The first part of this review provided a synopsis of the recent literature about superoxide anion (· O2 J) production, endothelial dysfunction, and the neurohormonal activation that follow long-term administration of organic nitrates. In this issue of Circulation, we will try to integrate these observations with other separate, and, to a certain extent, antagonistic hypotheses that have been proposed for the development of nitrate tolerance. 1–3 Hypotheses concerning the pathogenesis of tolerance have traditionally been grouped into 2 different categories. The “dispositional” or “metabolic” theory postulates that the effect of organic nitrates wanes during continuous use as the result of decreased biotransformation or decreased activity of the nitric oxide (NO) adjunct released in this process (end-organ tolerance). The “functional” theory emphasizes the importance of counterregulatory mechanisms that occur in response to nitrate therapy, including neurohormonal activation and plasma volume expansion. These mechanisms could counterbalance and overcome the effects of nitrates, a process that has been termed

“pseudotolerance.” 3, 4

Recent findings described in the first part of this article provide an opportunity to hypothesize explanations for a number of previous observations in the field of nitrate tolerance by applying increased· O2 J production as the underlying mechanism. In the following text, the evidence for this concept is reviewed, and a unifying hypothesis based on a self-promoting mechanism triggered by increased vascular· O2 J generation is proposed.