Intermittent hypoxia and neurorehabilitation

Journal of Applied Physiology

Volumn 119, Issue 12, 2015, Pages 1455-1465

  Gonzalez Rothi, Elisa J ^a   Lee, Kun Ze ^b   Dale, Erica A ^c   Reier, Paul J ^d   Mitchell, Gordon S ^a   Fuller, David D ^a  

^a UNIVERSITY OF FLORIDA   (United States)

^b NATIONAL SUN YAT SEN UNIVERSITY   (Taiwan)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

Cellular transplantation; Intermittent hypoxia; Neurorehabilitation; Spinal cord injury

Indexed keywords

ANIMAL; HUMAN; HYPOXIA; NERVOUS SYSTEM DISEASES; NEURAL STEM CELL; PATHOPHYSIOLOGY; SPINAL CORD INJURIES; TRANSPLANTATION;

ANIMALS; HUMANS; HYPOXIA; NERVOUS SYSTEM DISEASES; NEURAL STEM CELLS; SPINAL CORD INJURIES;

EID: 84949581423     PISSN: 87507587     EISSN: 15221601     Source Type: Journal    
DOI: 10.1152/japplphysiol.00235.2015     Document Type: Review

References (105)

1. Alexander JK, Popovich PG. Neuroinflammation in spinal cord injury: therapeutic targets for neuroprotection and regeneration. Prog Brain Res 175: 125-137, 2009.
2. Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain 137: 1394-1409, 2014.
3. Babcock M, Shkoukani M, Aboubakr SE, Badr MS. Determinants of long-term facilitation in humans during NREM sleep. J Appl Physiol 94: 53-59, 2003.
4. Bach KB, Mitchell GS. Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent. Respir Physiol 104: 251-260, 1996.
5. Baker-Herman TL, Fuller DD, Bavis RW, Zabka AG, Golder FJ, Doperalski NJ, Johnson RA, Watters JJ, Mitchell GS. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 7: 48-55, 2004.
6. Baker-Herman TL, Mitchell GS. Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis. J Neurosci 22: 6239-6246, 2002.
7. Baker TL, Mitchell GS. Episodic but not continuous hypoxia elicits long-term facilitation of phrenic motor output in rats. J Physiol 1529: 215-219, 2000.
8. Chen HL, Pistollato F, Hoeppner DJ, Ni HT, McKay RD, Panchision DM. Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells 25: 2291-2301, 2007.
9. Chow SY, Moul J, Tobias CA, Himes BT, Liu Y, Obrocka M, Hodge L, Tessler A, Fischer I. Characterization and intraspinal grafting of EGF/bFGF-dependent neurospheres derived from embryonic rat spinal cord. Brain Res 874: 87-106, 2000.
10. Dale-Nagle EA, Hoffman MS, MacFarlane PM, Mitchell GS. Multiple pathways to long-lasting phrenic motor facilitation. Adv Exp Med Biol 669: 225-230, 2010.
11. Dale-Nagle EA, Hoffman MS, MacFarlane PM, Satriotomo I, Lovett-Barr MR, Vinit S, Mitchell GS. Spinal plasticity following intermittent hypoxia: implications for spinal injury. Ann NY Acad Sci 1198: 252-259, 2010.
12. Dale EA, Ben Mabrouk F, Mitchell GS. Unexpected benefits of intermittent hypoxia: enhanced respiratory and nonrespiratory motor function. Physiology 29: 39-48, 2014.
13. Davidoff RA. Antispasticity drugs: mechanisms of action. Ann Neurol 17: 107-116, 1985.
14. Devinney MJ, Huxtable AG, Nichols NL, Mitchell GS. Hypoxiainduced phrenic long-term facilitation: emergent properties. Ann NY Acad Sci 1279: 143-153, 2013.
15. Di Filippo M, Sarchielli P, Picconi B, Calabresi P. Neuroinflammation and synaptic plasticity: theoretical basis for a novel, immune-centered, therapeutic approach to neurological disorders. Trends Pharmacol Sci 29: 402-412, 2008.
16. DiMarco AF, Kowalski KE. Activation of inspiratory muscles via spinal cord stimulation. Respir Physiol Neurobiol 189: 438-449, 2013.
