Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Peripheral Chemoreception and Arterial Pressure Responses to Intermittent Hypoxia

Nanduri R. Prabhakar, Ying‐Jie Peng, Ganesh K. Kumar, Jayasri Nanduri

10.1002/cphy.c140039

Source: Volume 5, Issue 2, April 2015

Published online: March 2015

Full Article on Wiley Online Library



ABSTRACT

Carotid bodies are the principal peripheral chemoreceptors for detecting changes in arterial blood oxygen levels, and the resulting chemoreflex is a potent regulator of blood pressure. Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in adult humans and infants born preterm. Adult patients with recurrent apnea exhibit heightened sympathetic nerve activity and hypertension. Adults born preterm are predisposed to early onset of hypertension. Available evidence suggests that carotid body chemoreflex contributes to hypertension caused by IH in both adults and neonates. Experimental models of IH provided important insights into cellular and molecular mechanisms underlying carotid body chemoreflex‐mediated hypertension. This article provides a comprehensive appraisal of how IH affects carotid body function, underlying cellular, molecular, and epigenetic mechanisms, and the contribution of chemoreflex to the hypertension. © 2015 American Physiological Society. Compr Physiol 5:561‐577, 2015.

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

Download a PowerPoint presentation of all images


Figure 1. Figure 1. The ex vivo carotid body responses to acute hypoxia (at black bar in left panels) and to acute intermittent hypoxia (AIH; at arrows in right panels) in control and rats exposed to 10 days of intermittent hypoxia (IH). pO2 = partial pressure of O2 in the medium irrigating the carotid body. Insets: represent superimposed action potentials of “single” fiber from which the data were derived. Note the augmented hypoxic sensory response and long‐lasting increase in baseline activity (sensory LTF) following AIH in IH‐exposed carotid bodies. [From Ref. (162) with permission.]
Figure 2. Figure 2. Effect of bosentan (50 μmol/L) on mild hypoxia‐evoked chemosensory discharges from a single control (A) and IH‐treated carotid body (B). Summary of the effect of bosentan on chemosensory responses elicited by mild and severe hypoxia in control (C) and IH‐treated carotid bodies (D) (n = 5 in each group). fx, frequency of chemosensory discharges expressed in Hz (A and B) or as percent of hypoxic responses in the absence of bosentan. Open bars represent the effects of hypoxia in the absence of bosentan; hashed and closed bars represent the effects of mild and severe hypoxia in the presence of bosentan, respectively. *P < 0.05; ‡P < 0.001, hypoxic responses following bosentan versus hypoxic responses without bosentan. [From Ref. (167) with permission.]
Figure 3. Figure 3. Schematic illustration of molecular and cellular mechanisms underlying the effects of intermittent hypoxia (IH) on the carotid body and chemoreflex‐dependent blood pressure changes. Keys: HIF‐1α and HIF‐2α, Hypoxia‐inducible factor 1 and 2α, respectively; Nox2, NADPH oxidase 2; Sod2, Superoxide dismutase 2; ROS, reactive oxygen species; LTF, long‐term facilitation.
Figure 4. Figure 4. Intermittent hypoxia (IH) augments carotid body response to hypoxia in neonatal rats. Examples of carotid body responses to hypoxia in rat pups exposed to 10 days of IH or to normoxia (Control) are shown. Black bars denote the duration of the hypoxic stimulus. Hypoxia: medium pO2 = 33 mmHg. Insets: superimposed action potential from a single unit. imp/s, impulses per second. [Modified from Ref. (140) with permission].
Figure 5. Figure 5. Schematic illustration of epigenetic mechanisms involving DNA hypermethylation of antioxidant enzymes on neonatal intermittent hypoxia‐induced hypertension in adults.


Figure 1. The ex vivo carotid body responses to acute hypoxia (at black bar in left panels) and to acute intermittent hypoxia (AIH; at arrows in right panels) in control and rats exposed to 10 days of intermittent hypoxia (IH). pO2 = partial pressure of O2 in the medium irrigating the carotid body. Insets: represent superimposed action potentials of “single” fiber from which the data were derived. Note the augmented hypoxic sensory response and long‐lasting increase in baseline activity (sensory LTF) following AIH in IH‐exposed carotid bodies. [From Ref. (162) with permission.]


Figure 2. Effect of bosentan (50 μmol/L) on mild hypoxia‐evoked chemosensory discharges from a single control (A) and IH‐treated carotid body (B). Summary of the effect of bosentan on chemosensory responses elicited by mild and severe hypoxia in control (C) and IH‐treated carotid bodies (D) (n = 5 in each group). fx, frequency of chemosensory discharges expressed in Hz (A and B) or as percent of hypoxic responses in the absence of bosentan. Open bars represent the effects of hypoxia in the absence of bosentan; hashed and closed bars represent the effects of mild and severe hypoxia in the presence of bosentan, respectively. *P < 0.05; ‡P < 0.001, hypoxic responses following bosentan versus hypoxic responses without bosentan. [From Ref. (167) with permission.]


Figure 3. Schematic illustration of molecular and cellular mechanisms underlying the effects of intermittent hypoxia (IH) on the carotid body and chemoreflex‐dependent blood pressure changes. Keys: HIF‐1α and HIF‐2α, Hypoxia‐inducible factor 1 and 2α, respectively; Nox2, NADPH oxidase 2; Sod2, Superoxide dismutase 2; ROS, reactive oxygen species; LTF, long‐term facilitation.


Figure 4. Intermittent hypoxia (IH) augments carotid body response to hypoxia in neonatal rats. Examples of carotid body responses to hypoxia in rat pups exposed to 10 days of IH or to normoxia (Control) are shown. Black bars denote the duration of the hypoxic stimulus. Hypoxia: medium pO2 = 33 mmHg. Insets: superimposed action potential from a single unit. imp/s, impulses per second. [Modified from Ref. (140) with permission].


