These studies are designed to address the overall hypothesis that arachidonic acid metabolism contributes to cerebrovascular perturbations induced by perivascular cerebral blood in the newborn brain. Specifically, it is proposed that this contribution involves disruptive activated oxygen species generated initially and during clot lysis that: 1) interfere with production of vasodilatory intermediates and/or prostanoids and 2) promote, either directly or indirectly through tissue damage, production of leukotrienes. To test this hypothesis, three specific aims will be addressed using newborn pigs: 1) determination of the relationship between cerebral production of activated oxygen species and cerebral vascular alterations secondary to perivascular blood; 2) definition of the functional significance of the relationship between production of activated oxygen species caused by perivascular blood and cerebral vascular alterations; and 3) investigation of the mechanisms by which perivascular blood alters vascular reactivity. Cerebral superoxide anion generation, prostanoid and leukotriene production, and hemodynamics during seven days after injection of blood onto the cortical surface and into the caudate nucleus-ventricle will be examined. Key methods include : cranial windows to study the cerebral microcirculation, detect superoxide anion generation, and collect cortical periarachnoid fluid for eicosanoid determinations; radioactively labeled microsphere determination of cerebral blood flow distribution; prostanoid and leukotriene measurement by radioimmunoassay; and superoxide anion detection by superoxide dismutase inhibitable nitroblue tetrazolium reduction. This research will provide important new information in an area where few data are available that ultimately may be of considerable clinical importance since neonatal intracranial hemorrhage is common and can produce lifelong mental and/or physical disability.
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