Phase 2 prolongation, in the absence of instability and triangulation, antagonizes class III proarrhythmia

Objective: To evaluate whether prolongation of the plateau of the action po tential duration, in the absence of instability and triangulation, can reve rse the proarrhythmia elicited by a class III antiarrhythmic agent. Methods : The effects of almokalant, erythromycin and their combination, on cardiac electrophysiological parameters (action potential duration (APD), instabil ity, triangulation and ectopics) were evaluated in isolated hearts from fem ale albino rabbits. In this study, proarrhythmia was estimated quantitative ly by number of ectopic beats. Results: Erythromycin lengthened the APD pri marily by a prolongation of the plateau, while having only minor effects up on phase 3 repolarization. The prolongation did not induce much instability , triangulation or reverse use dependence and, as expected, erythromycin di d not induce significant proarrhythmia. Almokalant also lengthened APD, but it did not lengthen the plateau; instead. it prolonged phase 3 repolarizat ion. The prolongation markedly triangulated the action potential, elicited much instability and marked reverse use dependence. This combination of eff ects induced very marked proarrhythmia. When almokalant and erythromycin we re combined, their effects upon APD appeared additive: both the plateau and the repolarization phase were prolonged. However, the larger prolongation of APD did not lead to more proarrhythmia; this suggests that a prolongatio n of APD is not proarrhythmic per se. On the contrary. proarrhythmia as a f unction of APD prolongation was reduced in the presence of erythromycin (P< 0.05). Conclusion: Instability plus triangulation consistently lead to seri ous proarrhythmia especially when combined with reverse use dependence, but prolongation of APD in itself is not necessarily proarrhythmic. In fact, A PD prolongation in the absence of instability and triangulation can be anti arrhythmic. <(c)> 2001 Elsevier Science B.V. All rights reserved.