High affinity blockade of the HERG cardiac K(+) channel by the neuroleptic pimozide.
Pimozide is an antipsychotic agent also used to treat facial tics. Pimozide can cause acquired long QT syndrome and ventricular arrhythmias. To elucidate the mechanism behind these clinical findings, we examined the effects of pimozide on the cloned human cardiac K(+) channels HERG (human ether-a-go-go-related gene; rapid component of delayed rectifier), Kv1.5 (ultra-rapid delayed rectifier) and KvLQT1/minK (slow component of delayed rectifier). Using patch clamp electrophysiology, we found that pimozide was a potent inhibitor of HERG displaying an IC(50) value of 18 nM. In contrast, pimozide (10 microM) was a weak inhibitor of KvLQT1/minK and Kv1.5. We conclude that pimozide is a specific, high affinity antagonist of HERG, and that this interaction leads to prolongation of cardiac repolarization.
Kang
J
J
Aventis Pharmaceuticals, Route 202-206, P.O. Box 6800, Bridgewater, NJ 08807-0800, USA.
Wang
L
L
Cai
F
F
Rampe
D
D
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016466:CHO Cells; D027682:Cation Transport Proteins; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010868:Pimozide / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D014150:Antipsychotic Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D010868:Pimozide