Summary. The changes with time in intrauterine tissue production and concentrations of PGE-2, PGF-2α, 6-keto PGF-1α and PGFM (13,14-dihydro-15-keto PGF-2α) in maternal and fetal plasma and amniotic fluid were investigated during the first 72 h of pulsatile administration of ACTH_1–24 to chronically catheterized fetal sheep.

By 72 h there were no changes in the frequency, maximum amplitude or duration of uterine contractions compared to preinfusion values. Basal concentrations of PGE-2 in maternal and fetal plasma were generally higher than those of PGF-2α, while 6-keto PGF-1α values were intermediate. The concentrations of all PGs increased in amniotic fluid during ACTH infusion. In fetal plasma and in maternal vena caval plasma, however, there were significant increases only in PGF-2α and PGFM. No changes were observed in plasma concentrations for any PG during saline infusion. The mean output of PGE-2, PGF-2α and 6-keto PGF-1α by dispersed cells prepared from chorioallantois and fetal and maternal cotyledons was consistently higher after ACTH for 72 h than from saline-infused animals, although significance (P < 0·05) was achieved only for PGE-2 in chorioallantois. There are 3 conclusions. (1) Increases in ovine intrauterine tissue PG production precede the occurrence of increased myometrial contractile activity after ACTH treatment of fetal sheep. The results imply a causal relationship between rising PG and later myometrial contractions, rather than PG changes resulting from enhanced uterine activity. (2) The major site(s) of increased PG output in vitro from endogenous precursors are fetal structures, especially the chorioallantoic membranes. (3) Although PGE-2 may be the major circulating PG during late gestation, there is a selective increase in plasma PGF-2α concentrations before the onset of delivery.

Epidemiological and animal studies strongly indicate that the environment experienced in utero determines, in part, an individual’s likelihood of developing cardiovascular disease in later life. This risk has been further linked to impaired kidney function, as a result of compromised development during fetal life. The present study therefore examined the influence of maternal nutrient restriction (NR), targeted at specific periods of kidney development during early to mid gestation, on the mRNA abundance of receptors for glucocorticoid (GCR), growth hormone (GHR) and insulin-like growth factors-I (IGF-IR) and -II (IGF-IIR), and the IGF-I and -II ligands. This was undertaken in both singleton and twin fetuses. At conception ewes were randomly allocated to either an adequately fed control group or one of four nutrient-restricted groups that were fed half the control amount from 0 to 30, 31 to 65, 66 to110 or 0 to110 days gestation. At 110 days gestation all ewes were humanely euthanased and fetal kidneys and surrounding adipose tissue sampled. There was no effect of NR or fetal number on kidney weight, shape or nephron number, but the surrounding fat mass was increased in singleton fetuses exposed to NR for 110 days. An increase in kidney mRNA abundance with NR only occurred in singleton fetuses where IGF-IR mRNA was enhanced with NR from 66–110 days gestation. In twin fetuses, NR had no effect on mRNA abundance. However, for all genes examined mRNA expression was lower in the kidneys of twin compared with singleton fetuses following NR, and the magnitude of the effect was dependent on the timing of NR. In conclusion, the abundance of mRNA for receptors which regulate fetal kidney development are lower in twin animals compared with singletons following periods of nutrient deficiency. This may impact on later kidney development and function.

Since glucocorticoids decrease and protein kinase C (PKC) activators increase amniotic PGE₂ production, the possibility that they regulate the activity of prostaglandin endoperoxide H synthase (PGHS), the rate-limiting enzyme of prostaglandin synthesis from arachidonate, was investigated. Glucocorticoids inhibited the production of PGE₂ from exogenous arachidonate specifically and in a concentration dependent fashion. Furthermore, cortisol decreased PGHS activity and the amount of PGHS protein in amnion microsomes, and reduced the rate of recovery of PGHS after acetylsalicylic acid (ASA) pretreatment. Actinomycin D blocked the inhibition of PGHS recovery by cortisol, but did not suppress the spontaneous recovery of the enzyme, indicating that the glucocorticoid induced a post-transcriptional inhibitor of PGHS synthesis. PKC-activating phorbol esters, such as 12-tetradecanoyl phorbol 13-acetate (TPA) increased the synthesis of PGE₂ from exogenous arachidonate, also in a specific and concentration dependent manner. PGHS recovery after ASA treatment was enhanced by TPA. PGHS activity and protein concentrations were increased by phorbol ester treatment; however, this was apparent only in tissues in which the concentrations of PGHS were initially low. These results show that the synthesis of PGHS is positively and negatively regulated in the human amnion by PKC and glucocorticoids, respectively, and suggest that effectors using these pathways may regulate the enzyme in vivo.