Figure 5. Schematic illustration of epigenetic mechanisms involving DNA hypermethylation of antioxidant enzymes on neonatal intermittent hypoxia‐induced hypertension in adults.
References
 1. Abu‐Shaweesh JM , Martin RJ . Neonatal apnea: What's new? Pediatr Pulmonol 43: 937‐944, 2008.
 2. Ambrosio G , Zweier JL , Duilio C , Kuppusamy P , Santoro G , Elia PP , Tritto I , Cirillo P , Condorelli M , Chiariello M . Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow. J Biol Chem 268: 18532‐18541, 1993.
 3. Anway MD , Cupp AS , Uzumcu M , Skinner MK . Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466‐1469, 2005.
 4. Atkeson A , Yeh SY , Malhotra A , Jelic S . Endothelial function in obstructive sleep apnea. Prog Cardiovasc Dis 51: 351‐362, 2009.
 5. Banfi B , Maturana A , Jaconi S , Arnaudeau S , Laforge T , Sinha B , Ligeti E , Demaurex N , Krause KH . A mammalian H+ channel generated through alternative splicing of the NADPH oxidase homolog NOH‐1. Science 287: 138‐142, 2000.
 6. Bao G , Metreveli N , Li R , Taylor A , Fletcher EC . Blood pressure response to chronic episodic hypoxia: Role of the sympathetic nervous system. J Appl Physiol 83: 95‐101, 1997.
 7. Barker DJ , Osmond C , Simmonds SJ , Wield GA . The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. BMJ 306: 422‐426, 1993.
 8. Becker HF , Jerrentrup A , Ploch T , Grote L , Penzel T , Sullivan CE , Peter JH . Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 107: 68‐73, 2003.
 9. Bedard K , Krause KH . The NOX family of ROS‐generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 87: 245‐313, 2007.
 10. Bisgard GE , Olson EB, Jr , Wang ZY , Bavis RW , Fuller DD , Mitchell GS . Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia. J Appl Physiol (1985) 95: 946‐952, 2003.
 11. Blanco CE , Dawes GS , Hanson MA , McCooke HB . The response to hypoxia of arterial chemoreceptors in fetal sheep and new‐born lambs. J Physiol 351: 25‐37, 1984.
 12. Braga VA , Soriano RN , Machado BH . Sympathoexcitatory response to peripheral chemoreflex activation is enhanced in juvenile rats exposed to chronic intermittent hypoxia. Exp Physiol 91: 1025‐1031, 2006.
 13. Buckler KJ . Two‐pore domain k(+) channels and their role in chemoreception. Adv Exp Med Biol 661: 15‐30, 2010.
 14. Carlson JT , Hedner J , Elam M , Ejnell H , Sellgren J , Wallin BG . Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 103: 1763‐1768, 1993.
 15. Carreau A , El Hafny‐Rahbi B , Matejuk A , Grillon C , Kieda C . Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med 15: 1239‐1253, 2011.
 16. Carroll JL . Developmental plasticity in respiratory control. J Appl Physiol 94: 375‐389, 2003.
 17. Chen J , He L , Dinger B , Fidone S . Cellular mechanisms involved in rabbit carotid body excitation elicited by endothelin peptides. Respir Physiol 121: 13‐23, 2000.
 18. Chen J , He L , Dinger B , Stensaas L , Fidone S . Role of endothelin and endothelin A‐type receptor in adaptation of the carotid body to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 282: L1314‐L1323, 2002.
 19. Chen X , Kombian SB , Zidichouski JA , Pittman QJ . Dopamine depresses glutamatergic synaptic transmission in the rat parabrachial nucleus in vitro. Neuroscience 90: 457‐468, 1999.
 20. Chitravanshi VC , Sapru HN . Chemoreceptor‐sensitive neurons in commissural subnucleus of nucleus tractus solitarius of the rat. Am J Physiol 268: R851‐R858, 1995.
 21. Christou K , Markoulis N , Moulas AN , Pastaka C , Gourgoulianis KI . Reactive oxygen metabolites (ROMs) as an index of oxidative stress in obstructive sleep apnea patients. Sleep Breath 7: 105‐110, 2003.
 22. Cistulli PA , Sullivan CE . Pathophysiology of sleep apnea. In: Saunders NA , Sullivan CE , editors. Sleep and Breathing. New York: Dekker, 1994. pp. 405‐448.
 23. Cohen G , Jeffery H , Lagercrantz H , Katz‐Salamon M . Long‐term reprogramming of cardiovascular function in infants of active smokers. Hypertension 55: 722‐728, 2010.
 24. Coleman CG , Wang G , Park L , Anrather J , Delagrammatikas GJ , Chan J , Zhou J , Iadecola C , Pickel VM . Chronic intermittent hypoxia induces NMDA receptor‐dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus. J Neurosci 30: 12103‐12112, 2010.
 25. Coleman ML , Ratcliffe PJ . Oxygen sensing and hypoxia‐induced responses. Essays Biochem 43: 1‐15, 2007.
 26. Comroe JH . The location and function of the chemoreceptors of the aorta. Am J Physiol 127: 176‐191, 1939.
 27. Costa‐Silva JH , Zoccal DB , Machado BH . Chronic intermittent hypoxia alters glutamatergic control of sympathetic and respiratory activities in the commissural NTS of rats. Am J Physiol Regul Integr Comp Physiol 302: R785‐R793, 2012.
 28. 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.
 29. Cutler MJ , Swift NM , Keller DM , Wasmund WL , Burk JR , Smith ML . Periods of intermittent hypoxic apnea can alter chemoreflex control of sympathetic nerve activity in humans. Am J Physiol Heart Circ Physiol 287: H2054‐H2060, 2004.
 30. Cutler MJ , Swift NM , Keller DM , Wasmund WL , Smith ML . Hypoxia‐mediated prolonged elevation of sympathetic nerve activity after periods of intermittent hypoxic apnea. J Appl Physiol 96: 754‐761, 2004.
 31. Dalziel SR , Parag V , Rodgers A , Harding JE . Cardiovascular risk factors at age 30 following pre‐term birth. Int J Epidemiol 36: 907‐915, 2007.
 32. De Castro F . Sur la structure et l'innervation de la glande intercarotidienne (glomus caroticum) de l'homme et des mammiferes et sur un nouveau systeme de l'innervation autonome du nerf glossopharyngien. Trav Lab Rech Biol 24: 365‐432, 1926.
