Abstract:

:Prostaglandin (PG) E analogues are used clinically to ripen the cervix and induce labour. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhoea and preterm labour. To characterise their therapeutic value, PGE2 analogues were used to investigate the functional EP receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a pre-clinical model. Uterine samples were obtained from mice at dioestrus (n=12), term gestation (n=14) and labour (n=12) and from the lower uterus of women undergoing hysterectomy (n=12) or Caesarean section (n=18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP4 agonists inhibited tissue activity in both non-pregnant species, whilst the EP2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP3/1 agonist sulprostone were more pronounced than the EP1 agonist ONO-D1-004, corresponding to abundant EP3 receptor expression in all samples. The contractile phenotype in mouse compared to human uteri may relate to regional differences as well as high expression of EP3 receptor transcripts. Similarities in non-pregnant and gestational tissues across species suggest that EP3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist. SIGNIFICANCE STATEMENT: This research validates the use of non-pregnant mice for pre-clinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labour, pharmacological agents interacting with EP3 receptors have clear translational value.