This application is concerned with mechanisms of defibrillation injury. Our overall aim is to demonstrate, using new real-time electron paramagnetic spin resonance techniques, that a major mechanism of defibrillation injury is oxygen free radicals which are generated by electric countershocks. We want to reduce defibrillation injury by pharmacologic interventions with free radical scavengers or inhibitors to reduce defibrillation injury. To accomplish these aims we propose a testable hypothesis: A major mechanism of defibrillation injury (which results in post shock ventricular dyskinesis) is generation of oxygen free radicals, due to a direct shock effect (passage of electrical current through physiologic solutions) rather than to the myocardial ischemia which accompanies ventricular fibrillation. Defibrillation injury can be reduced by pharmacologic interventions which reduce or scavenge free radicals. New defibrillation waveforms may reduce free radical generation. We will use a marker for the detection and quantification of free radical generation: ascorbyl free radicals. Ascorbate is the terminal small- molecule antioxidant; the ascorbyl radical is the end-product of higher radical generation and repair, and can be easily detected by our powerful and sophisticated new electron paramagnetic spin resonance technique. This real-time method is ideally suited to demonstrate the role of free radicals in defibrillation injury.
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