 33. de Paula PM , Tolstykh G , Mifflin S . Chronic intermittent hypoxia alters NMDA and AMPA‐evoked currents in NTS neurons receiving carotid body chemoreceptor inputs. Am J Physiol Regul Integr Comp Physiol 292: R2259‐R2265, 2007.
 34. Deane BM , Howe A , Morgan M . Abdominal vagal paraganglia: Distribution and comparison with carotid body, in the rat. Acta Anat (Basel) 93: 19‐28, 1975.
 35. Del Rio R , Moya EA , Iturriaga R . Carotid body and cardiorespiratory alterations in intermittent hypoxia: The oxidative link. Eur Respir J 36: 143‐150, 2010.
 36. Del Rio R , Moya EA , Iturriaga R . Contribution of inflammation on carotid body chemosensory potentiation induced by intermittent hypoxia. Adv Exp Med Biol 758: 199‐205, 2012.
 37. Del Rio R , Moya EA , Parga MJ , Madrid C , Iturriaga R . Carotid body inflammation and cardiorespiratory alterations in intermittent hypoxia. Eur Respir J 39: 1492‐1500, 2012.
 38. Del Rio R , Munoz C , Arias P , Court FA , Moya EA , Iturriaga R . Chronic intermittent hypoxia‐induced vascular enlargement and VEGF upregulation in the rat carotid body is not prevented by antioxidant treatment. Am J Physiol Lung Cell Mol Physiol 301: L702‐L711, 2011.
 39. Dhillon DP , Barer GR , Walsh M . The enlarged carotid body of the chronically hypoxic and chronically hypoxic and hypercapnic rat: A morphometric analysis. Q J Exp Physiol 69: 301‐317, 1984.
 40. Dick TE , Hsieh YH , Wang N , Prabhakar N . Acute intermittent hypoxia increases both phrenic and sympathetic nerve activities in the rat. Exp Physiol 92: 87‐97, 2007.
 41. Dolinoy DC , Weidman JR , Jirtle RL . Epigenetic gene regulation: Linking early developmental environment to adult disease. Reprod Toxicol 23: 297‐307, 2007.
 42. Donnelly DF . Developmental aspects of oxygen sensing by the carotid body. J Appl Physiol 88: 2296‐2301, 2000.
 43. Dudenbostel T , Calhoun DA . Resistant hypertension, obstructive sleep apnoea and aldosterone. J Hum Hypertens 26: 281‐287, 2012.
 44. Easton J , Howe A . The distribution of thoracic glomus tissue (aortic bodies) in the rat. Cell Tissue Res 232: 349‐356, 1983.
 45. Ema M , Taya S , Yokotani N , Sogawa K , Matsuda Y , Fujii‐Kuriyama Y . A novel bHLH‐PAS factor with close sequence similarity to hypoxia‐inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A 94: 4273‐4278, 1997.
 46. Fang JY , Xiao SD . Folic acid, polymorphism of methyl‐group metabolism genes, and DNA methylation in relation to GI carcinogenesis. J Gastroenterol 38: 821‐829, 2003.
 47. Feinberg AP . Phenotypic plasticity and the epigenetics of human disease. Nature 447: 433‐440, 2007.
 48. Fidone SJ , Gonzalez C . Initiation and control of chemoreceptor activity in the carotid body. In: Handbook of Physiology‐ The Respiratory System‐ Control of Breathing. (Eds: Fishman AP, Cherniack NS, Widdicombe JG, Geiger SR) Bethesda, MD, USA: American Physiological Society, 1986, pp. 247‐312.
 49. Fitzgerald RS , Lahiri S . Reflex responses to carotid/aortic body stimulation. In: Handbook of Physiology The Respiratory System Control of Breathing. (Eds: Fishman AP, Cherniack NS, Widdicombe JG, Geiger SR) Bethesda, MD: American Physiological Society, 1986, pp. 313‐362.
 50. Fletcher EC . An animal model of the relationship between systemic hypertension and repetitive episodic hypoxia as seen in sleep apnoea. J Sleep Res 4: 71‐77, 1995.
 51. Fletcher EC . Physiological consequences of intermittent hypoxia: Systemic blood pressure. J Appl Physiol 90: 1600‐1605, 2001.
 52. Fletcher EC , Lesske J , Behm R , Miller CC, III , Stauss H , Unger T . Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 72: 1978‐1984, 1992.
 53. Fletcher EC , Lesske J , Culman J , Miller CC , Unger T . Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension 20: 612‐619, 1992.
 54. Fletcher EC , Miller J , Schaaf JW , Fletcher JG . Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 10: 35‐44, 1987.
 55. Garcia‐Rio F , Racionero MA , Pino JM , Martinez I , Ortuno F , Villasante C , Villamor J . Sleep apnea and hypertension. Chest 117: 1417‐1425, 2000.
 56. Gardner PR . Aconitase: Sensitive target and measure of superoxide. Methods Enzymol 349: 9‐23, 2002.
 57. Gauda EB , Carroll JL , Donnelly DF . Developmental maturation of chemosensitivity to hypoxia of peripheral arterial chemoreceptors—Invited article. Adv Exp Med Biol 648: 243‐255, 2009.
 58. Gluckman PD , Cutfield W , Hofman P , Hanson MA . The fetal, neonatal, and infant environments‐the long‐term consequences for disease risk. Early Hum Dev 81: 51‐59, 2005.
 59. Gozal E , Shah ZA , Pequignot JM , Pequignot J , Sachleben LR , Czyzyk‐Krzeska MF , Li RC , Guo SZ , Gozal D . Tyrosine hydroxylase expression and activity in the rat brain: Differential regulation after long‐term intermittent or sustained hypoxia. J Appl Physiol 99: 642‐649, 2005.
 60. Greenberg HE , Sica A , Batson D , Scharf SM . Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 86: 298‐305, 1999.
 61. Greenberg HE , Sica AL , Scharf SM , Ruggiero DA . Expression of c‐fos in the rat brainstem after chronic intermittent hypoxia. Brain Res 816: 638‐645, 1999.
 62. Guzy RD , Schumacker PT . Oxygen sensing by mitochondria at complex III: The paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91: 807‐819, 2006.
 63. Halliwell B , Gutteridge JM . Role of free radicals and catalytic metal ions in human disease: An overview. Methods Enzymol 186: 1‐85, 1990.
 64. Hansen J , Sander M . Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia. J Physiol 546: 921‐929, 2003.
