While severe acidosis exacerbates brain injury due to global cerebral ischemia, moderate acidosis appears to promote recovery during reperfusion. This application proposes to test 3 mechanistic hypotheses related to the effects of ischemic and postischemic tissue acidosis and alkalosis on animal survival and neural cell death in a rat model of cardiac arrest and resuscitation. The first hypothesis is that the primary cause of death within the first 6 hr of reperfusion is metabolic and vascular failure as a result of cytotoxic edema initiated by activation of the Na exchanger in the brainstem nuclei that control cardiovascular and respiratory function. The second hypothesis is that death within a few days after resuscitation is metabolic and a result of vascular failure in the brainstem due to vasogenic edema caused by blood-brain barrier leakiness through factors such as VEGF induced by oxidative stress. The third hypothesis is that delayed neuronal death in selectively vulnerable areas such as the hippocampal CA1 region is promoted by acidosis during and immediately following cardiac arrest. The general experimental approach to testing these hypotheses will be to define the regional intracellular pH changes in the brainstem and hippocampus of rats in response to cardiac arrest and resuscitation and to correlate these changes to structural and functional indicators of metabolic stress and energy balance. The project will utilize animals that are either normoglycemic and normocapnic, hyperglycemic and normocapnic, or normoglycemic and hypercapnic. Some animals will also be treated with Na+/H+ transport inhibitors to provide further support that this transporter promotes postischemic intracellular alkalosis and worsens neurological outcome.
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