Ritodrine, a Beta2-adrenergic agonist, is widely used for suppression of premature labor. Ritodrine presumably mediates myometrial relaxation as well as many of its reported side effects such as tachycardia, hypertension, and changes in glucose metabolism through the B-adrenergic receptor effector cascade system, including the B-receptor, coupling protein, adenylate cyclase/cAMP and cAMP-dependent protein kinase. Ritodrine-induced tissue desensitization (tachyphylaxis) of the receptor-cyclase system may be a major determinate of the drug's physiological effects. The requirement for tissue samples from the mother or fetus normally makes study of drug tachyphylaxis in pregnancy difficult. Two readily available tissues, the placenta and the fetal membranes contain B-adrenergic receptor effector cascade systems, however. Further, catecholamines and cAMP appear to modulate estrogen and progesterone production in the placenta and prostaglandin production in the amnion. In addition, ritodrine lowers serum estrogen, progesterone and prostaglandin levels. Placenta and amnion thus provide available models for the study of ritodrine-induced tachyphylaxis. This proposal will test the hypothesis that ritodrine induces tachyphylaxis of the B-adrenergic effector cascade systems in human placenta and amnion which thereby inhibit catecholamine-stimulated increases in estrogen and progesterone production by the placenta, and prostaglandin production by the amnion. Trophoblastic cells, placental explants and amniotic membrane punches from term and preterm gestation placentae will be exposed to ritodrine in vitro following which differences in each component of the B-adrenergic effector cascade (listed above) and changes in catecholamine-stimulated estrogen and progesterone (placenta) or prostaglandin (amnion) production will be determined. Similarly, differences in placentas exposed to ritodrine under clinical conditions (in vivo) will be compared with controls of similar gestation. The results of this study should provide information concerning the capability of ritodrine, as used under clinical conditions, to regulate the sensitivity of B-adrenergic system and more clearly define the effect of catecholamines and B-adrenergic agents such as ritodrine upon the major hormones of pregnancy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD020459-01A2
Application #
3318544
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1987-01-01
Project End
1989-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Moore, J J; Moore, R M; Collins, P L (1993) Protein kinase A activators inhibit agonist induced prostaglandin production in human amnion. Prostaglandins Leukot Essent Fatty Acids 48:355-61
Hassan, N; Moore, R M; Moore, J J (1992) The adenylate cyclase system and prostaglandin production in human decidua parietalis. Placenta 13:241-53
Moore, J J; Moore, R M; Vander Kooy, D (1991) Protein kinase-C activation is required for oxytocin-induced prostaglandin production in human amnion cells. J Clin Endocrinol Metab 72:1073-80
Vander Kooy, D; Dubyak, G R; Moore, R M et al. (1989) Adenosine triphosphate activates the phospholipase-C cascade system in human amnion cells without increasing prostaglandin production. Endocrinology 124:2005-12
Moore, J J; Dubyak, G R; Moore, R M et al. (1988) Oxytocin activates the inositol-phospholipid-protein kinase-C system and stimulates prostaglandin production in human amnion cells. Endocrinology 123:1771-7
Moore, J J; Lundgren, D W; Moore, R M et al. (1988) Polyamines control human chorionic gonadotropin production in the JEG-3 choriocarcinoma cell. J Biol Chem 263:12765-9
Moore, J J; Suster, M A; Moore, R M (1988) Cyclic 3',5'-adenosine monophosphate-dependent kinase and phosphoproteins in human amnion. Proc Soc Exp Biol Med 189:84-93
Ward, S M; Caritis, S N; Chiao, J P et al. (1988) Dexamethasone effects on ritodrine-induced changes in myometrial contractility and beta-adrenergic receptor function. Am J Obstet Gynecol 159:1461-6