Nitric oxide plays a major role in oxygen-derived free radical generation in defibrillation and reperfusion injury; nitric oxide reacts with the superoxide radical to form peroxynitrite, which is toxic in itself and also forms further strongly oxidizing species resembling the hydroxyl radical. By limiting nitric oxide availability, nitric oxide synthase inhibitors may limit this process and ameliorate defibrillation/ reperfusion toxicity. Magnesium also has a role to play: it can also limit oxygen-derived free radical generation via its actions as a """"""""physiologic calcium antagonist"""""""", which include limiting the formation and release of endothelial-derived nitric oxide. The combination of NO synthase inhibitors and magnesium may be particularly effective. We will emphasize the direct detection of ascorbate radical to examine a series of testable hypotheses. Our overall hypotheses that the nitric oxide/superoxide/peroxynitrite pathway is a major source of free radicals that contribute to both defibrillation and reperfusion injury. Modulation of nitric oxide will alter bury from defibrillation and ischemia-reperfusion. The specific, testable hypotheses are: 1) Nitric oxide synthase inhibitors, by limiting the NO available to react with superoxide (forming peroxynitrite), reduce free radical generation and thereby ameliorate defibrillation and reperfusion injury. This preserves left ventricular function after defibrillation and/or reperfusion (i.e., less """"""""stunning""""""""). 2) Conversely, NO donors (SIN-1), by providing more NO substrate to react with superoxide and form toxic peroxynitrite, will increase free radical generation after defibrillation and/or reperfusion, worsening left ventricular function. 3) Magnesium, which we have already shown to reduce free radical generation in reperfusion injury, will be similarly cardioprotective in ameliorating defibrillation injury, reducing radical generation and deserving ventricular function. 4) The combination of nitric oxide synthase inhibitors and magnesium, which alter two different mechanisms/pathways to limit free radical generation, will be especially cardioprotective, ameliorating defibrillation and reperfusion injury.
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