Superoxide anion nitric oxide

Fig. 2. Interplay among superoxide anion, nitric oxide, and eicosanoids in high oxidative stress. The biological function of nitric oxide in target cells is influenced by the cellular redox state. In increased oxidative stress, which results in an oxidizing environment, NO readily form free radicals, including the highly reactive peroxynitrite (OONO ). Peroxynitrite can influence eicosanoid synthesis by interfering with different enzyme systems of the arachidonic acid cascade. Increased free radicals may also catalyze nonenzymic peroxidation of membrane PUFA (e.g., arachidonic acid), resulting in increased production of isoprostanes that possess potent vasoconstrictor activity. PLA, phospholipase NO, nitric oxide NOS, nitric oxide synthase NADPH oxidase, vascular NAD(P)H oxidase 02 , superoxide anion PUFA, polyunsaturated fatty acids EPA, eicosapentaenoic acid DHA, docosahexaenoic acid COX, cyclooxygenase PGI2 synthase, prostacyclin synthase.

The direct reaction of superoxide with nitric oxide is only one of at least four possible pathways that can form peroxynitrite (Fig. 40). For example, superoxide should also efficiently reduce nitrosyldioxyl radical to peroxynitrite. Alternatively, nitric oxide may be reduced to nitroxyl anion, which reacts with oxygen to form peroxynitrite. Superoxide dismutase could even catalyze the formation of peroxynitrite, since reduced (Cu or cuprous) superoxide dismutase can reduce nitric oxide to nitroxyl anion (Murphy and Sies, 1991). Thus, superoxide might first reduce superoxide dismutase to the cuprous form, with nitric oxide reacting with reduced superoxide dismutase to produce nitroxyl anion. A fourth pathway to form peroxynitrite is by the rapid reaction of nitrosonium ion (NO" ) with hydrogen peroxide. This is a convenient synthetic route for experimental studies (Reed et al., 1974), but not likely to be physiologically relevant due to the low concentrations of hydrogen peroxide and the difficulty of oxidizing nitric oxide to nitrosonium ion. 

Clancy, R.M., Leszczynska-Piziak, J. and Abramason, S.B. (1992). Nitric oxide inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J. Clin. Invest. 90, 1116-1121. 

Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A. and Freeman, B.A. (1990). Apparent hydroxyl radical formation by peroxynitrite implications for endothelial cell injury from nitric oxide and superoxide anion. Proc. Natl Acad. Sci. USA 87, 1620-1624. 

Results of a more recent series of investigations suggest that lead may cause hypertension in rats by increasing reactive oxygen species, which act as vasoconstrictors, and decreasing nitric oxide, a vasodilator released by the endothelium. The reactive oxygen species may be the hydroxyl radical, and did not appear to be the superoxide anion (Ding et al. 1998). 

K.Z. Kedziora-Kornatowska, M. Luciak, J. Blaszczyk, and W. Pawlak, Effect of aminoguanidine on the generation of superoxide anion and nitric oxide by peripheral blood granulocytes of rats with strep-tozotocin-induced diabetes. Clin. Chim. Acta 278, 45-53 (1998). 

C. Privat, S. Trevin, F. Bedioui, and J. Devynck, Direct electrochemical characterization of superoxide anion production and its reactivity toward nitric oxide in solution. J. Electroanal. Chem. 436, 261—265 (1997). 

At present, new developments challenge previous ideas concerning the role of nitric oxide in oxidative processes. The capacity of nitric oxide to oxidize substrates by a one-electron transfer mechanism was supported by the suggestion that its reduction potential is positive and relatively high. However, recent determinations based on the combination of quantum mechanical calculations, cyclic voltammetry, and chemical experiments suggest that °(NO/ NO-) = —0.8 0.2 V [56]. This new value of the NO reduction potential apparently denies the possibility for NO to react as a one-electron oxidant with biomolecules. However, it should be noted that such reactions are described in several studies. Thus, Sharpe and Cooper [57] showed that nitric oxide oxidized ferrocytochrome c to ferricytochrome c to form nitroxyl anion. These authors also proposed that the nitroxyl anion formed subsequently reacted with dioxygen, yielding peroxynitrite. If it is true, then Reactions (24) and (25) may represent a new pathway of peroxynitrite formation in mitochondria without the participation of superoxide. 

Pineda-Zavela, A.P. et al., Nitric oxide and superoxide anion production in monocytes from children exposed to arsenic and lead in region Lagunera, Mexico, Toxicol. Appl. Pharmacol. 198, 283, 2004. 

N. K., Palmer, R. M., Whittle, B. J., Moncada, S., Synthesis of nitric oxide from L-arginine by neutrophils. Release and interaction with superoxide anion, Biochem. J. 261 (1989), p. 293-296... 

Macrophages from endrin-exposed rats or mice showed an increase in the concentration of nitric oxide (Akubue and Stohs 1992 Bagchi et al. 1993d) and increased chemiluminescence and production of superoxide anion (Bagchi et al. 1993a). Based on these results and those described above for hepatic... 

Besides LPS, other particulate and soluble agents are known to stimulate the formation of eicosanoids, e.g. PGE2, PGD2, and thromboxane [57]. These agents also elicit nitric oxide and superoxide anion formation, which may help to destroy phagocytosed microorganisms or particles [58]. 

Nitric oxide also reacts with superoxide to form the stable peroxynitrite anion, which, however, decomposes on protonation [23]. 

It has now been more than a decade since Beckman and his collaborators first disclosed their observations that the combination of two relatively unreactive, yet biologically relevant free radicals, superoxide anion and nitric oxide, would produce a new highly reactive physiologically important reagent. The interaction of these two presumably innocuous species appears to be diffusion controlled and produces a thermally stable peroxy anion, peroxynitrite (equation 1). ... 

Superoxide (02 ) is the one electron reduced form of molecular oxygen. It reacts irreversibly and at close to the diffusion limit with nitric oxide (Huie and Padmaja, 1993) to form the powerful oxidant peroxynitrite anion (ONOO ). 

The reaction of nitric oxide with superoxide dismutase is a simple reversible equilibrium, whereas the catalytic cycle with superoxide involves a two step sequence. Consequently, superoxide dismutase may be reduced by superoxide and then react with nitric oxide to form nitroxyl anion. Nitroxyl anion may react with molecular oxygen to form peroxynitrite anion (ONOO"). 

Four routes to form peroxynitrite from nitric oxide. The reaction of nitric oxide with superoxide is only one mechanism leading to the formation of peroxynitrite. Supetoxide could also reduce the nitrosyidioxyl radical. If nitric oxide is directly reduced to nitroxyl anion, it will react with molecular oxygen to form peroxynitrite. At acidic pH, nitrite may form nitrous acid and nitrosonium ion, which reacts with hydrogen peroxide to form peroxynitrite. 

Murphy, M. E., and Sies, H. (1991). Reversible conversion of nitroxyl anion to nitric oxide by superoxide dismutase. Proc. Nad. Acad. Sci. U.S.A. 88, 10860-10864. 

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