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

Abstract

AbstractObjectivesWe studied the role of angiotensin II type 2 (AT2) receptors and kinins in the cardioprotective effect of angiotensin II type 1 antagonists (AT1-ant) in rats with heart failure (HF) after myocardial infarction.BackgroundThe AT1-ant is as effective as angiotensin-converting enzyme inhibitors in treating HF, but the mechanisms whereby AT1-ant exert their benefits on HF in vivo are more complex than previously understood.MethodsBrown 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) AT1-ant (L158809, Merck, Rahway, New Jersey); 3) AT1-ant + AT2-ant (PD-123319, Parke Davis, Ann Arbor, Michigan); or 4) AT1-ant + kinin B2receptor antagonist (B2-ant) (icatibant) (only BN). We measured left ventricular weight (LVW) gravimetrically, myocyte cross-sectional area (MCSA) and interstitial collagen fraction (ICF) histologically, and ejection fraction by ventriculography.ResultsDevelopment of HF was comparable in BN and BNK rats. The AT1-ant reduced LVW and MCSA and the AT2-ant blocked these effects in BN rats, but the B2-ant did not. The AT1-ant reduced LVW and MCSA in BNK rats, and this effect was reversed by the AT2-ant. In BN rats, ICF was reduced and LVEF increased by AT1-ant, and both AT2-ant and B2-ant reversed these effects. In BNK rats, the AT1-ant failed to reduce ICF, and its therapeutic effect on LVEF was significantly blunted.ConclusionsIn HF, the AT2receptor plays an important role in the therapeutic effects of AT1-ant, and this effect may be mediated partly through kinins; however, kinins appear to play a lesser role in the antihypertrophic effect of AT1-ant