ELECTROPHYSIOLOGIC RESPONSES TO ION CHANNEL BLOCKADE

对离子通道封锁的电生理反应

• 批准号: 2217143
• 负责人: C FRANK STARMER
• 金额: $ 18.61万
• 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/2217143
• 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.

此续订请求是为了继续支持专注于以下方面的研究 离子通道阻滞剂与心脏的相互作用 可激发膜及其相互作用如何改变电 细胞之间的通信。有了生物物理上准确的模型，我们 相信对渠道封锁机制的洞察可以用到 以改善对心脏电活动的控制。此外，这些 结果有助于根据电生理对药物进行分类 效果。为此，本工作的重点是继续开发一种 药物-通道相互作用的定量准确模型和 将生成的描述合并到标准模型中 心脏动作电位对经络作用的预测 阻断可观察到的细胞外电事件。 最近来自演员阵容调查人员的报告显示， 氟卡胺和安慰剂治疗患者猝死的发生率 恩卡胺。这两种药物都在缓慢释放依赖于使用的钠。 渠道拮抗者。计算机模拟表明，依赖于使用 钠通道阻断促进单向阻断和折返性 由过早刺激引起的心律失常。此外，A的混合物 快速释放的药物(如利多卡因)与缓慢释放的药物可以 逆转这种诱发心律失常的电势。初步的体外研究 确认缓慢解离使用依赖的钠通道拮抗剂 延长可能引发的过早刺激的延迟范围 折返性心律失常。因此，这些研究直接 对复杂心律失常处理的适用性和模型 提供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5年的目标是继续详细地 离子通道定量精确物理模型的建立 Blockade，将模型扩展到描述使用依赖的钾 通道阻塞(延迟整流和瞬时外向电流)，以及 探讨心绞痛患者的抗心律失常和致心律失常电位 一维和二维阵列的体外研究和计算机模型 耦合电池。钠、延迟整流和L的电压钳研究 型钙通道阻滞剂将用于估计运动速度 绑定和解除绑定。儿童对早产刺激反应的研究 离体兔左心房将被用来探索抗和 心律失常前潜伏期。一个主要的焦点将是将我们的 通过观察药物的细胞行为来理解药物的细胞行为 多细胞对过早刺激的反应以及这些反应是如何 相关性与当前药理学管理中的利益相关 心律失常。