Non-enzymatic nitric oxide synthesis in biological systems

Nitric oxide (NO) is an important regulator of a variety of biological func tions, and also has a role in the pathogenesis of cellular injury. It had b een generally accepted that NO is solely generated in biological tissues by specific nitric oxide synthases (NOS) which metabolize arginine to citrull ine with the formation of NO. However, NO call also be generated in tissues by either direct disproportionation or reduction of nitrite to NO under th e acidic and highly reduced conditions which occur in disease states, such as ischemia. This NO formation is not blocked by NOS inhibitors and with lo ng periods of ischemia progressing to necrosis, this mechanism of NO format ion predominates. In postischemic tissues, NOS-independent NO generation ha s been observed to result in cellular injury with a loss of organ function. The kinetics and magnitude of nitrite disproportionation have been recentl y characterized and the corresponding rate law of NO formation derived. It was observed that the generation and accumulation of NO from typical nitrit e concentrations found in biological tissues increases 100-fold when the pH falls from 7.4 to 5.5. It was also observed that ischemic cardiac tissue c ontains reducing equivalents which reduce nitrite to NO, further increasing the rate of NO formation more than 40-fold. Under these conditions, the ma gnitude of enzyme-independent NO generation exceeds that which call be gene rated by tissue concentrations of NOS. The existence of this enzyme-indepen dent mechanism of NO formation has important implications in our understand ing of the pathogenesis and treatment of tissue injury. (C) 1999 Elsevier S cience B.V. All rights reserved.