17. DiMarco AF, Kowalski KE. High-frequency spinal cord stimulation of inspiratory muscles in dogs: a new method of inspiratory muscle pacing. J Appl Physiol 107: 662-669, 2009.
18. Dimarco AF, Kowalski KE. Spinal pathways mediating phrenic activation during high frequency spinal cord stimulation. Respir Physiol Neurobiol 186: 1-6, 2013.
19. Durga A, Sepahpanah F, Regozzi M, Hastings J, Crane DA. Prevalence of testosterone deficiency after spinal cord injury. PM R 3: 929-932, 2011.
20. Elridge FL, Millhorn DE. Oscillation, gating, and memory in the respiratory system. In: Handbook of Physiology. The Respiratory System. Parts 1 & 2. Control of Breathing, edited by Cherniack NS, Widdicombe JD. Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. II, p. 93-114.
21. Erickson JT, Millhorn DE. Fos-like protein is induced in neurons of the medulla oblongata after stimulation of the carotid sinus nerve in awake and anesthetized rats. Brain Res 567: 11-24, 1991.
22. Erickson JT, Millhorn DE. Hypoxia and electrical stimulation of the carotid sinus nerve induce Fos-like immunoreactivity within catecholaminergic and serotoninergic neurons of the rat brainstem. J Comp Neurol 348: 161-182, 1994.
23. Falk DJ, Mah CS, Soustek MS, Lee KZ, Elmallah MK, Cloutier DA, Fuller DD, Byrne BJ. Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease. Mol Ther 21: 1661-1667, 2013.
24. Fields DP, Mitchell GS. Spinal metaplasticity in respiratory motor control. Front Neural Circuits 9: 2, 2015.
25. Fischer FR, Peduzzi JD. Functional recovery in rats with chronic spinal cord injuries after exposure to an enriched environment. J Spinal Cord Med 30: 147-155, 2007.
26. Fregosi RF, Mitchell GS. Long-term facilitation of inspiratory intercostal nerve activity following carotid sinus nerve stimulation in cats. J Physiol 477: 469-479, 1994.
27. Fuller DD, Johnson SM, Olson EB Jr, Mitchell GS. Synaptic pathways to phrenic motoneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury. J Neurosci 23: 2993-3000, 2003.
28. Fuller DD, Lee KZ, Tester NJ. The impact of spinal cord injury on breathing during sleep. Respir Physiol Neurobiol 188: 344-354, 2013.
29. Fuller DD, Zabka AG, Baker TL, Mitchell GS. Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia. J Appl Physiol 90: 2001-2006; discussion 2000, 2001.
30. Gerst DG, Yokhana SS, Carney LM, Lee DS, Badr MS, Qureshi T, Anthouard MN, Mateika JH. The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia. J Appl Physiol 110: 15-28, 2011.
31. Golder FJ, Fuller DD, Davenport PW, Johnson RD, Reier PJ, Bolser DC. Respiratory motor recovery after unilateral spinal cord injury: eliminating crossed phrenic activity decreases tidal volume and increases contralateral respiratory motor output. J Neurosci 23: 2494-2501, 2003.
32. Golder FJ, Mitchell GS. Spinal synaptic enhancement with acute intermittent hypoxia improves respiratory function after chronic cervical spinal cord injury. J Neurosci 25: 2925-2932, 2005.
33. Golder FJ, Ranganathan L, Satriotomo I, Hoffman M, Lovett-Barr MR, Watters JJ, Baker-Herman TL, Mitchell GS. Spinal adenosine A2a receptor activation elicits long-lasting phrenic motor facilitation. J Neurosci 28: 2033-2042, 2008.
34. Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat. J Neurosci 21: 2442-2450, 2001.