 65. Hanson MA . Role of chemoreceptors in effects of chronic hypoxia. Comp Biochem Physiol A Mol Integr Physiol 119: 695‐703, 1998.
 66. Heath D , Smith P , Fitch R , Harris P . Comparative pathology of the enlarged carotid body. J Comp Pathol 95: 259‐271, 1985.
 67. Hedner J , Ejnell H , Sellgren J , Hedner T , Wallin G . Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens Suppl 6: S529‐S531, 1988.
 68. Hedner JA , Wilcox I , Laks L , Grunstein RR , Sullivan CE . A specific and potent pressor effect of hypoxia in patients with sleep apnea. Am Rev Respir Dis 146: 1240‐1245, 1992.
 69. Hendricks JC , Kline LR , Kovalski RJ , O'Brien JA , Morrison AR , Pack AI . The English bulldog: A natural model of sleep‐disordered breathing. J Appl Physiol 63: 1344‐1350, 1987.
 70. Hendricks T , Francis N , Fyodorov D , Deneris ES . The ETS domain factor Pet‐1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. J Neurosci 19: 10348‐10356, 1999.
 71. Hendricks TJ , Fyodorov DV , Wegman LJ , Lelutiu NB , Pehek EA , Yamamoto B , Silver J , Weeber EJ , Sweatt JD , Deneris ES . Pet‐1 ETS gene plays a critical role in 5‐HT neuron development and is required for normal anxiety‐like and aggressive behavior. Neuron 37: 233‐247, 2003.
 72. Herman JP , Cullinan WE . Neurocircuitry of stress: Central control of the hypothalamo‐pituitary‐adrenocortical axis. Trends Neurosci 20: 78‐84, 1997.
 73. Heymans C , Bouckaert JJ . Sinus caroticus and respiratory reflexes. J Physiol 69: 254‐266, 1930.
 74. Heymans C , Bouckaert JJ , Dautrebande L . Sinus carotidien et reflexes respiratoires: Sensibilite des sinus carotidiens aux substances chimiques. Action stimulante respiratoire reflexe du sulfure de sodium, du cyanure de potassium, de la nicotine et de la lobeline. Arch Int Pharmacodyn Ther 40: 54‐91, 1931.
 75. Hibbs AM , Johnson NL , Rosen CL , Kirchner HL , Martin R , Storfer‐Isser A , Redline S . Prenatal and neonatal risk factors for sleep disordered breathing in school‐aged children born preterm. J Pediatr 153: 176‐182, 2008.
 76. Ho SM , Tang WY , Belmonte de Frausto J , Prins GS . Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res 66: 5624‐5632, 2006.
 77. Holmquist‐Mengelbier L , Fredlund E , Lofstedt T , Noguera R , Navarro S , Nilsson H , Pietras A , Vallon‐Christersson J , Borg A , Gradin K , Poellinger L , Pahlman S . Recruitment of HIF‐1alpha and HIF‐2alpha to common target genes is differentially regulated in neuroblastoma: HIF‐2alpha promotes an aggressive phenotype. Cancer Cell 10: 413‐423, 2006.
 78. Hornyak M , Cejnar M , Elam M , Matousek M , Wallin BG . Sympathetic muscle nerve activity during sleep in man. Brain 114(Pt 3): 1281‐1295, 1991.
 79. Huang J , Lusina S , Xie T , Ji E , Xiang S , Liu Y , Weiss JW . Sympathetic response to chemostimulation in conscious rats exposed to chronic intermittent hypoxia. Respir Physiol Neurobiol 166: 102‐106, 2009.
 80. Hui AS , Striet JB , Gudelsky G , Soukhova GK , Gozal E , Beitner‐Johnson D , Guo SZ , Sachleben LR , Haycock JW , Gozal D , Czyzyk‐Krzeska MF . Regulation of catecholamines by sustained and intermittent hypoxia in neuroendocrine cells and sympathetic neurons. Hypertension 42: 1130‐1136, 2003.
 81. Imadojemu VA , Gleeson K , Gray KS , Sinoway LI , Leuenberger UA . Obstructive apnea during sleep is associated with peripheral vasoconstriction. Am J Respir Crit Care Med 165: 61‐66, 2002.
 82. Imadojemu VA , Mawji Z , Kunselman A , Gray KS , Hogeman CS , Leuenberger UA . Sympathetic chemoreflex responses in obstructive sleep apnea and effects of continuous positive airway pressure therapy. Chest 131: 1406‐1413, 2007.
 83. Iyer NV , Kotch LE , Agani F , Leung SW , Laughner E , Wenger RH , Gassmann M , Gearhart JD , Lawler AM , Yu AY , Semenza GL . Cellular and developmental control of O2 homeostasis by hypoxia‐inducible factor 1 alpha. Genes Dev 12: 149‐162, 1998.
 84. Jacono F , Peng Y , Kumar G , Prabhakar N . Modulation of the hypoxic sensory response of the carotid body by 5‐hydroxytryptamine: Role of the 5‐HT2 receptor. Respir Physiol Neurobiol 145: 135‐142, 2005.
 85. Jones PA , Baylin SB . The epigenomics of cancer. Cell 128: 683‐692, 2007.
 86. Joyeux‐Faure M , Stanke‐Labesque F , Lefebvre B , Béguin P , Godin‐Ribuot D , Ribuot C , Launois SH , Bessard G , Lévy P . Chronic intermittent hypoxia increases infarction in the isolated rat heart. J Appl Physiol (1985) 98: 1691‐1696, 2005.
 87. Julien C , Bairam A , Joseph V . Chronic intermittent hypoxia reduces ventilatory long‐term facilitation and enhances apnea frequency in newborn rats. Am J Physiol Regul Integr Comp Physiol 294: R1356‐R1366, 2008.
 88. Jyung RW , LeClair EE , Bernat RA , Kang TS , Ung F , McKenna MJ , Tuan RS . Expression of angiogenic growth factors in paragangliomas. Laryngoscope 110: 161‐167, 2000.
 89. Kaczmarek E , Bakker JP , Clarke DN , Csizmadia E , Kocher O , Veves A , Tecilazich F , O'Donnell CP , Ferran C , Malhotra A . Molecular biomarkers of vascular dysfunction in obstructive sleep apnea. PLoS One 8: e70559, 2013.
 90. Kanagy NL , Walker BR , Nelin LD . Role of endothelin in intermittent hypoxia‐induced hypertension. Hypertension 37: 511‐515, 2001.
 91. Kara T , Narkiewicz K , Somers VK . Chemoreflexes—Physiology and clinical implications. Acta Physiol Scand 177: 377‐384, 2003.
 92. Katragadda S , Xie A , Puleo D , Skatrud JB , Morgan BJ . Neural mechanism of the pressor response to obstructive and nonobstructive apnea. J Appl Physiol (1985) 83: 2048‐2054, 1997.
