Synergistic antiarrhythmic effect of combining inhibition of Ca2+-activated K+ (SK) channels and voltage-gated Na+ channels in an isolated heart model of atrial fibrillation

BACKGROUND Application of antiarrhythmic compounds is limited by both proarrhythmic and extracardiac toxicities, as well as incomplete antiarrhythmic efficacy. An improved antiarrhythmic potential may be obtained by combining antiarrhythmic drugs with different modes of action, and a reduction of the adverse effect profile could be an additional advantage if compound concentrations could be reduced. OBJECTIVE The purpose of this study was to test the hypothesis that combined inhibition of Ca2+-activated K+ channels (SK channels) and voltage-gated Na+ channels, in concentrations that would be subefficacious as monotherapy, may prevent atrial fibrillation (AF) and have reduced proarrhythmic potential in the ventricles. METHODS Subefficacious concentrations of ranolazine, flecainide, and Lidocaine were tested alone or in combination with the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) in a Langendorff-perfused guinea pig heart model in which AF was induced after acetylcholine application and burst pacing. RESULTS AF duration was reduced when both flecainide and ranolazine were combined with ICA in doses that did not reduce AF as monotherapy. At higher concentrations, both flecainide and ranolazine revealed proarrhythmic properties. CONCLUSION A synergistic effect in AF treatment was obtained by combining low concentrations of SK and Na+ channel blockers.