35. Harkema S, Gerasimenko Y, Hodes J, Burdick J, Angeli C, Chen Y, Ferreira C, Willhite A, Rejc E, Grossman RG, Edgerton VR. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet 377: 1938-1947, 2011.
36. Harris DP, Balasubramaniam A, Badr MS, Mateika JH. Long-term facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans. Am J Physiol Regul Integr Comp Physiol 291: R1111-R1119, 2006.
37. Hayashi F, Coles SK, Bach KB, Mitchell GS, McCrimmon DR. Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats. Am J Physiol Regul Integr Comp Physiol 265: R811-R819, 1993.
38. Hayes HB, Jayaraman A, Herrmann M, Mitchell GS, Rymer WZ, Trumbower RD. Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology 82: 104-113, 2014.
39. Hochman S, Garraway SM, Machacek DW, Shay BL. 5-HT receptors and neuromodulatory control of spinal cord function. In: Motor Neurobiology of the Spinal Cord. Boca Raton, FL: CRC, 2001.
40. Hoffman MS, Golder FJ, Mahamed S, Mitchell GS. Spinal adenosine A2(A) receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia. J Physiol 588: 255-266, 2010.
41. Hoffman MS, Mitchell GS. Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation. J Physiol 589: 1397-1407, 2011.
42. Hoffman MS, Mitchell GS. Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation. Neuroscience 250: 632-643, 2013.
43. Hoffman MS, Nichols NL, Macfarlane PM, Mitchell GS. Phrenic long-term facilitation after acute intermittent hypoxia requires spinal ERK activation but not TrkB synthesis. J Appl Physiol 113: 1184-1193, 2012.
44. Houle JD, Tessler A. Repair of chronic spinal cord injury. Exp Neurol 182: 247-260, 2003.
45. Huxtable AG, Smith SM, Peterson T, Watters JJ, Mitchell GS. Intermittent hypoxia-induced spinal inflammation impairs respiratory motor plasticity by a spinal p38 MAP kinase-dependent mechanism. J Neurosci 35: 6871-6880, 2015.
46. Huxtable AG, Smith SM, Vinit S, Watters JJ, Mitchell GS. Systemic LPS induces spinal inflammatory gene expression and impairs phrenic long-term facilitation following acute intermittent hypoxia. J Appl Physiol 114: 879-887, 2013.
47. Huxtable AG, Vinit S, Windelborn JA, Crader SM, Guenther CH, Watters JJ, Mitchell GS. Systemic inflammation impairs respiratory chemoreflexes and plasticity. Respir Physiol Neurobiol 178: 482-489, 2011.
48. Jaiswal PB, Tester NJ, Davenport PW. Effect of acute intermittent hypoxia treatment on ventilatory load compensation and magnitude estimation of inspiratory resistive loads in an individual with chronic incomplete cervical spinal cord injury. J Spinal Cord Med 2014 Nov 15 [Epub ahead of print].
49. Kinkead R, Bach KB, Johnson SM, Hodgeman BA, Mitchell GS. Plasticity in respiratory motor control: intermittent hypoxia and hypercapnia activate opposing serotonergic and noradrenergic modulatory systems. Comp Biochem Physiol A Mol Integr Physiol 130: 207-218, 2001.
50. Kowalski KE, Hsieh YH, Dick TE, DiMarco AF. Diaphragm activation via high frequency spinal cord stimulation in a rodent model of spinal cord injury. Exp Neurol 247: 689-693, 2013.
51. Lee DS, Badr MS, Mateika JH. Progressive augmentation and ventilatory long-term facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration. J Physiol 587: 5451-5467, 2009.
52. Lee KZ, Lane MA, Dougherty BJ, Mercier LM, Sandhu MS, Sanchez JC, Reier PJ, Fuller DD. Intraspinal transplantation and modulation of donor neuron electrophysiological activity. Exp Neurol 251: 47-57, 2014.
