Endothelin-3-induced relaxation of rat thoracic aorta: a role for nitric oxide formation.
1. Endothelin-3 (ET-3) at concentrations below those which caused contraction (30 nM) elicited endothelium-dependent relaxation followed by rebound contraction in rat isolated thoracic aorta. 2. Endothelin-1 also relaxed the rat aorta with a similar potency. 3. The nitric oxide (NO) synthase inhibitor, NG-nitro L-arginine, the radical scavenger, haemoglobin and the soluble guanylate cyclase inhibitor, methylene blue, each inhibited the ET-3-induced relaxation. 4. The calmodulin inhibitor, calmidazolium, considerably attenuated the relaxation caused by ET-3 without affecting that to nitroprusside. 5. Concentrations of ET-3 that were necessary to induce the relaxation also caused concentration-dependent elevation of guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels. 6. NG-nitro L-arginine, haemoglobin, methylene blue, calmidazolium and removal of the endothelium completely abolished ET-3-stimulated cyclic GMP production. 7. These results suggest that ET-3 triggers NO formation possibly via ETB receptors on the endothelium to activate soluble guanylate cyclase, which in turn stimulates cyclic GMP production and smooth muscle relaxation. The enzyme contributing to the NO formation may be of the calcium/calmodulin-dependent, constitutive type.
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
H
H
Moritoki
H
H
Miyano
S
S
Takeuchi
M
M
Yamaguchi
T
T
Hisayama
W
W
Kondoh
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D006152:Cyclic GMP / Q000096:biosynthesis; D016232:Endothelins / Q000494:pharmacology*; D006454:Hemoglobins / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine; D051381:Rats; D017208:Rats, Wistar
D002147:Calmodulin; D016232:Endothelins; D006454:Hemoglobins; D007093:Imidazoles; D019335:Nitroarginine; D009569:Nitric Oxide; C031938:calmidazolium; D001120:Arginine; D006152:Cyclic GMP; D000109:Acetylcholine; D008751:Methylene Blue