Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women

Objective To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential. Design Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium. Setting The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland. Participants Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications. Interventions The binding affinities of oxytocin, arginine vasopressin, atosiban (1‐deamino‐2‐D‐Tyr(OEt)‐4‐Thr‐8‐Orn‐oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration–response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm– and term–delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC 50 concentrations of oxytocin and vasopressin were compared. Main outcome measures Receptor binding affinities. In vitro contractile effects and their inhibitions. Results Oxytocin had a high affinity for the oxytocin receptor (K i in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V 1a receptor ( K i = 34.9 nmol/L ). Vasopressin displayed higher affinities for vasopressin V 1a , V 1b , and V 2 receptors ( K i = 1.4,0.8 and 4.2 nmol/L , respectively) than for the oxytocin receptor ( K i = 48 nmol/L ). Atosiban and SR 49059 both had a high affinity for the vasopressin V 1a , receptor ( K i = 4.7 and 7.2 nmol/L , respectively, and a moderate one for the oxytocin receptor ( K i = 397 and 340 nmol/L , respectively). SR 121463 exerted a predominant binding to the V 2 receptor ( K i = 3.0 nmol/L ). In the concentration–response experiments levels of up to 10 nmol/L of SR 49059 had no influence on the effect of oxytocin on myometrium from women preterm and at term pregnancy. However, a concentration–dependent inhibition of the responses of both these type of tissues to vasopressin was seen. The effects of EC 50 concentrations of oxytocin and vasopressin on term pregnant myometrium were markedly inhibited by 10 nmol/L and higher concentrations of SR 49059, the inhibition of the response to vasopressin being more pronounced than that of the oxytocin response. SR 121463 at maximal concentration only caused slight inhibitions of the oxytocin and vasopressin responses. Conclusions Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V 1a one. We demonstrated that SR 49059 inhibits the response of term myometrium to oxytocin and that of both preterm and term myometrium to vasopressin. These observations suggest a therapeutic potential of SR 49059 in preterm labour. The vasopressin V 2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.