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How is this possible? The reaction of NO with superoxide (O 2 Paradoxically, the production of the same molecule can become highly damaging to the same neurons within a few minutes during pathological challenges as occur after cerebral ischemia.

In addition, NO can be produced for 80 years by neurons in human brain without overt toxicity. Inhaling low concentrations of gaseous NO is approved by the Food and Drug Administration for the treatment of persistent pulmonary hypertension of the newborn ( 53, 411, 412, 593, 680, 681, 1143). Although NO is often described as highly toxic and reactive, it is not. The biological production of NO is also important for nonspecific host defense, but NO itself is unlikely directly to kill intracellular pathogens and tumors. Nitric oxide (NO) is an omnipresent intercellular messenger in all vertebrates, modulating blood flow, thrombosis, and neural activity. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms.

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Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion.

Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine.