Background and Purpose: Experimental and human studies indicate that melatonin may regulate blood pressure and suggest the potential use of melatonin as adjunct antihypertensive therapy. However, melatonin levels have been shown decreased in patients treated with beta-adrenergic blockers as well as in spontaneously hypertensive rats (SHR). We aimed to examine whether treatment with melatonin will affect propensity of SHR heart to malignant arrhythmias and electrical coupling protein, connexin-43 (Cx43). Design and Methods: SHR and healthy Wistar rats fed a standard rat chow received orally melatonin (40 mikrog/ml) for 4 weeks and were compared with untreated rats. Systolic blood pressure (BP), plasma cholesterol (CH), triglycerides (TG) and blood glucose (BG) were registered at the end of experiment. Myocardial Cx43 mRNA level was determined by real time PCR, while the expression of Cx43 protein, protein kinase C (PKC) epsilon and delta by western blots. Isolated Langendorff-perfused heart was used to test its susceptibility to electrically inducible ventricular fibrillation (VF). Key Results: Melatonin significantly reduced BP (180+24 vs 206+10 mmHg) and normalized TG but did not affect body, heart and left ventricular weights in SHR. Compared to healthy rats the threshold to induce sustained VF was lower in SHR (18.7+2 vs 29.0+5 mA, p<0.05) and significantly increased in melatonin-treated SHR to 33.0+4 mA. Myocardial Cx43 mRNA levels did not differ from healthy rats but total Cx43 protein was decreased in SHR heart left ventricle. In contrast, melatonin treatment resulted in a significant increase of both Cx43 protein and mRNA in SHR as well as healthy rats. Moreover, melatonin normalized myocardial PKC-delta expression and enhanced PKC-epsilon in SHR as well as healthy rat hearts. Conclusions: Results indicate antiarrhythmic effects of melatonin in hypertensive rats that can be, in part, attributed to up-regulation of myocardial Cx43 and PKC signaling. Findings support monitoring of melatonin levels and its supplementation in patients with CVD.