Koepke J P, Bovy P R, McMahon E G, Olins G M, Reitz D B, Salles K S, Schuh J R, Trapani A J, Blaine E H
Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri.
Hypertension. 1990 Jun;15(6 Pt 2):841-7. doi: 10.1161/01.hyp.15.6.841.
Nonpeptidic imidazole derivatives were recently reported to be angiotensin II receptor antagonists with acute blood pressure-lowering activity. In the present study, we characterized the angiotensin II receptor antagonist properties of one such derivative, 4'-([2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl]methyl)- [1,1'-biphenyl]-2-carboxylic acid (IMI). In receptor binding studies, IMI displaced bound [125I]angiotensin II from rat uterine membranes with an IC50 of 0.17 microM. In isolated rabbit aortic rings, IMI shifted the angiotensin II concentration-response curve to the right in a parallel and concentration-dependent manner. A Schild plot of these data indicated a pA2 of 7.13 +/- 0.16 and a slope of 0.94 +/- 0.06. In rat kidney slices, IMI shifted the concentration-response curve for angiotensin II-induced inhibition of renin release to the right. Antagonism of the angiotensin II pressor response by IMI was dose dependent and reversible in ganglion-blocked, anesthetized rats. The water intake and pressor responses to intracerebroventricular angiotensin II (100 pmol) were inhibited by intracerebroventricular IMI (25 or 50 nmol) in conscious Sprague-Dawley rats. Similarly, the drinking and pressor responses to intravenous angiotensin II were blocked by intravenous IMI in conscious rats. IMI alone had no effects on mean arterial pressure or drinking when administered either intravenously or intracerebroventricularly. IMI decreased mean arterial pressure throughout 5 days of infusion in spontaneously hypertensive rats. In summary, IMI was a full competitive antagonist without partial agonist activity in peripheral tissues and the central nervous system. Moreover, the chronic administration of this angiotensin II receptor antagonist was antihypertensive in spontaneously hypertensive rats.
最近有报道称，非肽类咪唑衍生物是具有急性降压活性的血管紧张素II受体拮抗剂。在本研究中，我们对一种此类衍生物4'-([2-丁基-4-氯-5-(羟甲基)-1H-咪唑-1-基]甲基)-[1,1'-联苯]-2-羧酸（IMI）的血管紧张素II受体拮抗剂特性进行了表征。在受体结合研究中，IMI以0.17 microM的IC50从大鼠子宫膜上置换结合的[125I]血管紧张素II。在离体兔主动脉环中，IMI使血管紧张素II浓度-反应曲线平行且浓度依赖性地右移。这些数据的Schild图显示pA2为7.13±0.16，斜率为0.94±0.06。在大鼠肾切片中，IMI使血管紧张素II诱导的肾素释放抑制的浓度-反应曲线右移。在神经节阻断的麻醉大鼠中，IMI对血管紧张素II升压反应的拮抗作用是剂量依赖性且可逆的。在清醒的Sprague-Dawley大鼠中，脑室内注射IMI（25或50 nmol）可抑制对脑室内血管紧张素II（100 pmol）的饮水和升压反应。同样，静脉注射IMI可阻断清醒大鼠对静脉注射血管紧张素II的饮水和升压反应。单独静脉注射或脑室内注射IMI对平均动脉压或饮水均无影响。在自发性高血压大鼠中，IMI在整个5天的输注过程中均降低平均动脉压。总之，IMI是一种完全竞争性拮抗剂，在周围组织和中枢神经系统中无部分激动剂活性。此外，这种血管紧张素II受体拮抗剂的长期给药在自发性高血压大鼠中具有降压作用。