 93. Khan SA , Nanduri J , Yuan G , Kinsman B , Kumar GK , Joseph J , Kalyanaraman B , Prabhakar NR . NADPH oxidase 2 mediates intermittent hypoxia‐induced mitochondrial complex I inhibition: Relevance to blood pressure changes in rats. Antioxid Redox Signal 14: 533‐542, 2011.
 94. Kholwadwala D , Donnelly DF . Maturation of carotid chemoreceptor sensitivity to hypoxia: In vitro studies in the newborn rat. J Physiol 453: 461‐473, 1992.
 95. Kline DD , Ramirez‐Navarro A , Kunze DL . Adaptive depression in synaptic transmission in the nucleus of the solitary tract after in vivo chronic intermittent hypoxia: Evidence for homeostatic plasticity. J Neurosci 27: 4663‐4673, 2007.
 96. Kline DD , Takacs KN , Ficker E , Kunze DL . Dopamine modulates synaptic transmission in the nucleus of the solitary tract. J Neurophysiol 88: 2736‐2744, 2002.
 97. Knight WD , Little JT , Carreno FR , Toney GM , Mifflin SW , Cunningham JT . Chronic intermittent hypoxia increases blood pressure and expression of FosB/DeltaFosB in central autonomic regions. Am J Physiol Regul Integr Comp Physiol 301: R131‐R139, 2011.
 98. Kumar GK , Rai V , Sharma SD , Ramakrishnan DP , Peng YJ , Souvannakitti D , Prabhakar NR . Chronic intermittent hypoxia induces hypoxia‐evoked catecholamine efflux in adult rat adrenal medulla via oxidative stress. J Physiol 575: 229‐239, 2006.
 99. Kumar P , Prabhakar NR . Peripheral chemoreceptors: Function and plasticity of the carotid body. Comp Physiol 2: 141‐219, 2012.
 100. Lagercrantz H , Edwards D , Henderson‐Smart D , Hertzberg T , Jeffery H . Autonomic reflexes in preterm infants. Acta Paediatr Scand 79: 721‐728, 1990.
 101. Lagercrantz H , Sjöquist B . Deficient sympatho‐adrenal activity‐a cause of apnoea? Urinary excretion of catecholamines and their metabolites in preterm infants. Early Hum Dev 4: 405‐409, 1980.
 102. Laidler P , Kay JM . Ultrastructure of carotid body in rats living at a simulated altitude of 4300 metres. J Pathol 124: 27‐33, 1978.
 103. Lam SY , Leung PS . A locally generated angiotensin system in rat carotid body. Regul Pept 107: 97‐103, 2002.
 104. Lam SY , Leung PS . Chronic hypoxia activates a local angiotensin‐generating system in rat carotid body. Mol Cell Endocrinol 203: 147‐153, 2003.
 105. Lam SY , Liu Y , Ng KM , Lau CF , Liong EC , Tipoe GL , Fung ML . Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways. Histochem Cell Biol 137: 303‐317, 2012.
 106. Lam SY , Liu Y , Ng KM , Liong EC , Tipoe GL , Leung PS , Fung ML . Upregulation of a local renin‐angiotensin system in the rat carotid body during chronic intermittent hypoxia. Exp Physiol 99: 220‐231, 2014.
 107. Lam SY , Tipoe GL , Liong EC , Fung ML . Hypoxia‐inducible factor (HIF)‐1alpha and endothelin‐1 expression in the rat carotid body during intermittent hypoxia. Adv Exp Med Biol 580: 21‐27; discussion 351‐359, 2006.
 108. Lam SY , Tipoe GL , Liong EC , Fung ML . Differential expressions and roles of hypoxia‐inducible factor‐1alpha, ‐2alpha and ‐3alpha in the rat carotid body during chronic and intermittent hypoxia. Histol Histopathol 23: 271‐280, 2008.
 109. Lesske J , Fletcher EC , Bao G , Unger T . Hypertension caused by chronic intermittent hypoxia—Influence of chemoreceptors and sympathetic nervous system. J Hypertens 15: 1593‐1603, 1997.
 110. Leuenberger U , Jacob E , Sweer L , Waravdekar N , Zwillich C , Sinoway L . Surges of muscle sympathetic nerve activity during obstructive apnea are linked to hypoxemia. J Appl Physiol 79: 581‐588, 1995.
 111. Leuenberger UA , Brubaker D , Quraishi S , Hogeman CS , Imadojemu VA , Gray KS . Effects of intermittent hypoxia on sympathetic activity and blood pressure in humans. Auton Neurosci 121: 87‐93, 2005.
 112. Leung PS , Lam SY , Fung ML . Chronic hypoxia upregulates the expression and function of AT(1) receptor in rat carotid body. J Endocrinol 167: 517‐524, 2000.
 113. Li YL , Gao L , Zucker IH , Schultz HD . NADPH oxidase‐derived superoxide anion mediates angiotensin II‐enhanced carotid body chemoreceptor sensitivity in heart failure rabbits. Cardiovasc Res 75: 546‐554, 2007.
 114. Lonergan RP, III , Ware JC , Atkinson RL , Winter WC , Suratt PM . Sleep apnea in obese miniature pigs. J Appl Physiol 84: 531‐536, 1998.
 115. Lusina SJ , Kennedy PM , Inglis JT , McKenzie DC , Ayas NT , Sheel AW . Long‐term intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans. J Physiol 575: 961‐970, 2006.
 116. Machacek DW , Garraway SM , Shay BL , Hochman S . Serotonin 5‐HT(2) receptor activation induces a long‐lasting amplification of spinal reflex actions in the rat. J Physiol 537: 201‐207, 2001.
 117. Makarenko VV , Nanduri J , Raghuraman G , Fox AP , Gadalla MM , Kumar GK , Snyder SH , Prabhakar NR . Endogenous H2S is required for hypoxic sensing by carotid body glomus cells. Am J Physiol Cell Physiol 303: C916‐C923, 2012.
 118. Manalo DJ , Rowan A , Lavoie T , Natarajan L , Kelly BD , Ye SQ , Garcia JG , Semenza GL . Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF‐1. Blood 105: 659‐669, 2005.
 119. Marcus NJ , Li YL , Bird CE , Schultz HD , Morgan BJ . Chronic intermittent hypoxia augments chemoreflex control of sympathetic activity: Role of the angiotensin II type 1 receptor. Respir Physiol Neurobiol 171: 36‐45, 2010.
 120. Marrone O , Riccobono L , Salvaggio A , Mirabella A , Bonanno A , Bonsignore MR . Catecholamines and blood pressure in obstructive sleep apnea syndrome. Chest 103: 722‐727, 1993.
 121. Mauelshagen J , Sherff CM , Carew TJ . Differential induction of long‐term synaptic facilitation by spaced and massed applications of serotonin at sensory neuron synapses of Aplysia californica. Learn Mem 5: 246‐256, 1998.
