Kushida H, Nomura S, Morita O, Harasawa Y, Suzuki M, Nakano M, Ozawa K, Kunihara M
Tsukuba Research Laboratories, Upjohn Pharmaceuticals Limited, Japan.
J Pharmacol Exp Ther. 1995 Sep;274(3):1042-53.
We examined the pharmacological properties of U-97018, a novel nonpeptide angiotensin II (AII) receptor antagonist, in various in vitro and in vivo studies. U-97018 selectively displaced 125I-AII specific binding in the membrane fraction derived from the rat mesenteric artery and adrenal cortex (AT1 subtype) with IC50 of 1.3 +/- 0.2 and 7.7 +/- 1.3 nM, respectively, without altering the AII binding of the rat adrenal medulla (AT2 subtype). In rat adrenal cortical cells, U-97018 inhibited 1 nM AII-induced aldosterone secretion with an IC50 of 0.48 nM; it shifted concentration-secretion response curve for AII to the right and inhibited the maximal response to AII, yielding a pKB of 9.8. Similarly, U-97018 showed insurmountable antagonism with a pKB of 10.6 against the AII-induced contraction in the isolated rabbit aorta. U-97018 had no direct effect on the activities of renin and angiotensin converting enzyme in vitro. In pithed rats, U-97018 inhibited the AII-induced pressor response with an ED50 of 0.28 mg/kg, i.v. without any partial agonistic activity. In anesthetized rats and dogs, intraduodenal administration of U-97018 at a dose of 1 mg/kg inhibited the AII-induced pressor response by about 60%. In spontaneously hypertensive rats, U-97018 at 10 mg/kg p.o. produced antihypertensive effects which lasted for 24 hr after administration. Thus, U-97018 is an orally active, insurmountable AII receptor antagonist without any agonistic activity.
我们在各种体外和体内研究中检测了新型非肽类血管紧张素II（AII）受体拮抗剂U-97018的药理学特性。U-97018能选择性地取代大鼠肠系膜动脉和肾上腺皮质膜组分中125I-AII的特异性结合（AT1亚型），IC50分别为1.3±0.2和7.7±1.3 nM，而不改变大鼠肾上腺髓质的AII结合（AT2亚型）。在大鼠肾上腺皮质细胞中，U-97018抑制1 nM AII诱导的醛固酮分泌，IC50为0.48 nM；它使AII的浓度-分泌反应曲线右移并抑制对AII的最大反应，pKB为9.8。同样，U-97018对离体兔主动脉中AII诱导的收缩表现出不可克服的拮抗作用，pKB为10.6。U-97018在体外对肾素和血管紧张素转换酶的活性无直接影响。在脊髓麻醉大鼠中，U-97018静脉注射抑制AII诱导的升压反应，ED50为0.28 mg/kg，且无任何部分激动活性。在麻醉大鼠和犬中，十二指肠内给予1 mg/kg的U-97018可使AII诱导的升压反应抑制约60%。在自发性高血压大鼠中，口服10 mg/kg的U-97018产生降压作用，给药后持续24小时。因此，U-97018是一种口服活性、不可克服的AII受体拮抗剂，无任何激动活性。
