L-CANAVANINE IMPROVES ORGAN FUNCTION AND TISSUE ADENOSINE-TRIPHOSPHATE LEVELS IN RODENT ENDOTOXEMIA

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 pr esent study, we evaluated the effects of L-canavanine, a selective iNO S inhibitor, in an animal model of septic shock, with a particular foc us on tissue oxidative metabolism and organ functions. Anesthetized ra ts 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 f or 4 h. A third group (sham rats; n = 9) did not receive LPS and was t reated 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 progr essive fall in blood pressure, accompanied by biologic signs of liver and kidney failure, concomitant with a marked decrease in tissue ATP s tores. L-canavanine largely prevented hypotension and significantly in creased tissue ATP while reducing the signs of organ dysfunction. Thes e effects were associated with a significant improvement in survival d uring the 5 h of study. We conclude that L-canavanine not only reduces hypotension in endotoxin shock but also largely prevents the detrimen tal consequences of LPS on tissue oxidative metabolism and major organ functions, allowing a decrease in endotoxin lethality.