[Blockade of HERG K+ channels expressed in Xenopus oocytes by antipsychotic agents].
We have investigated the effects of neuroleptic agents, haloperidol, pimozide and fluspirilen, that are used in clinics to treat psychiatric disorders, but reportedly have proarrhythmic side effects, on HERG-encoded K+ channels responsible for the rapid component of cardiac delayed rectifier K+ current, IKr. All three agents blocked HERG-directed IKr in Xenopus oocytes in a voltage-dependent manner. The extent of the blockade increased with depolarization correlating with channels activation consistent with open-channel blocking mechanism. The IC50 values for the haloperidol-, pimozide- and fluspirilen-induced blockade of fully activated IKr were 1.36, 1.74 and 2.34 mcM respectively. Neuroleptics did not affect the HERG channels steady-state activation and inactivation properties. Thus, the blockade of HERG channels may underly proarrhythmic actions of neuroleptics resulting in a slowing down of the repolarization phase of cardiac action potential, and prolongation of the electrocardiographic QT interval.
Osypenko
V M
VM
A. A. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine.
Degtiar
V Ie
VIe
Naid'onov
V G
VG
Shuba
Ia M
IaM
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005484:Fluspirilene / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D010868:Pimozide / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D014982:Xenopus laevis
D014150:Antipsychotic Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D010868:Pimozide; D005484:Fluspirilene; D006220:Haloperidol