Dark-phase melatonin administration does not reduce blood pressure but induces changes in parameters related to the control of the cardiovascular system in spontaneously hypertensive rats

Melatonin is synthesised during the dark phase of the day, and its biosynthesis is inhibited by light. Exogenously supplied melatonin has been reported to have hypotensive effects. However, in animal experiments, melatonin is usually administered in one high dose and blood pressure (BP) is almost exclusively measured by plethysmography during the light phase of the day. We tested the effects of melatonin administration in drinking water during the dark phase of the day at different concentrations (2-45 mg/kg/12 h) for three weeks and telemetrically measured haemodynamic variables in spontaneously hypertensive rats (SHR). We measured gene and protein expression in the hypothalamus, brainstem, kidney and adrenal gland. We did not observe a BP decrease even at the highest melatonin concentration. We observed a dose-dependent increase in the percent recovery point and a decrease in dP/dt_max, particularly during the light phase at lower doses. The effects on the autonomic nervous system and baroreflex were equivocal, with changes observed in both experimental and placebo groups. Melatonin dose-dependently decreased vasopressin expression in the supraoptic nuclei. In the adrenal gland, melatonin increased tyrosine hydroxylase expression. In the kidney, low melatonin doses increased endothelial nitric oxide synthase, while higher doses decreased CD68 levels. Our results do not confirm the hypotensive effects of melatonin in SHR. The potential beneficial effects of melatonin could result from a long-term impact on various organs involved in BP regulation and interaction with multiple molecular pathways, some of which may manifest in improved cardiovascular health in the long term.