EFFECTS OF RU486 ON ESTROGEN, PROGESTERONE, OXYTOCIN, AND THEIR RECEPTORS IN THE RAT UTERUS DURING LATE-GESTATION

Oxytocin (OT) and its receptor (OTR) are synthesized in the endometriu m and myometrium of the pregnant rat during late gestation. Both are r egulated by estrogen and progesterone (P-4), and tissue concentrations of both increase markedly before parturition. The P-4 antagonist RU48 6 will induce parturition in the rat. The purpose of the present studi es was to investigate changes in OT and OTR messenger RNA (mRNA) and p eptide synthesis within the pregnant rat uterus during RU486-induced p arturition. Pregnant rats were given a single injection of RU486 (2.5 mg/rat in oil) on day 15 of pregnancy (normal delivery occurs on day 2 2). Control animals received injections of oil only. Groups of animals (n = 5 in each group) were euthanized at 0, 6, 12, 24, and 48 h after injection and during labor (immediately after delivery of the first p up). Maternal serum estradiol (E-2), P-4 and uterine OT, and PGE(2) co ncentrations were measured by RIA. Prostaglandin F-2 alpha and estroge n receptor levels were measured by enzyme immunoassay (EIA). OTR and P -4 receptor (PR) were measured using radioligand-binding assays. OT, O TR, and estrogen receptor mRNAs were measured with ribonuclease protec tion assays. The average time to delivery, after RU486 injection, was 27.0 +/- 1.2 h. Serum E-2 and P-4 levels were increased slightly, but significantly, at 24 h after RU486. In controls, OT mRNA increased sig nificantly, and this increase was blocked in the RU486 treatment group . OTR mRNA levels increased within 6 h of RU486 and remained elevated until delivery. OTR peptide was increased by 12 h. PGE(2) and PGF(2 al pha) were increased 3-fold and 16-fold, respectively, but not until af ter the increase in OTR had occurred. We conclude that the mechanism o f action of RU486 is to inhibit the P-4 suppression of OTR synthesis, allowing increased expression of OTR, which may directly stimulate myo metrial contractions or act indirectly through increased synthesis of PGs.