甲氧普胺阻滞心肌钠通道的计算机模拟研究

COMPUTER SIMULATION OF METOCLOPRAMIDE BLOCK OF CARDIAC SODIUM CHANNELS

根据闸门相关受体模型,应用计算机模拟研究了甲氧普胺阻滞心肌钠通道的动力学特点及其作用的状态依赖性。本文首次描述和分析了同时受两种门控机制调控的钠通道阻滞剂的作用特点,甲氧普胺即具此特点,其阻滞作用依赖于通道的激活态及失活态,其在刺激频率2.0Hz时的表观阻滞起效速率为0.49/AP,在膜电位—85mV时的阻滞恢复时间常数为2.82s.

Based on the gate-related receptor hypothesis, quantitative study on kin- etics and state-dependency of metoclopramide (Met) blockade of cardiac sodium channels was performed by computer simulation. The action characteristics of Met, a sodium channel blocker modulated simultaneously by both activation and inactivation gates were described and analyzed for the first time. The time constant of recovery from blocking by Met at resting potential-85 mV was 2.82s, which was increased during depolarization or hyperpolarization. Its apparent rate of onset of blocking was 0.49 AP-1 at stimulation frequency of 2.0 Hz. No shift of the midpoint of h∞ curve at 100 μmol/L Met was found, although a concentration-dependent shift of h∞ curve existed at higher doeses. This study provide a new test and verification for our gate-related receptor hypothesis .