NO at Work

Harald H. H. W. Schmidt and Ulrich Walter Medizinische Universitatsklinik Wiirzburg Klinische Biochemie und Pathobiochemie Versbacher Strasse 5 D-97078 Wiirzburg Federal Republic of Germany Nitroglycerine has been used for over a century to treat coronary heart disease, and it has long been suggested that humans synthesize oxides of nitrogen (Mitchell et al., 1916). These observations have recently been brought into focus by the demonstration that endogenous nitric oxide (NO) regulates mammalian blood vessels and other systems (Moncada and Higgs, 1991) such that virtually every mammalian cell is under the influence of NO. The three “classics” of NO-mediated functions-endothelium- dependent relaxation (Furchgott and Zawadzki, 1980) neurotransmission (Garthwaite et al., 1988; Gillespie et al., 1989) and cell-mediated immune response (Nathan and Hibbs, 1991)-have suggested principles for the mode of action of NO and for its functions. General Principles Networks In many systems, NO derives from two or more different cellular sources, forming networks of paracrine communi- cation (Figure 1). For example, we now know that vascular and bronchial NO originates not only from endothelial cells, where it iscalledendotheliumderived relaxing factor (EDRF), but also from adventitial nerves and epithelial cells (Schmidt et al., 1992a; Wilcox et al., 1992), where it mediates endothelium-independent smooth muscle relax- ation. Neurons use NO to regulate transmitter release of adjacent neurons (Meffert et al., 1994) and also to match cerebral blood flow with neuronal activity; similarly, bron- chial epithelial and endothelial cells use NO to match venti- lation and perfusion (Gaston et al., 1994). Macula densa renal tubular epithelial cells release NO to dilate the neigh- boring afferent artery and increase glomerular filtration (Wilcox et al., 1992). NO Toxicity NO is a double-edged sword (Table l), beneficial as a messenger or modulator and for immunologic self-defense, but potentially toxic. In several different scenarios (Figure 2) with factors such as oxidative stress, generation of reactive oxygen intermediates (ROls), and deficient anti- oxidant systems, NO switches from friend to foe. A pre- dominant mechanism by which this occurs is through the diffusion-limited reaction of NO with superoxide to gener- ate peroxynitrite (Beckman et al., 1990) which may modu- late signaling functions of NO (Gaston et al., 1994; Moro et al., 1994) and is directly cytotoxic (Beckman, 1991). e.g., by causing extensive protein tyrosine nitration (Beck- man et al., 1994).