Trachte G J, Ackerly J A, Peach M J
J Cardiovasc Pharmacol. 1981 Jul-Aug;3(4):838-46. doi: 10.1097/00005344-198107000-00017.
Angiotensins I, II, and III are potent cardiac inotropic agents, but vasoconstrictor and steroidogenic activities compromise their use in conditions of cardiac dysfunction. This study examines the inotropic and vascular actions of [alanyl7]-substituted angiotensin analogs in field-stimulated rabbit left atria and isometrically contracting aortic strips. Angiotensin II increased cardiac contractility in a dose-dependent manner with an ED50 of 30 nM. Sarcosine substitution at the amino terminus of angiotensin II increased its potency 10-fold. Inhibition of converting enzyme with teprotide (10 microgram/ml) had no effect on contractile responses to angiotensin II or [Sar1]angiotensin II. [Ala7]Angiotensin II was a weaker cardiac stimulant than angiotensin II, but addition of teprotide enhanced its potency to that of angiotensin II. [Sar1, Ala7]Angiotensin II also was equipotent to [Sar1]angiotensin II in the presence of teprotide. The potency of angiotensin I as an inotropic agent (ED50 = 100 nM) was significantly less than that of angiotensin II, and the angiotensin I response was attenuated by teprotide. [Sar1, Ala7]Angiotensin I was a more effective inotropic agent following teprotide administration. These findings indicate that atrial converting enzyme metabolizes angiotensin I and the [Ala7] analogs of angiotensin I and II. Angiotensin II and [Sar1]angiotensin II had activities in aorta similar to those in atria. As previously reported for uterus, [Ala7]Angiotensin II was inactive in aorta whether teprotide was present or not. The decapeptides were equally potent in the aorta and atria. Sarcosine substitution at the NH2 terminus also was observed to attenuate cardiac selectivity. These data indicate that [Ala7]angiotensin analogs are cardioselective inotropic agents.
血管紧张素I、II和III是强效的心脏正性肌力药物，但血管收缩和类固醇生成活性限制了它们在心脏功能障碍情况下的应用。本研究在电场刺激的兔左心房和等长收缩的主动脉条上检测了[丙氨酰7]取代的血管紧张素类似物的正性肌力和血管作用。血管紧张素II以剂量依赖的方式增加心脏收缩力，ED50为30 nM。血管紧张素II氨基末端的肌氨酸取代使其效力提高了10倍。用替普罗肽（10微克/毫升）抑制转化酶对血管紧张素II或[肌氨酸1]血管紧张素II的收缩反应没有影响。[丙氨酰7]血管紧张素II作为心脏兴奋剂比血管紧张素II弱，但加入替普罗肽可将其效力提高到血管紧张素II的水平。在替普罗肽存在的情况下，[肌氨酸1，丙氨酰7]血管紧张素II也与[肌氨酸1]血管紧张素II等效。血管紧张素I作为正性肌力药物的效力（ED50 = 100 nM）明显低于血管紧张素II，且血管紧张素I的反应被替普罗肽减弱。给予替普罗肽后，[肌氨酸1，丙氨酰7]血管紧张素I是一种更有效的正性肌力药物。这些发现表明，心房转化酶可代谢血管紧张素I以及血管紧张素I和II的[丙氨酰7]类似物。血管紧张素II和[肌氨酸1]血管紧张素II在主动脉中的活性与在心房中的相似。如先前关于子宫的报道，无论是否存在替普罗肽，[丙氨酰7]血管紧张素II在主动脉中均无活性。十肽在主动脉和心房中的效力相同。在NH2末端的肌氨酸取代也被观察到会减弱心脏选择性。这些数据表明，[丙氨酰7]血管紧张素类似物是具有心脏选择性的正性肌力药物。
