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, myomet rium of some oxytocin and vasopressin antagonists with respect to their the rapeutic potential. Design Receptor binding studies on transfected cell lines. In vitro contrac tility studies of human myometrium. Setting The Research Laboratory of Sanofi Recherche, Centre de Toulouse, Fr ance and the Departments of Obstetrics and Gynecology, Lund University Hosp ital, Sweden and Bialystok University Hospital, Poland. Participants Nine women delivered by caesarean section preterm and 37 deliv ered at term for routine obstetric indications. Interventions The binding affinities of oxytocin, arginine vasopressin, ato siban (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 wer e determined. Concentration-response curves with oxytocin and arginine vaso pressin 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 1214 63 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 c oncentrations of oxytocin and vasopressin were compared. Main outcome measures Receptor binding affinities. In vitro contractile eff ects 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 = 349 nmol/L). Vasopressin displayed higher affinities for vasopressin V-1a, V-1b and V-2 receptors (K-i = 14, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K-i = 48 nmol/L). Atosiban and SR 49059 bot h 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 = 3 97 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding t o the V-2 receptor (K-i = 3.0 nmol/L). In the concentration-response experi ments 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 EC50 concentrations of o xytocin 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 res ponse. 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 vasopressi n V-1a one. We demonstrated that SR 49059 inhibits the response of term myo metrium to oxytocin and that of both preterm and term myometrium to vasopre ssin. These observations suggest a therapeutic potential of SR 49059 in pre term labour. The vasopressin V-2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.