ELECTROPHYSIOLOGIC RESPONSES TO ION CHANNEL BLOCKADE

对离子通道封锁的电生理反应

• 批准号: 2217144
• 负责人: C FRANK STARMER
• 金额: $ 19.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-08-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2217144
• 关键词: action potentials; animal tissue; antiarrhythmic agent; calcium channel; chemical binding; dosage; drug interactions; drug metabolism; drug receptors; electrophysiology; heart pharmacology; inhibitor /antagonist; lidocaine; membrane permeability; microelectrodes; phenytoin; potassium channel; quinidine; sodium channel; voltage /patch clamp

This renewal request is for continued support of research focusing on the interaction between ion channel blocking agents and cardiac excitable membrane 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. 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 action potentials in order to predict the effect of channel blockade on observable extracellular electrical events. Recent reports from the CAST investigators indicate an increased incidence of sudden death in patients treated with flecainide and encainide. Both these drugs are slowly unbinding use-dependent sodium channel antagonists. Computer simulations suggest that use-dependent sodium channel blockade promotes unidirectional block and reentrant arrhythmias initiated by premature stimulation. Moreover, mixtures of a rapidly unbinding drug (e.g. lidocaine) with a slowly unbinding drug can reverse this proarrhythmic potential. Preliminary in vitro studies confirm that slowly unbinding use-dependent sodium channel antagonists prolong the range of delays of premature stimuli that can initiate reentrant arrhythmias. Consequently these studies have direct applicability to the management of complex arrhythmias and the models provide a way to integrate ion channel blockade at the cellular level with tissue responses to premature stimulation. Our objective for the next 5 years is to continue the detailed development of a quantitatively accurate physical model of ion channel blockade, to extend the model to describe use-dependent potassium channel blockade (delayed rectifier and transient outward currents), and to explore both the antiarrhythmic and proarrhythmic potential in in vitro studies and in computer models of 1 and 2 dimensional arrays of coupled cells. Voltage clamp studies of sodium, delayed rectifier and L type calcium channel blockade will be used to estimate kinetic rates of binding and unbinding. Studies of responses to premature stimulation in isolated rabbit left atria will be used to explore anti- and proarrhythmic potential. A major focus will be to couple our understanding of a drug's cellular behavior with observations of multicellular responses to premature stimulation and how these correlations relate to current interests in pharmacologic management of cardiac arrhythmias.

这一更新请求是为了继续支持研究， 离子通道阻滞剂与心脏的相互作用 可兴奋膜以及这种相互作用如何改变电 细胞之间的沟通。 有了生物病理学上的精确模型，我们 我相信，对通道阻断机制的了解可以用于 来改善对心脏电活动的控制。 而且这些 结果可以帮助根据药物的电生理特性对药物进行分类， 方面的影响. 为此，这项工作的重点是继续发展一个 药物-通道相互作用的定量精确模型， 将所得到的描述纳入标准模型， 心脏动作电位，以预测通道的作用 阻断可观察到的细胞外电事件。 CAST调查人员最近的报告表明， 接受氟卡尼治疗患者的猝死发生率， 恩卡尼 这两种药物都是缓慢解除使用依赖性钠 通道拮抗剂。 计算机模拟表明， 钠通道阻滞促进单向阻滞和折返 过早刺激引发的心律失常。 此外， 快速解结合药物（例如利多卡因）与缓慢解结合药物可 逆转这种潜在的危险。 初步体外研究 证实缓慢解结合的使用依赖性钠通道拮抗剂 延长过早刺激的延迟范围， 折返性心律失常 因此，这些研究直接 复杂心律失常管理的适用性和模型 提供了一种在细胞水平上整合离子通道阻断的方法 组织对过早刺激的反应 我们未来五年的目标是继续详细 离子通道定量精确物理模型的建立 阻断，以扩展模型来描述使用依赖性钾 通道阻滞（延迟整流和瞬时外向电流），以及 为了探索抗肿瘤和预防肿瘤的潜力， 体外研究和1维和2维阵列的计算机模型中， 耦合细胞 钠、延迟整流和L 型钙通道阻滞剂将用于估计 绑定和解除绑定。 早产儿对过早刺激反应的研究 将使用离体兔左心房来探索抗-和 预防性电位 一个主要的重点将是结合我们的 通过观察药物的细胞行为来了解药物的细胞行为， 多细胞对过早刺激的反应，以及这些反应是如何发生的。 相关性与当前药物管理的兴趣有关， 心律失常