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Interventricular heterogeneity as a substrate for arrhythmogenesis of decoupled mitochondria during ischemia in the whole heart.

Abstract
Myocardial ischemia results in metabolic changes, which collapse the mitochondrial network, that increase the vulnerability of the heart to ventricular fibrillation (VF). It has been demonstrated at the single cell level that uncoupling the mitochondria using carbonyl cyanide p-(tri-fluoromethoxy)phenyl-hydrazone (FCCP) at low concentrations can be cardioprotective. The aim of our study was to investigate the effect of FCCP on arrhythmogenesis during ischemia in the whole rabbit heart. We performed optical mapping of isolated rabbit hearts (n = 33) during control and 20 min of global ischemia and reperfusion, both with and without pretreatment with the mitochondrial uncoupler FCCP at 100, 50, or 30 nM. No hearts went into VF during ischemia under the control condition, with or without the electromechanical uncoupler blebbistatin. We found that pretreatment with 100 (n = 4) and 50 (n = 6) nM FCCP, with or without blebbistatin, leads to VF during ischemia in all hearts, whereas pretreatment with 30 nM of FCCP led to three out of eight hearts going into VF during ischemia. We demonstrated that 30 nM of FCCP significantly increased interventricular (but not intraventricular) action potential duration and conduction velocity heterogeneity in the heart during ischemia, thus providing the substrate for VF. We showed that wavebreaks during VF occurred between the right and left ventricular junction. We also demonstrated that no VF occurred in the heart pretreated with 10 μM glibenclamide, which is known to abolish interventricular heterogeneity. Our results indicate that low concentrations of FCCP, although cardioprotective at the single cell level, are arrhythmogenic at the whole heart level. This is due to the fact that FCCP induces different electrophysiological changes to the right and left ventricle, thus increasing interventricular heterogeneity and providing the substrate for VF.
AuthorsRebecca M Smith, Saalini S Velamakanni, Elena G Tolkacheva
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 303 Issue 2 Pg. H224-33 (Jul 15 2012) ISSN: 1522-1539 [Electronic] United States
PMID22636678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Heterocyclic Compounds, 4 or More Rings
  • Proton Ionophores
  • blebbistatin
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Glyburide
Topics
  • Action Potentials (drug effects, physiology)
  • Animals
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone (pharmacology)
  • Glyburide (pharmacology)
  • Heterocyclic Compounds, 4 or More Rings (pharmacology)
  • Mitochondria, Heart (drug effects, physiology)
  • Myocardial Ischemia (drug therapy, physiopathology)
  • Proton Ionophores (pharmacology)
  • Rabbits
  • Ventricular Fibrillation (drug therapy, physiopathology)

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