Oxytocin receptor antagonists, atosiban and nolasiban, inhibit prostaglandin F2α-induced contractions and inflammatory responses in human myometrium

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.