A representation of nitric oxide (NO)/hemoglobin reactions in the arterial microcirculation. Reactions that appear to predominate under physiologic conditions (center), as well as pathologic lesions due to hemolysis (right) and results of high or pharmacologic levels of NO (left) are indicated. Under basal conditions, NO (a short-lived free radical) produced by endothelial NO synthase enzymes largely diffuses into surrounding smooth muscle to activate soluble guanylyl cyclase (sGC) to produce cyclic GMP and regulate vascular tone. The interactions of NO with red cells under these conditions seem to be limited by several barriers to diffusion, at the red cell membrane and streaming of plasma near the endothelium. With hemolysis (or with administration of hemoglobin-based blood substitutes), cell-free oxyhemoglobin acts as an efficient scavenger of NO, causing vasoconstriction and perhaps pathological organ conditions. When endogenous NO levels become very high, or when it is administered by inhalation or by infusion of nitrite ions or other NO donors, reactions in the plasma and within erythrocytes become very important. Reactions with oxygen will tend to oxidize NO to nitrite and nitrate. Reactions with plasma molecules will form thiol (SNO) compounds and other species; plasma nitrite can also be reduced by endothelial xanthine oxidoreductase (XOR) to NO. Small amounts of SNO-Hb form, but its function is not at all clear. Nitrite from the plasma may enter the red cell or be formed in the cell itself, where reactions with hemoglobin and the ascorbate cycle can reduce it to NO. Although the prevalent reactions with oxyhemoglobin to form methemoglobin and nitrate tend to destroy NO bioactivity, these other reactions may allow its preservation and modulation for physiologic functions. Adapted from Schechter and Gladwin (N Engl J Med. 2003;348:1483-1485), with permission. Illustration by Alice Y. Chen.