Cerebral ischemia is an important and potentially fatal response in patients requiring nursing care related to cerebrovascular dysfunction or neurological injury. Severe reduction of blood flow to brain leads to tissue acidosis, one of several key factors in neuronal injury. The investigators previously found that reductions in cerebral intracellular pH (pHi) below 5.7 during cerebral ischemia is associated with an inability to restore pHi during reperfusion and eventual metabolic brain death. The mechanism(s) by which altered tissue pH leads to significant cerebral morbidity in an ischemic event is unclear.
Aims 1 -4 provide critical tests of two different molecular mechanisms of reperfusion injury associated with severe acidosis. The investigators will use 31P magnetic resonance spectroscopy to measure changes in brain pH and ATP during and following severe incomplete cerebral ischemia in anesthetized dogs, accompanied by somatosensory evoked potential monitoring and in vivo cerebral blood flow measurement.
In Aim 1, the investigators will determine if it is low pHi or [HCO3-]i that is critical to maintaining brain viability.
In Aims 2 -3, the investigators will investigate the overall hypothesis that reduction of [HCO3-]i permits proton cleavage of bound iron leading to enhanced membrane lipid peroxidation and delayed metabolic deterioration in vivo. The investigators will determine if antioxidant therapy alters recovery and cerebral vascular reactivity after potentially life-threatening brain injury with a therapeutic window of 8 hours.
Aim 4 will focus on the hypothesis that lactic acidosis facilitates peroxynitrite- mediated lipid peroxidation. Lastly, the investigators will determine if metabolic alkalosis also exacerbates ischemic injury and if excitotoxic mechanisms play a role in recovery deficits when acidosis is minimized (Aim 5). This study will establish the mechanistic rationale for monitoring acid-base abnormalities in acutely ill patients and for promoting optimal pH recovery after an ischemic event. By determining the significance of pH-mediated mechanisms of injury, the investigator can better focus nursing therapies that support acid-base balance in the critically ill or injured individual and directly enhance cerebrovascular recovery.
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