The critical problem of perioperative cerebral ischemia presents unique opportunities for therapeutic intervention. Recent advances in clinical anesthesiology have made it possible to prospectively identify both high-risk patients and high-risk settings (including neurosurgery, cardiac surgery requiring cardiopulmonary bypass, and intraoperative hypotension). Although techniques are now coming into clinical for monitoring cerebral function intraoperatively, no effective therapy is yet available to prevent or treat ischemic complications. Furthermore, little is known about the @potential beneficial or deleterious actions of clinical anesthetic agents on neurons under ischemic conditions. The proposed experiments will examine the cellular physiology and pharmacology of ischemic neuronal injury in vitro and then determine the effects of anesthetics on these processes. Initial experiments will characterize the neuronal injury produced in cultures cortical cells by acute depletion of oxygen aid glucose. Having defined this model system, several issues will be addressed: (1) the role of glutamate receptors and receptor subtypes in mediation of acute ischemic injury, (2) the effect of extracellular acidosis and lactate accumulation and (3) the importance of specific transmembrane ion fluxes. Beginning in the second year attention will shift to the effects of anesthetics on the mechanisms of injury defined during the first year. In years 3-5 additional metabolic aspects of injury in cell culturewill be studied and the effects of anesthetics on these processes defined. These will include changes in cellular energy charge with injury and protection, and changes in the cell cytoskeleton resulting from activation of calcium-dependent kinases and proteases. The ability to induce long-term potentiation and the preservation of the population spike will be compared as measures neuronal function after ischemic exposure in the rat hippocampal slice. Again, evaluation of anesthetic agents will be a primary interest. During the period covered by this proposal, clinical work in both general and neurosurgical anesthesia will provide expertise in clinical problems relating to perioperative ischemia, and allow participation in clinical trials of new therapeutic strategies.
