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.
