Beneficial Effects of L-Canavanine, a Selective Inhibitor of Inducible Nitric Oxide Synthase, during Rodent Endotoxaemia

Abstract

1. The cardiovascular failure in sepsis may result from increased nitric oxide biosynthesis, through the diffuse expression of an inducible nitric oxide synthase. In such conditions, nitric oxide synthase inhibitors might be of therapeutic value, but detrimental side effects have been reported with their use, possibly related to the blockade of constitutive nitric oxide synthase. Therefore, the use of selective inhibitors of inducible nitric oxide synthase might be more suitable. The aim of this study was to evaluate the effects of l-canavanine, a potentially selective inhibitor of inducible nitric oxide synthase, in an animal model of septic shock. 2. Anaesthetized rats were challenged with 10 mg/kg lipopolysaccharide intravenously. One hour later, they randomly received a 5 h infusion of either l-canavanine (20 mg h−1 kg−1, n = 15), nitro-l-arginine methyl ester (5 mgh−1 kg−1, n = 13) or 0.9% NaCl (2 ml h−1 kg−1, n = 21). Lipopolysaccharide induced a progressive fall in blood pressure and cardiac index, accompanied by a significant lactic acidosis and a marked rise in plasma nitrate. All these changes were significantly attenuated by l-canavanine, which also improved the tolerance of endotoxaemic animals to acute episodes of hypovolemia. In addition, l-canavanine significantly increased survival of mice challenged with a lethal dose of lipopolysaccharide. In contrast to l-canavanine, nitro-l-arginine methyl ester increased blood pressure at the expense of a severe fall in cardiac index, while largely enhancing lactic acidosis. This agent did not improve survival of endotoxaemic mice. In additional experiments, we found that the pressor effect of l-canavanine in advanced endotoxaemia (4 h) was reversed by l-arginine, confirming that it was related to nitric oxide synthase inhibition. In contrast, l-canavanine did not exert any influence on blood pressure in the very early stage (first hour) of endotoxaemia or in the absence of lipopolysaccharide exposure, indicating a lack of constitutive nitric oxide synthase inhibition by this agent. 3. In conclusion, l-canavanine produced beneficial haemodynamic and metabolic effects and improved survival in rodent endotoxic shock. The actions of l-canavanine were associated with a selective inhibition of inducible nitric oxide synthase and were in marked contrast to the deleterious consequences of nitro-l-arginine methyl ester, a non-selective nitric oxide synthase inhibitor, in similar conditions.