Contribution of L-type Ca2+ channels to early afterdepolarizations induced by IKr and IKs channel suppression in guinea pig ventricular myocytes

Early afterdepolizations (EADs) induced by suppression of cardiac delayed rectifier I(Kr) and/or I(Ks) channels cause fatal ventricular tachyarrhythmias. In guinea pig ventricular myocytes, partial block of one of the channels with complete block of the other reproducibly induced EADs. Complete block of both I(Kr) and I(Ks) channels depolarized the take-off potential and reduced the amplitude of EADs, which in some cases were not clearly separated from the preceding action potentials. A selective L-type Ca(2+) (I(Ca,L)) channel blocker, nifedipine, effectively suppressed EADs at submicromolar concentrations. As examined with the action potential-clamp method, I(Ca,L) channels mediated inward currents with a spike and dome shape during action potentials. I(Ca,L) currents decayed mainly due to inactivation in phase 2 and deactivation in phase 3 repolarization. When EADs were induced by complete block of I(Kr) channels with partial block of I(Ks) channels, repolarization of the action potential prior to EAD take-off failed to increase I(K1) currents and thus failed to completely deactivate I(Ca,L) channels, which reactivated and mediated inward currents during EADs. When both I(Kr) and I(Ks) channels were completely blocked, I(Ca,L) channels were not deactivated and mediated sustained inward currents until the end of EADs. Under this condition, the recovery and reactivation of I (Ca,L) channels were absent before EADs. Therefore, an essential mechanism underlying EADs caused by suppression of the delayed rectifiers is the failure to completely deactivate I(Ca,L) channels.