Balwierczak J L, Bruseo C W, DelGrande D, Jeng A Y, Savage P, Shetty S S
Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07940, USA.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S393-6.
IRL 2500 [N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alany l-L- tryptophan] inhibited the binding of [125I]-endothelin-1 (ET-1) to human ETB (IC50 1.3 +/- 0.2 nM) and ETA (IC50 94 +/- 3 nM) receptors expressed in transfected Chinese hamster ovary (CHO) cells. In in vitro studies, IRL 2500 inhibited the sarafotoxin S6c (STX6c)-mediated contraction of the dog saphenous vein (pKb 7.77) and the STX6c-induced relaxation of the preconstricted rabbit mesenteric artery (pKb 6.92). In the anesthetized rat, IRL 2500 (10 mg/kg, i.v.) inhibited the initial transient decrease in mean arterial pressure (MAP) induced by the ETB-selective agonist IRL 1620 (0.5 nmol/kg, i.v.). IRL 2500 also attenuated the IRL 1620-mediated increase in renal vascular resistance (RVR) in the anesthetized rat. Therefore, IRL 2500 is a potent and selective ETB receptor antagonist that can be used to delineate ET responses mediated by the ETB receptor.
IRL 2500 [N-(3,5-二甲基苯甲酰基)-N-甲基-(D)-(4-苯基苯基)-丙氨酰-L-色氨酸] 抑制 [125I]-内皮素-1（ET-1）与转染的中国仓鼠卵巢（CHO）细胞中表达的人ETB（IC50为1.3±0.2 nM）和ETA（IC50为94±3 nM）受体的结合。在体外研究中，IRL 2500抑制了狗隐静脉中萨拉托毒素S6c（STX6c）介导的收缩（pKb为7.77）以及STX6c诱导的预收缩兔肠系膜动脉的舒张（pKb为6.92）。在麻醉大鼠中，IRL 2500（10 mg/kg，静脉注射）抑制了ETB选择性激动剂IRL 1620（0.5 nmol/kg，静脉注射）诱导的平均动脉压（MAP）的初始短暂下降。IRL 2500还减弱了麻醉大鼠中IRL 1620介导的肾血管阻力（RVR）增加。因此，IRL 2500是一种强效且选择性的ETB受体拮抗剂，可用于描绘由ETB受体介导的ET反应。
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