Effect of endothelin-3 on cytosolic calcium level in vascular endothelium and on smooth muscle contraction.
In isolated rat aorta, endothelin (ET)-3 increased cytosolic Ca2+ ([Ca2+]i) in the endothelium at a concentration (100 nM) which had little effect on muscle resting tone. In the absence of external Ca2+, ET-3 still transiently increased endothelial [Ca2+]i. Verapamil (10 microM) did not change the effects of ET-3. In aortas stimulated with 100 nM norepinephrine, 100 nM ET-3 relaxed the muscle with an increase in endothelial [Ca2+]i. An inhibitor of nitric oxide synthase, 100 microM NG-monomethyl-L-arginine, inhibited the relaxant effect of ET-3 but not the increase in endothelial [Ca2+]i. In the absence of the endothelium or in the presence of an antagonist of ETB receptors, 3 microM IRL 1038, the ET-3-induced increase in endothelial [Ca2+]i and relaxation of norepinephrine-induced contraction were inhibited. Under these conditions, ET-3 increased smooth muscle [Ca2+]i and induced contraction, both of which were inhibited by an inhibitor of ETA receptors, 3 microM BQ123. These results suggest that ET-3 acts on ETB receptors in the vascular endothelium to increase [Ca2+]i by releasing Ca2+ from storage sites and by opening non-L type Ca2+ channels, activates nitric oxide synthase, releases nitric oxide and relaxes vascular smooth muscle. Although ET-3 also activates ETA receptors in smooth muscle to induce contraction, this effect is overcome by the relaxant effect mediated by ETB receptors.
Sudjarwo
S A
SA
Department of Veterinary Pharmacology, Faculty of Agriculture, University of Tokyo, Japan.
Hori
M
M
Karaki
H
H
D000595:Amino Acid Sequence; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology; D019323:omega-N-Methylarginine
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21); D019323:omega-N-Methylarginine; D001120:Arginine; D014700:Verapamil; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium; D009638:Norepinephrine