ANTIARRHYTHMIC DRUGS--SINGLE CHANNEL BLOCKING MECHANISMS

这项研究将描述分子机制， 心脏抗心律失常药物抑制内源性 膜蛋白：心脏钠（Na）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。 钠通道是作用部位 但详细说明了心脏Na通道 功能和机制的抑制Na+通量通过 渠道缺乏。 因为钠通道阻滞的许多细节 来自非哺乳动物神经（鱿鱼和青蛙）的研究 对哺乳动物心脏Na通道的了解较少。 既然是现在 明确神经元中存在多种类型的Na通道， 系统，并且在心脏和神经系统中存在众所周知的差异。 钠通道，研究心脏钠离子通道比以往任何时候都重要 渠道直接。 因此，本项目的目的是 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一起。 实验 旨在测试调制的概念中开发的 Na通道阻滞剂的受体假说（Hille，1977; Hondeghem 和Katzung，1977年）。 该模型已被广泛用于 解释离子通道的阻塞。 该模型指出，Na通道 阻断剂对三种主要的 钠通道的状态;和进入受体发生通过一个 疏水和亲水途径。 因为重要性 钠通道在心脏兴奋性和治疗 钠通道阻滞剂的重要性，有必要开发一种 更多地了解心脏钠通道，并探索这些 在通道蛋白水平构建。 酶促 来自豚鼠、小鼠、大鼠和人心肌的分离细胞 将用于 测量将确定Na阻滞 涉及通过单个通道的电流的减小，或者如果 通道开放的可能性被改变， pH、Na和Ca对通道功能和药物阻断的影响将被 测定 多种钠通道阻滞剂（TTX、利多卡因、奎尼丁） 也改变动作电位平台并调节 复极;因此，实验也将确定是否有 是第二群晚开放的Na通道或不同的 门控模式，对抗肿瘤药物具有不同的敏感性。

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.