© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Phase 2 prolongation, in the absence of instability and triangulation, antagonizes class III proarrhythmia
aDepartment of Pharmacology, K.U.L., Leuven B-3000, Belgium
bDepartment of Cardiology, H. Hart Ziekenhuis, 8800 Roeselare, Belgium
cDepartment of Cardiovascular Safety Pharmacology, Janssen Research Foundation, B-2340 Beerse, Belgium
* Corresponding author. Present address: H.P.C. nv, Westlaan 85, B-8400 Oostende, Belgium. Tel.: +32-59-510-047; fax: +32-59-510-048 luchondeghem{at}yahoo.com
Objective: To evaluate whether prolongation of the plateau of the action potential duration, in the absence of instability and triangulation, can reverse 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), instability, triangulation and ectopics) were evaluated in isolated hearts from female albino rabbits. In this study, proarrhythmia was estimated quantitatively by number of ectopic beats. Results: Erythromycin lengthened the APD primarily by a prolongation of the plateau, while having only minor effects upon phase 3 repolarization. The prolongation did not induce much instability, triangulation or reverse use dependence and, as expected, erythromycin did not induce significant proarrhythmia. Almokalant also lengthened APD, but it did not lengthen the plateau; instead, it prolonged phase 3 repolarization. The prolongation markedly triangulated the action potential, elicited much instability and marked reverse use dependence. This combination of effects induced very marked proarrhythmia. When almokalant and erythromycin were 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 prolongation of APD is not proarrhythmic per se. On the contrary, proarrhythmia as a function of APD prolongation was reduced in the presence of erythromycin (P<0.05). Conclusion: Instability plus triangulation consistently lead to serious proarrhythmia especially when combined with reverse use dependence, but prolongation of APD in itself is not necessarily proarrhythmic. In fact, APD prolongation in the absence of instability and triangulation can be antiarrhythmic.
KEYWORDS APD, action potential duration; APDx, APD to x% repolarization, e.g. APD60 is the APD to 60% repolarization; EAD, early afterdepolarization; TdP, torsade de pointes; Triangulation, difference between APD30 and APD90 prolongation, the action potential assumes a more triangular shape. The APD0 to APD30 is used as a quantitative index of the plateau or phase 2, while the APD30 to APD90 is used as a quantitative index of phase 3.
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