Antioxidants and the bioactivity of endothelium-derived nitric oxide

Time for primary view 21 days. Over the past two decades, investigators have increasingly recognized the importance of the endothelium as a central regulator of vascular homeostasis. In 1980, Furchgott and Zawadzki 1 reported that acetylcholine-mediated relaxation of isolated aortic tissue is dependent on release of an ‘endothelium-derived relaxing factor’. Subsequent studies by Ignarro and colleagues identified this factor as nitric oxide (NO) 2 or a closely related NO product 3. In addition to regulating vascular tone, it is now appreciated that endothelium-derived NO also acts to inhibit platelet activity, vascular smooth muscle cell growth, and adhesion of inflammatory cells to the endothelial surface 4. Loss of the bioactivity of endothelium-derived NO plays a critical role in the pathogenesis of a number of disease states including atherosclerosis and its risk factors 5. A large body of work suggests that the impaired NO action in atherosclerosis is related to increased oxidative stress in the vascular wall 6. Since oxidative stress may be defined as an excess of oxidants relative to antioxidant defenses 7, investigators were prompted to examine the possibility that increasing antioxidant availability would restore NO-dependent responses. This article will review the effects of antioxidants on NO bioactivity and the clinical implications of these observations. NO is synthesized in endothelial cells from l-arginine by the endothelial isoform of NO synthase (eNOS), which is the product of the NOS3 gene 8. eNOS is constitutively expressed and located to caveolae in the plasma membrane. When bound to caveolin, eNOS is catalytically inactive. In the presence of calcium, calmodulin displaces caveolin and binds to eNOS, and thereby activates the enzyme 8. Thus, NO production by endothelial cells is stimulated by factors that increase intracellular calcium concentration including receptor-dependent agonists like acetylcholine, bradykinin, substance P, and … * Corresponding author. Boston Medical Center, 88 East Newton Street, Boston, MA 02118, USA. Tel.: +1-617-638-8701; fax: +1-617-638-8712 jvitaatbu. edu