title: Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by reducing conduction velocity without affecting repolarization properties or myocardial refractoriness in Langendorff-perfused mouse hearts.
abstract: In the current study, arrhythmogenic effects of the gap junction inhibitor heptanol (0.05 mM) were examined in Langendorff-perfused mouse hearts. Monophasic action potential recordings were obtained from the left ventricular epicardium during right ventricular pacing. Regular activity was observed both prior and subsequent to application of heptanol in all of the 12 hearts studied during 8 Hz pacing. By contrast, induced ventricular tachycardia (VT) was observed after heptanol treatment in 6/12 hearts using a S1S2 protocol (Fisher's exact test; P<0.05). The arrhythmogenic effects of heptanol were associated with increased activation latencies from 13.2±0.6 to 19.4±1.3 msec (analysis of variance; P<0.001) and reduced conduction velocities (CVs) from 0.23±0.01 to 0.16±0.01 msec (analysis of variance; P<0.001) in an absence of alterations in action potential durations (ADPs) at x=90% (38.0±1.0 vs. 38.3±1.8 msec), 70% (16.8±1.0 vs. 19.5±0.9 msec), 50% (9.2±0.8 vs. 10.1±0.6 msec) or 30% (4.8±0.5 vs. 6.3±0.6 msec) repolarization (APDx) or in effective refractory period (ERPs) (39.6±1.9 vs. 40.6±3.0 msec) (all P>0.05). Consequently, excitation wavelengths (λ; CV x ERP) were reduced from 9.1±0.6 to 6.5±0.6 mm (P<0.01), however critical intervals for re‑excitation (APD90 ‑ ERP) were unaltered (‑1.1±2.4 vs. ‑2.3±1.8 msec; P>0.05). Together, these observations demonstrate for the first time, to the best of our knowledge, that inhibition of gap junctions alone using a low heptanol concentration (0.05 mM) was able to reduce CV, which alone was sufficient to permit the induction of VT using premature stimulation by reducing λ, which therefore appears central in the determination of arrhythmic tendency.
authors.affiliation: Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, P.R. China.
authors.forename: Gary
authors.initials: G
authors.lastname: Tse
authors.affiliation: Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: Jie Ming
authors.initials: JM
authors.lastname: Yeo
authors.affiliation: Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Vivian
authors.initials: V
authors.lastname: Tse
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, P.R. China.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwan
authors.affiliation: Department of Cardiology, Tongji University Affiliated Tongji Hospital, Shanghai 200065, P.R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D017629:Gap Junctions / Q000187:drug effects / Q000473:pathology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D019850:Heptanol / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000473:pathology; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D019850:Heptanol