 122. McCord JM , Roy RS , Schaffer SW . Free radicals and myocardial ischemia. The role of xanthine oxidase. Adv Myocardiol 5: 183‐189, 1985.
 123. Meneshian A , Bulkley GB . The physiology of endothelial xanthine oxidase: From urate catabolism to reperfusion injury to inflammatory signal transduction. Microcirculation 9: 161‐175, 2002.
 124. Mitchell GS , Johnson SM . Neuroplasticity in respiratory motor control. J Appl Physiol 94: 358‐374, 2003.
 125. Moraes DJ , da Silva MP , Bonagamba LG , Mecawi AS , Zoccal DB , Antunes‐Rodrigues J , Varanda WA , Machado BH . Electrophysiological properties of rostral ventrolateral medulla presympathetic neurons modulated by the respiratory network in rats. J Neurosci 33: 19223‐19237, 2013.
 126. Morgan BJ , Crabtree DC , Palta M , Skatrud JB . Combined hypoxia and hypercapnia evokes long‐lasting sympathetic activation in humans. J Appl Physiol 79: 205‐213, 1995.
 127. Nanduri J , Makarenko V , Reddy VD , Yuan G , Pawar A , Wang N , Khan SA , Zhang X , Kinsman B , Peng Y‐J , Kumar GK , Fox AP , Godley LA , Semenza GL , Prabhakar NR . Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis. Proc Natl Acad Sci U S A 109: 2515‐2520, 2012.
 128. Nanduri J , Vaddi DR , Khan SA , Wang N , Makerenko V , Prabhakar NR . Xanthine oxidase mediates hypoxia‐inducible factor‐2alpha degradation by intermittent hypoxia. PLoS One 8: e75838, 2013.
 129. Nanduri J , Wang N , Yuan G , Khan SA , Souvannakitti D , Peng YJ , Kumar GK , Garcia JA , Prabhakar NR . Intermittent hypoxia degrades HIF‐2alpha via calpains resulting in oxidative stress: Implications for recurrent apnea‐induced morbidities. Proc Natl Acad Sci U S A 106: 1199‐1204, 2009.
 130. Nanduri J , Yuan G , Kumar GK , Semenza GL , Prabhakar NR . Transcriptional responses to intermittent hypoxia. Respir Physiol Neurobiol 164: 277‐281, 2008.
 131. Narkiewicz K , Somers VK . The sympathetic nervous system and obstructive sleep apnea: Implications for hypertension. J Hypertens 15: 1613‐1619, 1997.
 132. Narkiewicz K , van de Borne PJ , Pesek CA , Dyken ME , Montano N , Somers VK . Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation 99: 1183‐1189, 1999.
 133. Nieto FJ , Young TB , Lind BK , Shahar E , Samet JM , Redline S , D'Agostino RB , Newman AB , Lebowitz MD , Pickering TG . Association of sleep‐disordered breathing, sleep apnea, and hypertension in a large community‐based study. Sleep Heart Health Study. JAMA 283: 1829‐1836, 2000.
 134. Nishino T . The conversion of xanthine dehydrogenase to xanthine oxidase and the role of the enzyme in reperfusion injury. J Biochem 116: 1‐6, 1994.
 135. Nock ML , Difiore JM , Arko MK , Martin RJ . Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants. J Pediatr 144: 291‐295, 2004.
 136. Okada H , Iwase S , Mano T , Sugiyama Y , Watanabe T . Changes in muscle sympathetic nerve activity during sleep in humans. Neurology 41: 1961‐1966, 1991.
 137. Ortiz FC , Del Rio R , Varas R , Iturriaga R . Contribution of TASK‐like potassium channels to the enhanced rat carotid body responsiveness to hypoxia. Adv Exp Med Biol 758: 365‐371, 2012.
 138. Paavonen EJ , Strang‐Karlsson S , Räikkönen K , Heinonen K , Pesonen AK , Hovi P , Andersson S , Järvenpää AL , Eriksson JG , Kajantie E . Very low birth weight increases risk for sleep‐disordered breathing in young adulthood: The Helsinki Study of Very Low Birth Weight Adults. Pediatrics 120: 778‐784, 2007.
 139. Pawar A , Nanduri J , Yuan G , Khan SA , Wang N , Kumar GK , Prabhakar NR . Reactive oxygen species‐dependent endothelin signaling is required for augmented hypoxic sensory response of the neonatal carotid body by intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 296: R735‐R742, 2009.
 140. Pawar A , Peng Y‐J , Jacono FJ , Prabhakar NR . Comparative analysis of neonatal and adult rat carotid body responses to chronic intermittent hypoxia. J Appl Physiol 104: 1287‐1294, 2008.
 141. Peng Y‐J , Nanduri J , Raghuraman G , Souvannakitti D , Gadalla MM , Kumar GK , Snyder SH , Prabhakar NR . H2S mediates O2 sensing in the carotid body. Proc Natl Acad Sci U S A 107: 10719‐10724, 2010.
 142. Peng Y‐J , Nanduri J , Zhang X , Wang N , Raghuraman G , Seagard J , Kumar GK , Prabhakar NR . Endothelin‐1 mediates attenuated carotid baroreceptor activity by intermittent hypoxia. J Appl Physiol 112: 187‐196, 2012.
 143. Peng YJ , Makarenko VV , Nanduri J , Vasavda C , Raghuraman G , Yuan G , Gadalla MM , Kumar GK , Snyder SH , Prabhakar NR . Inherent variations in CO‐H2S‐mediated carotid body O2 sensing mediate hypertension and pulmonary edema. Proc Natl Acad Sci U S A 111: 1174‐1179, 2014.
 144. Peng YJ , Nanduri J , Khan SA , Yuan G , Wang N , Kinsman B , Vaddi DR , Kumar GK , Garcia JA , Semenza GL , Prabhakar NR . Hypoxia‐inducible factor 2alpha (HIF‐2alpha) heterozygous‐null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. Proc Natl Acad Sci U S A 108: 3065‐3070, 2011.
 145. Peng YJ , Nanduri J , Raghuraman G , Wang N , Kumar GK , Prabhakar NR . Role of oxidative stress‐induced endothelin‐converting enzyme activity in the alteration of carotid body function by chronic intermittent hypoxia. Exp Physiol 98: 1620‐1630, 2013.
 146. Peng YJ , Nanduri J , Yuan G , Wang N , Deneris E , Pendyala S , Natarajan V , Kumar GK , Prabhakar NR . NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia. J Neurosci 29: 4903‐4910, 2009.
