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A classification of antiarrhythmic drugs based on the Na^+ channel blocking properties directly assessed by the cardiac Na^+ current recordings

基于通过心脏 Na^ 电流记录直接评估的 Na^ 通道阻断特性的抗心律失常药物的分类

基本信息

批准号：
03404032
负责人：
HIRAOKA Masayasu
金额：
$ 8.13万
依托单位：
Tokyo Medical & Dental University, Medical Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1993
项目状态：
已结题

项目摘要

There have been considerable variation as to the subclassification of the class I antiarrhythmic drugs depending on the methodology to assess the drug actions, different preparations and individual reporters. As a possible reason for the above confusion, most of the reports dealt with the Na^+ channel block as assessed by measuring V_<max> of action potentials, an indirect index of the Na^+ channel availability rather than the current measurement. Therefore we tried to explore the modes of the Na^+ channel block by class I antiarrhythmic drugs directly assessed by the recordings of the cardiac Na^+ current using the patch-clamp technique and to obtain a new classification of the drugs based on the results. We used isolated ventricular myocytes from guinea-pig hearts by collagenase treatment. The Na^+ currents were recorded by the patch-clamp technique of whole-cell configuration, cell-attached and inside-out patch configurations, Disopyramide, I_a agent, produced used-dependent block of the Na^+ current with two exponential functions, fast and slow component. It was further shown by the experiments conducted under different external pH that the slow block process was caused by ionized form of the drug having affinity to bind the activated state of the Na^+ channel, while the fast process was produced by the non-ionized form to the activated state of the channel. The fast and slow block fractions consisted nearly equal degrees. Lidocaine, I_b agent, also caused two exponential block developments, while the major portion of the block development was brought by the fast fraction with small part by the slow component. The fast block was made by the non-ionized drug to bind the inactivated state of the channel and the slow block was caused by the ionized drug to the activated state of the channel. Mexyletine also caused two exponential block development as similar to lidocaine. The ionized mexiletine pr

根据评估药物作用的方法、不同的制剂和个体报告者，I 类抗心律失常药物的细分存在相当大的差异。作为上述混乱的可能原因，大多数报告涉及通过测量动作电位的 V_<max> 来评估 Na^+ 通道阻滞，这是 Na^+ 通道可用性的间接指标，而不是当前测量。因此，我们尝试通过膜片钳技术记录心脏Na^+电流直接评估I类抗心律失常药物对Na^+通道的阻滞模式，并根据结果获得新的药物分类。我们使用通过胶原酶处理从豚鼠心脏分离的心室肌细胞。通过全细胞配置、细胞附着和内向外膜片配置的膜片钳技术记录Na^+电流，丙吡胺、I_a试剂产生具有两个指数函数、快速和慢速分量的Na^+电流的使用依赖性块。在不同外部pH下进行的实验进一步表明，缓慢的阻断过程是由具有与Na^+通道的激活状态结合的亲和力的电离形式的药物引起的，而快速的过程是由非电离形式与通道的激活状态结合产生的。快块和慢块的分数几乎相等。 I_b剂利多卡因也引起两次指数阻滞的发展，而阻滞发展的主要部分是由快部分引起的，小部分是由慢部分引起的。快速阻断是由非离子化药物与通道的失活状态结合而产生的，慢速阻断是由离子化药物与通道的激活状态结合引起的。与利多卡因类似，美西律也引起两个指数阻滞的发展。电离美西律PR