MODELS OF ION CHANNEL BLOCKADE BY ANTIARRHYTHMIC AGENTS

这一更新请求是为了继续支持研究重点 离子通道阻断和 代理人和兴奋膜（心脏和神经），以及如何这 相互作用改变细胞之间的电通信。 有了生物药理学上准确的模型，我们相信， 通道阻断的机制可用于改善 控制心脏（和神经系统）中的电事件。 此外，这些结果可以帮助药物分类， 电生理效应。 为此，这项工作的重点是 继续开发一个定量准确的模型， 药物-通道相互作用和由此产生的 描述成心脏和神经作用的标准模型 电位，以预测通道阻断对 可观察到的电子事件。 我们在本三年期间的工作重点是 验证了我们最初的钠通道阻断模型 一 主要目标是开发一个程序， 由非平衡数据得到的平衡离解常数 源自脉冲序列膜激发。 所得 该方法已部分验证了几种钠 通道阻断剂，并发现也准确地描述了 钾和钙通道阻滞剂。 我们未来五年的目标是继续详细 一个定量精确的离子物理模型的发展 通道阻塞，将阻塞模型耦合到 膜和细胞外动作电位，以延长 竞争相同结合位点的多种药物的模型，以及 扩展到单一药物结合不同通道的情况 类型 这最后一个目标已经成为关键的证据， 阻断不同类型的通道（Na+、K+和Ca++）已成为 available. 主要注意力将集中在翻译上 从细胞水平到临床 心律失常管理策略。

This renewal request is for continued support of research focusing on the macroscopic interaction between ion channel blocking agents and excitable membranes (cardiac and nerve) and how this interaction modifies electrical communication between cells. With a biophysically accurate model, we believe that insights into the mechanism of channel blockade can be used to improve control of electrical events in the heart (and nervous system). Moreover, these results can aid in classifying drugs as to their electrophysiological effects. To this end, this work focuses on continued development of a quantitatively accurate model of drug-channel interactions and incorporation of the resulting description into standard models of cardiac and nerve action potentials in order to predict the effect of channel blockade on observable electrical events. Our work during the current 3 year period has focused on validating our original model of sodium channel blockade. A primary goal was to develop a procedure for estimating equilibrium dissociation constants from nonequilibrium data derived from pulse train membrane excitation. The resulting methodology has been partially validated with several sodium channel blocking agents and found also to accurately describe potassium and calcium channel blockade. Our objective for the next 5 years is to continue the detailed development of a quantitatively accurate physical model of ion channel blockage, to couple the blockade model to models of membrane and extracellular action potentials, to extend the model to multiple drugs competing for the same binding site, and to extend to the case of a single drug binding to different channel types. This last goal has become critical as evidence for drugs blocking different channel types (Na+, K+, and Ca++) has become available. Major attention will be directed towards translating the understanding of events at the cellular level to clinical strategies for arrhythmia management.