ELECTROPHARMACOLOGIC ACTIONS OF ANTIARRHYTHMIC DRUGS

心律失常是老年人猝死的主要原因。 在美国，心律失常的治疗仍然是一个难点 对医生的挑战。此次竞争性续签的目标是 了解致心律失常干预和抗心律失常药物的作用 并相互作用以影响基本的主动和被动细胞属性 最终决定了心脏的异常兴奋性 心脏兴奋性异常，导致潜在的致命性心律失常， 并影响这些节律紊乱的治疗。我们早些时候 工作建议我们测试以下假设：(1)一个 主动和被动细胞特性的电生理学矩阵 确定正常的心脏兴奋性；(2)正常矩阵必须是 由影响一种或多种成分的致心律失常的影响而改变 兴奋性产生异常兴奋性和心律失常； (3)正常矩阵或因致心律失常而变形的矩阵 影响可能与抗心律失常药物相互作用，主要是 根据遇到的矩阵而有所不同的交互，导致 还有另一种母性结构。被认为重要的条件 缺血会被用来扰乱基质，包括暴露在 假定的缺血代谢物，如溶血磷脂酰胆碱，游离 氧自由基和离子环境、pH和氧的变化。 重要的抗心律失常原型药物将单独和在 这些导致心律失常的影响的存在。在行动上，我们的目标是 通过实验和建模进一步发展这一概念，并 将这一概念与心律失常及其临床现实联系起来 治疗。在方法论上，我们使用和开发了强大的 利用心脏浦肯野纤维的定量技术 细胞内电流施加和电压钳制以评估整体 兴奋性和主动和被动的细胞特性 确定兴奋性。有些问题是最好的解决办法，也将是 在隔离单元中使用电流和电压钳位进行研究，例如 跨膜电流的评估，缝隙连接的作用， 以及复极化的机制。被更改的概念 兴奋性提出了新的分类方法 抗心律失常药物和心律失常的治疗。

Heart rhythm disturbances are the leading cause of sudden death in the United States, the treatment of cardiac arrhythmias remains a difficult challenge to physicians. The goal of this competitive renewal is to discover how arrhythmogenic interventions and antiarrhythmic drugs act and interact to affect fundamental active and passive cellular properties that ultimately determine abnormal cardiac excitability to produce abnormal cardiac excitability, lead to potentially lethal arrhythmias, and influence the treatment of these rhythm disturbances. Our earlier work suggested we test the following hypotheses: (1) an electrophysiologic matrix of active and passive cellular properties determines normal cardiac excitability; (2) the normal matrix must be altered by arrhythmogenic influences which affect one or more components of excitability to produce abnormal excitability and cardiac arrhythmias; and (3) the normal matrix or the matrix deformed by arrhythmogenic influences may interact with antiarrhythmic drugs, the predominant interaction differing depending on the matrix encountered, resulting in yet another matrical configuration. Conditions thought important in ischemia will be used to perturb the matrix including exposure to putative metabolites of ischemia such as lysophosphatidylcholine, free oxygen radicals and changes in the ionic milieu, pH, and oxygen. Important prototypic antiarrhythmic drugs will be studied alone and in the presence of these arrhythmogenic influences. Operationally, we aim to further develop this concept through experiments and modeling and to relate the concept to the clinical realities of arrhythmias and their treatment. Methodologically, we have used and developed powerful quantitative techniques in cardiac Purkinje fibers that utilize intracellular current application and voltage-clamping to assess overall excitability and the active and passive cellular properties that determine excitability. Some issues are best approached and will be studied using current- and voltage-clamping in isolated cells, such as the assessment of transmembrane currents, the actions of gap junctions, and the mechanisms of repolarization. The concept of altered excitability suggests new approaches to the classification of antiarrhythmic drugs and the treatment of cardiac arrhythmias.