title: Endothelin receptor subtype antagonist activity of S-0139 in various isolated rabbit and canine arteries.
abstract: Vascular responses to endothelin peptides have been proposed to be mainly mediated via subtypes of the endothelin receptor, endothelin ET(A1), endothelin ET(B1), and endothelin ET(B2). The antagonist activity of 27-O-3-[2-(3-carboxy-acryloylamino)-5-hydroxyphenyl]acryloyloxy myricerone, sodium salt (S-0139) at these endothelin receptor subtypes was evaluated using isolated rabbit femoral, pulmonary, and mesenteric arteries. S-0139 competitively antagonized the endothelin-1-induced contraction mediated by the endothelin ET(A1) receptor in endothelium-denuded rabbit femoral arteries with a pA(2) value of 8.6+/-0.1. Endothelin ET(B2) receptor-mediated contraction induced by sarafotoxin S6c in endothelium-denuded rabbit pulmonary arteries was also inhibited by S-0139 with a pA(2) value of 5.6+/-0. 1. The pA(2) value of S-0139 for the endothelin ET(B1) receptor, evaluated from the endothelin-3-induced relaxant response in endothelium-intact rabbit mesenteric arteries, was 6.2+/-0.2. In isolated canine basilar, coronary, mesenteric and renal arteries, endothelin-1 caused concentration-dependent contractions with EC(50) values of 0.49+/-0.07, 0.61+/-0.25, 0.92+/-0.21 and 1.18+/-0.24 nM, respectively. S-0139 antagonized the endothelin-1-induced contraction in these arteries with pA(2) values of 8.0+/-0.1, 7. 6+/-0.2, 7.6+/-0.2 and 7.6+/-0.1, respectively. These results suggest that S-0139 is a potent and selective endothelin ET(A1) receptor antagonist, and that the contractions induced by endothelin-1 in canine basilar, coronary, mesenteric and renal arteries are mediated mainly via the endothelin ET(A1) receptor subtype.
authors.affiliation: Discovery Research Laboratories, Shionogi and Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, 561-0825, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Hayasaki-Kajiwara
authors.forename: T
authors.initials: T
authors.lastname: Shimamura
authors.forename: N
authors.initials: N
authors.lastname: Naya
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D002109:Caffeic Acids / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D019334:Endothelin-3 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000145:classification / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D002109:Caffeic Acids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C086421:S 0139; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D009828:Oleanolic Acid