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The role of a border zone in arrhythmogenesis is not fully understood. In this study we evaluated independent contributions of action potential duration (APD) and dispersion of repolarization (DOR) across the normal/ischemic border to the development of ventricular tachycardia and/or fibrillation (VT/VF). Ischemia-reperfusion episodes were induced in anesthetized rats by transient coronary occlusion. Unipolar electrograms were recorded from ischemic and perfused areas using a 64-lead array to obtain activation times (ATs), repolarization times (RTs), activation-repolarization intervals (ARIs, a surrogate for APD) and dispersion of repolarization (DOR, as a difference between the earliest and latest RTs). Pinacidil (0.3 mg/kg) and glibenclamide (2 mg/kg) were applied to reduce DOR and to clamp APD at a lower and upper levels, respectively. In the control animals, APD shortened in the ischemic zone, DOR increased to 9 ± 3 ms, and VT/VF developed at reperfusion (6 out of 10). Pre-occlusion application of glibenclamide prolonged APD in the ischemic and perfused zones, decreased DOR to 5 ± 2 ms and did not affect VT/VF development (4 out of 11). Post-occlusion infusion of pinacidil shortened APD in the perfused zone, decreased DOR to 6 ± 3 ms and VT/VF incidence (2 out of 11). Extrasystolic burden at reperfusion was associated with VT/VF incidence in logistic regression analysis (β = 1.182, 95%CI 1.008 - 1.386, p = 0.04) and was lesser (p < 0.01) in the pinacidil group as compared to the control and glibenclamide groups. In conclusion, the results of this study suggest that the APDs in the perfused zone were a superior arrhythmogenic factor in respect to DOR in the present ischemia-reperfusion model.

The mechanism of reentrant ventricular tachyarrhythmias complicating acute myocardial ischemia is largely based on the interaction between an arrhythmogenic substrate and triggers. Melatonin was proposed as an antiarrhythmic medication and was shown to ameliorate the arrhythmogenic substrate. Also, melatonin provides a sympatholytic effect in different settings and might attenuate ectopic activity, which provides reentry triggers. In the present study, we aimed at evaluating the melatonin effects on cardiac sympathetic activity and the incidence of premature ventricular beats during the episode of ischemia-reperfusion. Experiments were done in a total of 26 control and 28 melatonin-treated (10 mg/kg, daily, for 7 days) male rats. Sympathetic fibers density was assessed by glyoxylic acid-induced fluorescence. Continuous electrocardiograms recording was performed during ischemia-reperfusion episodes (5 min/5 min, respectively) induced by reversible coronary occlusion. Myocardial expression of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis was assessed by Western blotting. No differences in the state of sympathetic innervation were observed in histochemical analysis. However, Western blotting analysis demonstrated that melatonin treatment suppressed tyrosine hydroxylase expression in the non-ischemic (p < 0.05 versus control) but not ischemic regions of myocardium. The melatonin-treated animals had longer RR-intervals in the baseline state than the control animals (264 ± 48 ms versus 237 ± 33 ms, p = 0.044, respectively), but this difference decayed during the period of ischemia due to the increase of heart rate in the treated group. The number of premature ventricular beats did not differ between the control and treated groups during the ischemic and reperfusion periods. One-week melatonin pretreatment caused a slight peripheral sympatholytic effect that attenuated during ischemia and completely disappeared by the onset of reperfusion. The slight expression of sympathetic downregulation was associated with the lack of any effect of melatonin on extrasystolic burden. Collectively, the data suggest that melatonin cannot target the triggers of reentrant arrhythmias.

In this study we tested a hypothesis that reperfusion ventricular tachyarrhythmias can be modified by direct control of repolarization duration in the perfused myocardium during ischemic exposure. After induction of coronary occlusion, three groups of rats were given agencies affecting repolarization duration tetraethylammonium (TEA) 4 mg/kg, n = 9; pinacidil (Pin) 0.3 mg/kg, n = 11, and saline as placebo (control) n = 10. Unipolar electrograms were recorded from ischemic and perfused areas using an array of 64-electrodes to obtain activation times (ATs), repolarization times (RTs), activation-repolarization intervals (ARIs) and dispersion of repolarization (DOR). During ischemia/reperfusion ARIs in perfused area did not change in the control, significantly increased in the TEA and decreased in the Pin group in respect to baseline, whereas ARIs significantly decreased in the ischemic zone in all groups. DOR also significantly increased in all groups at ischemia and reperfusion. The incidence and total arrhythmia score of reperfusion tachyarrhythmias were significantly greater in TEA group compared to Pin and control groups. In multivariate regression analysis, incidence of VT/VFs and total arrhythmia score were associated with ARIs in the perfused area. Thus, the effect on repolarization durations in the perfused area modified the incidence and severity of the reperfusion-induced ventricular tachyarrhythmias.