Role of the At2 Receptor in the Cardioprotective Effect of At1 Antagonist in Mice with Chronic Heart Failure Induced by Coronary Ligation
Angiotensin II (Ang II) acts mainly on two receptor subtypes: type 1 (AT1) and type 2 (AT2). Most of the known biological actions of Ang II are mediated via AT1 receptors; however, the role of the AT2 receptor is less well defined. We hypothesized that blockade of AT1 receptors increases circulating Ang II levels, which in turn activates the AT2 receptor and induces cardioprotection. In mice which lack AT2 receptors, the effect of an AT1 antagonist (AT1-ant) would be diminished or absent. AT2 receptor knockout mice (-/-) and their wild-type littermates (+/+) were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. One month after MI, each strain of mice received either vehicle or AT1-ant (valsartan, 50 mg/kg/day in drinking water) for 3 months. Systolic blood pressure (SBP) was measured weekly and echocardiography performed once a month. Basal SBP and cardiac function did not differ between +/+ and -/-. Three months after MI, SBP and cardiac function changed similarly in both strains receiving vehicle. Valsartan significantly increased EF and decreased LVDd and mass and these effects were diminished in -/- (table). Our results suggest that under basal conditions, the AT2 receptor may not play an important role in regulation of blood pressure and cardiac function; however, it does appear to be an important component in the cardioprotective effect of AT1-ant.