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

Feb 12, 2017Molecular pharmacology

Different Effects of Oxytocin Blockers Atosiban and Nolasiban on Oxytocin Signaling in Human Uterine Lining and Muscle

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Abstract

Nolasiban significantly reduced the proinflammatory effects of oxytocin in human myometrial and amnion cells.

Oxytocin is known to induce uterine contractions and labor, but it also activates proinflammatory pathways.
Atosiban, an antagonist of the oxytocin receptor, fails to inhibit the proinflammatory effects of oxytocin and may activate prolabor genes.
Nolasiban, another oxytocin receptor antagonist, decreased activation of inflammatory mediators in response to oxytocin.
Oxytocin treatment was associated with increased expression of cyclooxygenase-2 and certain inflammatory cytokines.
Nolasiban inhibited the activation of nuclear factor-B and downstream gene expression linked to labor.
Nolasiban treatment alone did not stimulate contractions in the myometrium or amnion.

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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-B (NF-B) 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-B 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 A, which was reflected in prostaglandin Esynthesis. Inhibition of NF-B 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. κ κ κ κ 2 2

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

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