title: Desipramine prevents cardiac gap junction uncoupling.
abstract: OBJECTIVE
  Uncoupling of cardiac gap junction channels is an important arrhythmogenic mechanism in ischemia/reperfusion. Antiarrhythmic peptide AAP10 (H-Gly-Ala-Gly-Hyp-Pro-Tyr-CONH(2)) has been shown to prevent acidosis-induced uncoupling and ischemia-related increase in dispersion. Previous structure-effect investigations and subsequent computer modeling studies indicated that the tricyclic antidepressant desipramine may exert similar effects as AAP10.
  
  
  METHODS
  We assessed the binding of (14)C-AAP10 to membranes of rabbit cardiac ventricles and its displacement with desipramine in a classical radioligand binding and competition study. Gap junction currents were measured between isolated pairs of human atrial cardiomyocytes under normal and acidotic (pH 6.3) conditions with or without 1 μmol/l desipramine using dual whole-cell voltage clamp. The effect of 1 μmol/l desipramine was assessed in isolated rabbit hearts (Langendorff technique) undergoing local ischemia by coronary occlusion with 256-channel electrophysiological mapping and subsequent analysis of connexin43 (Cx43) expression, phosphorylation (Western blot), and subcellular localization (immunohistology).
  
  
  RESULTS
  We found saturable (14)C-AAP10 binding to cardiac membranes (K                   (D), 0.29 ± 0.11 nmol/l; B                   (max), 42.5 ± 7.2 pmol/mg) which could be displaced by desipramine with a K                   (D.High) = 0.14 μmol/l and a K                   (D.Low) = 22 μmol/l. Acidosis reduced the gap junction conductance in human cardiomyocyte pairs from 24.1 ± 4.7 to 11.5 ± 2.5 nS, which could be significantly reversed by desipramine (26.6 ± 4.8 nS). In isolated hearts, ischemia resulted in significantly increased dispersion of activation-recovery intervals, loss of membrane Cx43, and dephosphorylation of Cx43, which all could be prevented by desipramine.
  
  
  CONCLUSIONS
  Desipramine seems to prevent the uncoupling of cardiac gap junctions and ischemia-related increase in dispersion.
authors.affiliation: Clinic for Cardiology, University of Leipzig, Leipzig, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jozwiak
authors.forename: Anna
authors.initials: A
authors.lastname: Dietze
authors.forename: Rajiv
authors.initials: R
authors.lastname: Grover
authors.forename: Alex
authors.initials: A
authors.lastname: Savtschenko
authors.forename: Christian
authors.initials: C
authors.lastname: Etz
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Mohr
authors.forename: Stefan
authors.initials: S
authors.lastname: Dhein
mesh_terms: D000138:Acidosis / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D015153:Blotting, Western; D018031:Connexin 43 / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits
chemical_list: C090806:AAP 10; D000889:Anti-Arrhythmia Agents; D000929:Antidepressive Agents, Tricyclic; D018031:Connexin 43; D009842:Oligopeptides; D003891:Desipramine