Folate and Nitrate-Induced Endothelial Dysfunction

Abstract

Organic nitrates have served as mainstays of therapy for the treatment of coronary artery disease for more than a century. Their use, however, has been complicated by unwanted side effects, including hypotension and the development of nitrate tolerance. Nitrate tolerance is a term used to define tachyphylaxis to nitrates with long-term use. The mechanisms of nitrate tolerance have been debated for some time and include depletion of thiols, an increase in venous blood volume limiting vasodilator responsiveness, and increased generation of reactive oxygen species. See p 1119 Recent observations provide evidence for the reactive oxygen species hypothesis: nitrate tolerance is associated with an increase in the vascular production of superoxide anion,1 and the sources of this superoxide are membrane-bound NAD(P)H oxidase2,3 and endothelial nitric oxide synthase itself.4 The superoxide anion produced by these enzyme systems inactivates the nitric oxide derived from the metabolism of the organic nitrate by forming peroxynitrite; evidence for this process has been found by observing an increase in 3-nitrotyrosine in the urine of nitrate-tolerant subjects.5 An additional feature of nitrate tolerance is the recognition that cross-tolerance to endogenous endothelium-dependent vasodilators also occurs.1,6,7 The mechanism by which an organic nitrate suppresses the bioactivity of endothelial nitric oxide involves several determinants. Vascular superoxide anion can react with and inactivate endogenous nitric oxide just as it can nitrate-derived nitric oxide. In addition, organic nitrates increase superoxide production by …