Ventricular anti-arrhythmic effects of heptanol in hypokalaemic, 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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“…However, no single system is ideal, as there are species differences and other limitations of these model systems (4,5). Species, including mice, have been popular for the study of cardiometabolic disorders due to their amenability to genetic and pharmacological modification (6–12). It is not the aim of the present review to provide an exhaustive list of the different models, but to discuss historically important model systems whose use has significantly advanced our understanding of hypertension.…”

Section: Introductionmentioning

confidence: 99%

Animal models for the study of primary and secondary hypertension in humans

et al. 2016

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Hypertension is a significant cause of morbidity and mortality worldwide. It is defined as systolic and diastolic blood pressures (SBP/DBP) >140 and 90 mmHg, respectively. Individuals with an SBP between 120 and 139, or DBP between 80 and 89 mmHg, are said to exhibit pre-hypertension. Hypertension can have primary or secondary causes. Primary or essential hypertension is a multifactorial disease caused by interacting environmental and polygenic factors. Secondary causes are renovascular hypertension, renal disease, endocrine disorders and other medical conditions. The aim of the present review article was to examine the different animal models that have been generated for studying the molecular and physiological mechanisms underlying hypertension. Their advantages, disadvantages and limitations will be discussed.

“…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.