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

Abstract

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 growth while restraining cortisol production. This latter physiological 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 (K d values: MCA 64 ± 1 pm, BAT 98.44 ± 2.12 pm and 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.

Seasonal effects on plasma cortisol concentrations in the Bedouin buck: circadian studies and response to ACTH

“…Melatonin takes part in the regulation of circadian rhythms (Pevet and Challet, 2011) and exerts direct inhibitory actions on adrenal responses to ACTH in sheep (Torres-Farfan et al, 2008). In goats, melatonin was shown to inhibit heat stress responses, including plasma cortisol increase and expression of heat-shock proteins (HSP) in peripheral blood mononuclear cells (PBMC) (Sharma et al, 2013), as well as the cortisol response to weaning stress (Redondo et al, 2010).…”

Melatonin supplementation alters uteroplacental hemodynamics and fetal development in an ovine model of intrauterine growth restriction

“…In addition to the potential alterations in steroid and prostaglandin concentrations following melatonin supplementation, the observed alteration in umbilical blood flow and the disproportionate fetal growth following melatonin supplementation may be mediated through specific melatonergic receptors. These pathways are relevant in the fetus, where the addition of physiological concentrations of melatonin prevented the vasoconstriction caused by norepinephrine in lateterm fetal sheep cerebral arteries (57). It is interesting to note that fetal cardiac output and blood flow distribution may be altered via arterial melatonergic receptor pathways within the developing fetus, which could lead to disproportionate fetal growth.…”

“…Moreover, fetal organ development and functional capacity may be altered by supplementing the dam with melatonin throughout gestation. This is apparent in the sheep fetus that responded to elevated physiological concentrations of melatonin by preventing the norepinephrine-induced contraction of cerebral arteries, lipolysis in brown adipose tissue, and cortisol release from adrenal explants (57). Interestingly, melatonin receptors have been identified in the developing nephron of human fetal kidneys (13); however, an in vivo physiological role of these melatonin receptor pathways within the fetus remains elusive.…”

Antioxidant Therapies: A Potential Role in Perinatal Medicine

“…The modulatory and neuroprotective actions of melatonin may not be solely due to the scavenging of hydroxyl radicals [24] and increasing intracerebral antioxidant enzyme activity [65]. Melatonin directly inhibits noradrenalin-stimulated fetal cerebral artery contraction [66], and decreases cerebral vascular permeability following hypoxia [67]. Systemically, melatonin induces umbilical vasodilatation via the stimulation of nitric oxide synthase [68], which may prove a particularly useful property in pregnancies complicated by placental insufficiency.…”