The physiology and pathophysiology of the nitric oxide superoxide system

The endothelium modulates vascular tone by producing vasodilator vasoconstrictor substances. Of these, the most well characterized and potentially important are (NO)-N-. and O-.(2)-. These small molecules exhibit opposing effects on vascular tone, and chemically react with each other in a fashion which negates their individual effects and leads to the production of potentially toxic substances. These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis. (NO)-N-. is produced in endothelial cells by an enzyme termed nitric oxide synthase. The endothelial (NO)-N-.-synthase is activated when the Intracellular level of calcium is increased. This occurs in response to neurohormonal stimuli and in response to shear stress. Acetylcholine and substance P are examples of neurohumoral substances that are able to stimulate the release of nitric oxide and to assess endothelial regulation of vasomotor lone, Importantly, the vasodilator potency of nitric oxide released by the endothelium is abnormal in a variety of diseased states such as hypercholesterolemia, atherosclerosis and diabetes mellitus. This may be secondary to decreased synthesis of nitric oxide or increased degradation of nitric oxide due to superoxide anions. More recent experimental observations demonstrate increased production of superoxide in atherosclerosis, diabetes mellitus and high renin hypertension suggesting that endothelial dysfunction in these states is rather secondary to increased (NO)-N-. metabolism rather than due to decreased synthesis of (NO)-N-.. Superoxide rapidly reacts with nitric oxide to form the highly reactive intermediate peroxynitrite (ONOO-). Peroxynitrite can be protonated to form peroxynitrous acid which in turn can yield the hydroxyl radical (OH.). These reactive species can oxidize lipids, damage cell membranes, and oxidize thiol groups. (NO)-N-. given locally, exerts potent antiatherosclerotic effects such as inhibition of platelet aggregation, inhibition of adhesion of leukocytes and the expression of leukocyte adhesion molecules. It is important to note, however, that in-vivo treatment with (NO)-N-. (via organic nitrates) increases rather than decreases oxidant load within endothelial cells. it remains therefore questionable whether systemic treatment with (NO)-N-. may have antiatherosclerotic properties or whether (NO)-N-. may initiate or even accelerate the atherosclerotic process.