ROLE OF PROLONGED REPOLARIZATION IN CARDIAC ARRHYTHMIAS

人们对延长的概念非常感兴趣 心脏复极可能是一种重要的机制 药物可以抑制心律失常。然而，显著的复极 升高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- 挑衅行为表明，长周期长度和低周期 细胞外钾显著增强复极- 奎尼丁的延长作用；在此条件下，a 独特的多形性室性心动过速(Torsadesde 尖端)在患者和去极化后早期发生 (EADs)在犬浦肯野纤维中被诱导。在上一次 在支持期间，进行了研究以进一步评估我们的 EADS与EAD的起源有关的工作假说 尖端扭力。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 奎尼丁诱导浦肯野组织中的EAD。我们现在就会 进一步研究浦肯野-心室调制的影响 通过干预如改变的蔡氏(如洋地黄)和 CaO、药物(奎尼丁、胺碘酮)和中链醇。 我们已经实现了一个传播Purkinje的计算机模型 和心室肌动作电位类似的可变轴 一维电缆中的电阻率将在 与实验结果基本一致。通过这种方式，假设 EADS在体内会导致心律失常的说法将得到进一步测试和 对……的发生或抑制很重要的条件 EAD介导的心律失常被识别出来。 尽管人们对复极化延长法的使用越来越感兴趣 治疗心律失常的药物很少 关于离子机制的信息可用(S)，据此他们 发挥这种作用。在过去的一年里，我们积累了证据 奎尼丁和胺碘酮的相互作用与延迟性 电压钳豚鼠的Ik整流(复极电流) 心室肌细胞具有时间和电压依赖性。这些日期 提示药物对IK的影响是由这种状态调节的 钾通道。我们现在研究的第二个主要目标是 提出是为了进一步检验这一假说。我们最初会 奎尼丁和胺碘酮对Ik的影响 初始通道状态的函数。随后，我们将研究 这些和其他结构上相关的试剂在其他 组织(浦肯野、心房)。这一结果不仅将表征 通道状态对药物效应的影响，但也会用到 在药物通道的多态模型中量化药物作用 互动。因此，通过这一系列的研究，我们将 提高对根本机制的认识 药物延长复极并诱发心律失常； 这样，复极的发展和临床应用- 延长抗心律失常药物的使用时间将得到改善。

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.