Differential Effects of Oxytocin Receptor Antagonists, Atosiban and Nolasiban, on Oxytocin Receptor-Mediated Signaling in Human Amnion and Myometrium

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Title: Differential Effects of Oxytocin Receptor Antagonists, Atosiban and Nolasiban, on Oxytocin Receptor-Mediated Signaling in Human Amnion and Myometrium
Authors: Kim, SH
Pohl, O
Chollet, A
Gotteland, J-P
Fairhurst, ADJ
Bennett, PR
Terzidou, V
Item Type: Journal Article
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 E2 synthesis. 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.
Issue Date: 9-Mar-2017
Date of Acceptance: 30-Jan-2017
URI: http://hdl.handle.net/10044/1/47867
DOI: https://dx.doi.org/10.1124/mol.116.106013
ISSN: 0026-895X
Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
Start Page: 403
End Page: 415
Journal / Book Title: MOLECULAR PHARMACOLOGY
Volume: 91
Issue: 4
Copyright Statement: © 2017 The Author(s). This is an open access article distributed under the CC BY-NC Attribution 4.0 International license (https://creativecommons.org/licenses/by-nc/4.0/).
Keywords: Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
INFLAMMATORY PATHWAYS
CEREBRAL-PALSY
IN-VITRO
LABOR
METAANALYSIS
CELLS
Amnion
Chemokine CCL5
Enzyme Activation
Female
Humans
Inflammation Mediators
Labor, Obstetric
Mitogen-Activated Protein Kinases
Models, Biological
Myometrium
NF-kappa B
Oximes
Pregnancy
Prostaglandins
Pyrrolidines
Receptors, Oxytocin
Signal Transduction
Up-Regulation
Vasotocin
1115 Pharmacology And Pharmaceutical Sciences
1109 Neurosciences
Publication Status: Published
Appears in Collections:Division of Surgery



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