Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice

Angiotensin II (Ang II) acts mainly on two receptor subtypes: AT(1) and AT(2). Most of the known biological actions of Ang 11 are mediated by AT, receptors; however, the role of AT(2) receptors remains unclear. We tested the hypothesis that the cardioprotective effects of AT(1) receptor antagonists (AT(1)-ant) after myocardial infarction (MI) are partially mediated by activation of AT(2) receptors; thus in AT(2) receptor gene knockout mice (AT(2)-/Y), the effect of AT(1)-ant will be diminished or absent. MI was induced by ligating the left anterior descending coronary artery. Four weeks later, AT(2)-/Y and their wild-type littermates (AT(2)+/Y) were started on vehicle, AT(1)-ant (valsartan, 50 mg/kg per day), or ACE inhibitor (enalapril, 20 mg/kg per day) for 20 weeks. Basal blood pressure and cardiac function as well as remodeling after MI did not differ between AT(2)+/Y and AT(2)/Y. AT(1)-ant increased ejection fraction and cardiac output and decreased left ventricular diastolic dimension, myocyte cross-sectional area, and interstitial collagen deposition in AT(2)-/Y, and these effects were significantly diminished in AT(2)-/Y. ACE inhibitors improved cardiac function and remodeling similarly in both strains. We concluded that (1) activation of AT(2) during AT(1) blockade plays an important role in the therapeutic effect of AT(1)-ant and (2) the AT(2) receptor may not play an important role in regulation of cardiac function, either under basal conditions after MI remodeling or in the therapeutic effect of ACE inhibitors.