The possibilities of optimizing the parameters for phosphorus, sodium and proton spectroscopy of biochemicals and of imaging tissue volumes perturbed by hypoxic/ischemic stress is a principle goal of this research. Using these techniques we propose to follow the course of hypoxic/ischemic injury which, as established by biochemical and morphological studies, has lacked an identification of the primary events on the pathway to cell damage. The technological developments necessary for this research have already been evaluated and approved under Research Resource activity and we propose to utilize the technology for this work as it develops. This progression is to be followed by spectroscopy and imaging of phosphorus metabolism as a primary event, of glycolytic metabolism involving lactate production as a secondary event and by sodium and water movements as a tertiary event. In the animal model system employed, we will minimize the multiple parameters that precipitate hypoxic/ischemic cell damage by employing a protocol of manual stabilization of the energy state of the tissue through NMR observation of the phosphocreatine/phosphate (PCr/Pi) at values of approximately 1, employing not only manual control of Fi02, but also complete monitoring of correlated biochemical and physiological parameters. The insult is quantitated by its duration (T) to intensity (PCr/Pi) quotient and is scored by its impact on the rate of recovery (PCr/Pi/min) in response to restoration of tissue oxygen levels, or in terms of the time required for complete loss of control of tissue oxidative metabolism (PCr/Pi falls to less than 0.05). The guiding hypothesis is that hypoxic stress sets a metabolic operating point (PCr/Pi value) that is inherently unstable because the metabolic load line (ATPase level) becomes nearly parallel to the asymptote of the Michaelis-Menten transfer function for oxidative metabolism in the steady-state condition (tissue respiration rate = tissue ATPase). With this approach we expect to identify unstable operating points (PCr/Pi), quantified insults T/PCr/Pi) that lead to impaired oxidative metabolism and increased ATPase. By a comparison of the multiple nucleic in spectroscopic and imaging modes. We propose to have a data base appropriate to an objective evaluation of the relative merits in the two modes. Furthermore, the biochemical data obtained in this study, we believe, will be predictive of metabolic """"""""disasters"""""""" leading to acidosis, cell water and ion movements, and eventual cell disintegration and are applicable generally to animal models and neonate and adult human brains.
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