Potentiation of Nitric Oxide

We evaluated whether the Mn(ii)-based SOD mimics could potentiate the levels of nitric oxide, a potent vasorelaxant. Superoxide reacts with nitric oxide in a diffusion-controlled manner to produce peroxynitrite. By catalyzing the dismu-tation of superoxide, SOD mimics would be expected to increase nitric oxide levels. The SOD mimic SC-52608 enhanced nitric oxide levels (as assessed by cyclic GMP activity) in rat lung fibroblasts in a dose-dependent manner. SC-52608 induced the relaxation of preconstricted rat aortic rings. The aortic ring relaxation was endothelium-dependent and inhibitable by a nitric oxide synthase inhibitor. Intravenous administration of SC-52608 into conscious rats resulted in a transient, dose-dependent decrease in blood pressure. The results are consistent with the SOD mimic SC-52608 potentiating levels of nitric oxide, which causes the observed relaxation of the aortic rings and the decrease in blood pressure. 

Anti-Inflammatory Activities of Manganese(II)-based Superoxide Mimics 

Superoxide is a product of activated polymorphonuclear leukocytes, such as the neutrophils, and has been proposed to be a mediator of inflammation. - We have evaluated the role of superoxide in acetic acid-induced, neutrophil-depend- 

Monosubstituted Mn(ii)-based complexes, which catalyze the dismutation of superoxide as shown by stopped-flow kinetic analysis, were tested for antiinflammatory activity in the mouse acetic acid-induced colitis model. As can be seen from Table 3, all of the SOD mimics are anti-inflammatory. Histological analysis of the colonic tissue confirmed these results. Of particular importance is the observation that Mn(ii) complexes that have no SOD activity, specifically the Mn(ii) dichloro complexes of 1,4,7,10,13-pentaazacyclohexadecane and 1,4,7,11,14-pentaazacycloheptadecane, do not protect against the colonic inflammation induced by acetic acid when the compounds are administered in-tracolonically at a dose of 30mgkg These results are consistent with a role for superoxide as a mediator of neutrophil-dependent inflammation. Consistent with this hypothesis is the observation that SC-52608 inhibits neutrophil-dependent inflammation induced by the intradermal administration of leukotriene 64, a neutrophil chemoattractant.  

As shown by histological analysis, SC-52608 and the other SOD mimics attenuate the acetic acid-induced colitis in mice by inhibiting the influx of neutrophils A possible mechanism for inhibition of the neutrophil infiltration 

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Muscara, M.N. and Wallace, J.L. (1999) Nitric oxide. V. Therapeutic potential of nitric oxide donors and inhibitors. American Journal of Physiology 276, G1313-1316. 

The ionization potential of nitric oxide is nine volts, and the ratio of molecules reacting to ion-pairs produced by an energy input of 8.6 calories is 1.6. In Table I it is seen that for a given input of cathode rays the reaction is 2.3 times as great for nitric oxide as for oxygen. The very low yield with carbon dioxide is in perfect agreement with Lind s results with alpha particles.13 Apparently the C02 ions recombine without chemical rearrangement. 

The way in which the oxidizing power of the hexafluorides increases with atomic number in the third transition series is demonstrated by the nature of the reactions with nitric oxide which are summarized in Figure 7. Since the ionization potential of nitric oxide is 62 kcal. mole lower than for oxygen it can reduce osmium hexafluoride to the quinquevalent and platinum to the quadrivalent... 

Armstrong, R. (2001) The physiological role and pharmacological potential of nitric oxide in neutrophil activation. Int. Immunopharmacol., 1, 1501-1512. 

Nakano, T., Asagoshi, K., Terato, H., Suzuki, T., and Ide, H. (2005) Assessment of the genotoxic potential of nitric oxide-induced guanine lesions by in vitro reactions with Escherichia coli DNA polymerase I. Mutagenesis, 20, 209-216. 

Therapeutically, PDE V inhibitors are being developed as potentiators of nitric oxide, or in conjunction with nitrovasodilators. In several in vitro and in vivo models, it has been demonstrated that zaprinast, WIN 58237, and other PDE V inhibitors can reinstate vasorelaxant responsiveness after tolerance to nitrovasodilators has occurred by preventing cGMP breakdown (Silver et al., 1991, 1994 Pagani et al., 1993). Clinically, this may represent a way to maintain patients on continuous nitroglycerin therapy. In pulmonary medicine, Zapol and colleagues (Rossaint et al.,... 

Hirst DG, Flitney FW (1997) The physiological importance and therapeutic potential of nitric oxide in the tumour-associated vasculature. In Bicknell R, Lewis CE, Ferrara N (eds) Tumour angiogenesis. Oxford University Press, Oxford, pp 153-167... 

