Antiarrhythmic Effects of Melatonin and Omega-3 Are Linked with Protection of Myocardial Cx43 Topology and Suppression of Fibrosis in Catecholamine Stressed Normotensive and Hypertensive Rats

Abstract

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.

Cardiac contractility modulation attenuates structural and electrical remodeling in a chronic heart failure rabbit model

“… 34 Recently, a study reported that a reduction in fibrosis and upregulation of Cx43 rendered the heart less susceptible to malignant arrhythmias in the isoproterenol model of heart failure. 35 In the present study, we found that CCM partially restored the prolonged QTc interval and ERP, and reduced the susceptibility to ventricular arrhythmia. At the molecular level, CCM reversed downregulation of Kv4.3, KCNQ1, KCNH2 and Cx43 protein expression, which may contribute to attenuation of electrical remodeling in HF.…”

Melatonin to Rescue the Aged Heart: Antiarrhythmic and Antioxidant Benefits

“…Also, melatonin reduces arrhythmias when administered during reperfusion. Specifically, melatonin has shown to have a protective action when administered to isolated hearts of hypertensive rats [ 14 ]. These animals show greater activity of the enzyme NADPH oxidase, which is one of the main systems for generating free radicals, and, therefore, higher levels of oxidative stress, which is involved in the generation of early and delayed afterdepolarizations [ 229 ].…”

“…Therefore, the potential as an antiarrhythmic to act in the acute scenario is clearly available. However, the evidence is still mainly preclinical [ 14 , 198 , 221 , 229 , 236 ]. In the context of ischemia/reperfusion, simultaneous intravenous and intracoronary administration has been proven to be electrophysiologically safe.…”

Importance of Cx43 for Right Ventricular Function

“…Since impulse propagation in the heart is mediated via connexin-formed gap junctional channels and the preservation of connexin topology has anti-arrhythmic effects [78][79][80], the alterations of right atrial and ventricular electrophysical properties suggest a deregulation of connexin expression/function in experimental models of PH. The amount of Cx43 is assessed at different time periods after administration of monocrotaline.…”