Department of Physiology, Chonbuk National University Medical School, 2-20 Keum-Am-Dong-San, Jeonju, Korea.
Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1365-74. doi: 10.1152/ajpheart.00608.2009. Epub 2010 Feb 26.
Angiotensin-(1-7) [ANG-(1-7)], one of the bioactive peptides produced in the renin-angiotensin system, plays a pivotal role in cardiovascular physiology by providing a counterbalance to the function of ANG II. Recently, it has been considered as a potential candidate for therapeutic use in the treatment of various types of cardiovascular diseases. The aim of the present study is to explain the modulatory role of ANG-(1-7) in atrial natriuretic peptide (ANP) secretion and investigate the functional relationship between two peptides to induce cardiovascular effects using isolated perfused beating rat atria and a cardiac hypertrophied rat model. ANG-(1-7) (0.01, 0.1, and 1 muM) increased ANP secretion and ANP concentration in a dose-dependent manner at high atrial pacing (6.0 Hz) with increased cGMP production. However, at low atrial pacing (1.2 Hz), ANG-(1-7) did not cause changes in atrial parameters. Pretreatment with an antagonist of the Mas receptor or with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), or nitric oxide synthase blocked the augmentation of high atrial pacing-induced ANP secretion by ANG-(1-7). A similar result was observed with the inhibition of the Na(+)/H(+) exchanger-1 and Ca(2+)/calmodulin-dependent kinase II (CaMKII). ANG-(1-7) did not show basal intracellular Ca(2+) signaling in quiescent atrial myocytes. In an in vivo study using an isoproterenol-induced cardiac hypertrophy animal model, an acute infusion of ANG-(1-7) increased the plasma concentration of ANP by twofold without changes in blood pressure and heart rate. A chronic administration of ANG-(1-7) increased the plasma ANP level and attenuated isoproterenol-induced cardiac hypertrophy. The antihypertrophic effect was abrogated by a cotreatment with the natriuretic peptide receptor-A antagonist. These results suggest that 1) ANG-(1-7) increased ANP secretion at high atrial pacing via the Mas/PI3K/Akt pathway and the activation of Na(+)/H(+) exchanger-1 and CaMKII and 2) ANG-(1-7) decreased cardiac hypertrophy which might be mediated by ANP.
血管紧张素-(1-7)[ANG-(1-7)]，作为肾素-血管紧张素系统中产生的生物活性肽之一，通过对血管紧张素 II 功能提供一种平衡作用，在心血管生理学中发挥着关键作用。最近，它被认为是治疗各种类型心血管疾病的潜在候选药物。本研究旨在解释 ANG-(1-7)在心房利钠肽(ANP)分泌中的调节作用，并使用分离的灌注跳动大鼠心房和心脏肥厚大鼠模型研究两种肽之间的功能关系，以诱导心血管效应。ANG-(1-7)(0.01、0.1 和 1 μM)以剂量依赖性方式增加 ANP 分泌和 ANP 浓度，同时增加高心房起搏(6.0 Hz)时的 cGMP 产生。然而，在低心房起搏(1.2 Hz)时，ANG-(1-7)不引起心房参数的变化。Mas 受体拮抗剂或磷脂酰肌醇 3-激酶(PI3K)、蛋白激酶 B(Akt)或一氧化氮合酶抑制剂预处理阻断了 ANG-(1-7)对高心房起搏诱导的 ANP 分泌的增强作用。Na(+)/H(+)交换体-1 和 Ca(2+)/钙调蛋白依赖性激酶 II(CaMKII)的抑制也得到了类似的结果。ANG-(1-7)在静止的心房肌细胞中没有显示出基础细胞内 Ca(2+)信号。在异丙肾上腺素诱导的心脏肥厚动物模型的体内研究中，急性输注 ANG-(1-7)使血浆 ANP 浓度增加了一倍，而血压和心率没有变化。ANG-(1-7)的慢性给药增加了血浆 ANP 水平，并减轻了异丙肾上腺素诱导的心脏肥厚。用利钠肽受体-A 拮抗剂共同处理，抗高血压作用被阻断。这些结果表明：1)ANG-(1-7)通过 Mas/PI3K/Akt 途径和 Na(+)/H(+)交换体-1 和 CaMKII 的激活，在高心房起搏时增加 ANP 分泌，2)ANG-(1-7)减少心脏肥厚，这可能是通过 ANP 介导的。
