chem 277: 17733‐17742, 2002.
 295. Tan ZY , Lu Y , Whiteis CA , Benson CJ , Chapleau MW , Abboud FM . Acid‐sensing ion channels contribute to transduction of extracellular acidosis in rat carotid body glomus cells. Circ Res 101: 1009‐1019, 2007.
 296. Tenney SM , Brooks JG 3rd . Carotid bodies, stimulus interaction, and ventilatory control in unanesthetized goats. Respir Physiol 1: 211‐224, 1966.
 297. Teppema LJ . Multifaceted clinical effects of acetazolamide: Will the underlying mechanisms please stand up? J Appl Physiol 116: 713‐714, 2014.
 298. Teppema LJ , Barts PW , Evers JA . The effect of the phase relationship between the arterial blood gas oscillations and central neural respiratory activity on phrenic motoneurone output in cats. Respir Physiol 61: 301‐316, 1985.
 299. Teppema LJ , Berendsen RR . Response to the reply of J. Duffin to our letter entitled “Acetazolamide and cerebrovascular function at high altitude.” J Physiol 590: 3625‐3626, 2012.
 300. Teppema LJ , Bijl H , Romberg RR , Dahan A . Antioxidants reverse depression of the hypoxic ventilatory response by acetazolamide in man. J Physiol 572: 849‐856, 2006.
 301. Teppema LJ , Dahan A . The ventilatory response to hypoxia in mammals: Mechanisms, measurement, and analysis. Physiol Rev 90: 675‐754, 2010.
 302. Teppema LJ , Dahan A , Olievier CN . Low‐dose acetazolamide reduces CO(2)‐O(2) stimulus interaction within the peripheral chemoreceptors in the anaesthetised cat. J Physiol 537: 221‐229, 2001.
 303. Teppema LJ , van Dorp EL , Dahan A . Arterial [H+] and the ventilatory response to hypoxia in humans: Influence of acetazolamide‐induced metabolic acidosis. Am J Physiol Lung Cell Mol Physiol 298: L89‐L95, 2010.
 304. Teppema LJ , Smith CA . CrossTalk opposing view: Peripheral and central chemoreceptors have hyperadditive effects on respiratory motor control. J Physiol 591: 4359‐4361, 2013.
 305. Teppema LJ , Veening JG , Kranenburg A , Dahan A , Berkenbosch A , Olievier C . Expression of c‐fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia. J Comp Neurol 388: 169‐190, 1997.
 306. Teran FA , Massey CA , Richerson GB . Serotonin neurons and central respiratory chemoreception: Where are we now? Prog Brain Res 209: 207‐233, 2014.
 307. Tin C , Song G , Poon C‐S . Hypercapnia attenuates inspiratory amplitude and expiratory time responsiveness to hypoxia in vagotomized and vagal‐intact rats. Respir Physiol Neurobiol 181: 79‐87, 2012.
 308. Topor ZL , Pawlicki M , Remmers JE . A computational model of the human respiratory control system: Responses to hypoxia and hypercapnia. Ann Biomed Eng 32: 1530‐1545, 2004.
 309. Topor ZL , Vasilakos K , Remmers JE . Ventilatory instability during sleep: New insights from the computational model. Conf Proc Annu Int Conf IEEE Eng Med Biol Soc 6: 5828‐5831, 2005.
 310. Torrance RW . Prolegomena. In: Torrance RW , editor. Arterial Chemoreceptors. Oxford: Blackwell, 1968, pp. 1‐40.
 311. Trapp S , Aller MI , Wisden W , Gourine AV . A role for TASK‐1 (KCNK3) channels in the chemosensory control of breathing. J Neurosci 28: 8844‐8850, 2008.
 312. Travis DM . Molecular CO2 is inert on carotid chemoreceptor: Demonstration by inhibition of carbonic anhydrase. J Pharmacol Exp Ther 178: 529‐540, 1971.
 313. Turner PJ , Buckler KJ . Oxygen and mitochondrial inhibitors modulate both monomeric and heteromeric TASK‐1 and TASK‐3 channels in mouse carotid body type‐1 cells. J Physiol 591: 5977‐5998, 2013.
 314. Ungar A , Bouverot P . The ventilatory responses of conscious dogs to isocapnic oxygen tests. a method of exploring the central component of respiratory drive and its dependence on O2 and CO2 . Respir Physiol 39: 183‐197, 1980.
