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Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations.

Abstract：

BACKGROUND: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.

journal_name

Heart Rhythm

journal_title

Heart rhythm

authors

Maruyama M,Xiao J,Zhou Q,Vembaiyan K,Chua SK,Rubart-von der Lohe M,Lin SF,Back TG,Chen SR,Chen PS

doi

10.1016/j.hrthm.2012.09.006

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

101-7

issue

1

eissn

1547-5271

issn

1556-3871

pii

S1547-5271(12)00996-4

journal_volume

10

pub_type

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