During recent years, research has focused on an amino acid product the effects of which are known, but which has not been unequivocally characterized to date: endothelium-derived relaxing factor (EDRF). At this point, it is assumed that EDRF is probably identical with nitrogen monoxide (NO) or with a more stable NO-containing substance like S-nitrosocysteine (also called NO-R).
The enzyme responsible for NO synthesis in endothelial cells, NO synthase (NOS), has since been cloned and the encoding gene identified. In the brain, there is one isoform (type I); another (type II) was found in macrophages. The endothelial isoform (type III) is predominantly membrane-bound. Like all NO synthases, it uses Arg as a substrate (A). In addition, it needs molecular O2, Ca-calmodulin, as well as NADPH, BH4, FAD, and FMN as cofactors. NOS activity and hence NO release can be stimulated by a series of agonists: acetylcholine, histamine, serotonin, ADP, substance P, bradykinin, and generally through an increase in intracellular Ca2+ concentrations. Expression of this enzyme is, among others, induced by shearing forces along the endothelial surface.
The functional significance of EDRF for various organ systems is a subject of intense discussion. Until recently, endothelial NO synthesis was discussed only with regard to its relaxing effects on vascular tone (B). Vascular tone is based on the activation of guanylate cyclase with subsequent cGMP increase in muscle cells. Nitroglycerin treatment, which has been used for angina pectoris attacks for a long time, is based on the same effective principle, which is why EDRF (NO) has also been called an endogenous nitro-vasodilator. Today, the NO system is considered to play the role of physiological antagonist to the sympathetic nervous system and to the renin-angiotensin system in vascular tone regulation. Furthermore, NO is a potent inhibitor of thrombocyte aggregation and leukocyte adhesion to endothelial surfaces. Should platelet aggregation occur nevertheless, ADP and serotonin released from thrombo-cytes trigger NOS activation, causing increased NO release. NO also inhibits
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