Endogenous NO is synthesized by a family of enzymes collectively called nitric oxide synthase (NOS), Figure 19–1. These intracellular enzymes are activated by calcium influx or by cytokines. Arginine, the primary substrate, is converted by NOS to citrulline and NO. Three forms of NO synthase are known: isoform 1 (bNOS, cNOS, or nNOS, a constitutive form found in epithelial and neuronal cells); isoform 2 (iNOS or mNOS, an inducible form found in macrophages and smooth muscle cells); and isoform 3 (eNOS, a constitutive form found in endothelial cells). NOS can be inhibited by arginine analogs such as NG-monomethyl-L-arginine (L-NMMA). Under some circumstances (eg, ischemia), NO may be formed from endogenous nitrate ion. NO is not stored in cells. Because it is a gas at body temperature, NO very rapidly diffuses from its site of synthesis to surrounding tissues. Drugs that cause endogenous NO release do so by stimulating its synthesis by NOS. Such drugs include muscarinic agonists, histamine, and certain other vasodilators (bradykinin, hydralazine).