TY - JOUR
T1 - Hypoxia-induced dysfunction of rat diaphragm
T2 - Role of peroxynitrite
AU - Zhu, Xiaoping
AU - Heunks, Leo M.A.
AU - Versteeg, Elly M.M.
AU - Van Der Heijden, Henricus F.M.
AU - Ennen, Leo
AU - Van Kuppevelt, Toin H.
AU - Vina, Jose
AU - Dekhuijzen, P. N.Richard
PY - 2005/1/1
Y1 - 2005/1/1
N2 - 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 NG- 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.
AB - 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 NG- 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.
KW - Contractile properties
KW - Nitric oxide
KW - Nitrotyrosine
KW - Rat
KW - Respiratory muscles
UR - http://www.scopus.com/inward/record.url?scp=11144347758&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00412.2003
DO - 10.1152/ajplung.00412.2003
M3 - Article
C2 - 15361360
AN - SCOPUS:11144347758
VL - 288
JO - American Journal of Physiology. Lung Cellular and Molecular Physiology
JF - American Journal of Physiology. Lung Cellular and Molecular Physiology
SN - 1040-0605
IS - 1 32-1
ER -