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-endotheliumdependent 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 communication (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 relaxation. 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, bronchial epithelial and endothelial cells use NO to match ventilation and perfusion (Gaston et al., 1994). Macula densa renal tubular epithelial cells release NO to dilate the neighboring afferent artery and increase glomerular filtration (Wilcox et al., 1992).