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

各种I类抗心律失常药物与心脏钠通道的结合和解离动力学。

• 批准号: 60570087
• 负责人: KODAMA Itsuo
• 金额: $ 0.19万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1985
• 资助国家: 日本
• 起止时间: 1985 至 1986
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-60570087/
• 关键词: antiarrhythmic drugs; Vmax; action potential; ventricular muscles; voltage clamp; sodium channel; 使用依存性抑制

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.

1．基于“调节受体假说”，研究了Ⅰ类抗心律失常药物对离体豚鼠心室肌​​动作电位最大上冲速度（Vmax）的抑制作用。 2．使用单蔗糖间隙电压钳技术从静息电位施加调节钳脉冲至0mV水平，并测量钳脉冲终止后100毫秒引发的测试动作电位的Vmax作为钠通道可用性的指数。在药物存在的情况下，这种钳位脉冲会导致各种 Vmax 降低。将 Vmax 减少 10 毫秒钳位脉冲定义为激活通道阻滞 (ACB)，将钳位脉冲持续时间从 10 毫秒延长至 500 毫秒时 Vmax 减少定义为失活通道阻滞 (ICB)。对于丙吡胺和奎尼丁，ICB与ACB的比率小于1.0（0.36-0.51），对于美西律、利多卡因、妥卡尼和阿普林定，ICB与ACB的比率远大于1.0（2.61-11.23）。这些结果表明，前一组药物可能主要在动作电位的上升期阻断钠通道，而后者主要在动作电位的平台期阻断钠通道。3．还研究了阿普林定和利多卡因之间的相互作用。在额外应用利多卡因后，阿普林定对 Vmax 的使用依赖性阻断显着减弱。在阿普林定和利多卡因同时存在的情况下，1.0秒的钳位脉冲后的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的单次治疗的值。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位移。

项目成果

Kodama I,: "Competitive inhibition of cardiac sodium channels by aprindine and lidocaine studied using Vmax of action potential in guinea pig ventricular muscles." J Pharmacol Exp Ther.(1987)

Kodama I，：“使用豚鼠心室肌​​动作电位 Vmax 研究了阿普林定和利多卡因对心脏钠通道的竞争性抑制。”

Kodama I,: "Block of activated and inactivated sodium channels by Class-I antiarrhythmic drugs studied by using the maximum upstroke velocity (Vmax) of action potential in guinea pig cardiac muscles." J Mol and Cell Biol. (1987)

Kodama I，：“通过使用豚鼠心肌动作电位的最大上冲速度 (Vmax) 研究 I 类抗心律失常药物对激活和失活钠通道的阻断。”

Kodama I,: Japanese Heart J.27(supplement I). 11. 83-89 (1986)

Kodama I，：日本心脏 J.27（补充 I）。

Kodama I,: J Mol and Cell Cardiol.(1987)

Kodama I，：J Mol 和 Cell Cardiol。（1987）

Kodama I,: J Pharmacol Exp Ther.(1987)

Kodama I，：J Pharmacol Exp Ther.（1987）