Retosiban Prevents Stretch-Induced Human Myometrial Contractility and Delays Labor in Cynomolgus Monkeys.

Autor:	Aye ILMH; Department of Obstetrics and Gynaecology, University of Cambridge, National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, United Kingdom., Moraitis AA; Department of Obstetrics and Gynaecology, University of Cambridge, National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, United Kingdom., Stanislaus D; Department of Reproductive Toxicology, GlaxoSmithKline, Philadelphia Navy Yard, Philadelphia, Pennsylvania., Charnock-Jones DS; Department of Obstetrics and Gynaecology, University of Cambridge, National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, United Kingdom., Smith GCS; Department of Obstetrics and Gynaecology, University of Cambridge, National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, United Kingdom.
Jazyk:	angličtina
Zdroj:	The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2018 Mar 01; Vol. 103 (3), pp. 1056-1067.
DOI:	10.1210/jc.2017-02195
Abstrakt:	Context: Stretch of the myometrium promotes its contractility and is believed to contribute to the control of parturition at term and to the increased risk of preterm birth in multiple pregnancies. Objective: To determine the effects of the putative oxytocin receptor (OTR) inverse agonist retosiban on (1) the contractility of human myometrial explants and (2) labor in nonhuman primates. Design: Human myometrial biopsies were obtained at planned term cesarean, and explants were exposed to stretch in the presence and absence of a range of drugs, including retosiban. The in vivo effects of retosiban were determined in cynomolgus monkeys. Results: Prolonged mechanical stretch promoted myometrial extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Moreover, stretch-induced stimulation of myometrial contractility was prevented by ERK1/2 inhibitors. Retosiban (10 nM) prevented stretch-induced stimulation of myometrial contractility and phosphorylation of ERK1/2. Moreover, the inhibitory effect of retosiban on stretch-induced ERK1/2 phosphorylation was prevented by coincubation with a 100-fold excess of a peptide OTR antagonist, atosiban. Compared with vehicle-treated cynomolgus monkeys, treatment with oral retosiban (100 to 150 days of gestational age) reduced the risk of spontaneous delivery (hazard ratio = 0.07, 95% confidence interval 0.01 to 0.60, P = 0.015). Conclusions: The OTR acts as a uterine mechanosensor, whereby stretch increases myometrial contractility through agonist-free activation of the OTR. Retosiban prevents this through inverse agonism of the OTR and, in vivo, reduced the likelihood of spontaneous labor in nonhuman primates. We hypothesize that retosiban may be an effective preventative treatment of preterm birth in high-risk multiple pregnancies, an area of unmet clinical need.
Databáze:	MEDLINE
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