Direct effects of candesartan and eprosartan on human cloned potassium channels involved in cardiac repolarization

In the present study, we analyzed the effects of two angiotensin II type 1 receptor antagonists, candesartan (0.1 muM) and eprosartan (1 muM), on hKv1 .5, HERG, KvLQT1+minK, and Kv4.3 channels expressed on Ltk(-) or Chinese ha mster ovary cells using the patch-clamp technique. Candesartan and eprosart an produced a voltage-dependent block of hKv1.5 channels decreasing the cur rent at +60 mV by 20.9 +/- 2.3% and 14.3 +/- 1.5%, respectively. The blocka de was frequency-dependent, suggesting an open-channel interaction. Eprosar tan inhibited the tail amplitude of HERG currents elicited on repolarizatio n after pulses to +60 mV from 239 +/- 78 to 179 +/- 72 pA. Candesartan shif ted the activation curve of HERG channels in the hyperpolarizing direction, thus increasing the current amplitude elicited by depolarizations to poten tials between -50 and 0 mV. Candesartan reduced the KvLQT1+minK currents el icited by 2-s pulses to +60 mV (38.7 +/- 6.3%). In contrast, eprosartan tra nsiently increased (8.8 +/- 2.7%) and thereafter reduced the KvLQT1+minK cu rrent amplitude by 17.7 +/- 3.0%. Eprosartan, but not candesartan, blocked Kv4.3 channels in a voltage-dependent manner (22.2 +/- 3.5% at +50 mV) with out modifying the voltage-dependence of Kv4.3 channel inactivation. Candesa rtan slightly prolonged the action potential duration recorded in guinea pi g papillary muscles at all driving rates. Eprosartan prolonged the action p otential duration in muscles driven at 0.1 to 1 Hz, but it shortened this p arameter at faster rates (2-3 Hz). All these results demonstrated that cand esartan and eprosartan exert direct effects on Kv1.5, HERG, KvLQT1+minK, an d Kv4.3 currents involved in human cardiac repolarization.