TY - JOUR T1 - Direct Effects of Candesartan and Eprosartan on Human Cloned Potassium Channels Involved in Cardiac Repolarization JF - Molecular Pharmacology JO - Mol Pharmacol SP - 825 LP - 836 DO - 10.1124/mol.59.4.825 VL - 59 IS - 4 AU - Ricardo Caballero AU - Eva Delpón AU - Carmen Valenzuela AU - Mónica Longobardo AU - Teresa González AU - Juan Tamargo Y1 - 2001/04/01 UR - http://molpharm.aspetjournals.org/content/59/4/825.abstract N2 - In the present study, we analyzed the effects of two angiotensin II type 1 receptor antagonists, candesartan (0.1 μM) and eprosartan (1 μM), on hKv1.5, HERG, KvLQT1+minK, and Kv4.3 channels expressed onLtk − or Chinese hamster ovary cells using the patch-clamp technique. Candesartan and eprosartan produced a voltage-dependent block of hKv1.5 channels decreasing the current at +60 mV by 20.9 ± 2.3% and 14.3 ± 1.5%, respectively. The blockade was frequency-dependent, suggesting an open-channel interaction. Eprosartan inhibited the tail amplitude of HERG currents elicited on repolarization after pulses to +60 mV from 239 ± 78 to 179 ± 72 pA. Candesartan shifted the activation curve of HERG channels in the hyperpolarizing direction, thus increasing the current amplitude elicited by depolarizations to potentials between −50 and 0 mV. Candesartan reduced the KvLQT1+minK currents elicited by 2-s pulses to +60 mV (38.7 ± 6.3%). In contrast, eprosartan transiently increased (8.8 ± 2.7%) and thereafter reduced the KvLQT1+minK current 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) without modifying the voltage-dependence of Kv4.3 channel inactivation. Candesartan slightly prolonged the action potential duration recorded in guinea pig papillary muscles at all driving rates. Eprosartan prolonged the action potential duration in muscles driven at 0.1 to 1 Hz, but it shortened this parameter at faster rates (2–3 Hz). All these results demonstrated that candesartan and eprosartan exert direct effects on Kv1.5, HERG, KvLQT1+minK, and Kv4.3 currents involved in human cardiac repolarization. ER -