ARACHIDONIC ACID METABOLITES AND UTERINE CONTRACTIONS

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The broad, long-term objectives of this project are to elucidate the regulatory mechanisms controlling uterine contractions in parturition and to find new therapy for the prevention of premature birth, a major cause of perinatal normality and morbidity in this country. Specifically, the roles of oxytocin (OT), OT receptors and myometrial gap junctions in labor will be investigated. In the current project, the P.I. found that suppression of endogenous PG synthesis delayed OT receptor formations in the parturient uterus and prolonged gestation. In this competing continuation, the hypothesis that OT may auto-stimulate its own receptor formation in the myometrium via decidual OT receptor activation and PG release will be examined. OT receptor blockade will be produced by specific long-acting OT receptor antagonists (developed by P.I. and his collaborators) in pregnant rats beginning on day 19 of gestation. Effects of OT receptor inactivation on uterine PG release, decidual and myometrial OT receptor formations and myometrial gap junction developments will be determined. PGs will be quantified by specific radioimmunoassays (RIAs); OT receptors determined by radioligand-receptor binding assays and gap junctions by electron microscopy. The potential of OT antagonists as tocolytics for prevention of preterm labor will be studied and compared with naproxen sodium, a PG synthesis inhibitor with known tocolytic action. Effects of OT antagonist and naproxen sodium treatment on gestational period, parturition and outcome of pregnancy will be studied. The mechanism of action of PG on OT receptor and gap junction formations will be pursued. In vivo and in vitro rat models will be utilized to determine whether PG exerts its effects directly or indirectly via its luteolytic action.