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Effect of long-term intermittent and sustained hypoxia on hypoxic ventilatory and metabolic responses in the adult rat

Kosair Children's Hospital Research Institute, Departments of Pediatrics, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40202

Submitted 19 August 2002 ; accepted in final form 17 April 2003

The effects of chronic sustained hypoxia (SH) on ventilation have been thoroughly studied. However, the effects of intermittent hypoxia (IH), a more prevalent condition in health and disease are currently unknown. We hypothesized that the ventilatory consequences of SH and IH may differ and be related to changes in N-methyl-D-aspartate (NMDA) glutamate receptor subunit expression. To examine these issues, Sprague-Dawley adult male rats were exposed to 30 days of either SH (10% O₂) or IH (21% and 10% O₂ alternations every 90 s) or to normoxia (RA), at the end of which ventilatory and O₂ consumption responses to a 20-min acute hypoxic challenge (10% O₂) were conducted. In addition, dorsocaudal brain stem tissue lysates were harvested at 1 h, 6 h, 1 day, 3 days, 7 days, 14 days, and 30 days of SH and IH and analyzed for NR1, NR2A, and NR2B NMDA glutamate receptor expression by immunoblotting. Normoxic ventilation was higher after both SH and IH (P < 0.001). Peak hypoxic ventilatory response was higher after SH but not after IH compared with RA. However, hypoxic ventilatory decline was more prominent after SH than IH (P < 0.001). NR1 expression showed a biphasic pattern of expression over time that was essentially identical after IH and SH (P value not significant). However, NR2A and NR2B expression was higher in IH compared with SH and RA (P < 0.01). We conclude that long-lasting exposures to SH and IH enhance normoxic ventilation but are associated with different time domains of ventilation during acute hypoxia that may be accounted in part by changes in NMDA glutamate receptor subunit expression.

intermittent hypoxia; chronic sustained hypoxia; hypoxic ventilatory response; glutamate receptors; N-methyl-D-aspartate

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