L Liaudet, D Fishman, M Markert, C Perret and F Feihl
Institute of Pathophysiology, University Hospital, Lausanne, Switzerland.

Overproduction of NO by an inducible NO synthase (iNOS) plays a major role in the pathophysiology of septic shock, and selective inhibition of iNOS in this setting could be of great therapeutic value. In the present study, we evaluated the effects of L-canavanine, a selective iNOS inhibitor, in an animal model of septic shock, with a particular focus on tissue oxidative metabolism and organ functions. Anesthetized rats challenged intravenously with lipopolysacharide (LPS) were treated after 1 h by a continuous infusion of either L-canavanine (20 mg/kg/h; n = 11) or an equivalent volume of saline (2 ml/kg/h; n = 17) given for 4 h. A third group (sham rats; n = 9) did not receive LPS and was treated with a continuous infusion of saline (2 ml/kg/h). At the end of experiments, biopsies were taken from the liver, the kidney, and the small intestine for the measurement of tissue ATP. LPS induced a progressive fall in blood pressure, accompanied by biologic signs of liver and kidney failure, concomitant with a marked decrease in tissue ATP stores. L-canavanine largely prevented hypotension and significantly increased tissue ATP while reducing the signs of organ dysfunction. These effects were associated with a significant improvement in survival during the 5 h of study. We conclude that L- canavanine not only reduces hypotension in endotoxin shock but also largely prevents the detrimental consequences of LPS on tissue oxidative metabolism and major organ functions, allowing a decrease in endotoxin lethality.

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