Buchanan L V, Kabell G, Brunden M N, Gibson J K
Upjohn Company, Kalamazoo, Michigan 49001.
J Cardiovasc Pharmacol. 1993 Oct;22(4):540-9.
Class III agents have been associated with development of a polymorphic ventricular tachycardia (PVT) known as torsades de pointes. We compared the class III agent ibutilide, which prolongs repolarization through enhancement of an inward sodium current, with the potassium channel blockers E-4031, UK-68,798, clofilium, and D-sotalol for proarrhythmic effects in an anesthetized rabbit model. In these animals, prolongation of repolarization during alpha 1 stimulation with methoxamine produces early after depolarizations (EADs) and a pause-dependent torsades de pointes-like PVT. Agents were compared over dosage ranges that produced maximal increases in QTc interval and monophasic action potential duration (MAPD). PVT typically developed after atrioventricular (A-V) conduction block and slowing of heart rate (HR), and was preceded by development of repolarization arrhythmias characterized by EADs and triggered activity producing extrasystolic beats. Ibutilide administration resulted in significantly lower EAD amplitudes and a lower incidence of repolarization arrhythmias and PVT as compared with administration of other class III agents. The percentage of rabbits developing PVT for each agent was ibutilide 12%, D-sotalol 70%, E-4031 56%, UK-68,798 69%, and clofilium 80%. Rabbits receiving saline vehicle instead of a class III agent never developed conduction or repolarization abnormalities or PVT. Under the conditions of this study at doses that generate maximal class III effects, ibutilide produces lesser increases in QTc interval and MAPD, and EADs of lower amplitude, resulting in a lower incidence of repolarization arrhythmias and PVT as compared with other class III agents.
Ⅲ类药物与一种称为尖端扭转型室性心动过速的多形性室性心动过速（PVT）的发生有关。我们将通过增强内向钠电流来延长复极的Ⅲ类药物伊布利特，与钾通道阻滞剂E-4031、UK-68,798、氯非铵和D-索他洛尔在麻醉兔模型中进行促心律失常作用的比较。在这些动物中，用甲氧明进行α1刺激时复极的延长会产生早后去极化（EADs）和一种与暂停相关的尖端扭转型室性心动过速样PVT。在能使QTc间期和单相动作电位时程（MAPD）最大增加的剂量范围内对药物进行比较。PVT通常在房室（A-V）传导阻滞和心率（HR）减慢后发生，并且在以EADs和产生早搏的触发活动为特征的复极心律失常发生之后出现。与给予其他Ⅲ类药物相比，给予伊布利特导致EAD幅度显著降低，复极心律失常和PVT的发生率也更低。每种药物发生PVT的兔的百分比分别为：伊布利特12%，D-索他洛尔70%，E-4031 56%，UK-68,798 69%，氯非铵80%。接受生理盐水而非Ⅲ类药物的兔从未出现传导或复极异常或PVT。在本研究条件下，在产生最大Ⅲ类效应的剂量下，与其他Ⅲ类药物相比，伊布利特使QTc间期和MAPD增加较少，EAD幅度较低，导致复极心律失常和PVT的发生率较低。
