Document Detail


Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations.
MedLine Citation:
PMID:  22982970     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Mitsunori Maruyama; Jianmin Xiao; Qiang Zhou; Kannan Vembaiyan; Su-Kiat Chua; Michael Rubart-von der Lohe; Shien-Fong Lin; Thomas G Back; S R Wayne Chen; Peng-Sheng Chen
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-14
Journal Detail:
Title:  Heart rhythm : the official journal of the Heart Rhythm Society     Volume:  10     ISSN:  1556-3871     ISO Abbreviation:  Heart Rhythm     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-07     Completed Date:  2013-06-20     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  101200317     Medline TA:  Heart Rhythm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  101-7     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Action Potentials / drug effects,  physiology
Analysis of Variance
Animals
Calcium / metabolism
Carbazoles / pharmacology*
Heart Ventricles / drug effects,  physiopathology
Isoproterenol / pharmacology
Long QT Syndrome / drug therapy*,  physiopathology
Membrane Potentials / drug effects,  physiology
Mice
Morpholines / pharmacology*
Propanolamines / pharmacology*
Rabbits
Grant Support
ID/Acronym/Agency:
P01 HL078931/HL/NHLBI NIH HHS; P01HL78931/HL/NHLBI NIH HHS; R01 HL071140/HL/NHLBI NIH HHS; R01 HL075210/HL/NHLBI NIH HHS; R01 HL078932/HL/NHLBI NIH HHS; R01HL075210/HL/NHLBI NIH HHS; R01HL71140/HL/NHLBI NIH HHS; R01HL78932/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Carbazoles; 0/Morpholines; 0/Propanolamines; 0/VK-II-36 compound; 0K47UL67F2/carvedilol; L628TT009W/Isoproterenol; SY7Q814VUP/Calcium
Comments/Corrections
Comment In:
Heart Rhythm. 2013 Jan;10(1):108-9   [PMID:  23085093 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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