53. Lee KZ, Mattio R, Lane MA, Dougherty BJ, Sandhu MS, Sanchez J, Reier P, Fuller DD. Bursting patterns of embryonic spinal cord grafts following repetitive acute intermittent hypoxia training in cervical spinal cord injured rats. In: Neuroscience Meeting Planner Program No 255.03. Washington, DC: Soc. Neurosci., 2011.
54. Lepore AC, Bakshi A, Swanger SA, Rao MS, Fischer I. Neural precursor cells can be delivered into the injured cervical spinal cord by intrathecal injection at the lumbar cord. Brain Res 1045: 206-216, 2005.
55. Lepore AC, Fischer I. Lineage-restricted neural precursors survive, migrate, and differentiate following transplantation into the injured adult spinal cord. Exp Neurol 194: 230-242, 2005.
56. Ling L, Fuller DD, Bach KB, Kinkead R, Olson EB Jr, Mitchell GS. Chronic intermittent hypoxia elicits serotonin-dependent plasticity in the central neural control of breathing. J Neurosci 21: 5381-5388, 2001.
57. Lovett-Barr MR, Satriotomo I, Muir GD, Wilkerson JE, Hoffman MS, Vinit S, Mitchell GS. Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal injury. J Neurosci 32: 3591-3600, 2012.
58. MacFarlane PM, Mitchell GS. Respiratory long-term facilitation following intermittent hypoxia requires reactive oxygen species formation. Neuroscience 152: 189-197, 2008.
59. MacFarlane PM, Satriotomo I, Windelborn JA, Mitchell GS. NADPH oxidase activity is necessary for acute intermittent hypoxia-induced phrenic long-term facilitation. J Physiol 587: 1931-1942, 2009.
60. MacFarlane PM, Wilkerson JE, Lovett-Barr MR, Mitchell GS. Reactive oxygen species and respiratory plasticity following intermittent hypoxia. Respir Physiol Neurobiol 164: 263-271, 2008.
61. Mateika JH, Sandhu KS. Experimental protocols and preparations to study respiratory long term facilitation. Respir Physiol Neurobiol 176: 1-11, 2011.
62. Mateika JH, Syed Z. Intermittent hypoxia, respiratory plasticity and sleep apnea in humans: present knowledge and future investigations. Respir Physiol Neurobiol 188: 289-300, 2013.
63. McGuire M, Zhang Y, White DP, Ling L. Serotonin receptor subtypes required for ventilatory long-term facilitation and its enhancement after chronic intermittent hypoxia in awake rats. Am J Physiol Regul Integr Comp Physiol 286: R334-R341, 2004.
64. Millhorn DE, Eldridge FL, Waldrop TG. Prolonged stimulation of respiration by a new central neural mechanism. Respir Physiol 41: 87-103, 1980.
65. Mitchell GS. Respiratory plasticity following intermittent hypoxia: a guide for novel therapeutic approaches to ventilatory control disorders. In: Genetic Basis for Respiratory Control Disorders, edited by Gautier C. New York, NY: Springer, 2007.
66. Mitchell GS, Baker TL, Nanda SA, Fuller DD, Zabka AG, Hodgeman BA, Bavis RW, Mack KJ, Olson EB Jr. Invited review: intermittent hypoxia and respiratory plasticity. J Appl Physiol 90: 2466-2475, 2001.
67. Mitchell GS, Johnson SM. Neuroplasticity in respiratory motor control. J Appl Physiol 94: 358-374, 2003.
68. Morris KF, Arata A, Shannon R, Lindsey BG. Inspiratory drive and phase duration during carotid chemoreceptor stimulation in the cat: medullary neurone correlations. J Physiol 491: 241-259, 1996.
69. Musienko P, van den Brand R, Maerzendorfer O, Larmagnac A, Courtine G. Combinatory electrical and pharmacological neuroprosthetic interfaces to regain motor function after spinal cord injury. IEEE Trans Biomed Eng 56: 2707-2711, 2009.
