Melatonin Treatment Does Not Modify Ectopic Activity During Ischemia and Reperfusion in Rats

Abstract

Introduction Ventricular tachycardia and/or ventricular fibrillation (VT/VF), a life‐threatening complication of acute myocardial ischemia are based on the interaction between a vulnerable arrhythmogenic substrate and an arrhythmic trigger. Melatonin was proposed as a potential antiarrhythmic medication and was shown to ameliorate the arrhythmogenic substrate. Also, melatonin provides a sympatholytic effect and thereby can attenuate ectopic activity, which provides the triggers for VT/VF. However, little is known about a melatonin effect on the arrhythmic triggering. In the present study, we aimed at evaluation of the melatonin effects on catecholamine synthesis in normal and ischemic myocardium and heart rhythm disturbances during an episode of ischemia and reperfusion. Methods Experiments were done in 30 control and 32 melatonin‐treated (10 mg/kg, daily, for 7 days) male rats. The hearts from 10 control and 10 treated animals were taken for histochemical analysis of sympathetic fibers (glyoxylic acid‐induced fluorescence). Continuous ECG recording was performed in 20 control and 22 treated anesthetized animals before and during an ischemia‐reperfusion episode induced by reversible 5‐min occlusion of the left anterior descending coronary artery. Tyrosine hydroxylase expression in normal and ischemic myocardial regions was assessed by Western blotting analysis in 12 control and 12 melatonin‐treated animals. Results No differences in the state of sympathetic innervation (density and fluorescence intensity) were observed in histochemical analysis. However, Western blotting demonstrated that melatonin treatment suppressed tyrosine hydroxylase expression in normal (p<0.05 vs control) but not in ischemic regions of myocardium. Melatonin‐treated animals had longer RR‐intervals in the baseline state, but this difference progressively disappeared during the period of ischemia due to tachycardic response to ischemia in the treated group (Figure). No differences in the number of extrasystoles were found between the control and treated groups during ischemia and reperfusion periods (Figure). Conclusion Chronic melatonin treatment led to the peripheral sympatholytic effect in myocardium, which was associated with decreased heart rate in preischemic conditions. However, this effect attenuated during ischemia and no differences in heart rate or extrasystolic burden were found between the control and treated animals during ischemia and reperfusion.

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

“…In respect to arrhythmic vulnerability, it is noteworthy that the observed enhancement of the sodium current could increase cardiac excitability and promote extrasystolic activity, which might trigger reentrant arrhythmias. In the present study, we did not directly measure excitability, however, our previous work, 6 demonstrated that melatonin treatment did not change the extrasystolic burden during ischemia and reperfusion. These data suggest that CV enhancement should be considered as the most essential for arrhythmia prevention electrophysiological effect induced by melatonin treatment.…”

“…The animals were closely observed to have eaten the pellet completely before regular food was given. The dosage and duration of the treatment was the same as in our previous work 4,6 . The apparently high dose of 10 mg/kg was due to approximately 50% bioavailability of oral melatonin 7 .…”

“…The dosage and duration of the treatment was the same as in our previous work. 4,6 The apparently high dose of 10 mg/kg was due to approximately 50% bioavailability of oral melatonin. 7 In vivo measurements and tissue isolation were performed from 9 a.m. to 1 p.m.…”

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

“…It has been showed to reduce ischemic and reperfusion damage in animal models [ 8 , 9 , 10 ] and in clinical settings [ 11 , 12 ]. Although melatonin does not influence reentry triggers [ 13 ], it has been reported to ameliorate the arrhythmogenic substrate. Specifically, it enhanced ventricular activation [ 14 , 15 ], improved cell coupling [ 16 ], reduced adrenergic tone [ 17 ], and caused a faster and more complete restoration of action potential duration at reperfusion [ 14 , 18 ].…”

“…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 ].…”