The puzzle of nitrate tolerance: pieces smaller than we thought?

Abstract

Nitroglycerin (GTN) and other organic nitrates are important drugs commonly used in cardiovascular medicine, and, more recently, in obstetrics as tocolytic agents.1 The development of tolerance, ie, the reduction in effect or the requirement for higher doses that appears after continuous use,2 is a major factor limiting the efficacy of these drugs. Despite their clinical importance in the therapy of ischemic heart disease and heart failure, many aspects of the pharmacology of organic nitrates, including the mechanism(s) of tolerance, remain unclear. In the past decade, studies have demonstrated that organic nitrate therapy leads to complex interactions between the vasculature, neurohormones, and free oxygen radicals. In particular, the concept that GTN treatment causes increased vascular superoxide anion (·O2−) production, the mechanisms leading to this production, and the consequences of this phenomenon on endothelial function, have all been investigated. In the first part of this 2-part review, these recent findings, as well as the potential role of neurohormonal and autonomic abnormalities, will be described. In the second part, which will appear in the next issue of Circulation , we will propose a new, integrated view on the pathophysiology of nitrate tolerance. There is evidence from both animal and human studies that nitrate tolerance, especially when induced in vivo,3 is associated with an increased bioavailability of ·O2−, and that this process is responsible for the development of tolerance.4 Superoxide anion is normally scavenged by multiple intra- and extracellular mechanisms, including the enzyme superoxide dismutase (SOD). However, in higher concentrations, it can overcome these mechanisms and rapidly react with nitric oxide (NO), the active metabolite of GTN, to form peroxynitrite.5 This may reduce the bioavailability of GTN-derived NO, impairing its vasodilator activity (and that of other NO donors), and, possibly, directly counteract GTN-induced vasorelaxation, …