 147. Peng YJ , Overholt JL , Kline D , Kumar GK , Prabhakar NR . Induction of sensory long‐term facilitation in the carotid body by intermittent hypoxia: Implications for recurrent apneas. Proc Natl Acad Sci U S A 100: 10073‐10078, 2003.
 148. Peng YJ , Prabhakar NR . Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity. J Appl Physiol 96: 1236‐1242; discussion 1196, 2004.
 149. Peng YJ , Raghuraman G , Khan SA , Kumar GK , Prabhakar NR . Angiotensin II evokes sensory long‐term facilitation of the carotid body via NADPH oxidase. J Appl Physiol 111: 964‐970, 2011.
 150. Peng YJ , Rennison J , Prabhakar NR . Intermittent hypoxia augments carotid body and ventilatory response to hypoxia in neonatal rat pups. J Appl Physiol 97: 2020‐2025, 2004.
 151. Peng YJ , Yuan G , Jacono FJ , Kumar GK , Prabhakar NR . 5‐HT evokes sensory long‐term facilitation of rodent carotid body via activation of NADPH oxidase. J Physiol 576: 289‐295, 2006.
 152. Peng YJ , Yuan G , Khan S , Nanduri J , Makarenko VV , Reddy VD , Vasavda C , Kumar GK , Semenza GL , Prabhakar NR . Regulation of hypoxia inducible factor‐alpha isoforms and redox state by carotid body neural activity in rats. J Physiol 592: 3841‐3858, 2014.
 153. Peng YJ , Yuan G , Ramakrishnan D , Sharma SD , Bosch‐Marce M , Kumar GK , Semenza GL , Prabhakar NR . Heterozygous HIF‐1alpha deficiency impairs carotid body‐mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol 577: 705‐716, 2006.
 154. Pépin JL , Tamisier R , Barone‐Rochette G , Launois SH , Lévy P , Baguet JP . Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 182: 954‐960, 2010.
 155. Peppard PE , Young T , Palta M , Skatrud J . Prospective study of the association between sleep‐disordered breathing and hypertension. N Engl J Med 342: 1378‐1384, 2000.
 156. Pequignot JM , Hellstrom S , Johansson C . Intact and sympathectomized carotid bodies of long‐term hypoxic rats: A morphometric ultrastructural study. J Neurocytol 13: 481‐493, 1984.
 157. Pinilla PJ , Hernandez AT , Camello MC , Pozo MJ , Toescu EC , Camello PJ . Non‐stimulated Ca2+ leak pathway in cerebellar granule neurones. Biochem Pharmacol 70: 786‐793, 2005.
 158. Poets CF , Samuels MP , Southall DP . Epidemiology and pathophysiology of apnoea of prematurity. Biol Neonate 65: 211‐219, 1994.
 159. Prabhakar NR . Oxygen sensing by the carotid body chemoreceptors. J Appl Physiol 88: 2287‐2295, 2000.
 160. Prabhakar NR . Oxygen sensing during intermittent hypoxia: Cellular and molecular mechanisms. J Appl Physiol 90: 1986‐1994, 2001.
 161. Prabhakar NR . Sensory plasticity of the carotid body: Role of reactive oxygen species and physiological significance. Respir Physiol Neurobiol 178: 375‐380, 2011.
 162. Prabhakar NR , Peng Y‐H , Kumar GK , Pawar A . Altered carotid body function by intermittent hypoxia in neonates and adults: Relevance to recurrent apneas. Respir Physiol Neurobiol 157: 148‐153, 2007.
 163. Prabhakar NR , Semenza GL . Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia‐inducible factors 1 and 2. Physiol Rev 92: 967‐1003, 2012.
 164. Reeves SR , Gozal E , Guo SZ , Sachleben LR, Jr. , Brittian KR , Lipton AJ , Gozal D . Effect of long‐term intermittent and sustained hypoxia on hypoxic ventilatory and metabolic responses in the adult rat. J Appl Physiol 95: 1767‐1774, 2003.
 165. Rey S , Corthorn J , Chacon C , Iturriaga R . Expression and immunolocalization of endothelin peptides and its receptors, ETA and ETB, in the carotid body exposed to chronic intermittent hypoxia. J Histochem Cytochem 55: 167‐174, 2007.
 166. Rey S , Del Rio R , Alcayaga J , Iturriaga R . Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia. J Physiol 560: 577‐586, 2004.
 167. Rey S , Del Rio R , Iturriaga R . Contribution of endothelin‐1 to the enhanced carotid body chemosensory responses induced by chronic intermittent hypoxia. Brain Res 1086: 152‐159, 2006.
 168. Rey S , Del Rio R , Iturriaga R . Contribution of endothelin‐1 and endothelin A and B receptors to the enhanced carotid body chemosensory responses induced by chronic intermittent hypoxia. Adv Exp Med Biol 605: 228‐232, 2008.
 169. Rosen CL , Larkin EK , Kirchner HL , Emancipator JL , Bivins SF , Surovec SA , Martin RJ , Redline S . Prevalence and risk factors for sleep‐disordered breathing in 8‐ to 11‐year‐old children: Association with race and prematurity. J Pediatr 142: 383‐389, 2003.
 170. Saarelainen S , Seppala E , Laasonen K , Hasan J . Circulating endothelin‐1 in obstructive sleep apnea. Endothelium 5: 115‐118, 1997.
 171. Salman S , Buttigieg J , Nurse CA . Ontogeny of O2 and CO2//H+ chemosensitivity in adrenal chromaffin cells: Role of innervation. J Exp Biol 217: 673‐681, 2014.
 172. Santos F , Dean W . Epigenetic reprogramming during early development in mammals. Reproduction 127: 643‐651, 2004.
 173. Sawchenko PE , Brown ER , Chan RK , Ericsson A , Li HY , Roland BL , Kovacs KJ . The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res 107: 201‐222, 1996.
 174. Semenza GL . HIF‐1: Mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88: 1474‐1480, 2000.
 175. Shahar E , Whitney CW , Redline S , Lee ET , Newman AB , Javier Nieto F , O'Connor GT , Boland LL , Schwartz JE , Samet JM . Sleep‐disordered breathing and cardiovascular disease: Cross‐sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 163: 19‐25, 2001.
 176. Sharma S , Kelly TK , Jones PA . Epigenetics in cancer. Carcinogenesis 31: 27‐36, 2010.
 177. Shoemaker JK , Vovk A , Cunningham DA . Peripheral chemoreceptor contributions to sympathetic and cardiovascular responses during hypercapnia. Can J Physiol Pharmacol 80: 1136‐1144, 2002.
