COMPARISON OF PROARRHYTHMOGENIC EFFECTS OF 2 POTASSIUM CHANNEL OPENERS, LEVCROMAKALIM (BRL-38227) AND NICORANDIL (RP-46417) - A HIGH-RESOLUTION MAPPING STUDY ON RABBIT HEART

This study was designed (a) to test and (b) to compare proarrhythmic e ffects of levcromakalim and nicorandil; and (c) to determine the mecha nism of arrhythmia initiation by using high-resolution ventricular epi cardial mapping on 44 Langendorff-perfused rabbit hearts. Eighteen hea rts were kept intact and received incremental doses (1-500 mu M) of le vcromakalim, nicorandil, and isosorbide dinitrate. In 26 hearts, a thi n layer of epicardium was obtained after endocardial cryotechnique (fr ozen hearts). In intact hearts, isosorbide dinitrate did not produce a ny arrhythmia. In contrast, levcromakalim induced spontaneous ventricu lar fibrillation (VF) in all hearts at 50 mu M, whereas only one VF oc curred at 500 mu M nicorandil. These three drugs produced a dose-depen dent bradycardia in intact hearts. In frozen hearts, arrhythmias were induced by 5 mu M levcromakalim and 50 mu M nicorandil. Isosorbide din itrate had no proarrhythmogenic effect. Epicardial mapping showed that most of induced ventricular tachycardias were based on reentry around an are of functional conduction block. Ventricular conduction velocit ies did not change, but levcromakalim and nicorandil shortened ventric ular effective refractory period. We conclude that (a) levcromakalim a nd nicorandil, used in toxic concentrations, have direct proarrhythmic effects; (b) nicorandil proarrhythmogenic effects are 10 times less m arked than those of levcromakalim (arrhythmia is solely the result of the potassium channel opener property of nicorandil); and (c) most of ventricular tachycardias induced are based on reentry.