Document Detail


Role of late sodium current as a potential arrhythmogenic mechanism in the progression of pressure-induced heart disease.
MedLine Citation:
PMID:  23570977     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The aim of the study was to determine the characteristics of the late Na current (INaL) and its arrhythmogenic potential in the progression of pressure-induced heart disease. Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the hearts developed isolated hypertrophy with preserved systolic contractility. In patch-clamp experiments both, INaL and the action potential duration (APD90) were unchanged. In contrast, after five weeks animals developed heart failure with prolonged APDs and slowed INaL decay time which could be normalized by addition of the INaL inhibitor ranolazine (Ran) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Accordingly the APD90 could be significantly abbreviated by Ran, tetrodotoxin and the CaMKII inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) in myocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs. Moreover, the incidence of triggered activity was significantly increased in TAC myocytes and was largely prevented by Ran and AIP. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. In pressure overload-induced heart failure a CaMKII-dependent augmentation of INaL plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot be found in early and still compensated hypertrophy. Inhibition of INaL and CaMKII exerts potent antiarrhythmic effects and might therefore be of potential therapeutic interest. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".
Authors:
Karl Toischer; Nico Hartmann; Stefan Wagner; Thomas H Fischer; Jonas Herting; Bernhard C Danner; Can M Sag; Thomas J Hund; Peter J Mohler; Luiz Belardinelli; Gerd Hasenfuss; Lars S Maier; Samuel Sossalla
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-06
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  61     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-22     Completed Date:  2014-02-13     Revised Date:  2014-08-04    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  111-22     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Acetanilides / pharmacology
Action Potentials*
Animals
Arrhythmias, Cardiac / metabolism*,  physiopathology
Blood Pressure
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors,  metabolism
Cardiomegaly / metabolism,  physiopathology
Cells, Cultured
Female
Heart Failure / metabolism*,  physiopathology
Heart Ventricles / pathology
Mice
Mice, Inbred C57BL
NAV1.1 Voltage-Gated Sodium Channel / metabolism
Patch-Clamp Techniques
Peptides / pharmacology
Piperazines / pharmacology
Sodium / metabolism*
Sodium Channel Blockers / pharmacology
Tetrodotoxin / pharmacology
Grant Support
ID/Acronym/Agency:
HL083422/HL/NHLBI NIH HHS; HL084583/HL/NHLBI NIH HHS; HL096805/HL/NHLBI NIH HHS; R01 HL083422/HL/NHLBI NIH HHS; R01 HL084583/HL/NHLBI NIH HHS; R01 HL114383/HL/NHLBI NIH HHS; R01 HL114893/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Acetanilides; 0/CaMKII inhibitor AIP; 0/NAV1.1 Voltage-Gated Sodium Channel; 0/Peptides; 0/Piperazines; 0/Scn1a protein, mouse; 0/Sodium Channel Blockers; 110445-25-5/ranolazine; 4368-28-9/Tetrodotoxin; 9NEZ333N27/Sodium; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Type 2
Comments/Corrections

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