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
Whether nicorandil is effective at preventing ventricular tachyarrhythmia (VT) during acute myocardial ischaemia is still controversial. We examined effects of nicorandil on the induction of VT during acute myocardial ischaemia. Optical action potentials were recorded from the entire transmural wall of arterially perfused canine left ventricular wedges. Ischaemia was produced by arterial occlusion for 20 min. During endocardial pacing, nicorandil shortened mean action potential duration (APD) in the transmural wall before ischaemia and further shortened it during ischaemia without increasing dispersion of APD. HMR1098, a selective blocker of sarcolemmal ATP-sensitive K + channels, inhibited the shortening of APD by nicorandil before and during ischaemia. Ischaemia decreased transmural conduction velocity (CV). Nicorandil partially restored CV to a similar extent in the absence and presence of HMR1098. In contrast, HMR1098 did not suppress the ischaemic conduction slowing in the absence of nicorandil. Nicorandil suppressed the increased dispersion of local CV during ischaemia. Isochrone maps on the initiation of VT showed that reentry in the transmural surface resulted from the excitation of the epicardial region of transmural surface. Nicorandil significantly increased the size of non-excited area in the epicardial region of the transmural wall, thereby significantly reducing the incidence of VT induced during ischaemia. HMR1098 inhibited this effect of nicorandil. These results suggest that nicorandil prevents VT during acute global ischaemia primarily by augmenting the inactivation of epicardial muscle through the activation of sarcolemmal K ATP channels.
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