Lipopolysaccharide-induced diaphragmatic contractile dysfunction in mice lacking the inducible nitric oxide synthase.
The goal of this study was to evaluate the importance of the inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced diaphragmatic contractile dysfunction. Many investigators have proposed that iNOS induction in the ventilatory and limb muscles of animals injected with Escherichia coli LPS leads to impaired muscle contractility and increased fatigability. We tested this proposal by examining wild-type mice and iNOS-deficient (iNOS knockout) mice. Both types of mice were injected with either saline (control) or E. coli LPS and killed after 12 h. Diaphragm nitric oxide synthase (NOS) activity, NOS expression, and muscle contractility were assessed with L-citrulline assay, immunoblotting, and in vitro bath preparation, respectively. LPS injection in wild-type mice induced iNOS protein expression and augmented total diaphragmatic NOS activity, which coincided with impaired muscle force generated at frequencies higher than 30 Hz. In iNOS knockout mice, injection of LPS augmented constitutive muscle NOS activity, upregulated the expression of the neuronal NOS (nNOS), but elicited a significantly greater decline in force generated in response to high frequency of stimulation compared with wild-type animals. We conclude that iNOS may play a protective role in attenuating the inhibitory influence of LPS on muscle contractility.
Comtois
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Critical Care and Respiratory Divisions, Royal Victoria Hospital and Meakins-Christie Laboratories, McGill University, Montréal, Canada.
El-Dwairi
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Laubach
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Hussain
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D000818:Animals; D003964:Diaphragm / Q000187:drug effects* / Q000503:physiopathology*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009119:Muscle Contraction / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012016:Reference Values
D008070:Lipopolysaccharides; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse