Angiotensin AT2 receptor agonist stimulates high stretch induced-ANP secretion via PI3K/NO/sGC/PKG/pathway

Abstract

Angiotensin II (Ang II) type 1 receptor (AT(1)R) mediates the major cardiovascular effects of Ang II. However, the effects mediated via AT(2)R are still controversial. The aim of the present study is to define the effect of AT(2)R 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 1 mu M) 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 (0.1 mu M) on high stretch-induced ANP secretion was attenuated by the pretreatment with AT(2)R antagonist or inhibitor for phosphoinositol 3-kinase (PI3K), nitric oxide (NO), soluble guanylyl cyclase (sGC), or protein kinase G (PKG). However, antagonist for AT(1)R or Mas receptor did not influence CGP-induced ANP secretion. In vivo study, acute infusion of CGP for 10 min increased plasma ANP level without blood pressure change. In renal hypertensive rat atria, AT(2)R 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 AT(2)R antagonist for 10 min followed by CGP infusion attenuated an increased plasma ANP level induced by CGP. However, pretreatment with AT(1)R or Mas receptor antagonist unaffected CGP-induced increase in plasma ANP level. Therefore, we suggest that AT(2)R agonist CGP stimulates high stretch-induced ANP secretion through PI3K/NO/5GC/PKG pathway and these effects are augmented in renal hypertensive rats. (C) 2013 Elsevier Inc. All rights reserved.