70. Musienko P, van den Brand R, Marzendorfer O, Roy RR, Gerasimenko Y, Edgerton VR, Courtine G. Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries. J Neurosci 31: 9264-9278, 2011.
71. Nakamura A, Olson EB Jr, Terada J, Wenninger JM, Bisgard GE, Mitchell GS. Sleep state dependence ventilatory long-term facilitation following acute intermittent hypoxia Lewis rats. J Appl Physiol 109: 323-331, 2010.
72. Navarrete-Opazo A, Mitchell GS. Recruitment and plasticity in diaphragm, intercostal, and abdominal muscles in unanesthetized rats. J Appl Physiol 117: 180-188, 2014.
73. Navarrete-Opazo A, Mitchell GS. Therapeutic potential of intermittent hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol 307: R1181-R1197, 2014.
74. Navarrete-Opazo A, Vinit S, Dougherty BJ, Mitchell GS. Daily acute intermittent hypoxia elicits functional recovery of diaphragm and inspiratory intercostal muscle activity after acute cervical spinal injury. Exp Neurol 266C: 1-10, 2015.
75. Navarrete-Opazo AA, Vinit S, Mitchell GS. Adenosine 2A receptor inhibition enhances intermittent hypoxia-induced diaphragm but not intercostal long-term facilitation. J Neurotrauma 31: 1975-1984, 2014.
76. Nichols NL, Dale EA, Mitchell GS. Severe acute intermittent hypoxia elicits phrenic long-term facilitation by a novel adenosine-dependent mechanism. J Appl Physiol 112: 1678-1688, 2012.
77. Nichols NL, Gowing G, Satriotomo I, Nashold LJ, Dale EA, Suzuki M, Avalos P, Mulcrone PL, McHugh J, Svendsen CN, Mitchell GS. Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of amyotrophic lateral sclerosis. Am J Respir Crit Care Med 187: 535-542, 2013.
78. Pierchala LA, Mohammed AS, Grullon K, Mateika JH, Badr MS. Ventilatory long-term facilitation in non-snoring subjects during NREM sleep. Respir Physiol Neurobiol 160: 259-266, 2008.
79. Prabhakar NR, Kumar GK. Oxidative stress in the systemic and cellular responses to intermittent hypoxia. Biol Chem 385: 217-221, 2004.
80. Prabhakar NR, Peng YJ, Jacono FJ, Kumar GK, Dick TE. Cardiovascular alterations by chronic intermittent hypoxia: importance of carotid body chemoreflexes. Clin Exp Pharmacol Physiol 32: 447-449, 2005.
81. Prosser-Loose E, Hassan A, Mitchell GS, Muir GD. Delayed intervention with intermittent hypoxia and task-training improves forelimb function in a rat model of cervical spinal injury. J Neurotrauma 32: 1403-1412, 2015.
82. Reier PJ. Cellular transplantation strategies for spinal cord injury and translational neurobiology. NeuroRx 1: 424-451, 2004.
83. Richter DW, Schmidt-Garcon P, Pierrefiche O, Bischoff AM, Lalley PM. Neurotransmitters and neuromodulators controlling the hypoxic respiratory response in anaesthetized cats. J Physiol 514: 567-578, 1999.
84. Ross HH, Sandhu MS, Cheung TF, Fitzpatrick GM, Sher WJ, Tiemeier AJ, Laywell ED, Fuller DD. In vivo intermittent hypoxia elicits enhanced expansion and neuronal differentiation in cultured neural progenitors. Exp Neurol 235: 238-245, 2012.
85. Sajkov D, McEvoy RD. Obstructive sleep apnea and pulmonary hypertension. Prog Cardiovasc Dis 51: 363-370, 2009.
86. Sandhu MS, Baekey D, Mailing NG, Sanchez J, Reier PJ, Fuller DD. Mid-cervical neuronal discharge patterns during and following hypoxia. J Neurophysiol 113: 2091-2101, 2015.
