ANTIARRHYTHMIC DRUGS--SINGLE CHANNEL BLOCKING MECHANISMS

抗心律失常药物--单通道阻断机制

• 批准号: 3472047
• 负责人: PAUL B. BENNETT
• 金额: $ 10.32万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3472047
• 关键词: Anura; Cephalopoda; action potentials; antiarrhythmic agent; guinea pigs; heart cell; heart innervation; human tissue; hydropathy; laboratory mouse; laboratory rat; lidocaine; myocardium; quinidine; sodium channel; tetrodotoxin

This research will characterize the molecular mechanisms by which cardiac anti-arrhythmic drugs inhibit function of an intrinsic membrane protein: the cardiac sodium (Na) channel. Na+ influx causes the rapid initial upstroke of the cardiac action potential and allows impulse conduction. Na channels are the site of action of many antiarrhythmic drugs, but details cardiac Na channel function and of the mechanisms of inhibition of Na+ flux through channels are lacking. Because many details of Na channel block are derived from studies of non-mammalian nerves (squid and frog) much less is known about mammalian cardiac Na channels. Since it is now clear that there are multiple types of Na channel in the nervous system, and there are well know differences in cardiac and neuronal Na channels, it is more important than ever to study cardiac Na channels directly. Therefore, the aim of this project is to extensively characterize cardiac Na channels and their interactions with drugs and ions using the patch clamp technique. Experiments are designed to test the concepts developed in the modulated receptor hypothesis of Na channel blockers (Hille, 1977; Hondeghem and Katzung, 1977). This model has been used extensively to explain block of ion channels. The model states that Na channel blockers have unique affinities for each of the three primary states of the Na channel; and access to the receptor occurs via a hydrophobic and a hydrophilic pathway. Because of the importance of Na channels in cardiac excitability and the therapeutic importance of Na channel blockers, it is essential to develop a greater knowledge of the cardiac Na channel and to explore these constructs at the level of the channel protein. Enzymatically dissociated cells from guinea pig, mouse, rat and human myocardium will be used. Measurements will determine whether Na block involves a reduction of the current through a single channel or if the probability of channel opening is altered, and the effects of pH, Na and Ca on channel function and drug block will be determined. Many Na channel blockers (TTX, lidocaine, quinidine) also alter the action potential plateau and modulate repolarization; therefore, experiments will also determine if there is a second population of late opening Na channels or a different gating mode with a different sensitivity to antiarrhythmic agents.

这项研究将表征分子机制， 心脏抗心律失常药物抑制一种固有的功能 膜蛋白：心肌钠离子通道。Na+内流 引起心脏动作电位的快速上升 并允许脉冲传导。NA通道是行动的场所 在许多抗心律失常药物中，但详细说明了心脏钠通道 抑制Na+通量的作用及机制 渠道匮乏。因为钠通道阻滞剂的许多细节是 源自对非哺乳动物神经(鱿鱼和青蛙)的研究 对哺乳动物的心脏钠通道知之甚少。既然是现在 明确神经质中存在多种类型的钠通道 系统，在心脏和神经元上有众所周知的区别 钠离子通道，研究心肌钠离子比以往任何时候都重要 直接收看频道。因此，这个项目的目的是 广泛研究心肌钠离子通道及其相互作用 使用膜片钳技术的药物和离子。实验 旨在测试在调制中开发的概念 钠通道阻滞剂的受体假说(Hille，1977 和Katzung，1977)。该模型已被广泛应用于 解释离子通道的阻塞。该模型指出，钠通道 拦截者对三个主要的每一个都有独特的亲和力 钠通道的状态；而对受体的访问是通过 疏水和亲水途径。因为重要的是 钠通道在心脏兴奋性中的作用及其治疗 钠通道阻滞剂的重要性，开发一种 更多关于心脏钠通道的知识，并探索这些 在通道蛋白水平上构建。酶促 分离的豚鼠、小鼠、大鼠和人心肌细胞 将会被使用。测量结果将决定钠离子是否阻断 涉及通过单个通道的电流的减小，或者如果 改变了通道开放的概率，并且 PH、Na、Ca对通道功能的影响及药物阻断 下定决心。多种钠通道阻滞剂(TTX、利多卡因、奎尼丁) 也改变动作电位的平台期和调制 因此，实验还将确定是否存在 是第二批较晚开放的钠离子通道还是不同的 门控模式对抗心律失常药物的敏感性不同。