ANTIARRHYTHMIC DRUGS--SINGLE CHANNEL BLOCKING MECHANISMS

抗心律失常药物--单通道阻断机制

• 批准号: 3472045
• 负责人: PAUL B. BENNETT
• 金额: $ 7.81万
• 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/3472045
• 关键词: Anura; Cephalopoda; action potentials; antiarrhythmic agent; guinea pigs; heart cell; heart innervation; human tissue; hydropathy; laboratory mouse; laboratory rat; lidocaine; membrane proteins; 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.

这项研究将描述其分子机制 心脏抗心律失常药物抑制内在的功能 膜蛋白：心脏钠 (Na) 通道。 Na+流入 引起心脏动作电位的快速初始上升 并允许脉冲传导。 Na通道是作用部位 许多抗心律失常药物，但详细介绍了心脏 Na 通道 抑制Na+通量的功能和机制 缺乏渠道。 因为Na通道阻滞的很多细节是 来自对非哺乳动物神经（鱿鱼和青蛙）的研究 关于哺乳动物心脏Na通道知之甚少。 既然现在是 明确神经中存在多种类型的Na通道 系统，并且心脏和神经元之间存在众所周知的差异 Na通道，研究心脏Na比以往任何时候都更加重要 直接渠道。 因此，该项目的目的是 广泛表征心脏 Na 通道及其相互作用 使用膜片钳技术与药物和离子。 实验 旨在测试调制中开发的概念 Na 通道阻滞剂的受体假说（Hille，1977；Hondeghem 和 Katzung，1977）。 该模型已被广泛用于 解释离子通道阻塞。 该模型表明 Na 通道 阻断剂对三个主要的每一个都有独特的亲和力 Na通道的状态；并通过一个途径进入受体 疏水和亲水途径。 因为重要性 Na通道对心脏兴奋性的影响及其治疗 Na 通道阻滞剂的重要性，有必要开发一种 对心脏Na通道有更多的了解并探索这些 在通道蛋白水平上构建。 酶法 豚鼠、小鼠、大鼠和人心肌的分离细胞 将被使用。 测量将确定 Na 是否阻碍 涉及减少通过单个通道的电流，或者如果 通道打开的概率发生改变，并且影响 pH、Na 和 Ca 对通道功能和药物阻断的影响 决定。 许多钠通道阻滞剂（TTX、利多卡因、奎尼丁） 还可以改变动作电位平台并调节 复极化；因此，实验还将确定是否存在 是晚开 Na 通道的第二个群体还是不同的 门控模式对抗心律失常药物具有不同的敏感性。