Enhancement of delayed afterdepolarizations and triggered activity by class III antiarrhythmic drugs: multiple effects of E-4031 and dofetilide.

ABSTRACT

The effects of class III antiarrhythmic agents E-4031 and dofetilide were studied on action potentials and subthreshold delayed afterdepolarizations (DADs) induced by the cardiac glycoside acetylstrophanthidin (AS) in isolated cardiac Purkinje fibers. Action potentials were recorded from cardiac Purkinje fibers using microelectrode techniques. E-4031 and dofetilide consistently increased DAD amplitude, occasionally caused triggered action potentials and shortened action potential duration. The application of E-4031 without prior AS exposure, resulted in the typical class III antiarrhythmic effects of action potential lengthening and the induction of early afterdepolarizations. These findings suggest that under our conditions of AS-induced cell Ca2+ overload, the effects of the "pure" class III antiarrhythmic drugs, E-4031 and dofetilide, are markedly different from those found in non-Ca2+ loaded cells. This may represent an additional electrophysiological mechanism for class III antiarrhythmic drug toxicity.