The proposed studies investigate the cerebral metabolic responses of newborn animals induced by ischemia and hypoxia of varying intensity and duration. Cerebral metabolism will be assessed by in-vivo measurements of phosphorus cellular metabolites and intracellular pH with nuclear magnetic resonance of 31-Phosphorus and simultaneous measurements of cerebral metabolic rate for oxygen, glucose, and lactate. 31-P NMR spectroscopy allows repetitive and quantitative measurements of the dynamic aspects of metabolism of organophosphates and intracellular pH in the intact animal. Hemodynamic events occurring as a result of general or regional changes in oxygen content will be related to metabolic alterations reflecting the onset of transient or permanent tissue damage in newborn animals. Experimental protocols will be carried out on newborn piglets and lambs, investigating limits in brain energy reserves as identified by 31-Phosphorus NMR spectroscopy in-vivo in acute hypoxia and ischemia, identifying the critical level of oxygen delivery to brain (depending on the prevailing metabolic demand). Physiologic measurements of oxygen and glucose availability and uptake, acid-base balance, and hemodynamic measurements will be correlated with metabolic phosphorus containing compounds. These projects will test the overall hypotheses that single or repeated episodes of hypoxic and metabolic stress, as well as long-lasting states of hypoxia, may result in subtle alterations of metabolic function. Specific studies will investigate the efficiency of compensatory mechanisms maintaining cellular brain metabolism in newborn animals under conditions of impaired oxygenation and will establish the limits of this efficiency by comparing the microcirculatory and metabolic responses during various insults identified by NMR and CBF measurements.
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