Evidence of a role for melatonin in fetal sheep physiology: direct actions of melatonin on fetal cerebral artery, brown adipose tissue and adrenal gland

Although the fetal pineal gland does not secrete melatonin, the fetus is exposed to melatonin of maternal origin. In the non-human primate fetus, melatonin acts as a trophic hormone for the adrenal gland, stimulating growthwhile restraining cortisol production. This latterphysiological activity led us to hypothesize that melatonin may influence some fetal functions critical for neonatal adaptation to extrauterine life. To test this hypothesis we explored (i) the presence of G-protein-coupled melatonin binding sites and (ii) the direct modulatory effects of melatonin on noradrenaline (norepinephrine)-induced middle cerebral artery (MCA) contraction, brown adipose tissue (BAT) lypolysis and ACTH-induced adrenal cortisol production in fetal sheep. We found that melatonin directly inhibits the response to noradrenaline in the MCA and BAT, and also inhibits the response to ACTH in the adrenal gland.Melatonin inhibition was reversed by the melatonin antagonist luzindole only in the fetal adrenal. MCA, BAT and adrenal tissue displayed specific high-affinity melatonin binding sites coupled to G-protein (Kd values: MCA 64±1 pm, BAT 98.44±2.12 pmand adrenal 4.123±3.22 pm).Melatonin binding was displaced by luzindole only in the adrenal gland, supporting the idea that action in the MCA and BAT is mediated by different melatonin receptors. These direct inhibitory responses to melatonin support a role for melatonin in fetal physiology, which we propose prevents major contraction of cerebral vessels, restrains cortisol release and restricts BAT lypolysis during fetal life.This work was supported by Grant 1060-766 from Fondo Nacional de Desarrollo Cient´ıfico y Tecnol ´ ogico, Chile and a grant from The Department of Women’s Health, Arrowhead Regional Medical Center (CA, USA). F.J.V. was supported by a PhD Fellowship from ComiteNacional de Ciencia y Tecnologia, Chile. M.M. was supportedby aPhDFellowship fromProgramadeMejoramiento de la Calidad de la Educacion Superior, UCH313