Effects of the isoprostane, 8-epi-prostaglandin F2 alpha, on the contractility of the human myometrium in vitro.
8-epi-prostaglandin F2 alpha stimulated contraction of human myometrial strips obtained from five different donors at the time of hysterectomy with a pEC50 value of 6.3 +/- 0.5. In paired strips from the same donors the pEC50 value for the selective TP receptor agonist U46619 ([1R-[1a,4a,5b(Z),6a(1E,3S*)]]-7-[6-(3- hydroxy-1-octenyl)-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid) was 8.3 +/- 0.4. In strips from four other donors 8-epi-prostaglandin F2 alpha was ineffective whereas the pEC50 for U46619 was 6.9 +/- 0.3. Responses to 8-epi-prostaglandin F2 alpha 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 pIC50 values obtained when the TP receptor antagonists GR 32191 ([1R- [1 alpha(Z),2 beta,3 beta,5 alpha]]-(+)-7-[5-[[(1,1'-biphenyl)-4- yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid), ICI D1542 ((4(Z)-6-[(2S,4S,5R)-2-[1-methyl-1-(2-nitro-4-tolyloxy)ethyl]- 4-(3-pyridyl)-1,3-dioxan-5-yl]hex-4-enoic 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 ([1S-(1 alpha,2 beta(5Z),3 beta,4 alpha]]-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 EC80 concentration of 8-epi-prostaglandin F2 alpha were not significantly different from those obtained when an EC80 concentration of U46619 was used. The effects of 8-epi-prostaglandin F2 alpha on strips pre-contracted with an EC80 concentration of U46619 were not different from those of U46619 itself. It is concluded that in the non-pregnant human myometrium 8-epi-prostaglandin F2 alpha is a medium potency contractile agonist acting predominantly at the TP receptor.
Crankshaw
D
D
Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000328:Adult; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009215:Myometrium / Q000187:drug effects*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D011448:Prostaglandin Antagonists; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost