Nitrates As Nitric Oxide Mimetics

In experiments in blood vessels that exploited the sensitivity of ESR (electron spin resonance) detection using a tissue permeable spin trap, NO was measured from endogenous production and from addition of an exogenous nitrosothiol [47-49]. However, using the same methodology, NO was not detected from pharmacologically relevant concentrations of GTN and ISDN. At much higher, suprapharmacological concentrations of nitrates (>10 ^M), detection of NO was possible. A second recent study failed to detect NO in aortic tissue treated with GTN at pharmacological concentrations; in this study, a fluorescent indicator was used that responded to nitrosation of diaminorhodamine in the presence of NO [50,51]. In contrast, intracellular NO was detected using this fluorescent probe from a variety of agents that elevate NO: acetylcholine (that activates endothelial NOS; eNOS), and three separate NO donors (from different chemical classes). These agents were used at comparable concentrations to GTN and produced concentration-dependent responses. In addition, all four agents inhibited mitochondrial O2 consumption, an effect associated with the interaction between NO and cytochrome c oxidase, and of potential pathophysiological significance. Again, in contrast, GTN was reported to have no effect on mitochondrial respiration. In the same study, vasorelaxation induced by all agents was inhibited by the "NO trap" oxy-haemoglobin (oxyHb), although vasorelaxation by GTN was inhibited much less by oxyHb than by all other agents. In a third study reporting measurement of coronary vascular resistance in the isolated Langendorf heart, oxyHb did not inhibit the relaxation induced by GTN [49,52].

Several researchers use phrases such as "delivery of NO bioactivity." In part, this recognizes the problematic data supporting the exclusive and simplistic sequence:

nitrates ^ NO ^ bioactivity

But what is NO bioactivity, or bioactive NO? Part of the problem is that NO to a chemist is a very specific chemical formula for a nitrogen-monoxide-free-radical species, whereas to some others, NO is a catholic symbol incorporating various nitrogen oxides and sometimes related thiol adducts. The biological activity of NO may be exerted by NO coordination to the Fe2+ -haem of soluble guanylyl cyclase (sGC) and elevation of intracellular cGMP, and also through cGMP-independent mechanisms via a variety of other possible reactive nitrogen oxide species (RNOS) (Fig. 2). Furthermore, the oxidative metabolism of NO and RNOS is intimately linked with a number of factors: oxygen and thiol concentrations; cellular redox state; redox active transition metal ions; and microenvironment [53]. The chemical reactions that connect true NO to the various RNOS are discussed more extensively in Chapter 1. The reactions of NO and RNOS with endogenous thiols have particular relevance (discussed in nitrogen oxide species high oxidation number A low oxidation number may interconvert in redox reactions -may initiate the following reactions with biomolecules:

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