Ogata N, Nishimura M, Narahashi T
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois.
J Pharmacol Exp Ther. 1989 Feb;248(2):605-13.
Block of sodium current by chlorpromazine in single ventricular myocytes isolated from guinea pigs was studied using the whole cell patch clamp technique. Chlorpromazine in micromolar concentrations reduced the amplitude of peak sodium current associated with step depolarizations from a holding potential of -140 mV. Concentration-response curves obtained with a holding potential of -140 mV were best fit by a 2:1 stoichiometry, and were shifted in the direction of lower concentrations when a holding potential of -100 mV was used. In agreement with this observation, the steady-state inactivation curve was shifted to more negative potentials by chlorpromazine. The block was not associated with any change in the time course of sodium current activation or inactivation during a depolarizing step. Chlorpromazine also produced marked use-dependent block as demonstrated by a cumulative increase in the block during a train of depolarizing pulses. This use dependence was due to a higher affinity of chlorpromazine for the inactivated state of sodium channels than for the resting state and to a very slow repriming of the drug-bound sodium channels from inactivation. These blocking actions could contribute to the antiarrhythmic effects of chlorpromazine at low concentrations and to the cardiotoxic effects at high concentrations.
采用全细胞膜片钳技术研究了氯丙嗪对豚鼠单个心室肌细胞钠电流的阻断作用。微摩尔浓度的氯丙嗪降低了与从 -140 mV 的钳制电位进行阶跃去极化相关的钠电流峰值幅度。在 -140 mV 的钳制电位下获得的浓度 - 反应曲线以 2:1 的化学计量关系拟合最佳，当使用 -100 mV 的钳制电位时，曲线向较低浓度方向移动。与该观察结果一致，氯丙嗪使稳态失活曲线向更负的电位移动。在去极化步骤期间，这种阻断与钠电流激活或失活的时间过程的任何变化均无关。如在一串去极化脉冲期间阻断作用的累积增加所证明的，氯丙嗪还产生明显的使用依赖性阻断。这种使用依赖性是由于氯丙嗪对钠通道失活状态的亲和力高于对静息状态的亲和力，以及药物结合的钠通道从失活状态重新激活非常缓慢。这些阻断作用可能有助于氯丙嗪在低浓度时的抗心律失常作用以及在高浓度时的心脏毒性作用。
