Inhibitory effects of SR 49059 on oxytocin-and vasopressin-induced uterine contractions in non-pregnant women.

Background. Compounds that block uterine oxytocin and vasopressin V1a receptors have a therapeutic potential in preterm labor and primary dysmenorrhoea. The orally active vasopressin V1a receptor antagonist, SR49059, inhibits the effect of vasopressin on human uterine activity in vivo, but the influence on the response to oxytocin is unknown. Methods. In a placebo-controlled, double-blind, parallel-group, four-dose comparison, the inhibitory effect of SR 49059 on oxytocin- and vasopressin-induced uterine contractions in humans was investigated. Sixteen healthy female subjects, who had previously undergone sterilization with tubal ligation, participated in intrauterine pressure recordings at one of the first 3 days of bleeding of two menstrual cycles. Intravenous bolus injections of 10 pmol/kg body weight of vasopressin (Period 1) and of 50 pmol/kg body weight of oxytocin (Period 2) were given 1 h before and 1 , 2 and 4 h after oral administration of 0 (placebo), 25 , 75 or 200 mg of SR 49059. The area between the recording curve and zero level of intrauterine pressure (AUC) was calculated. Vital signs as well as urine and plasma safety parameters were measured. The plasma concentrations of oxytocin, vasopressin and the study drug were also estimated. Results. The plasma concentrations of SR 49059 appeared to be dose related, with mean maximal values of 62.0, 163.7 and 468.0 ng/ml in the 25, 75 and 200 mg dose groups, respectively, in Period 1 with vasopressin and 34.4, 116.7 and 418.0 ng/mL, respectively, in Period 2 with oxytocin. Tmax was observed at about 1 h. The cumulative AUC over 50 min after vasopressin injection per se was significantly higher than that after oxytocin in spite of a five times lower dose and lower plasma concentrations. Pretreatment by SR 49059 caused a dose-related reduction in AUCs for vasopressin, whereas no such effect was seen for oxytocin. With vasopressin as an agonist, a lower diastolic blood pressure was observed in all SR 49059 treatment groups, but not with oxytocin. Conclusions. The much higher potency of vasopressin compared with oxytocin on uterine activity in non-pregnant women at menstruation was confirmed. SR 49059 dose-dependently inhibits vasopressin-induced contractions, whereas such an effect was not seen with the present doses of SR 49059 and oxytocin. A marked reduction by SR 49059 of diastolic blood pressure after vasopressin injection was observed, indicating an inhibition by this compound of vascular vasopressin receptors