Nitric oxide, NO, exerts numerous important regulatory functions in biological tissues and has been hypothesized to have a role in the pathogenesis of cellular injury in a number of diseases. It has been suggested that alterations in NO generation are a critical cause of injury in the ischemic heart. However, the precise alterations in NO generation which occur are not known, and there is considerable controversy regarding whether myocardial ischemia results in increased or decreased NO formation. Therefore, electron paramagnetic resonance studies were performed to directly measure NO in isolated rat hearts subjected to global ischemia, using the direct NO trap Fe-N-methyl-D-glucamine dithiocarbamate, which specifically binds NO giving rise to a characteristic triplet EPR spectrum with g = 2.04 and a = 13.2 G. While only a small triplet signal was observed in normally perfused hearts, a 10-fold increase in this triplet EPR spectrum was observed after 30 min of ischemia indicating a marked increase in NO formation and trapping. Measurements were performed as a function of the duration of ischemia, and it was determined that with increased duration of ischemia NO formation and trapping was also increased. NO generation was inhibited by the nitric oxide synthase blocker, N-nitro-L-arginine methyl ester (L-NAME), suggesting that NO was generated via nitric oxide synthase. Blockade of NO generation with L-NAME resulted in more than a 2-fold increase in the recovery of contractile function in hearts reperfused after 30 min of global ischemia. Thus, ischemia causes a marked duration-dependent increase of NO in the heart which may in turn mediate postischemic injury.

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