Inhibition of nitric oxide formation with l-canavanine attenuates endotoxin-induced vascular hyporeactivity in the rat

Abstract

l-Canavanine, a selective inhibitor of inducible nitric oxide (NO) synthase, has beneficial effects on the circulatory failure of rats with endotoxin shock. To investigate the direct relationship between these beneficial effects and the inhibition of the formation of NO in response to l-canavanine in endotoxin shock in the rat, we detected changes in venous nitrosyl-hemoglobin (NO-hemoglobin) levels using an electron spin resonance (ESR) assay. Anaesthetized rats were injected with lipopolysaccharide (10 mg/kg i.v.). 1 h after the lipopolysaccharide injection, the rats were divided into four groups: a lipopolysaccharide group receiving 0.3 ml of saline hourly, an l-canavanine 10 or an l-canavanine 20 group receiving l-canavanine 10 or 20 mg/kg i.v. hourly, respectively, and an L-NAME group receiving N G-nitro- l-arginine methyl ester (L-NAME) 15 mg/kg followed by 10 mg/kg i.v. hourly. A sham group received saline instead of lipopolysaccharide, and an l-canavanine group received l-canavanine 20 mg/kg i.v. hourly, 1 h after the saline injection. At 5 h after the lipopolysaccharide or saline injection, pressor responses to noradrenaline (1 μg/kg i.v.) were obtained. In the lipopolysaccharide group, lipopolysaccharide caused a progressive decrease in mean arterial pressure and an impairment of pressor responsiveness to noradrenaline. Administration of l-canavanine or L-NAME attenuated the endotoxin-induced hypotension and vascular hyporeactivity to noradrenaline. l-Canavanine did not alter mean arterial pressure and the pressor response to noradrenaline in the l-canavanine group. The endotoxin-induced increases in venous levels of NO-hemoglobin were significantly inhibited by l-canavanine or L-NAME. These data indicate that the beneficial hemodynamic effects of l-canavanine are associated with inhibition of the enhanced formation of NO by inducible NO synthase in a rat model of endotoxin shock. l-Canavanine is a potential agent in the treatment of endotoxin shock.