MODELS OF ION CHANNEL BLOCKADE BY ANTIARRHYTHMIC AGENTS

此续订请求是为了继续支持专注于研究的 离子通道阻断之间的宏观相互作用 药物和可兴奋的膜(心脏和神经)以及如何 相互作用改变了细胞之间的电通讯。 有了生物物理上准确的模型，我们相信对 可以利用渠道堵塞的机制来改善 控制心脏(和神经系统)的电活动。 此外，这些结果还有助于对药物进行分类。 电生理效应。为此，本工作的重点是 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 心脏和神经活动的标准模型的描述 以预测通道阻断对脑电活动的影响 可观察到的电性事件。 我们在这三年的工作主要集中在 验证了我们最初的钠离子通道阻断模型。一个 主要目标是开发一种评估程序 非平衡数据中的平衡离解常数 源于脉冲串的膜激励。由此产生的 方法学已经用几种钠进行了部分验证 通道阻滞剂和发现也准确地描述了 钾和钙通道被阻断。 我们未来5年的目标是继续详细地 离子的定量精确物理模型的发展 通道阻塞，将阻塞模型与 膜和细胞外动作电位，以延长 模型到多个药物竞争同一结合部位，以及 推广到单一药物结合到不同渠道的情况 类型。这最后一个目标已经成为毒品的关键证据。 阻断不同类型的通道(钠、钾和钙)已成为 可用。主要的注意力将集中在翻译上 从细胞水平对临床事件的理解 心律失常的处理策略。

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.