Nitric oxide (NO) is a gaseous signaling molecule that readily diffuses across cell membranes and regulates a wide range of physiologic and pathophysiologic processes including cardiovascular, inflammatory, and neuronal functions. Nitric oxide should not be confused with nitrous oxide (N2O), an anesthetic gas; nor with nitrogen dioxide (NO2), a toxic pulmonary irritant gas.
DISCOVERY OF ENDOGENOUSLY GENERATED NITRIC OXIDE
Because NO is an environmental pollutant, the finding that NO is synthesized by cells and activates specific intracellular signaling pathways was unexpected. The first indication that NO is generated in cells came from studies of cultured macrophages, which showed that treatment with inflammatory mediators, such as bacterial endotoxin, resulted in the production of nitrate and nitrite, molecules that are byproducts of NO breakdown. Similarly, injection of endotoxin in animals elevated urinary nitrite and nitrate.
The second indication came from studies of vascular regulation. Several molecules, such as acetylcholine, were known to cause relaxation of blood vessels. This effect occurred only when the vessels were prepared so that the luminal endothelial cells covering the smooth muscle of the vessel wall were retained (see Figure 7–5). Subsequent studies showed that endothelial cells respond to these vasorelaxants by releasing a soluble endothelial-derived relaxing factor (EDRF). EDRF acts on vascular muscle to elicit relaxation. These findings prompted an intense search for the identity of EDRF.
At the same time, it was observed that administration of NO or organic nitrates, which are metabolized to NO, elicit a variety of effects including inhibition of platelet aggregation and vasorelaxation. Comparison of the biochemical and pharmacologic properties of EDRF and NO provided initial evidence that NO is the major bioactive component of EDRF. These findings also made it clear that exogenously applied NO and NO-releasing compounds (nitrates, nitrites, nitroprusside; see Chapters 11 and 12) elicit their effects by recruiting physiologic signaling pathways that normally mediate the actions of endogenously generated NO.
NITRIC OXIDE SYNTHESIS, SIGNALING MECHANISMS, & INACTIVATION
NO, written as NO• to indicate an unpaired electron in its chemical structure, or simply NO, is a highly reactive signaling molecule that is made by any of three closely related NO synthase (NOS, EC 22.214.171.124) isoenzymes, each of which is encoded by a separate gene and named for the initial cell type from which it was isolated (Table 19–1). These enzymes, neuronal NOS (nNOS or NOS-1), macrophage or inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3), despite their names, are each expressed in a wide variety of cell types, often with an overlapping distribution.
TABLE 19–1Properties of the three isoforms of nitric oxide synthase (NOS).