Hashimoto Y, Harada Y, Narita H, Naito K, Murata S
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
J Cardiovasc Pharmacol. 1997 Feb;29(2):284-90. doi: 10.1097/00005344-199702000-00019.
The pharmacologic profile of a novel angiotensin I (AT1) receptor antagonist 606A was studied in various in vitro and in vivo preparations. The 606A showed a high affinity at AT1 receptors [inhibition constant (Ki), 12.8 +/- 0.4 nM] in rabbit adrenal cortical membrane and a low affinity to AT2 receptors (Ki, > 1 mM) in bovine cerebellar membrane, indicating potent and selective AT1 properties. In the guinea pig aorta, 606A reduced the maximal angiotensin II-induced contraction (pD'2, 9.06 +/- 0.04), whereas EXP3174 showed suppression of the maximum response and a shift to the right of the concentration-response curve at lower and higher concentrations, respectively (conventionally calculated pd'2, 8.61 +/- 0.23). The 606A had no effects on KC1-, norepinephrine-, serotonin-, and endothelin-1-induced contractions or any agonist activities. In anesthetized dogs, 606A inhibited the angiotensin II-induced pressor response 35 times more potently than losartan. In renal hypertensive rats and spontaneously hypertensive rats (SHRs), 606A decreased systolic blood pressure 10 and 3 times more potently than losartan, respectively, without any chronotropic effects. By repeated administration of 606A to SHRs for 2 weeks, an augmentation of the hypotensive effect was observed No rebound phenomena occurred after discontinuation. These results indicate the 606A is a potent AT1-selective insurmountable angiotensin II receptor antagonist having more potent angiotensin II receptor antagonistic and hypotensive effects than losartan in in vivo models. 606A is suggested to be a useful agent for the treatment of patients with hypertension.
在多种体外和体内实验制剂中研究了新型血管紧张素I（AT1）受体拮抗剂606A的药理学特性。606A在兔肾上腺皮质膜中对AT1受体表现出高亲和力[抑制常数（Ki），12.8±0.4 nM]，而在牛小脑膜中对AT2受体亲和力低（Ki，>1 mM），表明其具有强效且选择性的AT1特性。在豚鼠主动脉中，606A降低了血管紧张素II诱导的最大收缩反应（pD'2，9.06±0.04），而EXP3174分别在较低和较高浓度下表现出对最大反应的抑制以及浓度 - 反应曲线右移（传统计算的pd'2，8.61±0.23）。606A对氯化钾、去甲肾上腺素、血清素和内皮素 - 1诱导的收缩或任何激动剂活性均无影响。在麻醉犬中，606A抑制血管紧张素II诱导的升压反应的效力比氯沙坦强35倍。在肾性高血压大鼠和自发性高血压大鼠（SHR）中，606A降低收缩压的效力分别比氯沙坦强10倍和3倍，且无任何变时作用。通过对SHR重复给药606A两周，观察到降压效果增强，停药后未出现反跳现象。这些结果表明，606A是一种强效的AT1选择性不可逾越的血管紧张素II受体拮抗剂，在体内模型中具有比氯沙坦更强的血管紧张素II受体拮抗和降压作用。606A被认为是治疗高血压患者的一种有用药物。