 178. Sica AL , Greenberg HE , Scharf SM , Ruggiero DA . Immediate‐early gene expression in cerebral cortex following exposure to chronic‐intermittent hypoxia. Brain Res 870: 204‐210, 2000.
 179. Silva AQ , Schreihofer AM . Altered sympathetic reflexes and vascular reactivity in rats after exposure to chronic intermittent hypoxia. J Physiol 589: 1463‐1476, 2011.
 180. Somers VK , Abboud FM . Chemoreflexes—Responses, interactions and implications for sleep apnea. Sleep 16: S30‐S33; discussion S33‐S34, 1993.
 181. Somers VK , Dyken ME , Clary MP , Abboud FM . Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 96: 1897‐1904, 1995.
 182. Somers VK , Dyken ME , Mark AL , Abboud FM . Sympathetic‐nerve activity during sleep in normal subjects. N Engl J Med 328: 303‐307, 1993.
 183. Souvannakitti D , Kumar GK , Fox A , Prabhakar NR . Neonatal intermittent hypoxia leads to long‐lasting facilitation of acute hypoxia‐evoked catecholamine secretion from rat chromaffin cells. J Neurophysiol 101: 2837‐2846, 2009.
 184. Souvannakitti D , Nanduri J , Yuan G , Kumar GK , Fox AP , Prabhakar NR . NADPH oxidase‐dependent regulation of T‐type Ca2+ channels and ryanodine receptors mediate the augmented exocytosis of catecholamines from intermittent hypoxia‐treated neonatal rat chromaffin cells. J Neurosci 30: 10763‐10772, 2010.
 185. Sterni LM , Bamford OS , Wasicko MJ , Carroll JL . Chronic hypoxia abolished the postnatal increase in carotid body type I cell sensitivity to hypoxia. Am J Physiol 277: L645‐L652, 1999.
 186. Stoohs R , Guilleminault C . Cardiovascular changes associated with obstructive sleep apnea syndrome. J Appl Physiol 72: 583‐589, 1992.
 187. Suh YA , Arnold RS , Lassegue B , Shi J , Xu X , Sorescu D , Chung AB , Griendling KK , Lambeth JD . Cell transformation by the superoxide‐generating oxidase Mox1. Nature 401: 79‐82, 1999.
 188. Suzuki YJ , Jain V , Park AM , Day RM . Oxidative stress and oxidant signaling in obstructive sleep apnea and associated cardiovascular diseases. Free Radic Biol Med 40: 1683‐1692, 2006.
 189. Tafil‐Klawe M , Thiele AE , Raschke F , Mayer J , Peter JH , von Wichert W . Peripheral chemoreceptor reflex in obstructive sleep apnea patients; a relationship between ventilatory response to hypoxia and nocturnal bradycardia during apnea events. Pneumologie 45(Suppl 1): 309‐311, 1991.
 190. Takeuchi Y , Mochizuki‐Oda N , Yamada H , Kurokawa K , Watanabe Y . Nonneurogenic hypoxia sensitivity in rat adrenal slices. Biochem Biophys Res Commun 289: 51‐56, 2001.
 191. Tamisier R , Pepin JL , Remy J , Baguet JP , Taylor JA , Weiss JW , Levy P . 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J 37: 119‐128, 2011.
 192. Thompson RJ , Jackson A , Nurse CA . Developmental loss of hypoxic chemosensitivity in rat adrenomedullary chromaffin cells. J Physiol 498(Pt 2): 503‐510, 1997.
 193. Tian H , McKnight SL , Russell DW . Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11: 72‐82, 1997.
 194. Veasey S . Insight from animal models into the cognitive consequences of adult sleep‐disordered breathing. ILAR J 50: 307‐311, 2009.
 195. Xie A , Skatrud JB , Puleo DS , Morgan BJ . Exposure to hypoxia produces long‐lasting sympathetic activation in humans. J Appl Physiol 91: 1555‐1562, 2001.
 196. Yu AY , Shimoda LA , Iyer NV , Huso DL , Sun X , McWilliams R , Beaty T , Sham JS , Wiener CM , Sylvester JT , Semenza GL . Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia‐inducible factor 1alpha. J Clin Invest 103: 691‐696, 1999.
 197. Yuan G , Adhikary G , McCormick AA , Holcroft JJ , Kumar GK , Prabhakar NR . Role of oxidative stress in intermittent hypoxia‐induced immediate early gene activation in rat PC12 cells. J Physiol 557: 773‐783, 2004.
 198. Yuan G , Khan SA , Luo W , Nanduri J , Semenza GL , Prabhakar NR . Hypoxia‐inducible factor 1 mediates increased expression of NADPH oxidase‐2 in response to intermittent hypoxia. J Cell Physiol 226: 2925‐2933, 2011.
 199. Yuan G , Nanduri J , Bhasker CR , Semenza GL , Prabhakar NR . Ca2+/calmodulin kinase‐dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J Biol Chem 280: 4321‐4328, 2005.
 200. Yuan G , Nanduri J , Khan S , Semenza GL , Prabhakar NR . Induction of HIF‐1alpha expression by intermittent hypoxia: Involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol 217: 674‐685, 2008.
 201. Zhang W , Mifflin SW . Excitatory amino acid receptors within NTS mediate arterial chemoreceptor reflexes in rats. Am J Physiol 265: H770‐H773, 1993.
 202. Zoccal DB , Bonagamba LG , Oliveira FR , Antunes‐Rodrigues J , Machado BH . Increased sympathetic activity in rats submitted to chronic intermittent hypoxia. Exp Physiol 92: 79‐85, 2007.
 203. Zoccal DB , Huidobro‐Toro JP , Machado BH . Chronic intermittent hypoxia augments sympatho‐excitatory response to ATP but not to L‐glutamate in the RVLM of rats. Auton Neurosci 165: 156‐162, 2011.
 204. Zoccal DB , Simms AE , Bonagamba LG , Braga VA , Pickering AE , Paton JF , Machado BH . Increased sympathetic outflow in juvenile rats submitted to chronic intermittent hypoxia correlates with enhanced expiratory activity. J Physiol 586: 3253‐3265, 2008.

Related Articles:

Systemic Hypertension

Contact Editor

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

* Required Field

Article Title: Peripheral Chemoreception and Arterial Pressure Responses to Intermittent Hypoxia
 

How to Cite

Nanduri R. Prabhakar, Ying‐Jie Peng, Ganesh K. Kumar, Jayasri Nanduri. Peripheral Chemoreception and Arterial Pressure Responses to Intermittent Hypoxia. Compr Physiol 2015, 5: 561-577. doi: 10.1002/cphy.c140039