Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University School of Medicine, Chuncheon 200-701, Korea.
Acta Pharmacol Sin. 2011 Sep;32(9):1128-37. doi: 10.1038/aps.2011.66.
To investigate the effects of hydroxyzine on human ether-a-go-go-related gene (hERG) channels to determine the electrolphysiological basis for its proarrhythmic effects.
hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp.
Hydroxyzine (0.2 and 2 μmol/L) significantly increased the action potential duration at 90% repolarization (APD(90)) in both concentration- and time-dependent manners. Hydroxyzine (0.03-3 μmol/L) blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC(50) for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ~6-fold.
The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.
研究羟嗪对人 ether-a-go-go 相关基因（hERG）通道的影响，以确定其致心律失常作用的电生理学基础。
在非洲爪蟾卵母细胞和 HEK293 细胞中表达 hERG 通道，分别采用双电极电压钳和膜片钳技术研究羟嗪对通道的影响。采用电流钳在豚鼠心室肌细胞中检测羟嗪对动作电位时程的影响。
羟嗪（0.2 和 2 μmol/L）以浓度和时间依赖的方式显著增加 90%复极化时程（APD(90)）。羟嗪（0.03-3 μmol/L）阻断稳态和尾 hERG 电流。阻断呈电压依赖性，在+20 mV 时阻断稳态和尾电流的 IC(50)值分别为 0.18±0.02 μmol/L 和 0.16±0.01 μmol/L。羟嗪（5 μmol/L）影响通道的激活和失活状态，但不影响关闭状态。S6 结构域突变 Y652A 将 hERG 电流的阻断作用减弱约 6 倍。
结果表明，羟嗪可阻断 hERG 通道并延长 APD。通道中 652 位的酪氨酸可能是羟嗪致心律失常作用的原因。
