PROARRHYTHMIC ACTIONS OF CLASS Ⅲ ANTIARRHYTHMIC DRUGS IN RABBIT SINO-ATRIAL NODAL CELLS

Abstract

Arrhythmias induced by class Ⅲ antiarrhythmic drugs (amiodarone, bretylium and sotalol) in spontaneously beating rabbit sino-atrial nodal cells were inves- tigated using voltage-clamp and Ca²⁺ -sensitive fluorescent dye (fura-2). These drugs caused a negative chronotropic effect, and amiodarone and sotalol prolonged the action potential duration. Amiodarone (10μM) induced arrhythmias in 3 out of 10 cells, and simultaneously elicited a transient inward current. Bretylium (10μM) increased the incidence of arrhythmias in 5 out of 11 cells, and sotalol (10μM) caused arrhythnias in only one of 10 cells. These drugs inhibited the Ca²⁺ and delayed rectifier K⁺ and hyperpolariza- tion-activated inward currents. The kinetics for activation and inactivation of these currents were unaffected. After a washout, the regular rhythm was resumed and the transient inward current also disappeared. Change in the cytosolic Ca²⁺ concentration was monitored with fura-2. Amiodarone (10-30 μM) and bretylium (0.1-10 μM) significantly elevated the cytosolic Ca²⁺ level, but sotalol, even at 1mM, did not affect it. These results indicate that the class Ⅲ antiarrhythmic drugs possess proarrhythmic actions, probably resulting from elevation of cellular Ca²⁺ concentration as well as the prolongation of action potential.