Effects of the isoprostane, 8-epi-prostaglandin F 2α, on the contractility of the human myometrium in vitro

Abstract

8-epi-prostaglandin F 2α stimulated contraction of human myometrial strips obtained from five different donors at the time of hysterectomy with a pEC 50 value of 6.3 ± 0.5. In paired strips from the same donors the pEC 50 value for the selective TP receptor agonist U46619 ([-[1a,4a,5b( Z),6a(1 E,3 S∗)]]-7-[6-(3-hydroxy-1-octenyl)-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoci acid) was 8.3 ± 0.4. In strips from four other donors 8-epi-prostaglandin F 2α was ineffective whereas the pEC 50 for U46619 was 6.9 ± 0.3. Responses to 8-epi-prostaglandin F 2α were unaffected by the selective DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin) at 50 nM but were blocked by the selective TP receptor antagonist L670596 ((−)6,8-difluoro-9- p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid) at 50 nM. The pIC 50 values obtained when the TP receptor antagonists GR 32191 ([1 R-[1α( Z),2β,3β,5α]]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid), ICI D1542 ((4( Z)-6-[(2 S,4 S,5 R)-2-[1-methyl-1-(2-nitro-4-tolyloxy)ethyl]-4-(3-pyridyl)-1,3-dioxan-5-yl]hex-4-enoci acid), ICI 192605 (4(Z)-6-[(2,4,5- cis)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl]hexenoic acid), L670596 and SQ 29548 ([1 S-(1α,2β(5Z),3β,4α]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid) were added cumulatively to strips pre-contracted with an EC 80 concentration of 8-epi-prostaglandin F 2α were not significantly different from those obtained when an EC 80 concentration of U46619 was used. The effects of 8-epi-prostaglandin F 2α on strips pre-contracted with an EC 80 concentration of U46619 were not different from those of U46619 itself. It is concluded that in the non-pregnant human myometrium 8-epi-prostaglandin F 2α is a medium potency contractile agonist acting predominantly at the TP receptor.