Comparison of antiprogestin stimulation of uterine prostaglandin synthesis in vitro.
Progesterone has an inhibitory effect on prostaglandin synthesis in urine tissue and this effect is reversible with progesterone receptor antagonists. Although antiprogesterone steroids such as RU486 (Mifepristone) are effective at inducing abortion in women they have an improved efficacy when used with exogenous synthetic prostaglandin. In the guinea-pig such antagonists sensitize the uterus but do not result in increased myometrial activity and therefore may not induce endogenous PG synthesis. In this study the effects of antiprogestins on a preparation of rat uterus perifused with progesterone were studied. ZK98 734 caused a rapid and sustained increase in 6-oxoPGF synthesis which rose within the first 90 minutes. This rapid response suggested that some mechanism other than the induction of fresh protein synthesis was involved. A similar increase was not seen with pregnant guinea-pig myometrium/decidua perifused in a similar manner, suggesting that some other mechanism was responsible for the relatively low PG production in pregnancy. However increases in 6-oxoPGF in response to antiprogestins were recorded when pregnant guinea-pig decidua/myometrium was incubated for 4 hours. In these experiments 1 microM ZK98 734 and 1 microM ZK98 299 (Onapristone) gave a 2.7 fold increase in PG production whereas RU486 gave a 1.6 fold increase. Both 1 microM ZK98 734 and 1 microM ZK98 299 also gave a significant increase in PGE production but no increase in PGF was observed. These findings suggest that some antiprogestins might have a better effect on the stimulation of endogenous PG synthesis or on the rate of catabolism of prostanoids.
Brooks
J
J
Medical Research Council Reproductive Biology Unit, University of Edinburgh, UK.
Holland
P
P
Kelly
R
R
D000818:Animals; D005260:Female; D005300:Fertility Agents, Female / Q000494:pharmacology*; D006067:Gonanes / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D010477:Perfusion; D011247:Pregnancy; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
D005300:Fertility Agents, Female; D006067:Gonanes; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D015735:Mifepristone; C053238:onapristone