Pervin, S, Singh, R., Gau, C.L., Edamatsu, H., Tamanoi, F., and Chaudhuri, G. (2001b). Potentiation of nitric oxide-induced apoptosis of MDA-MB-468 cells by famesyltransferase inhibitor implications in breast cancer. Cancer Res. 67(12), 4701 706. 

Bonavida, B., Khineche, S., Huerta-Yepez, S., and Garban, H. (2006). Therapeutic potential of nitric oxide in cancer. Drug Resist. Updat. 9,157-173. 

The reaction vessel (nitrator) is constructed of cast iron, mild carbon steel, stainless steel, or glass-lined steel depending on the reaction environment. It is designed to maintain the required operating temperature with heat-removal capabiUty to cope with this strongly exothermic and potentially ha2ardous reaction. Secondary problems are the containment of nitric oxide fumes and disposal or reuse of the dilute spent acid. Examples of important intermediates resulting from nitration are summarized in Table 3. 

The standard or formal potential of ferroin can be modified considerably by the introduction of various substituents in the 1,10-phenanthroline nucleus. The most important substituted ferroin is 5-nitro-l,10-phenanthroline iron(II) sulphate (nitroferroin) and 4,7-dimethyl-1,10-phenanthroline iron(II) sulphate (dimethylferroin). The former (E° = 1.25 volts) is especially suitable for titrations using Ce(IV) in nitric or perchloric acid solution where the formal potential of the oxidant is high. The 4,7-dimethylferroin has a sufficiently low formal potential ( e = 0.88 volt) to render it useful for the titration of Fe(II) with dichromate in 0.5 JVf sulphuric acid. 

Lonart G, Johnson KM Inhibitory effects of nitric oxide on the uptake of [3H]dopamine and [3H]glutamate by striatal synaptosomes. J Neurochem 63 2108—2117, 1994 Lovinger DM, White G Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons. Mol Pharmacol 40 263—270, 1991... 

Murphy S. Production of nitric oxide by glial cells regulation and potential roles in the CNS. Glia 2000 29 1-13. 

Kopelman et al.73 have prepared fiber optic sensors that are selective for nitric oxide and do not respond to most potential interferents. Both micro-and nanosensors have been prepared, and their response is fast (<1 s), reversible, and linear up to 1 mM concentrations of nitric oxide. The respective "chemistry" at the fiber tip was contacted with the sample, light was guided to the sample through the microfiber, and emitted light was collected by a microscope (without the use of fibers, however). 

K. Iijima, E. Henry, A. Moriya, A. Wirz, A.W. Kelman, and K.E.L. McColl, Dietary nitrate generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction. Gastroenterology 122, 1248-1257 (2002). 

Structure 20 and salts 115 and 116 are formed by condensation of nitric oxide with diethylmalonate. Arulsamy and Bohle warn that this new type of compact ring structure forms dense crystals, and compounds 20, 115, and 116 are potential energetic materials which decompose violently at high temperatures <2002AGE2089>. 

S-nitrosothiols (RSNO) have emerged as important species in the storage and transport of nitric oxide. As NO donors these S-N compounds have potential medical applications in the treatment of blood circulation problems. 

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. 

The NO/NO+ and NO/NO- self-exchange rates are quite slow (42). Therefore, the kinetics of nitric oxide electron transfer reactions are strongly affected by transition metal complexes, particularly by those that are labile and redox active which can serve to promote these reactions. Although iron is the most important metal target for nitric oxide in mammalian biology, other metal centers might also react with NO. For example, both cobalt (in the form of cobalamin) (43,44) and copper (in the form of different types of copper proteins) (45) have been identified as potential NO targets. In addition, a substantial fraction of the bacterial nitrite reductases (which catalyze reduction of NO2 to NO) are copper enzymes (46). The interactions of NO with such metal centers continue to be rich for further exploration. 

Zhang, Z., Naughton, D., Winyard, P. G., Benjamin, N., Blake, D. R., Symons, M. C. R., Generation of nitric oxide by a nitrite reductase activity of xanthine oxidase a potential pathway for nitric oxide formation in the absence of nitric oxide synthase activity. Biochem. Biophys. Res. Commun. 249 (1998), p. 767—772... 

Sexton, D. J., Muruganandam, A., McKenney, D. J., Mutus, B., Visible light photochemical release of nitric oxide from S-nitrosoglutathione potential photochemotherapeutic applications. Photochem. Photobiol. 59 (1994), p. 463-467... 

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