It is probable that prostaglandins that are formed by the action of fatty acid cyclooxygenase on the substrate, arachidonic acid, are of signal importance in the control of utero-placental blood flow and in the biochemical mechanisms that eventuate in parturition in women. Arachidonic acid also is metabolized by way of lipoxygenase enzyme pathways into substances with potent biological activities that include the modulation of prostaglandin biosynthesis. We propose to evaluate the metabolism of arachidonic acid, by way of the lipoxygenase pathways, in uterine and intrauterine tissues of pregnant women. The metabolism of arachidonic acid in such tissues will be investigated by use of homogenates of fresh tissues and by use of cells prepared from the tissues and maintained in monolayer culture. Arachidonate lipoxygenase activities in tissues will be evaluated by use of radiometric thin-layer chromatography; the individual metabolites of arachidonic acid formed by the tissues will be separated, identified, and quantified by high-performance liquid chromatography. The rate of formation of arachidonate lipoxygenase products by uterine and intrauterine tissues will be determined. The effect of gestational age, labor at term, preterm labor, and pregnancy-induced hypertension on the metabolism of arachidonic acid by way of lipoxygenase pathways in fresh tissue also will be evaluated. The effect(s) of hormones, and other substances, in plasma and amniotic fluid on arachidonate lipoxygenase acvtivities in uterine and intrauterine tissues and in cells prepared from such tissues and maintained in monolayer culture will be investigated. Substances in plasma and amniotic fluid that inhibit and stimulate arachidonate lipoxygenase activities will be isolated and characterized by use of techniques that include salt precipitation, ion-exchange chromatography, and preparative isoelectric focusing. 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 preterm labor and also 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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