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 mediated by nitric oxide synthase in the vascular smooth muscle, was investigated. 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 arteries. Treatment of the arteries with endotoxin initiated relaxation in response to 10 microM L-arginine with lag periods of 2-4 hours. The degree of relaxation increased on repeated applications of L-arginine, to reach a consistent level after several hours. Increase in the concentration of endotoxin shortened the lag period, enhanced the degree of relaxation and lowered the threshold concentration of L-arginine required to relax the arteries. In endotoxin-primed arteries, L-arginine, at concentrations necessary to induce relaxation, stimulated the cyclic GMP production. Prophylactic application of actinomycin D or dexamethasone, which inhibits the induction of nitric oxide synthase, prevented the induction by endotoxin of the L-arginine-induced relaxation and cyclic 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 solution 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 that endotoxin triggered the time-dependent development of the L-arginine-induced relaxation by expressing nitric oxide synthase in the vascular smooth muscle.
Moritoki
H
H
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
Takeuchi
S
S
Kondoh
W
W
Hisayama
T
T
Hashizume
M
M
Noda
K
K
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D011112:Polymyxin B / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012485:Salmonella typhi
D004731:Endotoxins; D005938:Glucocorticoids; D003609:Dactinomycin; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP; D011112:Polymyxin B