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Anti- or profibrillatory effects of Na(+) channel blockade depend on the site of application relative to gradients in repolarization.
MedLine Citation:
PMID:  21423353     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
Sodium channel blockers are associated with arrhythmic sudden death, although they are considered antiarrhythmic agents. The mechanism of these opposing effects is unknown. We used a model of induction of ventricular fibrillation (VF) based on selective perfusion of the vascular beds of isolated porcine hearts (n = 8). One bed was perfused with sotalol (220 μM), the adjacent bed with pinacidil (80 μM), leading to repolarization heterogeneity (late repolarization in the sotalol-, early in the pinacidil-area). Premature stimulation from the area with the short action potential was performed. Epicardial activation/repolarization mapping was done. In three of the eight hearts VF was inducible prior to infusion of flecainide. In those hearts the Fibrillation Factor (FF), the interval between the earliest repolarization of the premature beat (S2) in the early repolarizing (pinacidil) domain, and the last S2-activation in the late repolarizing (sotalol) domain, was significantly shorter than in the hearts without VF (33 ± 22 vs 93 ± 11 ms, m ± SEM, p < 0.05). In the three hearts with VF flecainide was infused in the pinacidil domain after defibrillation. This led to shortening of the line of block, local delay of S2 activation and repolarization, an increase in FF and failure to induce VF. In the five hearts without VF, flecainide was subsequently infused in the sotalol domain. This led to a local delay of S2 activation, a shortening of FF (by 47 ± 3 ms) and successful induction of VF in three hearts. In the two remaining hearts FF did not decrease enough (maximally 13 ms) to allow re-entry. Sodium channel blockade applied to myocardium with a short refractory period is antifibrillatory whereas sodium channel blockade of myocardium with a long refractory period is profibrillatory. Our study provides a mechanistic basis for pro- and antiarrhythmic effects of sodium channel blockers in the absence of structural heart disease.
Authors:
Ruben Coronel; Francien J G Wilms-Schopman; Michiel J Janse
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Publication Detail:
Type:  Journal Article     Date:  2010-06-07
Journal Detail:
Title:  Frontiers in physiology     Volume:  1     ISSN:  1664-042X     ISO Abbreviation:  Front Physiol     Publication Date:  2010  
Date Detail:
Created Date:  2011-03-22     Completed Date:  2011-05-09     Revised Date:  2013-08-13    
Medline Journal Info:
Nlm Unique ID:  101549006     Medline TA:  Front Physiol     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  10     Citation Subset:  -    
Affiliation:
Experimental Cardiology Group, Academic Medical Center Amsterdam, Netherlands. r.coronel@amc.uva.nl
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