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 microM) and eprosartan (1 microM), on hKv1.5, HERG, KvLQT1+minK, and Kv4.3 channels expressed on Ltk(-) 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.
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
R
R
Caballero
E
E
Delpón
C
C
Valenzuela
M
M
Longobardo
T
T
González
J
J
Tamargo
D000179:Acrylates / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D016466:CHO Cells; D027682:Cation Transport Proteins; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D051666:Kv1.5 Potassium Channel; D051379:Mice; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D051672:Shal Potassium Channels; D013777:Tetrazoles / Q000494:pharmacology*; D013876:Thiophenes; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C496981:KCNA5 protein, human; C497021:KCND3 protein, human; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C496982:Kcna5 protein, mouse; C497022:Kcnd3 protein, mouse; C496910:Kcnq1 protein, mouse; D051666:Kv1.5 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D051672:Shal Potassium Channels; D013777:Tetrazoles; D013876:Thiophenes; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C059983:potassium channel protein I(sk); C068373:eprosartan; C081643:candesartan