Studies on the temporal pattern of prostaglandin synthesis in the uterus of the delayed implanting rat with or without implantation inducing stimuli

Abstract

The model of delayed implantation produced by injection of progesterone (P 4) following hypophysectomy on day 3 of pregnancy, was used to study the temporal relationship between phospholipase A 2 (PLA 2) activity and endogenous concentrations and/or in vitro production of prostaglandins (PGs) in the rat uterus during the early phase of implantation. No definitive correlation between the endogenous concentration of uterine PGs and their in vitro production, or PLA 2 activity, was found following various treatments. However, an interesting interaction between various treatments and PLA 2 activity, as well as PG production, was evident within 0.5 h-4 h. The unaltered PLA 2 activity and PG production in the uterus at 0.5 h and 4 h after the last injection of P 4 only suggest that PLA 2 is probably the limiting step in PG synthesis in the P 4 dominated uterus. On the other hand, the depressed uterine PG production at 0.5 h, in the face of unaltered PLA 2 activity, in P 4-primed rats injected with an optimal dose of estradiol-17β (E 2: 20 ng/rat, i.v.) suggests a reduction in PG synthetase activity with estrogen. Because PLA 2 activity remained unchanged, the stimulation in PGE, and to some extent PGF, production at 0.5 h following superimposition of histamine on the E 2 treatment appears to be mediated via stimulation of PG synthetase. The increase in PGE and PGF production at 4 h as compared to 0.5 h following E 2 injection was accompanied by increased PLA 2 activity. However, PGF production did not exceed that obtained with only P 4. Addition of histamine to the P 4 and E 2 treatment potentiated the stimulation of PG production at 4 h without further elevation in PLA 2 activity. A suboptimal dose of E 2 (10 ng/rat, i.v.) failed to increase PLA 2 activity and PG production, compared to those obtained with 20 ng/rat of E 2. However, coadministration of histamine with the low dose of E 2 increased PG production to the level found with the optimal dose of E 2; this was achieved without a significant change in PLA 2 activity. On the other hand, histamine did not reverse the inhibitory effect of dexamethasone on E 2 stimulation of PLA 2 activity and PG production. Taken together these results suggest that histamine induced potentiation of PG production in P 4 and E 2 treated rats is probably mediated via activation of PG synthetase activity. PLA 2 activity was increased significantly at 8 h after the last injection of P 4. However, this increase in activity was reflected in increased PGE, but not PGF production. The superimposition of E 2 on P 4 treatment, although further increased PLA 2 activity, resulted in unaltered production of PGF but decreased production of PGE, compared to the 4 h values. These findings suggest an existence of a control mechanism between formation of PGs and PGH 2. The potentiating effect of histamine to E 2 stimulation disappeared by 8 h. By 12 h, both the activity of PLA 2 and PG production declined in the uterus following P 4 or P 4 and E 2 treatment. Analysis of uterine PG production under different experimental conditions offers an interesting temporal relationship in the ratio of PGF to PGE. The ratio was higher at 0.5 h and 4 h after P 4 treatment, while superimposition of E 2 or E 2 plus histamine lowered this ratio. On the contrary, this picture was reversed at 8 h and by 12 h no difference in the ratio was observed. It is suggested that one of the functions of estrogen in the induction of implantation in the rat is mediated through the regulation of the PGF: PGE ratio during the preparatory phase leading to implantation.