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Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations Maruyama M; Xiao J; Zhou Q; Vembaiyan K; Chua SK; Rubart-von der Lohe M; Lin SF; Back TG; Chen SR; Chen PSHeart Rhythm 2013[Jan]; 10 (1): 101-7BACKGROUND: Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor type 2 (RyR2). OBJECTIVE: To test a hypothesis that carvedilol analogue may also prevent triggered activities (TAs) through the suppression of early afterdepolarizations (EADs). METHODS: Intracellular Ca(2+) and membrane voltage were simultaneously recorded by using optical mapping technique in Langendorff-perfused mouse and rabbit hearts to study the effect of carvedilol analogue VK-II-36, which does not have significant beta-blocking effects. RESULTS: Spontaneous intracellular Ca(2+) elevations (SCaEs) during diastole were induced by rapid ventricular pacing and isoproterenol infusion in intact rabbit ventricles. Systolic and diastolic SCaEs were simultaneously noted in Langendorff-perfused RyR2 R4496(+/-) mouse hearts after creating atrioventricular block. VK-II-36 effectively suppressed SCaEs and eliminated TAs observed in both mouse and rabbit ventricles. We tested the effect of VK-II-36 on EADs by using a rabbit model of acquired long QT syndrome, in which phase 2 and phase 3 EADs were observed in association with systolic SCaEs. VK-II-36 abolished the systolic SCaEs and phase 2 EADs, and greatly decreased the dispersion of repolarization and the amplitude of phase 3 EADs. VK-II-36 completely prevented EAD-mediated TAs in all ventricles studied. CONCLUSIONS: A carvedilol analogue, VK-II-36, inhibits ventricular tachyarrhythmias in intact mouse and rabbit ventricles by the suppression of SCaEs, independent of beta-blocking activity. The RyR2 may be a potential target for treating focal ventricular arrhythmias triggered by either EADs or DADs.|Action Potentials/drug effects/physiology[MESH]|Analysis of Variance[MESH]|Animals[MESH]|Calcium/metabolism[MESH]|Carbazoles/*pharmacology[MESH]|Carvedilol[MESH]|Heart Ventricles/drug effects/physiopathology[MESH]|Isoproterenol/pharmacology[MESH]|Long QT Syndrome/*drug therapy/physiopathology[MESH]|Membrane Potentials/drug effects/physiology[MESH]|Mice[MESH]|Morpholines/*pharmacology[MESH]|Propanolamines/*pharmacology[MESH]|Rabbits[MESH] |