MODELS OF DRUG BINDING TO CARDIAC SODIUM CHANNELS

药物与心脏钠离子通道的结合模型

• 批准号: 3344592
• 负责人: C FRANK STARMER
• 金额: $ 12.27万
• 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 1987-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3344592
• 关键词: action potentials; antiarrhythmic agent; arrhythmia; chemical binding; chemical reaction; dosage; drug interactions; drug metabolism; electrophysiology; heart disorder chemotherapy; heart pharmacology; lidocaine; membrane permeability; membrane potentials; microelectrodes; myocardium; phenytoin; quinidine

The long term objective of this proposal is to develop a quantitative basis for action of antiarrhythmic drugs in cardiac muscle. The increase in number and modes of action (sodium channel, calcium channel blockers) of drugs has created expanded opportunities for pharmacologic management of a number of cardiac arrhythmias. There has been little progress in describing a quantitatively accurate process depicting drug-channel interaction and the associated effect on the cardiac conduction system. The modulated receptor hypothesis for cardiac tissue postulates a variable affinity receptor and interaction between channel gates and drug complexed channels. We have suggested a considerably simpler process based on gated control of the diffusion path between drug pool and channel binding site. An "apparent" variable affinity receptor arises as a natural consequence of this approach. Further, an "apparent" modification of gate kinetics arises naturally. This work will focus on extending this description of channel blocking agents to a propagating system; evaluate the potential effect of blocking agents on current, voltage and conductance relationships in a propagating and voltage clamped setting; and investigate the potential role of blocking agent mediated changes in propagation velocity. We expect our studies of propagated action potentials in the presence of channel blocking agents to illuminate the relationship between ionic currents, voltage and conductance, and thus aid in the design of appropriate experimental protocols focused on minimizing confounding effects.

本建议的长期目标是建立一个量化基础， 抗心律失常药物在心肌中的作用。 的增加 数量和作用方式（钠通道、钙通道阻滞剂） 药物为药物管理创造了更多的机会， 心律失常的数量。 进展甚微 描述了描述药物通道的定量精确过程 相互作用和对心脏传导系统的相关影响。 心脏组织的受调受体假说假定了一个变量 亲和受体和通道门与药物复合物之间的相互作用 渠道 我们已经提出了一个相当简单的过程， 控制药物池和通道结合位点之间的扩散路径。 “表观”可变亲和力受体是作为以下因素的自然结果而产生的： 这种方法。 此外，栅极动力学的“明显”修改出现 自然. 这项工作将集中在扩展这种描述的通道 阻断剂的传播系统;评估潜在的影响 阻断剂对电流、电压和电导关系的影响 传播和电压钳位设置;并调查潜在的作用 阻断剂介导的传播速度的变化。 我们期望我们 通道阻断时传播动作电位的研究 试剂，以阐明离子电流，电压和 电导，从而有助于设计适当的实验 方案侧重于最大限度地减少混淆效应。