Inducible nitric oxide synthase in long-term intermittent hypoxia: hypersomnolence and brain injury

Am J Respir Crit Care Med. 2005 Jun 15;171(12):1414-20. doi: 10.1164/rccm.200411-1564OC. Epub 2005 Mar 4.


Rationale: 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.

Objectives: 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.

Methods: 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.

Measurements and main results: 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.

Conclusions: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Disease Models, Animal
  • Disorders of Excessive Somnolence / etiology*
  • Disorders of Excessive Somnolence / physiopathology
  • Enzyme-Linked Immunosorbent Assay
  • Hypoxia, Brain / complications
  • Hypoxia, Brain / enzymology*
  • Isoprostanes / metabolism*
  • Lipid Peroxidation / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Nitric Oxide Synthase / metabolism*
  • Oxidative Stress / physiology
  • Probability
  • Random Allocation
  • Reference Values
  • Sensitivity and Specificity


  • Isoprostanes
  • Nitric Oxide Synthase