Background: Inhalational anesthetics inhibit the nitric oxide-guanylyl cyclase signaling pathway, but the site of this inhibition is not yet clear. This study was designed to test the hypothesis that receptor activation or downstream signaling events leading to nitric oxide synthase activation are important sites for this inhibition by comparing the effect of anesthetics on vasodilation caused by the calcium-dependent constitutive endothelial nitric oxide synthase versus the calcium-independent inducible nitric oxide synthase.
Methods: Endothelium-intact or -denuded rat thoracic aorta rings preincubated with or without lipopolysaccharide were mounted for isometric tension measurement, constricted with phenylephrine, then relaxed with methacholine in the presence or absence of halothane (1-3%) or isoflurane (1-3%). The cyclic guanosine 3,5-monophosphate content in the endothelium-denuded rings preincubated with or without lipopolysaccharide in the presence or absence of 3% halothane or 3% isoflurane was quantified by radioimmunoassay. The activity of partially purified inducible nitric oxide synthase from activated mouse macrophage was assayed in the presence or absence of halothane (1-4%) or isoflurane (1-5%) by the conversion of 3H-L-arginine to 3H-L-citrulline.
Results: Halothane and isoflurane inhibited methacholine-stimulated, nitric oxide-mediated vasorelaxation in endothelium-intact aortic rings. Neither halothane nor isoflurane affected the vasorelaxation caused by basal endothelial nitric oxide synthase or inducible nitric oxide synthase activity. Neither anesthetic altered the cyclic guanosine 3,5-monophosphate increase caused by inducible nitric oxide synthase in the lipopolysaccharide-treated rings.
Conclusions: The results demonstrated that halothane and isoflurane inhibit only receptor/calcium-activated nitric oxide synthase action and that direct inhibition of nitric oxide synthase, soluble guanylyl cyclase, or an interaction with nitric oxide are not responsible for anesthetic inhibition of endothelium-dependent vasorelaxation.