Department of Pharmacology, Taishan Medical University, Shandong, China.
Peptides. 2013 Sep;47:36-44. doi: 10.1016/j.peptides.2013.06.008. Epub 2013 Jun 18.
Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the major cardiovascular effects of Ang II. However, the effects mediated via AT2R are still controversial. The aim of the present study is to define the effect of AT2R agonist CGP42112A (CGP) on high stretch-induced ANP secretion and its mechanism using in vitro and in vivo experiments. CGP (0.01, 0.1 and 1μM) stimulated high stretch-induced ANP secretion and concentration from isolated perfused rat atria. However, atrial contractility and the translocation of extracellular fluid did not change. The augmented effect of CGP (0.1μM) on high stretch-induced ANP secretion was attenuated by the pretreatment with AT2R antagonist or inhibitor for phosphoinositol 3-kinase (PI3K), nitric oxide (NO), soluble guanylyl cyclase (sGC), or protein kinase G (PKG). However, antagonist for AT1R or Mas receptor did not influence CGP-induced ANP secretion. In vivo study, acute infusion of CGP for 10min increased plasma ANP level without blood pressure change. In renal hypertensive rat atria, AT2R mRNA and protein levels were up-regulated and the response of plasma ANP level to CGP infusion in renal hypertensive rats augmented. The pretreatment with AT2R antagonist for 10min followed by CGP infusion attenuated an increased plasma ANP level induced by CGP. However, pretreatment with AT1R or Mas receptor antagonist unaffected CGP-induced increase in plasma ANP level. Therefore, we suggest that AT2R agonist CGP stimulates high stretch-induced ANP secretion through PI3K/NO/sGC/PKG pathway and these effects are augmented in renal hypertensive rats.
血管紧张素 II（Ang II）1 型受体（AT1R）介导 Ang II 的主要心血管效应。然而，AT2R 介导的作用仍存在争议。本研究旨在通过体外和体内实验，确定 AT2R 激动剂 CGP42112A（CGP）对高拉伸诱导的 ANP 分泌的影响及其机制。CGP（0.01、0.1 和 1μM）刺激分离灌注大鼠心房的高拉伸诱导的 ANP 分泌和浓度。然而，心房收缩力和细胞外液的迁移没有改变。用 AT2R 拮抗剂或磷酸肌醇 3-激酶（PI3K）、一氧化氮（NO）、可溶性鸟苷酸环化酶（sGC）或蛋白激酶 G（PKG）抑制剂预处理可减弱 CGP（0.1μM）对高拉伸诱导的 ANP 分泌的增强作用。然而，AT1R 或 Mas 受体拮抗剂对 CGP 诱导的 ANP 分泌没有影响。在体内研究中，CGP 急性输注 10min 可增加血浆 ANP 水平而不改变血压。在肾高血压大鼠心房中，AT2R mRNA 和蛋白水平上调，肾高血压大鼠对 CGP 输注的血浆 ANP 水平反应增强。CGP 输注前用 AT2R 拮抗剂预处理 10min 可减弱 CGP 引起的血浆 ANP 水平升高。然而，用 AT1R 或 Mas 受体拮抗剂预处理不影响 CGP 诱导的血浆 ANP 水平升高。因此，我们认为 AT2R 激动剂 CGP 通过 PI3K/NO/sGC/PKG 途径刺激高拉伸诱导的 ANP 分泌，这些作用在肾高血压大鼠中增强。
