Nitric oxide and peroxynitrite in lipid peroxidation

Nitric oxide (.NO) can mediate tissue protective reactions during oxidant stress, as well as toxic and tissue prooxidant effect. Nitric oxide regulates critical lipid membrane and lipoprotein oxidation events, by 1) contributing to the formation of more potent secondary oxidants from superoxide (i.e. peroxynitrite) and 2) termination of lipid radicals to possibly less reactive secondary nitrogen-containing products (LONO, LOONO) which are in part organic peroxynitrites and are expected to be produced in vivo. Relative rates of production and steady state concentrations of superoxide and NO and cellular sites of production will profoundly influence expression of the differential oxidant injury-enhancing and protective effects of .NO. Full understanding of the physiological roles of .NO, coupled with detailed insight into .NO regulation of oxygen radical-dependent reactions, will yield a more rational basis for the use of .NO donors for therapeutic purposes.

The double action of nitric oxide on free radical-mediated oxidations

Nitric oxide (.NO) is a free radical species synthesized by the oxidation of the amino acid L-arginine to citrulline, by the action of the enzyme nitric oxide synthase (NOS). Nitric oxide has been recognized as a key mediator of diverse physiological functions by direct interactions with critical biomolecules. In addition, nitric oxide can up- or downregulate biological oxidations and therefore modulate free radical mediated injury. Nitric oxide reaction with superoxide radical (O2.-) leads to the formation of a strong oxidizing and cytotoxic molecule, peroxynitrite anion (ONOO-). Peroxynitrite is a much stronger oxidant than any of its precursors being capable of oxidizing and/or nitrating a significant number of biomolecules including protein and nonprotein thiols, different amino acids, lipids and DNA; it has been shown that peroxynitrite is cytotoxic against bacteria, parasite and mammalian cells and has been proposed to participate in various pathological states. On the other hand, nitric oxide can also inhibit free radical reactions by a series of different mechanisms at the molecular level. Nitric oxide can bind to iron and inhibit metal-mediated free radical chemistry, it can terminate free radical processes via combination reactions with free radical intermediates and it can cause redirection of superoxide-mediated toxicity. The dual role of nitric oxide in free radical-mediated oxidations is clearly demonstrated in the oxygen radical-mediated lipid oxidation model, where low fluxes of nitric oxide promete lipid oxidation via formation of the reactive peroxynitrite while under excess nitric oxide, lipid peroxidation reactions are inhibited due to termination reactions between nitric oxide and lipid radicals.