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Human cardiac gap-junction coupling: effects of antiarrhythmic peptide AAP10.

Cardiovascular research (2009-01-30)
Anja Hagen, Anna Dietze, Stefan Dhein
RESUMEN

Ventricular arrhythmia is one of the most important causes of death in industrialized countries and often accompanies myocardial infarction and heart failure. In recent years modification of gap-junctional coupling has been proposed as a new antiarrhythmic principle. We wanted to examine whether the gap junction modulator (antiarrhythmic peptide) AAP10 exerts effects on human cardiac gap junctions, whether the effect might be enhanced in uncoupled cells, whether it affects electrical and metabolic coupling, and which of the cardiac connexin isoforms (Cx40, Cx43, Cx45) may be affected. We determined the influence of 50 nM AAP10 (H(2)N-Gly-Ala-Gly-4Hyp-Pro-Tyr-CONH(2)) on macroscopic gap junction conductance by dual whole-cell voltage clamping in human and rat cardiomyocytes. Cells were partially uncoupled by CO(2)-mediated acidosis (pH 6.3) or kept at 'normal' conditions (pH 7.4, T 36 degrees C). Furthermore, we investigated effects of AAP10 in HeLa cells stably transfected with connexin 40, 43, or 45 and on metabolic coupling determined by dye transfer (Lucifer yellow). AAP10 (50 nM)-enhanced gap-junctional intercellular coupling in human and rat cardiomyocytes, completely prevented CO(2)-acidosis-induced uncoupling and improved metabolic coupling. The coupling effect of AAP10 was significantly enhanced in previously uncoupled cells. Regarding the connexin isoforms, AAP10-enhanced electrical and metabolic coupling in HeLa cells expressing Cx43 or Cx45, but not in HeLa cells expressing Cx40. We conclude that the antiarrhythmic peptide AAP10, which improves gap-junctional intercellular coupling and prevents uncoupling by acidification in human cardiomyocytes, might be useful for antiarrhythmic strategies regarding arrhythmias caused by uncoupling of Cx43 and Cx45, but not Cx40.

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Anti-Connexin 40 Antibody, Chemicon®, from rabbit