利多卡因对hERG钾通道的影响

The effect of lidocaine on hERG K^+ channels

研究利多卡因对克隆h ERG钾通道的作用,探讨其对心脏电生理的影响。利用全细胞膜片钳技术和Western blot技术,观察利多卡因对稳定表达h ERG钾通道的HEK 293细胞h ERG电流和蛋白表达的影响,同时观察利多卡因对离体兔心脏心电图的影响。结果显示,利多卡因在0.3~1 000μmol·L^(-1)内呈浓度依赖性抑制h ERG电流,IC50值为88.63±7.99μmol·L^(-1);抑制作用在大于20 m V电压下更明显,不影响通道激活曲线,但具有频率依赖性特点;慢性孵育利多卡因不影响h ERG蛋白的表达;利多卡因对QTc间期没有明显影响,但浓度大于100μmol·L^(-1)可减慢心率,延长PR间期以及QRS波。结果表明,尽管利多卡因在较高浓度下具有潜在的h ERG电流抑制作用,但并不引起QTc间期延长。

We studied the effects of the lidocaine on the hERG K^＋ channels with a focus on the electrophysiology of the heart. The hERG current was recorded using the conventional whole-cell patch clamp technique and the channel protein expression level was measured with Western blot in HEK 293 cells stablely expressed hERG K^＋ channels. The langendorff perfusion system was used to record the ECG from isolated rabbit heart. Lidocaine inhibited bERG current in a concentration-dependent manner at 0.3-1 000 μmol·L^-1, the IC50 value was 88.63± 7.99μmol·L^-1. The inhibitory action was enhanced by positive votalge without changing the votalge-dependent activation of the channel. However, lidocaine inhibited hERG current in a frequency-dependent manner. In addition, chronic incubation of lidocaine did not change the bERG K^＋ channel protein expression. ECG recordings in the isolated perfused rabbit heart demonstrated that lidocaine （〉 100 μmol·L^-1） did not affected QTc interval, but decreased the heart rate and prolonged the PR interval and QRS duration. Our results demonstrate that lidocaine potentially inhibits the hERG K^＋ current at a high concentration, but does not prolonged the QTc of ECG.