ROLE OF ENDOTOXIN IN L-ARGININE-INDUCED RELAXATION OF RAT THORACIC AORTA MEDIATED BY MUSCLE-DERIVED NITRIC-OXIDE

The contribution of endotoxin to the L-arginine-induced relaxation of the endothelium-denuded rat thoracic aorta, which appears to be mediat ed by nitric oxide synthase in the vascular smooth muscle, was investi gated. Special attention was paid to the time course of the phenomenon and its dependence on the concentration of endotoxin. In the absence of endotoxin, L-arginine induced scarcely any relaxation of the arteri es. Treatment of the arteries with endotoxin initiated relaxation in r esponse to 10 muM L-arginine with lag periods of 2-4 hours. The degree of relaxation increased on repeated applications of L-arginine, to re ach a consistent level after several hours. Increase in the concentrat ion of endotoxin shortened the lag period, enhanced the degree of rela xation and lowered the threshold concentration of L-arginine required to relax the arteries. In endotoxin-primed arteries, L-arginine, at co ncentrations necessary to induce relaxation, stimulated the cyclic GMP production. Prophylactic application of actinomycin D or dexamethason e, which inhibits the induction of nitric oxide synthase, prevented th e induction by endotoxin of the L-arginine-induced relaxation and cycl ic GMP formation. Polymyxin B, which inhibits the action of endotoxin, also prevented the development of the endotoxin-sensitized relaxation and the cyclic GMP formation induced by L-arginine. When the Krebs so lution was prepared using deionized water, the amount of endotoxin in the reservoir was above the level required to initiate the L-arginine- induced relaxation and cyclic GMP formation. These results suggest tha t endotoxin triggered the time-dependent development of the L-arginine -induced relaxation by expressing nitric oxide synthase in the vascula r smooth muscle.