Role of angiotensin II type 2 receptors and kinins in the cardioprotective effect of angiotensin II type 1 receptor antagonists in rats with heart failure

OBJECTIVES We studied the role of angiotensin II type 2 (AT(2)) receptors and kinins in the cardioprotective effect of angiotensin II type 1 antagonists (AT(1)-ant) in rats with heart failure (HF) after myocardial infarction. BACKGROUND The AT(1)-ant is as effective as angiotensin-converting enzyme inhibitors in treating HF, but the mechanisms whereby AT(1)-ant exert their benefits on HF in vivo are more complex than previously understood. METHODS Brown Norway Katholiek rats (BNK), which are deficient in kinins because of a mutation in the kininogen gene, and their wild-type control (Brown Norway [BN]) underwent myocardial infarction. Two months later, they were treated for two months with: 1) vehicle; 2) AT(1)-ant (L158809, Merck, Rahway, New Jersey); 3) AT(1)-ant + AT(2)-ant (PD-123319, Parke Davis, Ann Arbor, Michigan); or 4) AT(1)-ant + kinin B-2 receptor antagonist (B-2-ant) (icatibant) (only BN). We measured left ventricular weight (LVW) gravimetrically, myocyte crosssectional area (MCSA) and interstitial collagen fraction (ICF) histologically, and ejection fraction by ventriculography. RESULTS Development of HF was comparable in BN and BNK rats. The AT(1)-ant reduced LVW and MCSA and the AT(2)-ant blocked these effects in BN rats, but the B-2-ant did not. The AT(1)-ant reduced LVW and MCSA in BNK rats, and this effect was reversed by the AT(2)-ant. In BN rats, ICF was reduced and LVEF increased by AT(1)-ant, and both AT(2)-ant and B-2-ant reversed these effects. In BNK rats, the AT(1)-ant failed to reduce ICF, and its therapeutic effect on LVEF was significantly blunted. CONCLUSIONS In HF, the AT(2) receptor plays an important role in the therapeutic effects of AT(1)-ant, and this effect may be mediated partly through kinins; however, kinins appear to play a lesser role in the antihypertrophic effect of AT(1)-ant. (C) 2004 by the American College of Cardiology Foundation