ARACHIDONIC ACID METABOLITES AND UTERINE CONTRACTIONS

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The long-term objective of this project is to elucidate the role of prostaglandins (PGs) and oxytocin (OT) in uterine contractions, particularly in parturition and preterm labor. There are two specific aims in the proposed project. 1. To investigate the mechanism of action of PGs on the development of OT sensitivity in the parturient uterus. The pregnant uterus at term develops a marked sensitivity to the uterotonic action of OT. Inhibition of endogenous PG synthesis prevents the development of OT sensitivity. The mechanism of this action of PG on OT is not known. Understanding how PG stimulates OT sensitivity is fundamental to our knowledge of the mechanism of parturition and to our research for effective treatment methods for preterm labor. Conceivably, PGs may stimulate OT receptor and/or gap junction formations and thus enhance the action of OT. We will determine the effects of inhibition of endogenous PG synthesis in day 19, 20, 21 and 22 pregnant and day 2 postpartum rats on myometrial OT receptor concentrations and gap junction formations. OT receptor concentration will be determined by classical ligand-receptor binding and Scathard plot analysis. Gap junction formations will be measured quantitatively by electron microscopy. 2. To determine leukotrienes (LTs) and PG production and uterine contractility in immunologically sensitized rats or guinea pigs. In addition to PGs, the uterus also synthesizes LTs. The functions of LTs in the uterus has not been explored. LTs and PGs are mediators of inflammatory and hypersensitivity reactions. Prostanoids such as LTs, PFG-2 alpha, TXA-2 may be greatly elevated in the pregnant uterus during infection, inflammatory or hypersensitivity reactions, producing contractions and vascular changes incompatible to fetal growth. This mechanism may be responsible, in some cases, for miscarriage or spontaneous abortion. We propose to determine the production of LTs, PGE-2, PGF-2 Alpha, PGI-2 and TXA-2 and uterine contractility in immunologically sensitized rats or guinea pigs. Animals will be actively sensitized with ovalbumin. Uterine contractions and release of prostanoids will be determined under antigen challenge. Tissue contents and release of prostanoids will be measured by radioimmunoassays and bioassays.