FUNCTIONAL-CHARACTERIZATION OF THE PROSTANOID DP RECEPTOR IN HUMAN MYOMETRIUM

Spontaneous contractile activity of strips of human myometrium obtaine d from non-pregnant donors at the time of hysterectomy was inhibited b y the selective prostanoid DP receptor agonists BW 245C yhexyl)-1-(3-c yclohexyl-3-hydroxypropyl)hydantoin) and ZK110841 ((5Z,13E)-(9R,11R,15 S)-9 hydroxy-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 L670 596 ((-)-6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarb azol-1-yl-acetic acid), contractile activity induced by the FP recepto r agonist, cloprostenol ([1R-[1 alpha(Z),2 beta(1E,3R),3 alpha,5 y-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 9 alpha,11 beta-prostaglandin F-2 were inhibitory partial agonists. A ll compounds were antagonized by the selective DP receptor antagonist BW A868C l)-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 ver sus 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 sug gests that putative DP receptor agonists relax human myometrium by mor e than one mechanism. These observations may be explained by the exist ence of subtypes of DP receptor in human myometrium.