ELECTROPHARMACOLOGIC ACTIONS OF ANTIARRHYTHMIC DRUGS

心率异常仍然是一个主要的公共健康威胁， 心律失常的治疗是对 医生。我们计划继续调查被动和 心肌细胞的活性膜特性决定了正常和 异常兴奋性包括发育迟缓的类型 心性心律失常。此外，我们将继续调查 抗心律失常药物对兴奋性决定因素的影响 在正常和异常的心脏组织中。多个微电极 细胞内电流施加和电压钳制技术是 用于心脏浦肯野纤维，并允许选择性地控制 无数的电生理变量，进而允许直接 许多与以下相关的主动和被动膜性能的评估 心脏兴奋性。其中包括离子电导、有源发电机 属性、电缆属性和电流-电压关系。在 过去，评估兴奋性的一个主要限制是无法 确定细胞内重要的离子活度 建立离子物种的驱动力。我们现在使用的是 用于测量离子活度的离子敏感微电极。我们也 开发了一个基于计算机的数据分析系统，使我们能够跟踪 术后兴奋性决定因素在时间上的变化 干预。赠款的头几年展示了这些东西的力量 阐明致心律失常的基本机制的方法 干预和抗心律失常药物奏效了，调查已经 对许多早期文献提出了严重质疑。这一更新提议 通过这些改进进一步定义兴奋性的组成部分 正常组织和异常组织中的技术。后者的结果将是 通过以下方式改变组织的生理或药物环境 使用在缺血心脏中积累的有毒代谢物，并通过 改变PO2离子浓度和pH值。抗心律失常药物的作用 对这些改动也将进行调查。就像第一次一样 ，我们预计续期将进一步延长我们的 了解抗心律失常药物的作用。我们计划继续 心律失常发生与抗心律失常药物的发展分类 基于我们的基本发现，这些发现在电生理上是合理的 在临床上很有用。

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.