No

Biomolecule adducts

PSNO2, ArNO2

cGMP independent cGMP dependent

Fig. 3. (A) The listed drugs range in oxidation number at nitrogen from +5 to -3. All chemical species listed as mediators of NO bioactivity are implicated in the metabolism or activity of nitrogen oxides. Conversion of a drug to a mediator of the same oxidation number does not require redox activation. Several mediators, or RNOS, undergo reaction with biomolecules yielding a range of potential products. (B) Nitrates, in the highest oxidation state, can carry out nitroxidation and nitrosation without the intermediacy of NO, either directly or via intermediates such as nitrites. cGMP-independent activity includes that mediated via nitrosation, nitroxidation, and radical scavenging by NO.

P2NNO, PSNO

This sequence requires several NO equivalents, consumes O2, and generates RNOS: higher concentrations of NO are associated with formation of the oxidizing, cytotoxic RNOS, NO2, and peroxynitrite:

NO + O2- ^ ONOO-3ONOO- + H+ ^ NO2 + HO^ + 2NO-or 3ONOO- + CO2 ^ NO2 + CO3- + 2NO-

The corollary of this argument is that nitrates are not predicted to manifest identical physiological actions to other agents and drugs that are generally classed as true donors of free NO.

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