Functional characterization of the prostanoid DP receptor in human myometrium

Abstract

Spontaneous contractile activity of strips of human myometrium obtained from non-pregnant donors at the time of hysterectomy was inhibited by the selective prostanoid DP receptor agonists BW 245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin) and ZK110841 ((5 Z,13 E)-(9 R,11 R,15 S)-9β-chlor-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5,13-prostadienoic acid) with pEC 50 values of 8.4 and 7.3 respectively but prostaglandin D 2 produced a biphasic effect. In the presence of the TP receptor antagonist L670596 ((−)-6,8-difluoro-9- p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid), contractile activity induced by the FP receptor agonist, cloprostenol ([1 R-[1α( Z),2β(1 E,3 R∗),3α,5α]]-7-[2-[4-(3-chlorophenoxy-3-hydroxy-7-butenyl]-3,5-dihydroxycyclopentyl]-5-heptenoic acid), was inhibited by BW 245C ( pEC 50 = 7.5), ZK110841 ( pEC 50 = 6.7) and prostaglandin D 2 ( pEC 50 = 6.3). Under these conditions both prostaglandin J 2 and 9α,11β-prostaglandin F 2 were inhibitory partial agonists. All compounds were antagonized by the selective DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin), but the pK B values were both concentration-dependent ( pK B versus BW 245C at 10 nM = 9.1, at 50 nM = 8.3) and agonist-dependent ( pK B at 10 nM versus BW 245C = 9.1, versus ZK110841 = 7.4). Both agonist and antagonist potencies support the existence of DP receptors in human myometrium. The concentration and agonist dependence of the action of BW A868C suggests that putative DP receptor agonists relax human myometrium by more than one mechanism. These observations may be explained by the existence of subtypes of DP receptor in human myometrium.