Barium-induced nondriven action potentials as a model of triggered potentials from early afterdepolarization: Significance of slow channel activity and differeing effects of quinidine and amiodarone

AbstractTriggered activity due to early afterdepolarizations in the content of prolonged repolarization is believed to cause torsade de pointes. The nature of such triggered activity is not clearly defined. Spontaneous action potentials developing from depolarized membrane potentials were studied in canine Purkinje fibers with use of a standard microelectrode technique. Action potentials due to abnormal automaturity and additional depolarizations developing over the repolarization phase were induced by 5 m-M barium superfusion. These action potentials were abolished by 1.0 × 10−5M verapamil and by calcium-free solution, whereas action potential amplitude (Vmax) and spontaneous firing frequency were markedly enhanced by 2.0 × 10−6M isoproterenol. High calcium solution shortened the action potential duration and precluded additional depolarizations.Quinidine, 1.0 × 10−5M, reduced action potential amplitude (6.9 ± 1.8 %: p < 0.01), Vmax (15.7 ± 4.0 %; p < 0.05) and spontaneous firing frequency (18.5 ± 2.1%; p < 0.01), but it increased action potential duration measured at −40 mV (19.1 ± 5.9 %; p < 0.01), which produced additional depolarizations. Amiodarone, 5.0 × 10−5M, reduced action potential amplitude (23.4 ± 3.6 %; p < 0.01), Vmax (44.6 ± 3.9 %; p < 0.01) and spontaneous firing frequency (41.9 ± 5.1 %; p < 0.01). Amiodarone obviated the development of additional depolarizations without effect on action potential duration.The data indicate that 1) triggered potentials from early afterdepolarizations are slow calcium channel dependent; 2) the duration of the plateau phase mediates the development of triggered activity from low membrane potential; 3) the effects on plateau currents but not direct effects on triggered potentials may contribute to the arrhythmogenic action of quinidine; and 4) the known associated slow channel blocking property of amiodarone may account for the low incidence of torsade de pointes during long-term amiodarone therapy