Endogenous Nitrates And Nitrites

In mammalian systems, nitrates and nitrites theoretically may be formed as products of the reactions of RNOS: nitrates may be produced by nitrating RNOS or by the action of nitrosating and nitroxidizing RNOS; nitrites may be produced by nitrosating RNOS. Nitrates and nitrites have been proposed as endogenous products of the reactions of NO, peroxynitrite, or NO2 with lipids, and other biomolecules, under oxidative and nitrosative stress. In particular, nitrite and nitrate derivatives of lipids were proposed to result from the antioxidant activity of NO towards lipid peroxyl radicals [56-59]. The capacity of NO2 to react via H atom abstraction and via radical addition underlies its reactions with olefins, including polyunsaturated fatty acids, leading to formation of nitro, nitroso (nitrite), and nitrooxy (nitrate) derivatives, under both anaerobic conditions and in the presence of O2 [60-64]. Both homolytic decomposition pathways for peroxynitrite and oxidation of NO- by enzymes such as peroxidase represent physiological sources of NO2 [60,64-66].

NO is an efficient antioxidant acting via lipid peroxyl radical chain termination. The potential for formation of nitrite and nitrate products as natural components of lipid membranes from the trapping of peroxyl radicals by NO is apparent [58,67-69].

This possibility begs the question as to whether nitrites and nitrates would exacerbate or attenuate lipid peroxidation. Study of the effects on lipid peroxidation of a variety of nitrates, nitrites, and NONOate NO donors in rat brain synaptosomes and in model systems demonstrated that true donors of free NO inhibited lipid peroxidation [70-72]. Thus, classical nitrates such as GTN had no effect in contrast to novel NO releasing nitrates. Furthermore, the alkyl nitrites studied showed an antioxidant capacity deriving from NO release and from additional antioxidant mechanisms.

Trapping of lipid peroxyl radicals by NO is anticipated to form a number of potential nitrogen oxide derivatives, however, to date, the only characterized nitrated lipid is nitroli-noleic acid, a nitroalkane [73]. This nitrolipid is reported to contain a P-hydroxynitroalkane moiety similar to that formed on treatment of olefins with peroxynitrite (Fig. 4) [74]. This nitrolipid has been reported to be a store of NO bioactivity; the proposed mechanism of NO release involves formation of a nitronic acid intermediate followed by NO release from a nitrosoalkane (Fig. 4) [73]. Nitrosoalkanes and related C-nitroso compounds have recently been reviewed and several are known to be sources of NO bioactivity [75]. Interestingly, a class of nitroalkane NO-donor drugs previously developed by Fujisawa from oxidative nitrosation of microbial broths, are likely to release NO by a pathway almost identical to nitrolinoleic acid, via a nitronic acid intermediate and a nitrosoalkane NO progenitor (Fig. 4) [76]. These nitroalkanes are commercially available as the NOR family of NO donors.

A. Formation of nitrolipids

1. lipid peroxidation and scavenging by NO

2. lipid nitration

H O2 OO OONO

lipid olefin oxidation termination

B. NO release from nitrolipi

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