 315. Vidruk EH , Olson EB Jr , Ling L , Mitchell GS . Responses of single‐unit carotid body chemoreceptors in adult rats. J Physiol 531: 165‐170, 2001.
 316. Wang S , Benamer N , Zanella S , Kumar NN , Shi Y , Bévengut M , Penton D , Guyenet PG , Lesage F , Gestreau C , Barhanin J , Bayliss DA . TASK‐2 channels contribute to pH sensitivity of retrotrapezoid nucleus chemoreceptor neurons. J Neurosci 33: 16033‐16044, 2013.
 317. Wang W , Tiwari JK , Bradley SR , Zaykin RV , Richerson GB . Acidosis‐stimulated neurons of the medullary raphe are serotonergic. J Neurophysiol 85: 2224‐2235, 2001.
 318. Ward DS , Bellville JW . Effect of intravenous dopamine on hypercapnic ventilatory response in humans. J Appl Physiol 55: 1418‐1425, 1983.
 319. Washburn CP , Sirois JE , Talley EM , Guyenet PG , Bayliss DA . Serotonergic raphe neurons express TASK channel transcripts and a TASK‐like pH‐ and halothane‐sensitive K+ conductance. J Neurosci 22: 1256‐1265, 2002.
 320. Weizhen N , Engwall MJ , Daristotle L , Pizarro J , Bisgard GE . Ventilatory effects of prolonged systemic (CNS) hypoxia in awake goats. Respir Physiol 87: 37‐48, 1992.
 321. Wenker IC , Kréneisz O , Nishiyama A , Mulkey DK . Astrocytes in the retrotrapezoid nucleus sense H+ by inhibition of a Kir4.1‐Kir5.1‐like current and may contribute to chemoreception by a purinergic mechanism. J Neurophysiol 104: 3042‐3052, 2010.
 322. Wenker IC , Sobrinho CR , Takakura AC , Moreira TS , Mulkey DK . Regulation of ventral surface CO2/H+‐sensitive neurons by purinergic signalling. J Physiol 590: 2137‐2150, 2012.
 323. Wiemer W , Kiwull P . Der Einflub des PACO2 auf die Wirkung der Sinusnervenreizung bei intakten und ausgeschalteten. Pfliigers Arch 330: 28‐44, 1971.
 324. Wilding TJ , Cheng B , Roos A . pH regulation in adult rat carotid body glomus cells. Importance of extracellular pH, sodium, and potassium. J Gen Physiol 100: 593‐608, 1992.
 325. Williams RH , Jensen LT , Verkhratsky A , Fugger L , Burdakov D . Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci USA 104: 10685‐10690, 2007.
 326. Williams SE , Wootton P , Mason HS , Bould J , Iles DE , Riccardi D , Peers C , Kemp PJ . Hemoxygenase‐2 is an oxygen sensor for a calcium‐sensitive potassium channel. Science 306: 2093‐2097, 2004.
 327. Wilson CR , Satoh M , Skatrud JB , Dempsey JA . Non‐chemical inhibition of respiratory motor output during mechanical ventilation in sleeping humans. J Physiol 518: 605‐618, 1999.
 328. Wilson RJA , Day TA . CrossTalk opposing view: Peripheral and central chemoreceptors have hypoadditive effects on respiratory motor output. J Physiol 591: 4355‐4357, 2013.
 329. Wilson RJA , Day TA . Rebuttal by Richard J. A. Wilson and Trevor A. Day. J Physiol 591: 4365, 2013.
 330. Younes MK . Comments on the CrossTalk opposing views: Peripheral and central chemoreflexes have additive/hypoadditive/ hyperadditive effects on ventilation in humans. Why the controversy? J Physiol 591: 0, 2013.
 331. Zhang M , Nurse CA . CO2/pH chemosensory signaling in co‐cultures of rat carotid body receptors and petrosal neurons: Role of ATP and ACh. J Neurophysiol 92: 3433‐3445, 2004.
 332. Zhong H , Zhang M , Nurse CA . Synapse formation and hypoxic signalling in co‐cultures of rat petrosal neurones and carotid body type 1 cells. J Physiol 503(Pt 3): 599‐612, 1997.

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Richard J.A. Wilson, Luc J. Teppema. Integration of Central and Peripheral Respiratory Chemoreflexes. Compr Physiol 2016, 6: 1005-1041. doi: 10.1002/cphy.c140040