The objectives of this research plan are to clarify the relationships among endocrine, paracrine, and cellular events during pregnancy which culminate in parturition. It is our expectation that data obtained in pregnant rhesus monkeys and baboons will provide insights into the mechanisms of normal and preterm human labor. Physiological studies in unanesthetized chronically catheterized maternal-fetal preparations in a mobile tether assembly and complementary in vitro studies of intrauterine tissues will be conducted to answer the following questions: (1) How do pituitary and adrenal factors, oxytocin, catecholamines, and environmental cues (e.g., light:dark cycles) regulate circadian patterns in uterine activity? (2) Is progesteron (P4) receptor blockade by RU486 in late gestation associated with the same paracrine (amniotic fluid eicosanoids), structural (gap junctions), and functional (uterine activity) changes seen in spontaneous parturition? (3) Are changes in steroid receptors, their tissue localization or their interaction with DNA related to the onset of labor? (4) Is eicosanoid production by intrauterine tissues altered near term, and if so, by what mechanism (e.g., increased synthesis, decreased inhibition, or redirection of arachidonate metabolism)? Estrone, estradiol, pregnenolone and the sulfate, P4DHEAS, DHEA, androstenedione, cortisol, ACTH, prolactin, oxytocin, prostaglandins (PGE, PGF, PGFM, PGEM-II, 6-keto-PGF 1 alpha), and lipoxygenase metabolites (5, 12, and 15-HETE; leukotriene B4 and C4) will be measured by specific RIA; catecholamines by radioenzymatic assay; steroid receptors by immunocytochemistry, exchange assay and immunoassay; gap junction morphometry by EM; PG production rates in a tissue superfusion system; PG inhibitory and stimulatory substances by bovine seminal vesicles and amnion cell cultures. Results of hormone and tissue assays will be correlated with continuous measurements of fetal heart rate and uterine activity (by amniotic fluid pressure and electromyography). Computer methods will be used for on-line data acquisition and statistical analyses of wave forms, biorhythms and hormonal trends.
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