87. Satriotomo I, Dale EA, Dahlberg JM, Mitchell GS. Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus. Exp Neurol 237: 103-115, 2012.
88. Schwab JM, Zhang Y, Kopp MA, Brommer B, Popovich PG. The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. Exp Neurol 258: 121-129, 2014.
89. Sipski ML. The impact of spinal cord injury on female sexuality, menstruation and pregnancy: a review of the literature. J Am Paraplegia Soc 14: 122-126, 1991.
90. Studer L, Csete M, Lee SH, Kabbani N, Walikonis J, Wold B, McKay R. Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci 20: 7377-7383, 2000.
91. Syed Z, Lin HS, Mateika JH. The impact of arousal state, sex, and sleep apnea on the magnitude of progressive augmentation and ventilatory long-term facilitation. J Appl Physiol 114: 52-65, 2013.
92. Terada J, Mitchell GS. Diaphragm long-term facilitation following acute intermittent hypoxia during wakefulness and sleep. J Appl Physiol 110: 1299-1310, 2011.
93. Tester NJ, Fuller DD, Fromm JS, Spiess MR, Behrman AL, Mateika JH. Long-term facilitation of ventilation in humans with chronic spinal cord injury. Am J Respir Crit Care Med 189: 57-65, 2014.
94. Theele DP, Reier PJ. Immunomodulation with intrathymic grafts or anti-lymphocyte serum promotes long-term intraspinal allograft survival. Cell Transplant 5: 243-255, 1996.
95. Theele DP, Schrimsher GW, Reier PJ. Comparison of the growth and fate of fetal spinal iso- and allografts in the adult rat injured spinal cord. Exp Neurol 142: 128-143, 1996.
96. Trumbower RD, Jayaraman A, Mitchell GS, Rymer WZ. Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehab Neural Repair 26: 163-172, 2012.
97. Vinit S, Lovett-Barr MR, Mitchell GS. Intermittent hypoxia induces functional recovery following cervical spinal injury. Respir Physiol Neurobiol 169: 210-217, 2009.
98. Vinit S, Windelborn JA, Mitchell GS. Lipopolysaccharide attenuates phrenic long-term facilitation following acute intermittent hypoxia. Respir Physiol Neurobiol 176: 130-135, 2011.
99. White TE, Lane MA, Sandhu MS, O'Steen BE, Fuller DD, Reier PJ. Neuronal progenitor transplantation and respiratory outcomes following upper cervical spinal cord injury in adult rats. Exp Neurol 225: 231-236, 2010.
100. Wilkerson JE, Macfarlane PM, Hoffman MS, Mitchell GS. Respiratory plasticity following intermittent hypoxia: roles of protein phosphatases and reactive oxygen species. Biochem Soc Trans 35: 1269-1272, 2007.
101. Wilkerson JE, Mitchell GS. Daily intermittent hypoxia augments spinal BDNF levels, ERK phosphorylation and respiratory long-term facilitation. Exp Neurol 217: 116-123, 2009.
102. Wilkerson JE, Satriotomo I, Baker-Herman TL, Watters JJ, Mitchell GS. Okadaic acid-sensitive protein phosphatases constrain phrenic long-term facilitation after sustained hypoxia. J Neurosci 28: 2949-2958, 2008.
103. Zabka AG, Behan M, Mitchell GS. Selected contribution: Timedependent hypoxic respiratory responses in female rats are influenced by age and by the estrus cycle. J Appl Physiol 91: 2831-2838, 2001.
104. Zabka AG, Mitchell GS, Behan M. Conversion from testosterone to oestradiol is required to modulate respiratory long-term facilitation in male rats. J Physiol 576: 903-912, 2006.
105. Zielinski J. Effects of intermittent hypoxia on pulmonary haemodynamics: animal models versus studies in humans. Eur Respir J 25: 173-180, 2005.