THE ROLE OF NITRIC-OXIDE IN ENDOTOXIC-SHOCK - EFFECTS OF N(G)-MONOMETHYL-L-ARGININE

The role of nitric oxide (NO) in the changes in blood pressure and plasma levels of nitrate and nitrite (NO(x)) and alanine aminotransferase (ALT) were determined over a 5-h period in anesthesized rats after intravenous administration of S. typhosa endotoxin (LPS, 4 mg/kg). Rats treated with LPS showed a sustained fall in blood pressure accompanied by an increase in plasma NO(x) and ALT. Forty percent of these rats died during the experiment. There was no change in blood pressure in rats treated with dexamethasone (1 mg/kg) 1 h before and 2 h after LPS and the increase in NO(x) and ALT was significantly inhibited. None of the rats in this group died. Administration of 10 mg/kg of N(G)-monomethyl-L-arginine (L-NMMA) prevented the fall in blood pressure and partially prevented the increase in NO(x), and ALT. None of the animals in this group died. In contrast, 300 mg/kg of L-NMMA caused an initial increase in blood pressure followed by a rapid fall and enhanced the increase in ALT while abolishing the elevation of NO(x). All of these animals died before the end of the experiment. However, when rats treated with high doses of L-NMMA were given a continuous infusion of S-nitroso-N-acetylpenicillamine (SNAP, 300 mug/kg/h), the blood pressure was maintained at control levels and no mortality was observed. These results indicate that the NO synthetized by the inducible NO synthase plays a role in the hypotension and tissue damage of endotoxic shock and that the critical factor determining the difference between a beneficial or an adverse effect of L-NMMA is the degree of inhibition of NO synthesis.