Nitric oxide and reactive oxygen species in vascular injury

Nitric oxide (^.NO), a free radical species produced by several mammalian cell types, plays a role in regulation of vascular, neurological and immunological signal transduction and function. The role of ^.NO in cytotoxic events is acquiring increased significance. The high rate of production and broad distribution of sites of production of ^.NO, combined with its facile direct and indirect reactions with metalloproteins, thiols and various oxygen radical species, assures that ^.NO will play a central role in regulating vascular, physiological and cellular homoeostasis, as well as critical intravascular free radical and oxidant reactions. At the same time, there are contradictions as to whether ^.NO mediates or limits free-radical-mediated tissue injury, and uncertainty regarding its mechanisms of action. ^.NO has been portrayed as a pathogenic mediator during ischaemia-reperfusion, and inflammatory and septic tissue injury. In contrast, cell-, metal- and oxidant-induced lipoprotein oxidation events, as well as hepatic, cerebrovascular, pulmonary and myocardial inflammatory and ischaemia-reperfusion injury studies, show convincingly that stimulation of endogenous ^.NO production or exogenous administration of ^.NO-donating molecules can serve a protective role by inhibition of often oxidant-related mechanisms. The final outcome of toxic versus tissue-protective reactions of ^.NO will depend on several factors, including sites and relative concentrations of individual reactive species and their diffusion distances. The following sections address these issues and conclude with a proposal as to how ^.NO serves as a central regulator of oxidant reactions and diverse free radical-related disease processes.