L-canavanine, a selective inhibitor of inducible NO synthase, increases plasma endothelin-1 concentrations in dogs with endotoxic shock

Abstract

The purpose of this article is to elucidate the effect of L-canavanine, a selective inhibitor of inducible NO synthase (iNOS), on hemodynamics, blood gas parameters, and plasma concentrations of lactate and endothelin-1 (ET-1) during endotoxic shock. Eleven mongrel dogs under pentobarbital anesthesia were divided into two groups: (1) bacterial lipopolysaccharide (LPS) plus vehicle group (n = 5) receiving infusion of LPS (3 mg/kg/h for 1 h) followed by vehicle (2 mL/h for 5 hours); (2) LPS plus L-canavanine group (n = 6) receiving infusion of LPS (3 mg/kg/h for 1 hour) followed by L-canavanine (10 mg/kg/h for 5 hours). LPS caused a significant (P < .05) decrease in mean arterial pressure (MAP) at 1 hour, but there was no significant difference in MAP during 6-hour period between the two groups. LPS alone did not cause significant changes in other hemodynamics, whereas L-canavanine caused a significant (P < .05) increase in pulmonary vascular resistance index (PVRI) and a decrease in oxygen delivery at 6 hours. The LPS-induced lactic acidosis and hypersecretion of ET-1 were aggravated after L-canavanine infusion. Plasma ET-1 showed positive correlations to lactate levels and PVRI, and negative correlations to cardiac output and oxygen delivery only in the LPS plus L-canavanine group, but not in the LPS plus vehicle group. This study suggests that L-canavanine induces tissue hypoperfusion and ischemia with concomitant hypersecretion of ET-1 in dogs with endotoxic shock.