In 1980, Furchgott and Zawadzki showed that the endothelial lining of blood vessels was essential for the vasorelaxant effect of acetylcholine and showed that this effect was mediated by release of an endothelial substance that relaxed vascular smooth muscle. This substance later became known as endothelium-derived relaxing factor (EDRF).’Over the next several years, the pharmacological and chemical properties of EDRF were characterized, but the identity of EDRF remained unknown. In 1987, two groups working independently using chemical assay and bioassay showed that NO was released from vascular endothelial cells and that the effects of NO and EDRF were indistinguishable. 3re EDRF is now thought to be endothelium-derived NO. NO has properties that make it unlike any known biologic mediator.’It is a colorless gas that is slightly soluble in water. In dilute solution, NO has a half-life of-40 seconds because of rapid oxidation to inorganic nitrite and nitrate. NO is also destroyed by superoxide anion. Superoxide dismutase protects NO from breakdown by superoxide anion.‘*’NO binds to oxyhemoglobin and other heme-containing proteins; its biologic actions are rapidly terminated by binding to oxyhemoglobin. 3* 6* 10 In biologic systems, NO has a half-life of< 5 seconds. 3

Vascular endothelial cells synthesize NO enzymatically from the terminal guanidine nitrogen atom of L-arginine (Figure 1).‘1*‘2 The activity of the enzyme NO synthase is dependent on NADPH, calcium, and calmodulin.‘2~ 13 The enzymatic synthesis of NO can be competitively inhibited by structural analogs of L-arginine, such as NG-monomethyl+ arginine(L-NMMA) and NC-nitro+ arginine(L-NNA). 14-‘” NO is very lipophilic and can readily permeate biologic membranese7 NO formed by endothelial cells is thought to diffuse into the cytosol of the adjacent vascular smooth muscle cells where it binds to soluble guanylate cyclase, a cytosolic heme-containing protein. 17 Binding of NO to this enzyme increases production of S-cyclic guanosine monophosphate (cGMP) with subsequent relaxation of smooth mus-