Inhibition of nitric oxide formation does not affect endotoxin lethality in rats

Endotoxin causes release of nitric oxide (NO) from different types of cells. A causative role has been suggested for NO in endotoxin-induced hypotension. In order to test the hypothesis that NO may be involved in the high mortality rate following endotoxin challenge, the competitive NO synthase inhibitors N^w nitro-L-arginine methyl ester (L-NAME) and NG methyl L-arginine (L-NMA), or the NOS substrate L-arginine, were administered to rats in the presence and absence of endotoxin. Death rates were examined after drug injection. Urine nitrite concentration and mean arterial blood pressure were examined for 24 h following endotoxin injection. It was found that endotoxin injection increased mortality rates. The mortality rate of rats injected with NOS inhibitors or an NOS substrate concomitantly with endotoxin was similar to that observed in rats treated with endotoxin alone. Endotoxin elicited a decrease in mean arterial blood pressure, whereas treatment with NOS inhibitors prevented this decrease. Treatment with L-arginine markedly exacerbated the endotoxin effects on blood pressure and resulted in hypotension 6 h after the endotoxin injection. The urine nitrite concentration increased after injection of endotoxin or L-arginine alone, or after injection of endotoxin concomitantly with L-arginine. The urine nitrite concentration after injection of endotoxin together with L-NAME was smaller than after injection of endotoxin alone. The effects of L-NAME on the urine nitrite concentration and on the blood pressure were reversed with L-arginine. These results do not support the hypothesis that NO mediates the high mortality rates following administration of endotoxin.