Angiotensin AT(1) receptor subtype as a cardiac target of aldosterone - Role in aldosterone-salt-induced fibrosis

This study tests the hypothesis that aldosterone induces cardiac fibrosis t hrough an increase of cardiac angiotensin II (Ang II) AT(1) receptor levels , thereby potentiating the fibrotic effect of Ang II by determining the eff ects 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 Sir ius red-stained collagen. AT(1) receptor density was determined by (I-125-S ar(1)-Ile(8))-Ang II competition binding, and AT(1) mRNA levels were analyz ed by quantitative reverse transcriptase polymerase chain reaction. One mon th 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 ef fective as spironolactone in preventing ventricular collagen mRNA increase and fibrosis. Ventricular density of AT(1) receptors increased 2-fold and w as accompanied by a 3-fold increase in the corresponding mRNA in aldosteron e-salt compared with sham-operated rats. Both spironolactone and losartan p revented the elevation of ventricular AT(1) density and that of right ventr icular AT(1) mRNA levels. These results demonstrate that the mechanism by w hich aldosterone-salt induces cardiac fibrosis involves Ang II acting throu gh AT(1) receptors. They also suggest that the cardiac AT(1) receptor is a target for aldosterone.