ROLE OF PROLONGED REPOLARIZATION IN CARDIAC ARRHYTHMIAS

有强烈的兴趣的概念，延长的 心脏复极化可能是一个重要的机制， 药物抑制心律不齐。 然而，明显的复极 增加也与心律失常的诱发有关。 我们对这种心律失常的初步临床和体外研究- 挑衅行动表明，长周期和低 细胞外钾显著增强复极， 奎尼丁的延长作用;在这些条件下， 特异性多形性室性心动过速 点）的患者和早期后去极化 在犬浦肯野纤维中诱发埃兹。 上一 支持期间，进行了研究，以进一步评估我们的 工作假设，埃兹与 尖端扭转型室性心动过速 迄今为止最重要的发现之一 是心室肌钝化了动作电位的延长 以及在浦肯野组织中奎尼丁诱导的EAD。 我们现在将 进一步检查浦肯野-心室肌调制的影响， 通过干预如改变Cai（例如洋地黄）和 曹，药物（奎尼丁，胺碘酮）和中链醇。 我们已经实现了一个计算机模型， 和心室肌动作电位喜欢可变轴 一维电缆中的折射率， 与实验结果平行。 因此，假设 将进一步测试埃兹在体内引起心律失常， 对发生或抑制的重要条件 识别出EAD介导的心律失常。 尽管人们对使用复极延长 药物治疗心律失常， 关于离子机制的信息是可用的， 发挥这种效果。 在过去的一年里，我们已经积累了证据， 奎尼丁和胺碘酮与延迟的 电压钳位豚鼠整流器IK（复极化电流） 心室肌细胞是时间和电压依赖性的。 这些日期 表明药物对IK的作用受这种状态的调节， 钾离子通道 我们现在研究的第二个主要目标是 我的建议是进一步验证这一假设。 我们将初步 表征奎尼丁和胺碘酮对IK的作用， 初始信道状态的函数。 随后，我们将研究 这些和其他结构上相关的药物在其他疾病中的作用 组织（浦肯野，心房）。 研究结果不仅能描述 通道状态对药物作用的影响，但也将使用 在药物通道的多状态模型中量化药物作用 交互. 通过这一系列的研究，我们将 加深我们对基本机制的理解 由此药物延长复极并诱导心律失常; 这样，复极的发展和临床应用- 延长抗抑郁药的使用将得到改善。

There is intense interest in the concept that prolongation of cardiac repolarization may be an important mechanism whereby drugs suppress arrhythmias. However, marked repolarization increases have also been associated with induction of arrhythmias. Our initial clinical and in vitro studies of this arrhythmia- provoking action demonstrated that long cycle lengths and low extracellular potassium markedly potentiated the repolarization- prolonging effect of quinidine; under these conditions, a distinctive polymorphic ventricular tachycardia (Torsades de Pointes) developed in patients and early after depolarizations (EADS) were elicited in canine Purkinje fibers. In the previous period of support, studies were conducted to further evaluate our working hypothesis that EADs are linked to the genesis of Torsades de Pointes. One of the most important findings to date is that ventricular muscle blunts the action potential prolongation and EAD induction by quinidine in Purkinje tissue. We will now further examine the impact of modulation of Purkinje-ventricular coupling by interventions such as altered Cai (e.g. digitalis) and Cao, drugs (quinidine, amiodarone) and medium chain alcohols. We have implemented a computer model of porpagating Purkinje and ventricular muscle action potentials liked with variable axial resistivities in a one-dimensional cable which will be refined in parallel with experimental results. In this way, the hypothesis that EADs cause arrhythmias in vivo will be further tested and conditions which are important for the genesis or suppression of EAD-mediated arrhythmias identified. Despite increasing interest in the use of repolarization-prolonging drugs in the management of cardiac arrhythmias, little information is available on the ionic mechanism(s) whereby they exert this effect. In the past year we have accumulated evidence that the interaction of quinidine and amiodarone with the delayed rectifier IK (a repolarizing current) in voltage-clamped guinea pig ventricular myocytes is time- and voltage-dependent. These date suggest that drug effects on IK are modulated by the state of this potassium channel. A second major goal of the studies we now propose is to further test this hypothesis. We will initially characterize the effects of quinidine and amiodarone on IK as a function of initial channel state. Subsequently, we will examine the effects of these and other structurally related agents in other tissues (Purkinje, atrial). The results will not only characterize the impact of channel state on drug effect, but will also be used to quantify drug action in a multistate model of drug-channel interactions. Through this series of studies, therefore, we will increase our understanding of the fundamental mechanisms whereby drugs prolong repolarization and induce arrhythmias; in this way, the development and clinical use of repolarization- prolonging antiarrhythmic drugs will be improved.