title: Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs.
abstract: The role of gap junction intercellular communication (GJIC) in ischemia-induced focal ventricular tachycardia (VT) is unknown. We have developed a new, stable antiarrhythmic peptide analog named ZP123 that selectively increases GJIC and prevents reentrant VT. Our aim in this study was to use ZP123 as a tool to assess the role of GJIC on occurrence of ischemia-induced focal VT and triggered activity (TA) due to delayed afterdepolarizations (DADs). Focal VT was induced by programmed stimulation in alpha-chloralose-anesthetized, open-chest dogs 1-4 h after coronary artery occlusion. Three-dimensional activation mapping was done using 6 bipolar electrograms on each of 23 multipolar needles in the risk zone. Dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (an intravenous bolus followed by a 30-min infusion per dose). Attempts to induce VT were repeated in each dose. Mass spectrometry was used to measure plasma ZP123 concentrations. Standard microelectrode techniques were used for in vitro study of DADs and TA. Twenty-six dogs with focal VT were included. ZP123 did not affect the inducibility of focal VT at any plasma concentrations vs. saline (0.8 +/- 0.1 nM, 77 vs. 75%; 7.8 +/- 0.4 nM, 86 vs. 77%; and 78.8 +/- 5.0 nM, 77 vs. 91%). In vitro, ZP123 did not affect the induction of DADs (12/12) and TAs (10/10) in ischemic tissues or tissue removed from the origin of focal VT (DADs, 8/8; TAs, 4/4). Therefore, although indirect, the data with the doses and concentrations used suggest that GJIC may not play a major role in the genesis of focal activity in the ischemic models studied.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, USA.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Xing
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Kjølbye
authors.forename: Jørgen S
authors.initials: JS
authors.lastname: Petersen
authors.forename: James B
authors.initials: JB
authors.lastname: Martins
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology*; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology*
chemical_list: D009842:Oligopeptides; C477643:rotigaptide