Brighton, Paul (Paul J.), Fossler, Michael J., Quenby, Siobhan and Blanks, Andrew M. (2020) Functionally selective inhibition of the oxytocin receptor by retosiban in human myometrial smooth muscle. Endocrinology, 161 (2). bqz043. doi:10.1210/endocr/bqz043 ISSN 0013-7227.
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Abstract
Context:
Novel small molecule inhibitors of the oxytocin receptor (OTR) may have distinct pharmacology and mode of action when compared to first generation oxytocin antagonists when used for the prevention of preterm birth.
Objective:
To determine the mechanism of action of small molecule OTR antagonists retosiban and epelsiban in comparison to the currently used peptide-based compound atosiban.
Design:
Human myometrial samples were obtained at cesarean section and subjected to pharmacological manipulations to establish the effect of antagonist binding to OTR on downstream signaling.
Results:
Retosiban antagonism of oxytocin action in human myometrium was potent, rapid and reversible. Inhibition of inositol 1,4,5-trisphosphate (IP3) production followed single site competitive binding kinetics for epelsiban, retosiban and atosiban. Retosiban inhibited basal production of IP3 in the absence of oxytocin. Oxytocin and atosiban, but not retosiban inhibited forskolin and calcitonin stimulated cAMP production. Inhibition of cAMP was reversed by pertussis toxin. Oxytocin and atosiban, but not retosiban and epelsiban, stimulated ERK1/2 activity in a time a concentration dependent manner. Oxytocin and atosiban stimulated cyclo oxygenase 2 (COX2) activity and subsequent production of prostaglandin E2 and F2α. Prostaglandin production was inhibited by rofecoxib, pertussin toxin, and ERK inhibitor U0126. Oxytocin but not retosiban or atosiban stimulated coupling of the OTR to Gαq G-proteins. Oxytocin and atosiban but not retosiban stimulated coupling of the OTR to Gαi G-proteins.
Conclusions:
Retosiban and epelsiban demonstrate distinct pharmacology when compared to atosiban in human myometrial smooth muscle. Atosiban displays agonist activity at micromolar concentrations leading to stimulation of prostaglandin production.
| Item Type: | Journal Article |
|---|---|
| Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine R Medicine > RG Gynecology and obstetrics R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Science, Engineering and Medicine > Engineering > WMG (Formerly the Warwick Manufacturing Group) |
| Library of Congress Subject Headings (LCSH): | Oxytocin, Pharmacology, Premature labor, Myometrium, Endocrinology |
| Journal or Publication Title: | Endocrinology |
| Publisher: | Oxford University Press |
| ISSN: | 0013-7227 |
| Official Date: | February 2020 |
| Dates: | Date Event February 2020 Published 7 January 2020 Available 30 December 2019 Accepted |
| Volume: | 161 |
| Number: | 2 |
| Article Number: | bqz043 |
| DOI: | 10.1210/endocr/bqz043 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Re-use Statement: | This is a pre-copyedited, author-produced version of an article accepted for publication in Endocrinology following peer review. The version of record Paul J Brighton, Michael J Fossler, Siobhan Quenby, Andrew M Blanks, Functionally selective inhibition of the oxytocin receptor by retosiban in human myometrial smooth muscle, Endocrinology, , bqz043, https://doi.org/10.1210/endocr/bqz043 is available online at: https://doi.org/10.1210/endocr/bqz043 |
| Access rights to Published version: | Restricted or Subscription Access |
| Date of first compliant deposit: | 24 January 2020 |
| Date of first compliant Open Access: | 7 January 2021 |
| RIOXX Funder/Project Grant: | Project/Grant ID RIOXX Funder Name Funder ID |
| URI: | https://wrap.warwick.ac.uk/132459/ |
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