P242Non-pharmacological interventions protect from malignant arrhythmias partially by targeting myocardial Cx43 channels in experimental model of hypertension

Abstract

Background: Hypertension remains the most prevalent risk factor that increases propensity of the heart to the malignant arrhythmias due to myocardial remodeling. Data, including ours, suggest that hypertension is accompanied by melatonin and omega-3 FA deficiency but enhanced free radicals production. In turn, high BP was reduced in pts and/or animals supplemented with omega-3 FA, melatonin - potent scavenger of free radicals and antioxidant-rich red palm oil (RPO). We aimed to prove our hypothesis that these compounds may also exert antiarrhythmic potential in hypertensive rats via modulation of myocardial electrical coupling protein connexin-43 (Cx43). Design and Methods: Adult, male spontaneously hypertensive rats (SHR) and age-matched healthy rats were treated more than one month with highly purified omega-3 FA (200mg/day), RPO (200mg/day) or melatonin (40 μg/ml drinking water/day, during the night) and compared with untreated rats. Biometrical parameters were registered and left ventricular tissue was taken for Cx43 and PKC analysis using immunolabeling, immunoblotting and real time PCR. Susceptibility to the electrically-induced sustained ventricular fibrillation (VF) was examined in isolated heart setup. Key results: All tested compounds significantly reduced BP but did not affect heart or left ventricular mass. Comparing to healthy, SHR heart was much prone to VF. In contrast, the threshold to induce VF and its incidence was significantly decreased upon treatment of SHR with examined compounds. Antiarrhythmic effect was associated with increased expression of either mRNA or protein for Cx43 and its functional phosphorylated forms in left ventricles of treated SHR compared to untreated ones. Moreover, abnormal hypertension-related cardiomyocyte localization (lateralization) of Cx43 was attenuated by treatment of SHR. There was also an increase of PKCe that is implicated in Cx43 phosphorylation and decrease of PKCδ that is involved in pro-hypertrophic signaling. In conclusion, these findings indicate that non-pharmacological interventions can protect the heart from malignant arrhythmias partially by targeting myocardial Cx43 in experimental model of hypertension. It appears challenging to fight hypertension by including non-pharmacological agents in treatment regimen.