Enzyme-independent formation of nitric oxide in biological tissues

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Abstract
The gaseous free radical nitric oxide (NO˙) is an important regulator of a variety of biological functions and also has a role in the pathogenesis of cellular injury. It has been generally accepted that NO˙ is solely generated in biological tissues by specific nitric oxide synthases, NOSs, which metabolize arginine to citrulline with the formation of NO˙. We report that NO˙ can also be generated in the ischaemic heart by direct reduction of nitrite to NO˙ under the acidotic and highly reduced conditions that occur. This NO˙ formation is not blocked by NOS inhibitors, and with long periods of ischaemia progressing to necrosis, this mechanism of NO˙ formation predominates. We observe that enzyme-independent NO˙ generation results in myocardial injury with a loss of contractile function. The existence of this enzyme independent mechanism of NO˙ formation has important implications in our understanding of the pathogenesis and treatment of tissue injury.