title: Differential Effects of Oxytocin Receptor Antagonists, Atosiban and Nolasiban, on Oxytocin Receptor-Mediated Signaling in Human Amnion and Myometrium.
abstract: One of the most established roles of oxytocin (OT) is in inducing uterine contractions and labor. Apart from inducing contractions, our recent studies showed that OT can also activate proinflammatory pathways in both human myometrial and amnion cells, which suggests that the proinflammatory role of OT should be taken into account when developing tocolytics targeting the OT/oxytocin receptor (OTR) system. The OTR antagonist, atosiban, is currently used therapeutically for the treatment of preterm labor. We previously showed that atosiban fails to inhibit the proinflammatory effects of OT in human amnion; atosiban alone activates nuclear factor-κB (NF-κB) and mitogen activated protein kinases, thus upregulating downstream prolabor genes. In contrast with our findings with atosiban, the presence of the orally active OTR antagonist, nolasiban, reduced the effect of OT on NF-κB and p38 kinase activation in both myometrial and amnion cells. Consistent with the activation of these inflammatory mediators, OT led to increases in the expression of cyclooxygenase-2 and phosphorylated cytosolic phospholipase A2, which was reflected in prostaglandin E2synthesis. Inhibition of NF-κB activation by nolasiban also translated to suppression of downstream prolabor gene expression, such as cyclooxygenase-2, C-C motif chemokine ligand 2, interleukin-6, and interleukin-8. We also demonstrated that nolasiban treatment alone has no significant stimulatory effect on both the myometrium and amnion. In conclusion, our findings indicate that nolasiban possesses promising potential as a novel tocolytic agent for both acute and maintenance therapy, as it inhibits both myometrial contractions and the proinflammatory effects of OT without the biased agonist effects.
authors.affiliation: Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus (S.H.K., A.D.J.F., P.R.B., V.T.) and Chelsea and Westminster Hospital (V.T.), Imperial College London, London, United Kingdom; and ObsEva SA, Geneva, Switzerland (O.P., A.C., J.-P.G.).
authors.forename: Sung Hye
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus (S.H.K., A.D.J.F., P.R.B., V.T.) and Chelsea and Westminster Hospital (V.T.), Imperial College London, London, United Kingdom; and ObsEva SA, Geneva, Switzerland (O.P., A.C., J.-P.G.).
authors.forename: Oliver
authors.initials: O
authors.lastname: Pohl
authors.affiliation: Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus (S.H.K., A.D.J.F., P.R.B., V.T.) and Chelsea and Westminster Hospital (V.T.), Imperial College London, London, United Kingdom; and ObsEva SA, Geneva, Switzerland (O.P., A.C., J.-P.G.).
authors.forename: Andre
authors.initials: A
authors.lastname: Chollet
authors.affiliation: Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus (S.H.K., A.D.J.F., P.R.B., V.T.) and Chelsea and Westminster Hospital (V.T.), Imperial College London, London, United Kingdom; and ObsEva SA, Geneva, Switzerland (O.P., A.C., J.-P.G.).
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gotteland
authors.affiliation: Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus (S.H.K., A.D.J.F., P.R.B., V.T.) and Chelsea and Westminster Hospital (V.T.), Imperial College London, London, United Kingdom; and ObsEva SA, Geneva, Switzerland (O.P., A.C., J.-P.G.).
authors.forename: Adam D J
authors.initials: AD
authors.lastname: Fairhurst
authors.affiliation: Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus (S.H.K., A.D.J.F., P.R.B., V.T.) and Chelsea and Westminster Hospital (V.T.), Imperial College London, London, United Kingdom; and ObsEva SA, Geneva, Switzerland (O.P., A.C., J.-P.G.).
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Bennett
authors.affiliation: Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus (S.H.K., A.D.J.F., P.R.B., V.T.) and Chelsea and Westminster Hospital (V.T.), Imperial College London, London, United Kingdom; and ObsEva SA, Geneva, Switzerland (O.P., A.C., J.-P.G.) v.terzidou@imperial.ac.uk.
authors.forename: Vasso
authors.initials: V
authors.lastname: Terzidou
mesh_terms: D000650:Amnion / Q000187:drug effects / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007743:Labor, Obstetric / Q000187:drug effects / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D011247:Pregnancy; D011453:Prostaglandins / Q000096:biosynthesis; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D014668:Vasotocin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018946:Chemokine CCL5; D018836:Inflammation Mediators; D016328:NF-kappa B; D010091:Oximes; D011453:Prostaglandins; D011759:Pyrrolidines; D018045:Receptors, Oxytocin; C047046:atosiban; C000618265:nolasiban; D020928:Mitogen-Activated Protein Kinases; D014668:Vasotocin