EFFECTS OF THE VASOPRESSIN V-1A RECEPTOR ANTAGONIST, SR-49059, ON THERESPONSE OF HUMAN UTERINE ARTERIES TO VASOPRESSIN AND OTHER VASOACTIVE SUBSTANCES

Background. Arginine vasopressin (AVP) activates the uterus via V-1a r eceptors and is apparently an important factor for the myometrial hype ractivity, uterine ischemia and pain of primary dysmenorrhea. The oral ly active and selective, non-peptide AVP (1a) receptor antagonist, SR 49059, has been shown to inhibit the myometrial action of AVP, but the specific influence of this substance on the effects of AVP and other vasoactive agents on human uterine arteries is unknown. Methods. Conce ntration-responses of AVP on isolated medium-sized human uterine arter ies were studied after incubation with only vehicle (DMSO, 0.1%) and w ith SR 49059 in concentrations of 0.5, 2.5 and 10 nmol/L. Furthermore, the concentration-responses of AVP were investigated without and with SR 49059 (2 and 10 nmol/L) on small and medium-sized arteries. Finall y, the influence of 2.5 nmol/L of SR 49059 on concentration-responses of endothelin-l, noradrenaline and prostaglandin F-2 alpha was studied . Results. The EC50 for AVP on medium-sized arteries was 0.53+/-13 nmo l/L. SR 49059 caused a competitive, dose-dependent inhibition of AVP-r esponses, the highest concentration giving an EC50 of 460 nmol/L. The pA(2) value was 9.84. The responses of the small artery preparations t o AVP, both without and with the antagonist, were more pronounced than those of the medium-sized ones. The vesoconstrictive effects of endot helin-1, noradrenaline and prostaglandin F-2 alpha were less pronounce d than those of AVP and unaffected by pre-exposure to SR 49059. Conclu sions. The high potency of AVP on human uterine arteries, particularly those of small size, supports an involvement of the peptide in the re gulation of uterine blood flow in both physiological and pathophysiolo gical condition. SR 49059 is a potent and selective AVP V-1a receptor antagonist in the smooth muscle of human uterine arteries.