Role of nitric oxide on diaphragmatic contractile failure in Escherichia coli endotoxemic rats.
Contractile dysfunction of the respiratory muscles plays an important role in the genesis of respiratory failure during sepsis. Nitric oxide (NO), a free radical that is cytotoxic and negatively inotropic in the heart and skeletal muscle, is produced in large amounts during sepsis by a NO synthase inducible (iNOS) by LPS and/or cytokines. The aim of this study was to investigate whether iNOS was induced in the diaphragm of Escherichia coli endotoxemic rats and whether inhibition of iNOS induction or of NOS synthesis attenuated diaphragmatic contractile dysfunction. Rats were inoculated intravenously (IV) with 10 mg/kg of E. coli endotoxin (LPS animals) or saline (C animals). Six hours after LPS inoculation animals showed a significant increase in diaphragmatic NOS activity (L-citrulline production, P < 0.005). Inducible NOS protein was detected by Western-Blot in the diaphragms of LPS animals, while it was absent in C animals. LPS animals had a significant decrease in diaphragmatic force (P < 0.0001) measured in vitro. In LPS animals, inhibition of iNOS induction with dexamethasone (4 mg/kg IV 45 min before LPS) or inhibition of NOS activity with N(G)-methyl-L-arginine (8 mg/kg IV 90 min after LPS) prevented LPS-induced diaphragmatic contractile dysfunction. We conclude that increased NOS activity due to iNOS was involved in the genesis of diaphragmatic dysfunction observed in E. coli endotoxemic rats.
Institut Nationale de la Santé et de la Recherche Médicale (INSERM) U408, Paris, France.
A
A
Sambe
D
D
Ungureanu-Longrois
G
G
Danialou
S
S
Lanone
J
J
Benessiano
M
M
Aubier
J
J
Boczkowski
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000503:physiopathology*; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004927:Escherichia coli Infections / Q000503:physiopathology*; D005938:Glucocorticoids / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D004731:Endotoxins; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D003907:Dexamethasone; D019001:Nitric Oxide Synthase