Cardiac β-adrenergic overstimulation results in oxidative stress, hypertrophy, ischemia, lesion, and fibrosis rendering the heart vulnerable to malignant arrhythmias. We aimed to explore the anti-arrhythmic efficacy of the anti-oxidative and anti-inflammatory compounds, melatonin, and omega-3, and their mechanisms of actions in normotensive and hypertensive rats exposed to isoproterenol (ISO) induced β-adrenergic overdrive. Eight-month-old, male SHR, and Wistar rats were injected during 7 days with ISO (cumulative dose, 118 mg/kg). ISO rats were either untreated or concomitantly treated with melatonin (10 mg/kg/day) or omega-3 (Omacor, 1.68 g/kg/day) until 60 days of ISO withdrawal and compared to non-ISO controls. Findings showed that both melatonin and omega-3 increased threshold current to induce ventricular fibrillation (VF) in ISO rats regardless of the strain. Prolonged treatment with these compounds resulted in significant suppression of ISO-induced extracellular matrix alterations, as indicated by reduced areas of diffuse fibrosis and decline of hydroxyproline, collagen-1, SMAD2/3, and TGF-β1 protein levels. Importantly, the highly pro-arrhythmic ISO-induced disordered cardiomyocyte distribution of electrical coupling protein, connexin-43 (Cx43), and its remodeling (lateralization) were significantly attenuated by melatonin and omega-3 in Wistar as well as SHR hearts. In parallel, both compounds prevented the post-ISO-related increase in Cx43 variant phosphorylated at serine 368 along with PKCε, which are known to modulate Cx43 remodeling. Melatonin and omega-3 increased SOD1 or SOD2 protein levels in ISO-exposed rats of both strains. Altogether, the results indicate that anti-arrhythmic effects of melatonin and omega-3 might be attributed to the protection of myocardial Cx43 topology and suppression of fibrosis in the setting of oxidative stress induced by catecholamine overdrive in normotensive and hypertensive rats.

Centre of Experimental Medicine SAS 84104 Bratislava Slovakia

Department of Physiology Faculty of Medicine Charles University 50003 Hradec Kralove Czech Republic

Faculty of Medicine Comenius University 81499 Bratislava Slovakia

L M College of Pharmacy Ahmedabad Gujarat 380009 India

Research Center for Molecular Medicine of the Austrian Academy of Sciences A 1090 Vienna Austria

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