Prostaglandins formed by the action of fatty acid cyclooxygenase on the substrate, arachidonic acid, are of signal importance in the control of uteroplacental blood flow and in the biochemical mechanisms that result in parturition. Arachidonic acid is metabolized also by way of lipoxygenase enzyme pathways into leukotrienes and related substances with potent biological activities that include the modulation of prostaglandin biosynthesis. The studies will provide an evaluation both of the metabolism of arachidonic acid by way of lipoxygenase pathways in uterine and intrauterine tissues of sheep during late pregnancy and of the regulation of such metabolism. The metabolism of arachidonic acid in these tissues will be investigated by use of homogenates of fresh tissues and by use of cells prepared from the tissues and maintained in culture. Arachidonate lipoxygenase metabolites formed in tissues will be separated, identified and quantified by high-performance liquid chromatography. The effects of gestational age, labor at term and induced-labor both on the metabolism of arachidonic acid by way of lipoxygenase enzymes in fresh tissues and on plasma, amniotic and allantoic fluid concentrations of products of such metabolism will be investigated. An evaluation will be conducted of the regulation of arachidonic acid metabolism by hormones and other substances in amniotic and allantoic fluids. These substances will be added to homogenates of uterine and intrauterine tissues and cells derived from such tissues which are maintained in culture and effects on arachidonate lipoxygenase activities determined. Thus, acute and chronic effects will be studied. Moreover, these substances will be administered to pregnant sheep and arachidonate lipoxygenase metabolism measured by use of radioimmunoassays and also tissues excised and arachidonic acid metabolism evaluated. Thus, cell to cell and """"""""whole animal"""""""" effects will be studied. It is our belief that the findings of the studies proposed will provide exciting insights into the mechanisms not only of parturition, but also of fetal development.
