The overall goals remain the same: 1) To compare the regulation of cerebral blood flow (CBF) in fetal and newborn animals with that in adults and 2) To use insights gained from those studies to understand fundamental mechanisms of CBF responses to hypoxia. We propose to extend our work into three new areas: the microcirculation, mathematical modeling of oxygen transport and the study of very immature fetal animals. We will propose experiments designed to improve our understanding of the pathophysiology of central nervous system disorders in anemia and polycythemia because, in spite of the frequency of anemia and the considerable morbidity and mortality that accom- panies polycythemia, we have little understanding of basic mechanisms of CBF regulation in those circumstances. We will determine the effect of large-vessel hematocrit on microvascular diameter, microvascular red cell velocity and flux, and microvascular hematocrit using protocols that enable us to separate the effects of changes in arterial oxygen content from concomitant changes in red cell number. The separation of oxygen content from cell number is a unique feature of these studies that will permit us to gain a detailed understanding of hematocrit-induced changes in CBF. We will furthermore develop a mathematical model of cerebral oxygen transport which we will use both for analysis of data previously collected in our laboratory as well as for analysis of data on the microcirculation. We will extend studies of fetal CBF and metabolism to the immature, mid-gestational fetal sheep. Large numbers of infants at comparable stages of brain development survive with the help of contemporary neonatal intensive care. The physiology of the brain at this stage of development is thus of particular interest. Finally, we will attempt to determine if the postnatal risk in arterial P02 is in part responsible for the postnatal rise in cerebral oxygen uptake that occurs in sheep and other species. Since the resistance of the developing brain to anoxia is closely correlated with its oxygen uptake, factors determining the need for oxygen need to be defined.
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