Binding and unbinding kinetics of various Class-I antiarrhythmic drugs with cardiac sodium channels.

1.基于“受体调制假说”，研究了I类抗心律失常药物对豚鼠心室肌动作电位最大上升速度（Vmax）的抑制作用.使用单蔗糖间隙电压钳技术施加从静息电位到0 mV水平的条件钳脉冲，并测量在钳脉冲终止后100 msec引起的测试动作电位的Vmax作为钠通道可用性的指标。在药物存在下，这种钳脉冲引起各种Vmax降低。将10 msec钳位脉冲导致的Vmax降低定义为激活通道阻滞（ACB），将钳位脉冲持续时间从10 msec延长至500 msec导致的Vmax降低定义为失活通道阻滞（ICB）。丙吡胺和奎尼丁的ICB/ACB比值小于1.0（0.36-0.51），而美西律、利多卡因、妥卡尼和阿普林定的ICB/ACB比值远大于1.0（2.61-11.23）。这些结果表明，前一组药物主要在动作电位上升期阻断钠通道，而后者主要在动作电位平台期阻断钠通道.还研究了阿普林定和利多卡因之间的相互作用。应用利多卡因后，阿普林定对Vmax的使用依赖性阻滞明显减弱。在同时存在阿普林定和利多卡因的情况下，1.0秒钳位脉冲后的Vmax以双指数函数恢复，其中短时间常数和长时间常数对应于每种药物单次治疗的值。这些发现表明，这两种药物可能通过以不同的动力学结合到共同的受体位点来阻断钠通道，从而导致彼此竞争性置换。

1. The inhibitory effect of Class-I antiarrhythmic drugs on the maximum upstroke velocity (Vmax) of action potential was investigated in isolated guinea pig ventricular muscles based on the "modulated receptor hypothesis".2. A conditioning clamp pulse was applied from the resting potential to 0 mV level using the single sucrose-gap voltage clamp technique, and Vmax of test action potential elicited 100 msec after termination of the clamp pulse was measured as an index of sodium channel availability. Such clamp pulses caused various Vmax decreases in the presence of the drugs. The decrease in Vmax by 10 msec clamp pulse was defined as the activated channel block (ACB), and the decrease in Vmax as the clamp pulse duration was prolonged from 10 to 500 msec was defined as the inactivated channel block (ICB). The ratio of ICB to ACB was less than 1.0 (0.36-0.51) for disopyramide and quinidine, and much greater than 1.0 (2.61-11.23) for mexiletine, lidocaine, tocainide and aprindine. These findings suggest that the former group of drugs may block the sodium channel mainly during the upstroke phase of action potential, while the latter do so mainly during the plateau phase of action potential.3. An interaction between aprindine and lidocaine was also investigated. The use-dependent block of Vmax by aprindine was significantly attenuated after additional application of lidocaine. In the presence of both aprindine and lidocaine, Vmax after a clamp pulse of 1.0 sec recovered in dual exponential function, where the short and the long time constant corresponded to the values for single treatment with each drug. These findings suggest that the two drugs may block the sodium channel by binding to a common receptor site with different kinetics, leading to a competitive displacement with each other.