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This Article Full Text Full Text (PDF) All Versions of this Article: 288/1/L16    most recent 00412.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Zhu, X. Articles by Dekhuijzen, P. N. R. Search for Related Content PubMed PubMed Citation Articles by Zhu, X. Articles by Dekhuijzen, P. N. R.

Hypoxia-induced dysfunction of rat diaphragm: role of peroxynitrite

Departments of ¹Pulmonary Diseases and ³Biochemistry, University Medical Centre Nijmegen, Nijmegen, The Netherlands; ²Department of Pulmonary Diseases, NingXia Medical College Hospital, Yinchuan, NingXia, China; and ⁴Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain

Submitted 26 November 2003 ; accepted in final form 7 August 2004

Oxidants may play a role in hypoxia-induced respiratory muscle dysfunction. In the present study we hypothesized that hypoxia-induced impairment in diaphragm contractility is associated with elevated peroxynitrite generation. In addition, we hypothesized that strenuous contractility of the diaphragm increases peroxynitrite formation. In vitro force-frequency relationship, isotonic fatigability, and nitrotyrosine levels were assessed under hypoxic (PO₂ 6.5 kPa) and hyperoxic (PO₂ 88.2 kPa) control conditions and also in the presence of authentic peroxynitrite (60 min), ebselen (60 min), and the nitric oxide synthase inhibitor N^G-monomethyl-L-arginine acetate (L-NMMA) (90 min). A hypoxia-induced downward shift of the force-frequency relationship was associated with elevated nitrotyrosine level in the diaphragm. During hypoxia, both ebselen and L-NMMA decreased nitrotyrosine levels but did not affect force generation. Strenuous contractions impaired force generation but did not affect nitrotyrosine levels in the diaphragm during hypoxia. But under hyperoxic conditions, fatiguing contractions were associated with elevated diaphragm nitrotyrosine levels. Under hyperoxic conditions exogenous peroxynitrite impaired force generation and increased nitrotyrosine level. These studies show that hypoxia-induced impairment in diaphragm contractility is associated with increased diaphragm protein nitration, but no causal relationship was found between diaphragm nitrotyrosine formation and in vitro force generation.

nitrotyrosine; respiratory muscles; rat; contractile properties; nitric oxide

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