Angiotensin AT1 receptor subtype as a cardiac target of aldosterone -: Role in aldosterone-salt-induced fibrosis

This study tests the hypothesis that aldosterone induces cardiac fibrosis through an increase of cardiac angiotensin II (Ang II) AT(1) receptor levels, thereby potentiating the fibrotic effect of Ang II by determining the effects of spironolactone and losartan on cardiac fibrosis, AT(1) density, and gene expression in aldosterone-salt-treated rats. Fibrosis was quantified by slot blots of collagen I and III mRNA levels and videomorphometry of Sirius red-stained collagen. AT(1) receptor density was determined by (I-125-Sar(1)-Ile(8))-Ang II competition binding, and AT(1) mRNA levels were analyzed by quantitative reverse transcriptase polymerase chain reaction. One month of aldosterone-salt treatment induced a decrease in plasma Ang II and an increase in blood pressure, left ventricular hypertrophy, and ventricular fibrosis. Spironolactone (20 mg/kg per day) and losartan spironolactone (10 mg/kg per day) had no effect on the first 3 parameters. Losartan was as effective as spironolactone in preventing ventricular collagen mRNA increase and fibrosis. Ventricular density of AT(1) receptors increased 2-fold and was accompanied by a 3-fold increase in the corresponding mRNA in aldosterone-salt compared with sham-operated rats. Both spironolactone and losartan prevented the elevation of ventricular AT(1) density and that of right ventricular AT(1) mRNA levels. These results demonstrate that the mechanism by which aldosterone-salt induces cardiac fibrosis involves Ang II acting through AT(1) receptors. They also suggest that the cardiac AT(1) receptor is a target for aldosterone.