Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by reducing conduction velocity without affecting repolarization properties or myocardial refractoriness in Langendorff-perfused mouse hearts
Author(s)
Tse, Gary
Yeo, Jie Ming
Tse, Vivian
Kwan, Joseph
Sun, Bing
Type
Journal Article
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.
Date Issued
2016-11-01
Date Acceptance
2016-09-01
Citation
Molecular Medicine Reports, 2016, 14 (5), pp.4069-4074
ISSN
1791-2997
Publisher
Spandidos Publications
Start Page
4069
End Page
4074
Journal / Book Title
Molecular Medicine Reports
Volume
14
Issue
5
Copyright Statement
© Tse et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000387241600009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Oncology
Medicine, Research & Experimental
Research & Experimental Medicine
conduction
conduction velocity
repolarization
refractory period
wavelength
gap junction
arrhythmia
SPATIALLY DISCORDANT ALTERNANS
THERAPEUTIC HYPOTHERMIA
CONNEXIN43
MICE
MECHANISMS
INSIGHTS
SODIUM
DEATH
NULL
SUSCEPTIBILITY
Publication Status
Published
Date Publish Online
2016-09-13