MODELS OF ION CHANNEL BLOCKADE BY ANTIARRHYTHMIC AGENTS

此更新请求是为了继续支持研究重点 离子通道阻断之间的宏观相互作用 剂和可兴奋膜（心脏和神经）以及这是如何 相互作用改变细胞之间的电通讯。 凭借生物物理学上准确的模型，我们相信可以深入了解 可以利用通道封锁机制来改善 控制心脏（和神经系统）中的电事件。 此外，这些结果可以帮助对药物进行分类 电生理效应。 为此，本工作重点 持续开发定量准确的模型 药物通道相互作用和由此产生的掺入 描述心脏和神经活动的标准模型 势以预测通道封锁的影响 可观察到的电事件。 我们当前 3 年期间的工作重点是 验证我们最初的钠通道阻断模型。 一个 主要目标是开发一个估算程序 非平衡数据的平衡解离常数 来自脉冲串膜激发。 由此产生的 方法已通过多种钠的部分验证 通道阻断剂并发现也准确地描述 钾和钙通道阻断。 我们未来 5 年的目标是继续详细 开发定量精确的离子物理模型 通道阻塞，将阻塞模型耦合到模型 膜和细胞外动作电位，以延长 多种药物竞争同一结合位点的模型，以及 扩展到单一药物结合不同通道的情况 类型。 最后一个目标已成为药物证据的关键 阻断不同的通道类型（Na、K 和 Ca）已成为 可用。 主要注意力将集中在翻译上 对细胞水平事件的理解到临床 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.