ELECTROPHARMACOLOGIC ACTIONS OF ANTIARRHYTHMIC DRUGS

心律失常仍然是一个主要的公共卫生威胁， 心律失常的治疗是一个严格的挑战， 医生。 我们计划继续调查 心脏细胞的活性膜特性决定了正常和 异常兴奋性，包括那些类型的基础发展 心律失常的症状 此外，我们会继续调查 抗抑郁药对兴奋性决定因素的影响 在正常和异常的心脏组织中。 多微电极 细胞内电流施加和电压箝位技术， 用于心脏浦肯野纤维，并允许选择性控制 许多电生理变量，反过来，允许直接 评估与以下方面相关的许多主动和被动膜特性： 心脏兴奋性 这些包括离子电导、有源发电机 特性、电缆特性和电流-电压关系。 在 过去，评估兴奋性的一个主要限制是无法 确定细胞内离子活性，其在以下方面是重要的： 建立离子种类的驱动力。 我们现在使用 离子敏感微电极来测量离子活性。 我们也 开发了一个基于计算机的数据分析系统， 兴奋性的决定因素在一个 干预 第一年的赠款证明了这些权力， 方法来阐明致癌的基本机制 干预措施和抗疟疾药物的工作，和调查， 他对许多早期的文学作品提出了质疑。 此次更新建议 为了进一步定义兴奋性的组成部分， 技术在正常和异常组织。 后者将导致 改变组织的生理或药理环境， 使用在缺血心脏中积累的有毒代谢物， 改变了PO 2离子浓度和pH值， 这些变化也将被调查。 就像第一次一样 多年来，这项赠款，我们预计，更新将进一步扩大我们的 了解抗癫痫药物的作用。 我们计划继续 发展肿瘤发生和抗肿瘤药物的分类 基于我们的基本发现， 临床上有用。

Abnormalities of the heart rhythm remain a major public health threat and the treatment of cardiac arrhythmias is a strict challenge to the physician. We plan to continue our investigations into the passive and active membrane properties of heart cells that determine normal and abnormal excitability including those types which underly the development of cardiac arrythmias. Moreover, we will continue to investigate the effects that antiarrhythmic drugs have on the determinants of excitability in normal and abnormal cardiac tissues. The multiple microelectrode techniques of intracellular current application and voltage clamping are used in cardiac Purkinje fibers and permit the selective control of numerous electrophysiologic variables which, in turn, allows the direct assessment of many active and passive membrane properties relevant to cardiac excitability. These include ionic conductances, active generator properties, cable properties, and current-voltage relationships. In the past, a major limitation in assessing excitability was the inability to determine intracellular ionic activities which are of importance in establishing the driving force for ionic species. We are now using ion-sensitive microelectrodes to measure ionic activities. We also developed a computer based data analysis system that allows us to track alterations in the determinants of excitability in time after an intervention. The first years of the grant demonstrated the power of these methods to elucidate fundamental mechanisms by which arrhythmogenic intervensions and antiarrhythmic drugs work, and the investigations have seriously questioned much of the earlier literature. This renewal proposes to further define the components of excitability by these improved techniques in normal and abnormal tissues. The latter will result from altering the physiologic or pharmacologic environment of the tissue by using toxic metabolites that accumulate in the ischemic heart, and by changing the po2 ionic milium and pH. The effects of antiarrhythmic drugs on these alterations will also be investigated. As was true for the first years of this grant, we anticipate that the renewal will further extend our understanding of the actions of antiarrhythmic drugs. We plan to continue developing classifications of arrhythmogenesis and anti-arrhythmic drugs based on our fundamental findings that are electrophysiologically sound and clinically useful.