Iwasaki T, Hayasaki-Kajiwara Y, Shimamura T, Naya N, Nakajima M
Discovery Research Laboratories, Shionogi and Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, 561-0825, Osaka, Japan.
Eur J Pharmacol. 2000 Jul 21;400(2-3):255-62. doi: 10.1016/s0014-2999(00)00417-9.
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.
血管对内皮素肽的反应被认为主要通过内皮素受体亚型介导，即内皮素ET(A1)、内皮素ET(B1)和内皮素ET(B2)。使用离体兔股动脉、肺动脉和肠系膜动脉评估了27-O-3-[2-(3-羧基丙烯酰氨基)-5-羟基苯基]丙烯酰氧基杨梅酮钠盐（S-0139）在这些内皮素受体亚型上的拮抗活性。S-0139竞争性拮抗内皮素-1诱导的、由内皮素ET(A1)受体介导的内皮剥脱兔股动脉收缩，其pA(2)值为8.6±0.1。S-0139也抑制了内皮剥脱兔肺动脉中由sarafotoxin S6c诱导的内皮素ET(B2)受体介导的收缩，pA(2)值为5.6±0.1。从内皮完整兔肠系膜动脉中内皮素-3诱导的舒张反应评估，S-0139对内皮素ET(B1)受体的pA(2)值为6.2±0.2。在离体犬基底动脉、冠状动脉、肠系膜动脉和肾动脉中，内皮素-1引起浓度依赖性收缩，EC(50)值分别为0.49±0.07、0.61±0.25、0.92±0.21和1.18±0.24 nM。S-0139拮抗这些动脉中内皮素-1诱导的收缩，pA(2)值分别为8.0±0.1、7.6±0.2、7.6±0.2和7.6±0.1。这些结果表明S-0139是一种强效且选择性的内皮素ET(A1)受体拮抗剂，并且内皮素-1在犬基底动脉、冠状动脉、肠系膜动脉和肾动脉中诱导的收缩主要通过内皮素ET(A1)受体亚型介导。
