The effect of combination tocolysis on the inhibition of human myometrial contractions and inflammation in preterm labour

Abstract

Introduction: Preterm birth is a major cause of neonatal morbidity and mortality worldwide. Current management of preterm labour (PTL) focuses on the reduction of myometrial contractions and has limited efficacy. We hypothesise that combining tocolytics that act via different pathways can lead to additive or synergistic inhibitory effects. Oxytocin (OT) receptor antagonist, atosiban, is the only licensed tocolytic in Europe. A novel prostaglandin F2α (PGF2α) receptor antagonist, OBE002, has been developed for management of PTL. In this study, we aimed to investigate the effects of these tocolytics on myometrial contractility and inflammation. Methods: Human myometrial biopsies from term, non-labouring patients were used for the study of contractility and pro-inflammatory signalling in response to OT and PGF2α stimulation in presence of tocolytics. Results: We have demonstrated that OT- and PGF2α-induced myometrial contractility was suppressed by both atosiban and OBE002 via inhibition of an increase in intracellular calcium levels in response to OT or PGF2α stimulation. The combination of atosiban and OBE002 had an enhanced inhibitory effect on OT-induced, but not PGF2α-induced contractions. Both OT and PGF2α activated pro-inflammatory signalling in human myometrial cells. No significant additive effect was observed for the combination of atosiban and OBE002 on OT- or PGF2α-mediated inflammation but their combination showed a trend of an enhanced inhibitory effect on OT-mediated COX-2 expression. Using proximity ligation assay, we detected interaction between OT and PGF2α receptors, potentially indicating a crosstalk between OT and PGF2α signalling through the formation of heteromers. Conclusion: We have shown that combining atosiban and OBE002 has an additive inhibitory effect on myometrial contractility. Additionally, they both suppress pro-inflammatory effects of OT and PGF2α. This may be through direct receptor interaction leading to functional crosstalk. In conclusion, this study highlights the potential use of combining OT and PGF2α receptor antagonists for the development of future tocolytic strategies.