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 × 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.

The influence of electrically conductive and non-conductive nanocomposite scaffolds on the maturation and excitability of engineered cardiac tissues

“…Heptanol has been widely used to uncouple electrical gap junctions, such as Cx43, which leads to reduced conduction velocity and unsynchronized contractions in CMs. 44,58,59 Excitation voltage thresholds of the heptanol-treated cardiac tissue are illustrated in Figure 5 for 0.5, 1 and 2 Hz frequencies. As can be seen, after 20 min exposure to 2 mM heptanol, GelMA (5%) tissue constructs were no longer able to follow the electrical stimulation at any of the applied frequencies ( Figure 5A and 5E and Supplementary movies M5).…”

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

“…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.…”

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

“…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 .…”