The broad long-term objectives of the application are elucidation of mechanisms of local regulation of fetal blood flow in human term placenta and effects of parturition and complications of pregnancy on these mechanisms. Arachidonate metabolites, particularly 5-lipoxygenase products, and purities may contribute directly and/or indirectly to local regulation of fetoplacental vascular resistance. Their contributions will be investigated using in vitro preparations of human term placenta and cord blood. The dual-perfused placental cotyledon will be used to study release of leukotrienes and thromboxane associated with the increase in fetoplacental vascular resistance elicited by hypoxic maternal perfusion, examining actions of leukotriene and thromboxane synthesis inhibitors and receptor antagonists on release and the hypoxic pressor response, using HPLC and RIA to measure released autacoids. The contribution of adenosine to fetoplacental vasoconstriction elicited by maternal ischemia in the perfused cotyledon will be investigated, examining effects of pharmacologic modulation of intraluminal adenosine and adenosine receptor blockers on the ischemic pressor response and concomitant release of adenosine, measuring adenosine via fluorescence HPLC. The fetoplacental adenosine receptor type will be determined via dose response curves and relative potencies of adenosine analogues selective for A1 and A2 receptors. The contribution of endothelium to purine- (adenosine, ATP, ADP) and leukotriene-mediated pressor responses and to hypoxia will be investigated in isolated chorionic and stem vessel strips, measuring relaxation or contraction elicited by the autacoids in the presence and absence of endothelium and in the presence of inhibitors of endothelium-derived relaxing factor. Leukotriene synthesis by placental vessels segments under control and hypoxic conditions will be analyzed by HPLC and RIA. Purine levels in umbilical artery and vein plasma from patients with normal and complicated pregnancies will be determined by HPLC and correlated with clinical indices such as antepartum fetal testing, Doppler flow studies, progress of labor, acute or chronic fetal distress, scalp pH, cord blood pH and neonatal outcome. It is expected that this integrated approach of assessing both vascular and biochemical responses of the placenta in vitro and relating cord blood purities to clinical parameters will lead to a better understanding of the local control mechanisms regulating fetoplacental blood flow in normal and abnormal conditions and provide information pertinent to understanding intrauterine growth retardation and preeclampsia.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD014888-10
Application #
3312831
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1982-04-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
10
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Kansas
Department
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Maguire, M H; Szabo, I; Valko, I E et al. (1998) Simultaneous measurement of adenosine and hypoxanthine in human umbilical cord plasma using reversed-phase high-performance liquid chromatography with photodiode-array detection and on-line validation of peak purity. J Chromatogr B Biomed Sci Appl 707:33-41
Dobronyi, I; Hung, K S; Satchell, D G et al. (1997) Evidence for a novel P2X purinoceptor in human placental chorionic surface arteries. Eur J Pharmacol 320:61-4
Szabo, I; Maguire, M H (1993) On-line recognition and quantitation of coeluting hypoxanthine and guanine in reversed-phase high-performance liquid chromatography of placental tissue extracts: photodiode-array detection and spectral analysis of coeluting peaks. Anal Biochem 215:253-60
Maguire, M H; Szabo, I; Slegel, P et al. (1992) Determination of concentrations of adenosine and other purines in human term placenta by reversed-phase high-performance liquid chromatography with photodiode-array detection: evidence for pathways of purine metabolism in the placenta. J Chromatogr 575:243-53
Slegel, P; Kitagawa, H; Maguire, M H (1988) Determination of adenosine in fetal perfusates of human placental cotyledons using fluorescence derivatization and reversed-phase high-performance liquid chromatography. Anal Biochem 171:124-34
Howard, R B; Hosokawa, T; Maguire, M H (1987) Hypoxia-induced fetoplacental vasoconstriction in perfused human placental cotyledons. Am J Obstet Gynecol 157:1261-6
Maguire, M H; Westermeyer, F A; King, C R (1986) HPLC determination of adenosine, inosine and hypoxanthine levels in human term placenta. Adv Exp Med Biol 195 Pt A:583-5
Maguire, M H; Westermeyer, F A; King, C R (1986) Measurement of adenosine, inosine and hypoxanthine in human term placenta by reversed-phase high-performance liquid chromatography. J Chromatogr 380:55-66
Howard, R B; Hosokawa, T; Maguire, M H (1986) Pressor and depressor actions of prostanoids in the intact human fetoplacental vascular bed. Prostaglandins Leukot Med 21:323-30
Maguire, M H; Howard, R B; Hosokawa, T (1985) Autacoid receptors in the human fetoplacental vasculature. Contrib Gynecol Obstet 13:170-2

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