title: Hypoxia-induced dysfunction of rat diaphragm: role of peroxynitrite.
abstract: 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 (Po(2) approximately 6.5 kPa) and hyperoxic (Po(2) approximately 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.
authors.affiliation: Dept. of Pulmonary Diseases, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.forename: Leo M A
authors.initials: LM
authors.lastname: Heunks
authors.forename: Elly M M
authors.initials: EM
authors.lastname: Versteeg
authors.forename: Henricus F M
authors.initials: HF
authors.lastname: van der Heijden
authors.forename: Leo
authors.initials: L
authors.lastname: Ennen
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Jose
authors.initials: J
authors.lastname: Vina
authors.forename: P N Richard
authors.initials: PN
authors.lastname: Dekhuijzen
mesh_terms: D000818:Animals; D001393:Azoles / Q000494:pharmacology; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D054833:Isoindoles; D015227:Lipid Peroxidation; D008297:Male; D009119:Muscle Contraction; D018763:Muscle Fatigue; D016566:Organoselenium Compounds / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001393:Azoles; D004791:Enzyme Inhibitors; D054833:Isoindoles; D016566:Organoselenium Compounds; D030421:Peroxynitrous Acid; D019323:omega-N-Methylarginine; C002744:3-nitrotyrosine; C042986:ebselen; D014443:Tyrosine