Atrial Anti-Arrhythmic Effects of Heptanol in Langendorff-Perfused Mouse Hearts

Yeo

Molecular Medicine Reports

et al. 2016

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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 × 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.

Section: Resultsmentioning

confidence: 97%

“…The right ventricular epicardium was electrically stimulated using either regular 8 Hz or S1S2 pacing (2,3,5,7,12). MAP recordings were obtained from the left ventricular epicardium.…”

Section: Resultsmentioning

confidence: 99%

Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by reducing conduction velocity without affecting repolarization properties or myocardial refractoriness in Langendorff-perfused mouse hearts

Yeo

Molecular Medicine Reports

et al. 2016

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“…Besides voltage sensitivity, both mechanosensitivity and chemosensitivity have been reported (Bao et al, 2004; Bukauskas and Verselis, 2004). Connexin activity is influenced by intracellular Ca 2+ , pH, chemical uncouplers (Tse et al, 2016b,c,d,e,f), phosphorylation events (Musil and Goodenough, 1991; Bennett and Verselis, 1992), and lipid availability in the immediate environment, including low-density lipoprotein, apolipoprotein-B (Meyer et al, 1991) and cholesterol (Meyer et al, 1990). Gap junctions allow the passive diffusion of ions, intracellular molecules that include metabolites and messengers such as cyclic AMP, cyclic GMP and IP 3 .…”

Section: Introductionmentioning

confidence: 99%

The Role of Connexins in Wound Healing and Repair: Novel Therapeutic Approaches

et al. 2016

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Gap junctions are intercellular proteins responsible for mediating both electrical and biochemical coupling through the exchange of ions, second messengers and small metabolites. They consist of two connexons, with (one) connexon supplied by each cell. A connexon is a hexamer of connexins and currently more than 20 connexin isoforms have been described in the literature thus far. Connexins have a short half-life, and therefore gap junction remodeling constantly occurs with a high turnover rate. Post-translational modification, such as phosphorylation, can modify their channel activities. In this article, the roles of connexins in wound healing and repair are reviewed. Novel strategies for modulating the function or expression of connexins, such as the use of antisense technology, synthetic mimetic peptides and bioactive materials for the treatment of skin wounds, diabetic and pressure ulcers as well as cornea wounds, are considered.

“…In this case, optical mapping using a microelectrode array would be a better technique [50]. Furthermore, the MAP electrode would cover the entire mouse atrial surface for studying atrial electrophysiological properties, but MAPs have been successfully recorded from the mouse atria [51]. Other methods such as bipolar electrograms can also be used to determine repolarization properties [51,52].…”

Section: Practical Considerations and Limitationsmentioning

confidence: 99%

“…It is unclear as to the minimum degree of intercellular coupling needed for obtaining MAP recordings and the effects of impaired gap junction function on the MAP waveform. Experimental studies in mouse hearts have demonstrated stable MAP recordings obtained from myocardium when gap junctions were uncoupled by the agent heptanol at a concentration of 0.1 mM [20,35,51]. At a higher concentration of 2 mM, conduction velocity was progressively reduced and MAP amplitudes were decreased, eventually leading to conduction block and abolition of the MAP waveform.…”

Section: Practical Considerations and Limitationsmentioning

confidence: 99%

Monophasic action potential recordings: which is the recording electrode?

Wong

Journal of Basic and Clinical Physiology and Pharmacology

et al. 2016

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The aim of this article is to provide an overview of current debate on the monophasic action potential (MAP) recording technique, specifically whether the depolarizing or the reference electrode is responsible for recording the MAP waveform. A literature search was made using key words including monophasic action potential, MAP, electrophysiological basis, recording electrode, depolarizing electrode, contact electrode, indifferent electrode, and reference electrode. References from articles were screened for additional relevant papers. Articles published by the different experimental groups claim that depolarizing electrode, but not reference electrode, records MAPs from the myocardium. This can be more accurately described when considering biophysical theory, which states that MAP is a bipolar signal with contributions from not only the depolarizing electrode but also remote activation at the reference electrode. It is not meaningful to claim that one is the recording electrode because potential differences must be measured between two points in space. Nevertheless, the MAP technique is useful for assessing the local electrical activity of the myocardium in contact with the depolarizing electrode. It is important to have the recording electrode in close proximity with the reference electrode to minimize contamination from far-field signals.