S Phaneuf

Effect of oxytocin antagonists on the activation of human myometrium in vitro: Atosiban prevents oxytocin-induced desensitization

OBJECTIVE Our purpose was to investigate whether the sensitivity of myometrial cells to oxytocin is affected by prolonged exposure to oxytocin antagonists. STUDY DESIGN Tissue slices or cultured myometrial cells were exposed to peptides in vitro. Myometrial activation was studied by measuring the formation of inositol phosphates and the changes in intracellular calcium. Oxytocin binding was measured by saturation analysis. RESULTS Atosiban and related peptides inhibited oxytocin-induced myometrial activation as pure antagonists (inhibition constant 10 nmol/L) but had no effect on prostaglandin E2-induced activation. Long-term (> or = 24 hours) exposure to atosiban had no residual effect on oxytocin sensitivity. However, long-term exposure to oxytocin resulted in homologous desensitization and loss of oxytocin receptors. Oxytocin-induced desensitization was prevented by coincubation with atosiban. CONCLUSIONS Atosiban is a pure oxytocin antagonist and has a specific, reversible effect on myometrial cells in vitro. Its potential use for the management or even prevention of idiopathic preterm labor or to reverse uterine hypertony during oxytocin-induced labor should be tested in controlled clinical trials.

Urocortin in pregnancy

OBJECTIVES The aim of this study was to investigate the possibility that urocortin is the ligand that displaces corticotropin-releasing hormone from its binding protein in the maternal circulation during pregnancy and, if so, to determine whether urocortin, like corticotropin-releasing hormone, is synthesized in substantial quantities in the placenta. STUDY DESIGN A radioimmunoassay specific for urocortin was developed and used for measurement of the peptide in chorionic villi and fetal membranes (amnion and chorion) from normal and preeclamptic pregnancies. These tissues were also assayed for corticotropin-releasing hormone. Assays for urocortin were also carried out on normal term pregnant and nonpregnant myometrium and on plasma from nonpregnant individuals, and assays for both peptides were performed on sequential normal pregnancy plasma samples taken from mid gestation until term. RESULTS Corticotropin-releasing hormone was present in normal term (1904 +/- 489 pg/g) and preeclamptic placentas (5897 +/- 1526 pg/g) and in normal term fetal membranes (645 +/- 155 pg/g, n = 6 in all cases). Urocortin was not detected in any of the tissues studied, nor was it found in the normal human plasma samples. Unlike the situation for corticotropin-releasing hormone, no pregnancy-related pattern was seen for urocortin in the plasma from pregnant women. CONCLUSIONS Urocortin is not translated to any great extent in the pregnancy tissues investigated, nor is it present in the circulation of pregnant women in detectable amounts. Furthermore, it is unlikely that urocortin is responsible for the high maternal plasma levels of free corticotropin-releasing hormone circulating in the latter stages of pregnancy, but this does not preclude the possibility that another, as yet uncharacterized, corticotropin-releasing hormone-like peptide may be.

Preterm labour: a pharmacological challenge

Preterm labour is a major cause of perinatal mortality and morbidity, but its prevention is difficult because most of the available drugs lack uterine selectivity and have potentially serious side-effects for the mother or the foetus. In this article, Andrés López Bernal and colleagues discuss new evidence that shows pregnancy is associated with changes in G protein signalling and second messenger formation in human myometrium. During gestation uterine relaxation is favoured by a pronounced increase in G alpha s levels, thereby facilitating the effect of agonists that increase cAMP formation. The change in G alpha s is reversed in spontaneous labour enabling the uterus to become responsive to contractile agents. Although it is not established that these changes in G protein function are causally related to the spontaneous onset of labour, nevertheless they provide a novel viewpoint towards increased understanding of the cellular mechanisms of uterine contractility, which may result in better drugs for the management of preterm labour.