We have previously shown that aldosterone downregulates delayed rectifier potassium currents (I-Ks) via activation of the mineralocorticoid receptor (MR) in adult guinea pig cardiomyocytes. Here, we investigate whether angiotensin II/angiotensin type 1 receptor (AngII/AT1R) and intracellular calcium also play a role in these effects. Ventricular cardiomyocytes were isolated from adult guinea pigs and incubated with aldosterone (1 mu mol.L-1) either alone or in combination with enalapril (1 mu mol.L-1), losartan (1 mu mol.L-1), nimodipine (1 mu mol.L-1), or BAPTA-AM (2.5 mu mol.L-1) for 24 h. We used the conventional whole cell patch-clamp technique to record the I-Ks component. In addition, we evaluated expression of the I-Ks subunits KCNQ1 and KCNE1 using Western blotting. Our results showed that both enalapril and losartan, but not nimodipine or BAPTA-AM, completely reversed the aldosterone-induced inhibition of I-Ks and its effects on KCNQ1/KCNE1 protein levels. Furthermore, we found that AngII/AT1R mediates the inhibitory effects of aldosterone on I-Ks. Finally, the downregulation of I-Ks induced by aldosterone did not occur secondarily to a change in intracellular calcium concentrations. Taken together, our findings demonstrate that crosstalk between MR and AT1R underlies the effects of aldosterone, and provide new insights into the mechanism underlying potassium channels.