I Soto-Arape, MD Burton and H Kazemi
Department of Medicine, Massachusetts General Hospital, Boston.

Acute sustained hypoxia causes an early rise in ventilation, followed by a reduction in ventilation ("roll off") after several minutes to levels below the peak but above baseline. The underlying mechanism(s) of this biphasic response is unclear. Hypoxia induces changes in the release and metabolic turnover of glutamate and gamma aminobutyric acid (GABA). These endogenous neuroactive agents may play a role in mediating the biphasic hypoxic ventilatory response. Therefore, their role was studied in anesthetized (isoflurane), isocapnic, mechanically ventilated rats. Hypoxia alone (FIO2 = 0.1) produced the characteristic biphasic response in the phrenic neurogram (n = 6). When the glutamate receptor was blocked with application of two different N-methyl-D- aspartate (NMDA) antagonists, MK-801 or AP-5, to the ventrolateral medullary surface (VMS), the phrenic output fell by 90% during normoxia and demonstrated no response to hypoxia (n = 6 for each group). There was a rise of 60% in phrenic nerve output during normoxia when GABA antagonist bicuculline was applied to the VMS, and with hypoxia it rose another 15%, and no fall off was seen during hypoxia (n = 6). These findings suggest that during hypoxia the initial hyperventilation has a glutamatergic component and the subsequent fall off its mediated by GABAergic mechanisms.

This article has been cited by other articles:

				S. R. Reeves and D. Gozal Respiratory: Protein kinase C activity in the nucleus tractus solitarii is critically involved in the acute hypoxic ventilatory response, but is not required for intermittent hypoxia-induced phrenic long-term facilitation in adult rats Exp Physiol, November 1, 2007; 92(6): 1057 - 1066. [Abstract] [Full Text] [PDF]

				S. Chung, G. O. Ivy, and S. G. Reid GABA-mediated neurotransmission in the nucleus of the solitary tract alters resting ventilation following exposure to chronic hypoxia in conscious rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1449 - R1456. [Abstract] [Full Text] [PDF]

				V. Marchenko and R. F. Rogers Selective loss of high-frequency oscillations in phrenic and hypoglossal activity in the decerebrate rat during gasping Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1414 - R1429. [Abstract] [Full Text] [PDF]

				E. V. S. Faustino and D. F. Donnelly An important functional role of persistent Na+ current in carotid body hypoxia transduction J Appl Physiol, October 1, 2006; 101(4): 1076 - 1084. [Abstract] [Full Text] [PDF]

				S. R. Reeves, E. S. Carter, S. Z. Guo, and D. Gozal Calcium/calmodulin-dependent kinase II mediates critical components of the hypoxic ventilatory response within the nucleus of the solitary tract in adult rats Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R871 - R876. [Abstract] [Full Text] [PDF]

				M. Tabata, H. Kurosawa, Y. Kikuchi, W. Hida, H. Ogawa, S. Okabe, Y. Tun, T. Hattori, and K. Shirato Role of GABA within the nucleus tractus solitarii in the hypoxic ventilatory decline of awake rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1411 - R1419. [Abstract] [Full Text] [PDF]

				S.-D. Lee, H. Nakano, and G. A. Farkas GABAergic modulation of ventilation and peak oxygen consumption in obese Zucker rats J Appl Physiol, May 1, 2001; 90(5): 1707 - 1713. [Abstract] [Full Text] [PDF]

				P. J. OHTAKE, N. SIMAKAJORNBOON, M. D. FEHNIGER, Y.-D. XUE, and D. GOZAL N-Methyl-D-Aspartate Receptor Expression in the Nucleus Tractus Solitarii and Maturation of Hypoxic Ventilatory Response in the Rat Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 1140 - 1147. [Abstract] [Full Text]

				J. M. Bissonnette Mechanisms regulating hypoxic respiratory depression during fetal and postnatal life Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1391 - R1400. [Abstract] [Full Text] [PDF]

				D. Gozal and E. Gozal Episodic hypoxia enhances late hypoxic ventilation in developing rat: putative role of neuronal NO synthase Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1999; 276(1): R17 - R22. [Abstract] [Full Text] [PDF]

				A. McCormick, C. Suguihara, J. Huang, C. Devia, D. Hehre, J. H. Bruce, and E. Bancalari Depressed ventilatory response to hypoxia in hypothermic newborn piglets: role of glutamate J Appl Physiol, March 1, 1998; 84(3): 830 - 836. [Abstract] [Full Text] [PDF]

				D. Gozal, G. R. Graff, J. E. Torres, S. G. Khicha, G. S. Nayak, N. Simakajornboon, and E. Gozal Cardiorespiratory responses to systemic administration of a protein kinase C inhibitor in conscious rats J Appl Physiol, February 1, 1998; 84(2): 641 - 648. [Abstract] [Full Text] [PDF]