Septic shock is a life-threatening condition that results from exposure to bacterial endotoxin. It is manifested by cardiovascular collapse and mediated by the release of cytokines such as tumor necrosis factor. Some of these cytokines cause the release of vasoactive substances. In the present study, administration of 40 W/kg of bacterial endotoxin to dogs caused a 33% decrease in peripheral vascular resistance and a 54% fail in mean arterial blood pressure within 30 to 90 minutes. Vascular resistance and systemic arterial pressure returned to normal within 1.5 minutes after intravenous administration of NG-methyl-L-arginine (20 mg/kg), a potent and selective inhibitor of nitric oxide synthesis. L-Arginine reversed the effect of L-NMA and restored the endotoxin-induced hypotension. Although NCmethyl-L-arginine injection increased blood pressure in control dogs, the hypertensive effect was much greater in endotoxemic dogs (24.8 f 2.7 mmHg vs 47.8 f 6.8 mmHg, p=O.Ol, n=4). NG-Methyl-L-arginine caused only a modest increase in blood pressure in dogs made hypotensive by continuous intravenous infusion of nitroglycerin (17.1 f 5.0 mm Hg,n=3). These findings suggest that nitric oxide overproduction is an important contributor to endotoxic shock. Moreover, our findings demonstrate for the first time, the utility of nitric oxide synthesis inhibitors in endotoxic shock and suggest that such inhibitors may be of therapeutic value in the treatment of septic shock. G 1990 ?icadmnc press, Inc. Septic shock, a life-threatening complication of bacterial infections, affects 150,000 to 300,000 patients annually in the United States (1). The cardiovascular collapse and multiple metabolic derangements associated with septic shock are due largely to bacterial endotoxin, which has been shown to elicit a septic shock-like condition when administered to animals (2). Endotoxin is known to stimulate the synthesis and release of several cytokines and biological mediators having hypotensive activity; among the factors released, tumor necrosis factor (TNF), platelet activating factor (PAF), prostacyclin and complement-derived C5a anaphylatoxin have been proposed as important contributors to the cardiovascular collapse of septic shock (3-6). Although it has been shown that animals pretreated with anti-TNF antibodies (7), PAF receptor antagonists (8), and prostacyclin synthesis inhibitors (9) are significantly protected against septic shock, the relative importance of these mediators in the pathology of septic ITo whom reprint requests should be addressed, . .