Electrophysiological effects of imipramine on ovine cardiac Purkinje and ventricular muscle fibers.

In man, therapeutic doses of imipramine suppress ventricular arrhythmias, and toxic doses can cause severe intraventricular conduction disturbances and cardiac arrest. To determine the cellular mechanisms responsible for these actions, we studied the effects of imipramine hydrochloride at concentrations from 3 x 1<T to 3 x 10~ g/ml on the transmembrane potentials of sheep and calf Purkinje and ventricular muscle fibers using standard microelectrode techniques. All imipramineinduced changes in transmembrane potentials became more marked with increasing concentration. At 1 x 10"' g/ml (a low therapeutic concentration in man), imipramine shortened the Purkinje fiber action potential (18%) and reduced upstroke velocity slightly (6%). At 1 x 10" g/ml (a high therapeutic or toxic concentration in man), imipramine reduced the upstroke velocity of Purkinje fiber action potential by 23% and of ventricular muscle by 53%; conduction velocity fell by 26%. In Purkinje fibers, imipramine at 1 x 10~ g/ml suppressed spontaneous firing elicited by isoproterenol and hypokalemia, due to a +7.9-mV shift in threshold voltage with little or no effect on spontaneous phase 4 depolarization. Depression of action potential phase 0 and action potential shortening may play a role in the antiarrhythmic effect of imipramine at therapeutic concentrations. At toxic imipramine concentrations, depression of phase 0 is marked and can account for the potentially fatal conduction defects and arrhythmias seen during imipramine toxicity in man. Circ Res 46:167-175, 1980