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
NG-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 microgram/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.