Melatonin treatment improves ventricular conduction via upregulation of Nav1.5 channel proteins and sodium current in the normal rat heart

Abstract

Melatonin treatment was reported to reduce the risk of cardiac arrhythmias, and crucial for this antiarrhythmic action was the effect of melatonin on activation spread. The aim of the present study was evaluation of the mechanisms of this activation enhancement. Experiments were performed in a total of 123 control and melatonin-treated (10 mg/kg, daily, for 7 days) male Wistar rats. In epicardial mapping studies (64 leads, interlead distance 0.5 mm) in the anesthetized animals, activation times (ATs) were determined in each lead as dV/dt minimum during QRS complex under sinus rhythm. Epicardial pacing was performed to measure conduction velocity (CV) across the mapped area. Average left ventricular ATs were shorter in the treated animals as compared to the controls, whereas the minimal epicardial ATs indicating the duration of activation propagation via the ventricular conduction system did not differ between the groups. CV was higher in the treated groups indicating that melatonin affected conduction via contractile myocardium The area of Cx43-derived fluorescence, as well as the expression of Cx43 protein, was similar in ventricles in the control and melatonin-treated groups. Expression of Gja1 gene transcripts encoding Cx43, was increased in the last group. An uncoupling agent octanol modified myocardial conduction properties (time of activation, action potential upstroke velocity, passive electrotonic phase duration) similarly in both groups. On the other hand, the expression of both Scn5a gene transcripts encoding Nav1.5 proteins, as well as peak density of transmembrane sodium current were increased in the ventricular myocytes from the melatonin-treated animals. Thus, a week-long melatonin treatment caused the increase of conduction velocity via

Blockade of Melatonin Receptors Abolishes Its Antiarrhythmic Effect and Slows Ventricular Conduction in Rat Hearts

“…For the elucidation of the acute antiarrhythmic effect of melatonin, its electrophysiological targets should be identified. Our study in the chronic model of melatonin treatment [28] demonstrated that conduction enhancement was caused by the melatonin-related increase in the sodium channel protein expression (Scn5a/Nav1.5) resulting in the augmentation of the sodium current INa. We tested INa in the present study, having in mind the hypothesis that similar effects might be induced by acute melatonin application.…”

“…The procedure of epicardial mapping has been described elsewhere [28,55]. In brief, in 12 animals of the melatonin group (MEL), 10 animals of the luzindole group (LUZ), 11 animals of melatonin + luzindole (MEL + LUZ) group, and 17 animals of the control group (CONTROL), unipolar electrograms were recorded in the left ventricle (LV) using a 64-lead array.…”

“…The previously described isolation and recording procedures were used [28]. Cardiomyocytes were enzymatically isolated from the excised hearts of 10 control animals after in vivo electrophysiological examination.…”

“…The further studies performed in the chronic models showed that the antiarrhythmic melatonin effects were related to the improvement in myocardial impulse conduction mediated by the enhancement of sodium channels [28] and/or Cx43 channel function [29]. On the other hand, changes in ventricular repolarization were not associated with malignant arrhythmia incidence [27].…”

ECG Markers of Acute Melatonin Treatment in a Porcine Model of Acute Myocardial Ischemia

“…To date, the antiarrhythmic and electrophysiological effects of melatonin have been assessed only in animal experimental models [ 13 , 14 , 15 , 18 , 21 , 22 , 23 , 24 , 25 ]. In our previous study, we analyzed the intramyocardial electrograms in the experimental porcine model, and melatonin demonstrated the prevention the early ischemic VF via reduction in conduction delay in the border myocardium [ 15 ].…”