NITRIC-OXIDE SYNTHASES IN THE CARDIOVASCULAR-SYSTEM

The endothelium-derived relaxing factor that mediates the endothelium- dependent vasodilatation first observed in 1980 has been identified as nitric oxide (NO). In addition to the endothelium, NO is formed in ot her cells such as neuronal cells of the brain (where it mediates synap tic plasticity), peripheral nonadrenergic noncholinergic (NANC) nerves (where it acts as an atypical neurotransmitter relaxing vascular and nonvascular smooth muscle), and various specialized epithelial cells. other cell types such as macrophages and smooth muscle cells can be in duced with bacterial endotoxin and/or cytokines to synthesize large am ounts of the radical At low concentrations, NO is an inter- and intrac ellular messenger molecule whose target enzyme is the soluble isoform of guanylyl cyclase. At high concentrations, the NO radical has cytost atic effects on parasitic microorganisms and tumor cells. In the vascu lar system, endothelium-derived NO is a physiologically significant va sodilator and inhibitor of platelet aggregation and adhesion. NANC ner ve-derived NO may also contribute to vasodilatation. In addition, NO c an prevent leukocyte adhesion to the endothelium by interfering with t he adhesion molecule CD11/CD18, and NO has been shown to inhibit the p roliferation of vascular smooth muscle cells. In sepsis and during cyt okine therapy, a different NOS is induced in the vascular wall (presum ably in smooth muscle cells) where it synthesizes large amounts of NO that contribute to the massive vasodilatation and shock.