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 3repolarization. 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.2
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