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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD020839-03
Application #
3319251
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1986-01-01
Project End
1989-06-30
Budget Start
1988-01-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Manning, M; Cheng, L L; Stoev, S et al. (1995) An exploration of the effects of L- and D-tetrahydroisoquinoline-3-carboxylic acid substitutions at positions 2, 3 and 7 in cyclic and linear antagonists of vasopressin and oxytocin and at position 3 in arginine vasopressin. J Pept Sci 1:66-79
Manning, M; Cheng, L L; Klis, W A et al. (1995) Advances in the design of selective antagonists, potential tocolytics, and radioiodinated ligands for oxytocin receptors. Adv Exp Med Biol 395:559-83
Chen, D L; Chan, W Y; Manning, M (1994) Agonist and antagonist specificities of decidual prostaglandin-releasing oxytocin receptors and myometrial uterotonic oxytocin receptors in pregnant rats. J Reprod Fertil 102:337-43
Chan, W Y; Chen, D L; Manning, M (1993) Oxytocin receptor subtypes in the pregnant rat myometrium and decidua: pharmacological differentiations. Endocrinology 132:1381-6
Manning, M; Chan, W Y; Sawyer, W H (1993) Design of cyclic and linear peptide antagonists of vasopressin and oxytocin: current status and future directions. Regul Pept 45:279-83
Cao, L; Chan, W Y (1993) Effects of oxytocin and uterine and luteal prostaglandins on the functional regression of the corpus luteum in pseudopregnant rats. J Reprod Fertil 99:181-6
Manning, M; Bankowski, K; Barberis, C et al. (1992) Novel approach to the design of synthetic radioiodinated linear V1A receptor antagonists of vasopressin. Int J Pept Protein Res 40:261-7
Manning, M; Przybylski, J; Grzonka, Z et al. (1992) Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids. J Med Chem 35:3895-904
Chan, W Y; Chen, D L (1992) Myometrial oxytocin receptors and prostaglandin in the parturition process in the rat. Biol Reprod 46:58-64
Chan, W Y; Berezin, I; Daniel, E E et al. (1991) Effects of inactivation of oxytocin receptor and inhibition of prostaglandin synthesis on uterine oxytocin receptor and gap junction formation and labor in the rat. Can J Physiol Pharmacol 69:1262-7

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