Increasing our knowledge of the physiological control mechanisms of the human placental vasculature will improve understanding of how blood flow is reduced in intrauterine growth retardation and pregnancy-induced hypertension. These conditions are major causes of increased fetal, perinatal, and neonatal morbidity and mortality. In the absence of innervation of this vasculature humoral agents must participate in the control of its tone. We will test the hypothesis that the various families of eicosanoids (the prostaglandins, leukotrienes, hydroxy- and epoxy fatty acids) derived from arachidonic acid have vasoactive effects and interact both with each other and with other endogenous humoral agents in regulating blood flow in the human placenta. These compounds will be injected into the fetal circulation or maternal intervillous space of the isolated perfused human placental cotyledon and the effects of these agents on fetal-placental vascular resistance determined. Perfusion effluents from both circulations will be collected for measurement of selected prostaglandins, thromboxane,leukotrienes and mono-hydroxy fatty acids by established specific radioimmunoassays (RlA). Normal and reverse phase HPLC will separate and characterize metabolites and improve RlA specificity if necessary. Specific inhibitors of the various pathways of eicosanoid metabolism (cyclo-oxygenase, thromboxane synthase, lipoxygenase or cytochrome P450 mono- oxygenase) will be infused into both maternal and fetal circulations of placental cotyledons to determine the participation of the products of these pathways in maintenance of basal vascular resistance and vasoactive responses to other humoral agents. We will investigate: I. The vasoactive effects of naturally occurring lipoxygenase metabolites of arachidonic acid (the leukotrienes and hydroxy- eicosatetraenoic acids) in the perfused placenta. II. The interactions of the prostaglandins, leukotrienes and hydroxy-eicosatetraenoic acids with angiotensin 11, epinephrine, norepinephrine and 5-hydroxytryptamine. III. The vasoactive effects of naturally occurring epoxy- eicosatrienoic acid metabolites of arachidonic acid in the perfused placenta.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039873-02
Application #
3356820
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Eis, A W; Mitchell, M D; Myatt, L (1992) Endothelin transfer and endothelin effects on water transfer in human fetal membranes. Obstet Gynecol 79:411-5
Myatt, L; Brewer, A S; Brockman, D E (1992) The comparative effects of big endothelin-1, endothelin-1, and endothelin-3 in the human fetal-placental circulation. Am J Obstet Gynecol 167:1651-6
Myatt, L (1992) Control of vascular resistance in the human placenta. Placenta 13:329-41
Myatt, L; Brewer, A S; Langdon, G et al. (1992) Attenuation of the vasoconstrictor effects of thromboxane and endothelin by nitric oxide in the human fetal-placental circulation. Am J Obstet Gynecol 166:224-30
Myatt, L; Langdon, G; Brewer, A S et al. (1991) Endothelin-1-induced vasoconstriction is not mediated by thromboxane release and action in the human fetal-placental circulation. Am J Obstet Gynecol 165:1717-22
Myatt, L; Brewer, A; Brockman, D E (1991) The action of nitric oxide in the perfused human fetal-placental circulation. Am J Obstet Gynecol 164:687-92