It is believed that prostaglandins are of signal importance in the control of uteroplacental blood flow and in the biochemical mechanisms that result in parturition in women. Increased rates of conversion of arachidonic acid to prostaglandins by gestational tissues obtained during labor, compared with rates of conversion by tissues taken before the onset of labor, have been demonstrated. In the research proposed we seek to evaluate the role(s) and nature of both intracellular stimulants of the conversion of arachidonic acid to prostaglandins in uterine and intrauterine tissues of pregnant women and a similar stimulant activity found in amniotic fluid. Substances that are present in uterine and intrauterine tissues and in amniotic fluid, that are stimulatory of prostaglandin biosynthesis, will be isolated and characterized by use of techniques that will include salt precipitation, gel-filtration, ion-exchange chromatography, and preparative isoelectric focusing. Putative stimulants of prostaglandin synthase will be prepared from uterine and intrauterine tissues by ultracentrifugation and from amniotic fluid by ultrafiltration. The fractions will be treated in several ways that should permit us to delineate substances of different characteristics, i.e., exposure to activated charcoal, dialysis, boiling, treatment with ammonium sulfate, and then will be added to incubations of microsomal preparations of uterine and intrauterine tissues (or of bovine seminal vesicles) with arachidonic acid and the effect(s) on prostaglandin formation will be determined. Similar incubations will be conducted (a) with oxygen consumption determined as an index of prostaglandin endoperoxide synthase (EC 1.14.99.1) activity and (b) with radiolabeled prostaglandin H2 rather than arachidonic acid as substrate to assess prostaglandin endoperoxide isomerase activities. The putative stimulants also will be added to cells prepared from uterine and intrauterine tissues and maintained in monolayer culture and the effect(s) on prostaglandin production determined. Furthermore, the actions of the putative stimulants on phospholipase A2 activity will be determined. We are of the view that the findings of the studies proposed will provide insight into the mechanisms that lead to the timely onset of parturition as well as cause preterm labor and also will provide insights into the pathogenesis of pregnancy-induced hypertension. Such knowledge should enable us to develop more effective approaches to the prevention or arrest of preterm labor and to the management of pregnancy-induced hypertension.
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