Inducible Nitric Oxide Synthase in Long-term Intermittent Hypoxia
- 15 June 2005
- journal article
- research article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 171 (12), 1414-1420
- https://doi.org/10.1164/rccm.200411-1564oc
Abstract
Long-term intermittent hypoxia (LTIH) exposure in adult mice, modeling oxygenation patterns of moderate-severe obstructive sleep apnea, results in lasting hypersomnolence and is associated with nitration and oxidation injuries in many brain regions, including wake-active regions. We sought to determine if LTIH activates inducible nitric oxide synthase (iNOS) in sleep/wake regions, and if this source of NO contributes to the LTIH-induced proinflammatory gene response, oxidative injury, and wake impairments. Mice with genetic absence of iNOS activity and wild-type control animals were exposed to 6 weeks of long-term hypoxia/reoxygenation before behavioral state recordings, molecular and biochemical assays, and a pharmacologic intervention. Two weeks after recovery from hypoxia/reoxygenation exposures, wild-type mice showed increased iNOS activity in representative wake-active regions, increased sleep times, and shortened sleep latencies. Mutant mice, with higher baseline sleep times, showed no effect of long-term hypoxia/reoxygenation on sleep time latencies and were resistant to hypoxia/reoxygenation increases in lipid peroxidation and proinflammatory gene responses (tumor necrosis factor alpha and cyclooxygenase 2). Inhibition of iNOS after long-term hypoxia/reoxygenation in wild-type mice was effective in reversing the proinflammatory gene response. These data support a critical role for iNOS activity in the development of LTIH wake impairments, lipid peroxidation, and proinflammatory responses in wake-active brain regions, and suggest a potential role for inducible NO inhibition in protection from proinflammatory responses, oxidative injury, and residual hypersomnolence in obstructive sleep apnea.Keywords
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