These studies are designed to address the overall hypothesis that arachidonic acid metabolism contributes to cerebrovascular alterations that follow ischemia and reperfusion of the newborn brain. Specifically, we propose that this contribution involves three potential mechanisms: 1) generation of disruptive activated oxygen species; 2) production of vasoconstrictor, platelet aggregatory, chemotaxic, inflammatory eicosanoids; and 3) production of vasodilatory, antiaggregatory, eicosanoids. To test this hypothesis, three specific aims will be addressed using newborn pigs: 1) determination of the relationship between cerebral production of arachidonic acid metabolic products (activated oxygen species and eicosanoids) and cerebral vascular alterations secondary to ischemia-reperfusion; 2) definition of the functional significance of the relationship between alterations in arachidonic acid metabolism and cerebral vascular alterations; and 3) investigation of the mechanisms by which ischemia- reperfusion alters cerebral arachidonic acid metabolism. Using techniques we have developed for production of global cerebral ischemia and reperfusion in newborn pigs, we will study cerebral arachidonic acid metabolism and cerebral hemodynamics during 24 h of reperfusion. Methods to be employed will include many approaches that were applied to the study of the newborn cerebral circulation for the first time during the present period as well as more traditional methods. Key methods include: cerebral blood flow and regional distribution using radioactive microspheres; cerebral oxygen and glucose consumption by the arterial-venous method; cranial windows to study the cerebral microcirculation, detect superoxide anion generation, and collect cortical subarachnoid fluid for eicosanoid determinations; eicosanoid determinations by high pressure liquid chromatography and radioimmunoassay; superoxide anion detection by superoxide dismutase inhibitable nitroblue tetrazolium reduction; and effects of subsequent reactive species by examining lipid peroxidation by measuring conjugated dienes. The proposed studies will extend investigations from the current period to examine the significance of arachidonic acid metabolism in cerebral hemodynamics of the newborn brain during post-ischemic reperfusion. We will provide important new information in an area where few data are available that ultimately may be of considerable clinical importance since neonatal hypoxic-ischemic encephalopathy produces varying degrees of mental and/or physical disability.
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