Involvement of vasopressin and oxytocin in the regulation of human uterine activity

Abstract: Vasopressin and oxytocin seem to have pivotal roles in the pathophysiology of primary dysmenorrhoea and preterm labour. Prostaglandins are also involved in the regulation of uterine activity with different receptors mediating both stimulation and relaxation. We explored different aspects of synthesis, release and receptor pharmacology of vasopressin and oxytocin. We also tested a vasopressin and oxytocin antagonist as tocolytic in preterm labour and studied the effect of an EP2 agonist on uterine contractions in non-pregnant volunteers. Oxytocin mRNA expression was found in endometrial glands of non-pregnant women, with the highest amount around midcycle. Oestrogen was shown to increase basal vasopressin secretion in postmenopausal women, an effect that was counteracted by progesterone. Osmotically-induced vasopressin secretion was reduced by ovarian hormones. Their influence on basal and induced oxytocin secretion was minimal. The vasopressin and oxytocin antagonists atosiban and SR 49059 were both found to have a high binding affinity for the human vasopressin V1a receptor and a moderate one for the oxytocin receptor. SR 49059 inhibited vasopressin-induced activity in vitro of human myometrium and to a lesser degree the response to oxytocin. Vasopressin was a potent vasoconstrictor in the non-pregnant human uterus, particularly on small-sized arteries. SR 49059 selectively antagonised this effect. In women with preterm labour, orally administered SR 49059 significantly reduced the frequency of uterine contractions, confirming the importance of vasopressin and oxytocin in the condition. The EP 2 agonist ONO-8815Ly markedly inhibited both spontaneous and oxytocin-induced uterine contractions, suggesting a therapeutic potential in primary dysmenorrhoea and preterm labour.