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Abstract
Pharmacological concentrations of melatonin reduce reperfusion arrhythmias, but less is known about the antiarrhythmic protection of the physiological circadian rhythm of melatonin. Bilateral surgical removal of the superior cervical ganglia irreversibly suppresses melatonin rhythmicity. This study aimed to analyze the cardiac electrophysiological effects of the loss of melatonin circadian oscillation and the role played by myocardial melatonin membrane receptors, SERCA2A, TNFα, nitrotyrosine, TGFβ, KATP channels, and connexin 43. Three weeks after bilateral removal of the superior cervical ganglia or sham surgery, the hearts were isolated and submitted to ten minutes of regional ischemia followed by ten minutes of reperfusion. Arrhythmias, mainly ventricular tachycardia, increased during reperfusion in the ganglionectomy group. These hearts also suffered an epicardial electrical activation delay that increased during ischemia, action potential alternants, triggered activity, and dispersion of action potential duration. Hearts from ganglionectomized rats showed a reduction of the cardioprotective MT2 receptors, the MT1 receptors, and SERCA2A. Markers of nitroxidative stress (nitrotyrosine), inflammation (TNFα), and fibrosis (TGFβ and vimentin) did not change between groups. Connexin 43 lateralization and the pore-forming subunit (Kir6.1) of KATP channels increased in the experimental group. We conclude that the loss of the circadian rhythm of melatonin predisposes the heart to suffer cardiac arrhythmias, mainly ventricular tachycardia, due to conduction disorders and changes in repolarization.
Highlights
Sudden death is the leading cause of cardiovascular mortality worldwide [1]
This study aimed to analyze the cardiac electrophysiological effects of the loss of melatonin circadian oscillation, and the role played by myocardial melatonin membrane receptors, sarco/endoplasmic reticulum Ca2+-ATPase 2A (SERCA2A), Tumor necrosis factor α (TNFα), nitrotyrosine, TGFβ, KATP channels, and connexin 43
Reperfusion ventricular arrhythmias increased in rat hearts isolated after three weeks of surgical removal of the superior cervical ganglia (SCGx) (Figure 1)
Summary
Sudden death is the leading cause of cardiovascular mortality worldwide [1]. Sudden cardiac death varies depending on the prevalence of coronary heart disease, and it has a circadian distribution with a peak in the morning hours [2,3,4,5,6,7,8]. Preservation of circadian oscillations from the level of intracellular organelles to the integrated cardiovascular system appears to be essential for maintaining health and preventing diseases [8,9,10,11,12]. A cardioprotective role of physiological levels of melatonin has been observed in the clinical scenario, and it has been tested under experimental conditions using pinealectomy [3,5,6,13,14,18]
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