MECHANISMS OF MODIFIED NA CHANNELS IN CARDIAC ISCHEMIA

改良 NA 通道在心脏缺血中的机制

基本信息

批准号：
2231937
负责人：
ALBERTAS I UNDROVINAS
金额：
$ 16.4万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-06-17 至 1999-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2231937
关键词：
antiarrhythmic agent arrhythmia cytoskeleton drug interactions electrophysiology heart pharmacology laboratory rabbit laboratory rat lysolecithins mathematical model membrane channels myocardial ischemia /hypoxia sarcolemma sodium channel voltage /patch clamp

项目摘要

This new application for three years of support has the long term objective to investigate mechanisms for modified ion channel function in cardiac ischemia. The ischemic metabolite lysophosphatidylcholine (LPC) has long been implicated as a key mediator of electrophysiological changes and arrhythmias in acute ischemia. Indirect evidence has suggested that both LPC and ischemia disturb the cytoskeleton. The cytoskeleton disrupting agent cytochalasin modified Na channel gating similarly to that of how LPC. This suggests that the mechanism for the LPC effect on Na channels may be through the cytoskeleton. Alternatively, LPC may act through a mechanism not involving the cytoskeleton such as lipid channel protein interactions or direct effects. LPC has been little studied at the cellular level, and the role of the cytoskeleton in cardiac ion channels gating is unknown. Both are likely to be important links in the pathogenesis of ischemia. In this proposal, the kinetics of LPC-modified cardiac Na channels will be fully described by patch clamping isolated rat and rabbit cardiac cells (Aim 1). The role of the cytoskeleton in Na channel gating will be investigated by using cytoskeleton disrupting (e.g., colchicine, cytochaIasin) and stabilizing (e.g., phalloidin and taxol) agents, cytoskeleton elements (actin, spectrin and linkage protein ankyrin) and antibodies to these elements (Aim 2). The interaction of antiarrhythmic drugs (lidocaine, flecainide, quinidine) with these modified channels will be studied by patch clamp (Aim 3). Mathematical models will be used for both channel gating and drug-channel interaction. These results may help explain why ischemic tissue is apparently more sensitive to the action of some antiarrhythmic drugs as well as cytoskeleton role in Na channel function. Since cardiac arrhythmias ischemic heart disease remain major public health problems, knowledge of the underlying mechanisms may lead to better understanding of cardiac arrhythmias and provide insight into treatment.

这项三年支持的新应用具有长期的长期目的研究修饰离子通道功能的机制心脏缺血。缺血性代谢物溶血磷脂酰胆碱（LPC）长期以来一直被视为电生理变化的关键介体和急性缺血性心律失常。间接证据表明 LPC和缺血都会干扰细胞骨架。细胞骨架破坏剂细胞切拉斯蛋白修饰的Na通道门控与此类似 LPC的方式。这表明LPC对Na的作用机制通道可能通过细胞骨架。或者，LPC可以行动通过不涉及细胞骨架（例如脂质通道）的机制蛋白质相互作用或直接影响。 LPC在细胞水平以及细胞骨架在心脏离子通道中的作用门票未知。两者都可能是重要的链接缺血的发病机理。在此提案中，LPC修饰的动力学心脏NA通道将通过贴片夹隔离的大鼠充分描述和兔心脏细胞（AIM 1）。细胞骨架在Na中的作用通道门控将通过使用细胞骨架破坏来研究（例如，秋水仙碱，细胞chai素）和稳定（例如，髓样蛋白和紫杉醇），细胞骨架元素（肌动蛋白，光谱和链接蛋白 Ankyrin）和对这些元素的抗体（AIM 2）。相互作用抗心律失常药物（利多卡因，氟卡因，奎尼丁）修改通道将通过斑块夹（AIM 3）研究。数学模型将用于通道门控和药物通道相互作用。这些结果可能有助于解释为什么缺血组织显然更多对某些抗心律失常药物的作用敏感 Na通道功能中的细胞骨架作用。由于心律不齐缺血性心脏病仍然是主要的公共卫生问题，了解基本机制可能会更好地理解心脏心律不齐并提供有关治疗的洞察力。