Yatsu T, Tomura Y, Tahara A, Wada K, Tsukada J, Uchida W, Tanaka A, Takenaka T
Pharmacology Laboratory, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Eur J Pharmacol. 1997 Feb 26;321(2):225-30. doi: 10.1016/s0014-2999(96)00940-5.
The pharmacological profile of YM087 (4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin -6-yl) carbonyl]-2-phenylbenzanilide monohydrochloride) was investigated in dogs. YM087 showed high affinity for vasopressin V1A and V2 receptors in radioligand receptor binding studies with dog platelets (V1A) and kidney (V2). Intravenously injected YM087 (3-100 micrograms/kg) dose dependently inhibited the pressor response to exogenous vasopressin in anesthetized dogs. Intravenous (10-100 micrograms/kg) and oral (30-300 micrograms/kg) administration of YM087 dose dependently increased urine flow with little effect on urinary sodium and potassium excretion in normally hydrated conscious dogs. Concomitantly, the urine osmolality dropped below the plasma osmolality (300 mOsm/kg H2O). In contrast, intravenously injected furosemide (300 micrograms/kg) increased urine flow with marked increases in urinary sodium and potassium excretion. These results indicate that YM087 is the first orally effective dual vasopressin V1A and V2 receptor antagonist and that it will be a new tool in the investigation of the physiological and pathophysiological role of vasopressin in the cardiovascular system and kidney. YM087 may be useful for the treatment of patients with congestive heart failure, renal diseases and water-retaining diseases.
在犬类动物中研究了YM087（4'-[(2-甲基-1,4,5,6-四氢咪唑并[4,5-d][1]苯并氮杂卓-6-基)羰基]-2-苯基苯甲酰苯胺盐酸盐）的药理学特性。在对犬血小板（V1A）和肾脏（V2）进行的放射性配体受体结合研究中，YM087对血管加压素V1A和V2受体显示出高亲和力。静脉注射YM087（3 - 100微克/千克）剂量依赖性地抑制麻醉犬对外源性血管加压素的升压反应。静脉注射（10 - 100微克/千克）和口服（30 - 300微克/千克）YM087剂量依赖性地增加正常水合清醒犬的尿流量，对尿钠和钾排泄影响很小。同时，尿渗透压降至血浆渗透压（300 mOsm/kg H2O）以下。相比之下，静脉注射速尿（300微克/千克）增加尿流量，同时尿钠和钾排泄显著增加。这些结果表明，YM087是首个口服有效的血管加压素V1A和V2受体双重拮抗剂，并且它将成为研究血管加压素在心血管系统和肾脏中的生理和病理生理作用的新工具。YM087可能对治疗充血性心力衰竭、肾脏疾病和潴留性疾病患者有用。
