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Effects of chronic hypoxia on MK-801-induced changes in the acute hypoxic ventilatory response

Division of Physiology, Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 25 October 2004 ; accepted in final form 17 August 2005

Chronic hypoxia increases the sensitivity of the central nervous system to afferent input from carotid body chemoreceptors. We hypothesized that this process involves N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms and predicted that chronic hypoxia would change the effect of the NMDA receptor blocker dizocilpine (MK-801) on the poikilocapnic hypoxic ventilatory response (HVR). Male Sprague-Dawley rats were studied before and after acclimatization to hypoxia (70 Torr inspiratory PO₂ for 9 days). We measured ventilation (I) and the HVR before and after systemic MK-801 treatment (3 mg/kg ip). MK-801 resulted in a constant respiratory frequency (175 min^–1) during acute exposure to 10% and 30% O₂ before and after acclimatization. MK-801 had no effect on tidal volume (VT) before acclimatization, but it significantly decreased VT when the animals were breathing 10% O₂ after acclimatization. The net effect of MK-801 was to eliminate the O₂ sensitivity of I before (via changes in respiratory frequency) and after (via changes in VT) acclimatization. Hence, chronic hypoxia altered the effect of MK-801 on the acute HVR, primarily because of increased effects on VT. This indicates that changes in NMDA receptor-mediated neurotransmission may be involved in ventilatory acclimatization to hypoxia. However, further experiments are necessary to determine the precise location of such plasticity in the central nervous system.

chronic hypoxia; control of breathing; hypobaric hypoxia; hypoxic ventilatory response; rat

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