Regulation of the myocardial endothelin system by angiotensin-II and losartan

Evidence for interactions between the endothelin (ET) and renin-angiotensin systems is plentiful in vitro, but few studies have investigated these int eractions in vivo. In the study reported here, we have investigated the inf luence of chronic angiotensin-II (A-II) infusion in vivo on expression of p reproendothelin-l (PPET-1) and endothelin-A- (ETA) and endothelin-B- (ETB) receptor mRNA in the heart. The role of the angiotensin type 1 (AT1)recepto r in mediating the actions of A-II was studied using losartan, the selectiv e At1-receptor antagonist. Male rats received an infusion of A-II (200 ng/k g/min) or vehicle for 14 days via mini-osmotic pumps; losartan (10 mg/kg/da y) was administered in the drinking water. PPET-1 and ETA- and ETB-receptor mRNA were detected in heart sections using nonradioactive antisense in sit u hybridization. Independent treatments with either A-II or losartan had no significant effect on PPET-1, ETA- or ETB-receptor expression. Combined tr eatment resulted in an increase in PPET-1 mRNA (p < 0.001) and ETB-receptor mRNA expression (p < 0.01), while ETA-receptor mRNA expression was decreas ed (p < 0.001). These results suggest that selective AT1-receptor blockade, in the presence of an elevated plasma A-II concentration, causes upregulat ion of ET-1 synthesis in the myocardium as well as modification of ET recep tor expression. These effects may be mediated via angiotensin type 2 (AT2)- receptors.