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

Abstract

Inhibitory effects of SR 49059 on oxytocin-and vasopressin-induced uterine contractions in non-pregnant women.Steinwall, Margareta; Bossmar, Thomas; Gaud, Christine; Åkerlund, Mats Link to publication Citation for published version (APA): Steinwall, M., Bossmar, T., Gaud, C., & Åkerlund, M. (2004). Inhibitory effects of SR 49059 on oxytocin-and vasopressin-induced uterine contractions in non-pregnant women. Acta Obstetricia et Gynecologica Scandinavica, 83(1), 12-18. DOI: 10.1111/j.1600-0412.2004 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Background. Compounds that block uterine oxytocin and vasopressin V 1a receptors have a therapeutic potential in preterm labor and primary dysmenorrhoea. The orally active vasopressin V 1a 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. T max 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 bl...

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

“…Thus agents that block uterine contractility such as OT/V1a receptor antagonists, nitric oxide, and calcium channel blockers may be effective in the treatment of this disorder (10,406,466). The plasma concentration of OT was found to be significantly higher at menstruation, and that of AVP was found to be significantly lower at ovulation in dysmenorrheic women than in healthy women (304).…”

“…Both atosiban and SR49059 have a high affinity for the V1a receptor (K i ϭ 4.7 and 7.2 nM, respectively), and a moderate affinity for the OT receptor (K i ϭ 397 and 340 nM, respectively) (11). Clinical studies have demonstrated that SR49059 inhibited uterine contraction not only in nonpregnant women but also in pregnant women with preterm labor (62,465,466). When SR49059 was administered at a single dose of 400 mg to women with preterm labor (465), the frequency of uterine contractions significantly decreased in the SR49059 group, but not in the placebo group.…”

Three-Dimensional Power Doppler Assessment of Uterine Vascularization in Women With Primary Dysmenorrhea

“…Several studies suggested that increased intrauterine pressure constricts uterine resistance arteries by activating vasopressin receptors, resulting in ischemia. [9][10][11] Accordingly, it has been reported 12-14 that transdermal glyceryl trinitrate reduces pain in women with primary dysmenorrhea. These studies could indicate the importance of vascular blood flow changes in women with primary dysmenorrhea.…”

“…All ultrasound scans were performed by the same examiner (P.R.) during the same time range (7)(8)(9) to minimize the effect of circadian rhythms on uterine artery blood flow. 8 Vascularity assessment was done on the basis of 3D vascularity indices: the vascularization index (VI), flow index (FI), and vascularizationflow index (VFI).…”

How to Understand the Complexity of Endometriosis-Related Pain

“…OT and VP receptor antagonist are competitive for therapeutic treatment of patients with primary dysmenorrhea (35-36-37-38). This method has been proven by using oral contraceptives.…”