ELECTROPHARMACOLOGIC ACTIONS OF ANTIARRHYTHMIC DRUGS

心脏节律紊乱是猝死的主要原因， 在美国，心律失常的治疗仍然是一个难题， 挑战医生。 这次竞争性更新的目标是 发现促癌干预和抗肿瘤药物如何起作用 并相互作用以影响基本的主动和被动细胞特性 最终决定了异常的心脏兴奋性， 异常的心脏兴奋性，导致潜在的致命心律失常， 并影响这些心律失常的治疗。 我们早先 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基质 确定正常的心脏兴奋性;（2）正常矩阵必须是 通过影响一种或多种成分的致炎影响而改变的 产生异常兴奋性和心律失常; （3）正常基质或因孕激素作用而变形的基质 影响可能与抗肿瘤药物相互作用， 根据遇到的基质，相互作用不同，导致 另一种基质结构。 重要条件 局部缺血将用于扰动基质，包括暴露于 缺血的推定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。 重要的原型抗肿瘤药物将单独研究，并在 这些潜在影响的存在。 在操作上，我们的目标是 通过实验和建模进一步发展这一概念， 将这一概念与心律失常的临床现实及其 治疗 在方法上，我们使用并开发了强大的 心脏浦肯野纤维的定量技术， 细胞内电流施加和电压钳位以评估总体 兴奋性和主动和被动的细胞特性， 确定兴奋性。 有些问题是最好的办法， 研究使用电流和电压钳位在隔离的细胞，如 跨膜电流的评估，缝隙连接的作用， 以及复极化的机制。 改变的概念 兴奋性提出了新的分类方法， 抗心律失常药物和治疗心律失常。

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.