Osypenko V M, Degtiar V Ie, Naid'onov V G, Shuba Ia M
A. A. Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine.
Fiziol Zh (1994). 2001;47(1):17-25.
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.
我们研究了临床上用于治疗精神疾病但据报道有促心律失常副作用的抗精神病药物氟哌啶醇、匹莫齐特和氟司必林，对负责心脏延迟整流钾电流（IKr）快速成分的HERG编码钾通道的影响。这三种药物均以电压依赖性方式阻断非洲爪蟾卵母细胞中HERG介导的IKr。阻断程度随去极化增加，与通道激活相关，符合开放通道阻断机制。氟哌啶醇、匹莫齐特和氟司必林诱导完全激活的IKr阻断的IC50值分别为1.36、1.74和2.34μM。抗精神病药物不影响HERG通道的稳态激活和失活特性。因此，HERG通道的阻断可能是抗精神病药物促心律失常作用的基础，导致心脏动作电位复极化阶段减慢和心电图QT间期延长。
