Effect of actinomycin D on prostaglandin synthesis by and output from the guinea-pig uterus

Abstract

The intra-uterine administration of actinomycin D on Day 10 reduced the output of prostaglandin (PG) F_2α (the major PG released) from the Day 15 guinea-pig uterus $\text{in vitro}$ by 80 to 85%. PGE₂ output was reduced by 50%, while 6-keto-PGF_1α output was unaffected. Plasma progesterone levels were high (3 to 15 ng/ml) on Day 15 due to the reduction in uterine PGF_2α output. Endometrial PGF_2α synthesizing capacity was reduced by 50% by actinomycin D treatment, while endometrial PGE₂ and 6-keto-PGF_1α synthesizing capacities were unaffected. Oestradiol treatment $\text{in vivo}$ did not reverse the inhibitory effects of actinomycin D on uterine PG production.A23187 increased uterine PGF_2α, 6-keto-PGF_1α and PGE₂ outputs irrespective of treatment, indicating that substrate supply was always rate limiting. Actinomycin D inhibited the uterotrophic action of oestradiol indicating that fresh protein synthesis had been inhibited. Overall, this study suggests that increased protein synthesis is involved in stimulating endometrial PGF_2α synthesis and release.Previous studies have shown that increases in enzyme activities induced by oestradiol are only secondary events in the stimulation of endometrial PGF_2α production. We propose that oestradiol induces the synthesis of a protein (‘lipostimulin’) which, acting on a progesterone-primed uterus, “switches on” endometrial PGF_2α synthesis and release by causing the activation of endometrial phospholipase A₂.