Cardiac arrest is almost always fatal. Despite marked improvements in emergency medical care in the United States, the prognosis for victims of cardiac arrest remains bleak. Cardiac arrest interrupts nutritive perfusion of the heart and brain, leading to tissue energy depletion, intracellular calcium accumulation, and massive production of cytotoxic oxygen-centered free radicals upon reperfusion, culminating in failure of these vital organs. Interventions that both supply metabolic energy and neutralize oxyradicals would be particularly effective at mitigating cellular injury and preserving physiological function of myocardium and cerebral cortex following cardiac arrest and resuscitation. Recent work in our laboratory indicates that the natural carbohydrate pyruvate may be the first such pluripotent treatment identified. In post-ischemic myocardium, exogenous pyruvate markedly increases energy reserves and bolsters antioxidant redox potential in parallel with its enhancement of contractile performance. Pyruvate is nontoxic and readily traverses plasma membranes and the blood-brain barrier, so it could be an effective means of protecting the brain from ischemic injury, too. The overall objective of this application is to determine the therapeutic efficacy of pyruvate to protect myocardium and cerebral cortex during cardiac arrest and closed chest cardiopulmonary resuscitation (CPR). Experiments will be conducted in dogs chronically instrumented to measure left ventricular contractile function and cerebrocortical electrophysiological activity. After 5 min cardiac arrest, CPR will be administered by precordial chest compressions for 20 min, then hearts will be defibrillated to restore spontaneous circulation, while cardiac and cerebral function are monitored. Pyruvate will be infused intravenously at defined intervals and dosages during CPR and/or after defibrillation. Energy and antioxidant reserves, regional perfusion and tissue injury will be determined in biopsies of myocardium and cerebral cortex. Pyruvate's long-term impact on cardiac and cerebral function will be studied for 3 d post-arrest. By systematically determining the effective dosages, therapeutic window and cellular mechanisms of pyruvate's salutary effects, this investigation will establish the foundation for clinical development of pyruvate to treat cardiac arrest.
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