Non-pharmacological interventions up-regulate myocardial connexin-43 and decrease a risk of malignant arrhythmias in experimental model of essential hypertension

Objective: Available data suggest that meta-inflammation and oxidative stress as well as endogenous deficiency of omega-3 and melatonin may be involved in hypertension-induced myocardial abnormalities that increase propensity to cardiac arrhythmias. We aimed to explore whether supplementation with omega-3 and melatonin as well as cold acclimation may affect arrhythmogenicity of rats suffering from essential hypertension. We focused on myocardial connexin-43(Cx43) channel protein, which ensures cardiac cell-cell coupling for electrical signal propagation, thereby is crucial factor impacting susceptibility of the heart malignant arrhythmias. Design and method: Experiments were performed using adult, male, spontaneously hypertensive rats (SHR, wild type), hairless SHR (mutant strain) and normotensive Wistar rats. SHR were treated for two-month with omega-3 (Omacor,200mg/day) or melatonin (400ug/day) and compared with untreated rats. Hairless SHR adapted to cold were compared with wild type SHR and normotensive Wistar rats. Biometrical parameters were registered and left ventricular heart tissue was taken for analysis of Cx43 and PKC↙, which via phosphorylation affects Cx43 channel function. Isolated perfused heart was used for the examination of its susceptibility to electrically-induced sustained ventricular fibrillation (VF). Results: Supplementation with omega-3 or melatonin and cold acclimation did not affect significantly blood pressure as well as heart or left ventricular weights of SHR or hairless SHR. However, the electrical threshold to induce VF was significantly lower (∼20mA) in non-treated compared with treated SHR (∼35mA) as well as in wild type SHR compared to hairless SHR (∼40mA). Antiarrhythmic effect was associated with increased protein levels of Cx43 and its functional phosphorylated forms in left ventricles of treated SHR and hairless SHR compared to untreated wild type SHR. Moreover, pro-arrhythmic myocardial Cx43 distribution on lateral sides of the cardiomyocytes was attenuated by treatment or cold acclimation. In parallel, there was an increase of PKC↙ expression that may enhance cardio-protective Cx43 phosphorylation. Conclusions: In conclusion, findings indicate that non-pharmacological interventions can protect hypertensive rat heart from malignant arrhythmias, at least in part, by targeting myocardial Cx43. It is challenging to pay attention to non-pharmacological approaches in humans suffering from primary hypertension.