Abstract
Oxytocin receptor antagonists (OTR-A) have been developed as tocolytics for the management of preterm labour due to the significant role of oxytocin (OT) in the onset of both term and preterm labour. Similar to OT, prostaglandins (PGs) play key roles in myometrial contractility and cervical ripening. Inhibition of PG synthesis/activity is used to delay preterm birth. Thus, targeting the PG pathway in combination with an OTR-A may be an effective strategy for delaying preterm delivery. In this study, we examined the effects of atosiban and nolasiban on PGF2α-induced contractions and pro-inflammatory responses in human pregnant myometrium. Both OTR-As, atosiban and nolasiban, inhibited PGF2α-induced contractions in a dose-dependent manner (p < 0.001 and p < 0.01, respectively). These inhibitory effects involved the suppression of PGF2α-mediated increase in intracellular calcium levels. In addition, the OTR-As significantly suppressed PGF2α-induced activation of pro-inflammatory pathways such as NF-κB and mitogen activated protein kinases (MAPKs), and the subsequent expression of contraction-associated-protein, COX-2. We have demonstrated that atosiban and nolasiban not only inhibit contractions elicited by OT, but also inhibit contractions and inflammation induced by PGF2α. This suggests a possible crosstalk between OTR and PG receptor signalling and highlights the importance of understanding G protein-coupled receptor interactions/crosstalk in the development of future tocolytics.
Highlights
Oxytocin receptor (OTR) is commonly used as a target for the development of tocolytics, and the only drugs developed for the management of preterm labour are the oxytocin receptor (OTR) antagonists (OTR-As). Due to their increased specificity to the uterus, Oxytocin receptor antagonists (OTR-A) such as atosiban can act as a suppressant of contractions with improved safety profiles[11]
Incubation with atosiban or nolasiban had no significant effect on spontaneous contractility when compared to its vehicle control, the stimulatory effect of OT was suppressed by atosiban (Fig. 1a) and nolasiban (Fig. 1b)
Nolasiban at 60 nM was sufficient to significantly decrease OT-induced myometrial contractility (p < 0.001 vs DMSO), whereas atosiban exerted its effects at 600 nM (p < 0.05 vs DMSO)
Summary
Oxytocin receptor (OTR) is commonly used as a target for the development of tocolytics, and the only drugs developed for the management of preterm labour are the OTR antagonists (OTR-As) Due to their increased specificity to the uterus, OTR-As such as atosiban can act as a suppressant of contractions with improved safety profiles[11]. Available PG inhibitors such as the NSAID, indomethacin, act by non-selective inhibition of PG-forming enzymes, blocking the generation and signalling of many PG sub-types, including PGF2α. Because they potentially adversely affect fetal physiology, NSAIDs are no longer recommended for pregnant women[16]. FP antagonists, such as the peptide THG113.31, have been developed for the management of preterm labour[20], their clinical efficacy is yet to be demonstrated
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
