Studies from many laboratories including ours have shown that NOS enzyme-independent NO formation occurs in biological systems. The NO formation is a generalized phenomenon which can occur in many biological tissues. In many disease states, such as ischemia or shock, where acidosis and marked hypoxia occur, this pathway becomes the major source of NO and the magnitude of NO generation can be much greater than that which would be formed by normal tissue concentrations of NOS. The substrate source of this NO formation is nitrite, rather than the NOS substrate and a number of pathways of nitrite reduction to NO was proposed, which include nitrite disproportionation, nitrite reduction by myo-globin [3,74-80], reduction by anoxic mitochondria [81,82], by xanthine oxidoreductase [2,4,37,40,41,83], by hemoglobin [84-90]. For in-depth critical review of hemoglobin/RBC mechanism NO production, look at Ref. [91]. Thus, these pathways may "substitute" NO production from NOS in pathophysiological conditions, when NOS function is impaired and conditions might be favorable for nitrite reduction. From first glance, nitrite should display cytoprotective effect, since knockout of endothelial NOS leaves the hearts of mice more sensitive to ischemic damage [92,93]. Protection should be similar to that observed with NO^ donors [94-97]. Indeed, in models of infarction, nitrite has been reported to protect against ischemia-reperfusion damage [98-101] in a way similar to NO donors. However, there is contradiction in literature. Studies including ours, in isolated rat hearts, suggest that nitrite-derived cellular NO (or its derivatives) may be contributing to damage [3,7,54,67,102,103] and, therefore, the effects of NO, derived from nitrite in myocardial injury are uncertain [95,96].

Potentially, there are great therapeutical benefits in control of the process of nitrite reduction; however present state of understanding of nitrite biochemistry does allow this control, thus demanding further efforts of research in this field.

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