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Ca(2+)/calmodulin-dependent protein kinase inhibition suppresses post-ischemic arrhythmogenesis and mediates sinus bradycardic recovery in reperfusion.
MedLine Citation:
PMID:  21392835     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Ca(2+)/calmodulin-dependent protein kinase (CaMKII) activation is known to be associated with conditions where the incidence of arrhythmias is increased, and where cardiomyocyte Ca(2+)-overload occurs. The goal of this study was to determine whether CaMKII inhibition in the intact heart may be linked to the suppression of ventricular arrhythmias occurring during reperfusion after an ischemic insult. METHODS: Non-paced male rat hearts (n=8-11) were treated with a CaMKII inhibitor (KN93, 2.5μmol/L) 10min prior to global ischemia (20min) and for the initial 10min of reperfusion. Cardiac mechanical and arrhythmic responses were evaluated under constant pressure perfusion conditions and myocyte damage assessed by measurement of coronary effluent lactate dehydrogenase (LDH). RESULTS: Under basal conditions, KN93 increased coronary flow (41±8% increase, p<0.05) and was negatively inotropic (29±7% decrease, p<0.05), but did not affect heart rate. Ischemic contracture was significantly diminished in KN93-treated hearts (onset, min: 11.48±0.50 vs 16.27±1.23, p<0.05). CaMKII inhibition in early reperfusion almost completely abolished the incidence of ventricular tachycardia/fibrillation in reperfusion (11/11 control vs 1/8 KN93). In the absence of ventricular arrhythmias, heart rate was substantially reduced (% basal; 100±3% vs 46±8%, p<0.05) throughout reperfusion. Left ventricular developed pressure was initially low in KN93 hearts post-ischemia, but recovered to control levels by the end of 60min reperfusion (68±5% vs 56±5%, p=ns). LDH was significantly reduced in KN93-treated hearts. CONCLUSION: Although CaMKII inhibition diminishes contractile performance of the intact heart in the initial post-ischemic period, it provides crucial benefits through protection against potentially lethal reperfusion-induced arrhythmias and cardiomyocyte sarcolemmal rupture.
Authors:
James R Bell; Claire L Curl; Wendy T K Ip; Lea M D Delbridge
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-8
Journal Detail:
Title:  International journal of cardiology     Volume:  -     ISSN:  1874-1754     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-3-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8200291     Medline TA:  Int J Cardiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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