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“调制受体假设”的分离的豚鼠心室肌​​肉，研究了I级抗心律失常药物对动作电位最大上风速度（VMAX）的抑制作用。2。使用单个蔗糖间隙电压夹技术从静息电势到0 mV水平应用了调节夹脉冲，在终止夹具脉冲后，测量夹具脉冲后引起了100毫秒的VMAX作为钠通道可用性的指标。这种夹具脉冲在存在药物的情况下导致各种VMAX降低。将VMAX降低10毫秒夹具脉冲被定义为活化的通道块（ACB），并且随着夹具脉冲持续时间从10到500毫秒延长，VMAX的降低定义为将其定义为灭活通道块（ICB）。对于氨基酰胺和奎尼丁，ICB与ACB的比率小于1.0（0.36-0.51），而对于墨西利，利多卡因，tocainide和aprintine的甲吡丁胺和ACB的比率小于1.0（2.61-11.23）。这些发现表明，以前的药物可能主要在上风阶段的动作电位上阻止钠通道，而后者主要是在高原阶段的作用阶段进行的。3。还研究了Aprindine和Lidocaine之间的相互作用。额外施用利多卡因后，Aprindine的使用依赖性vmax被显着减弱。在存在Aprindine和Lidocaine的情况下，在双重指数函数中恢复了1.0秒后的VMAX，其中短和长时间常数与每种药物单一处理的值相对应。这些发现表明，两种药物可以通过与具有不同动力学的常见受体位点结合来阻止钠通道，从而导致彼此的竞争位移。

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）