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(Circulation. 2002;106:2510.)
© 2002 American Heart Association, Inc.

Mini-Review

Nitrate Tolerance

A Unifying Hypothesis

Tommaso Gori, MD; John D. Parker, MD

From the Division of Cardiology, Department of Medicine, Mount Sinai and University Health Network Hospitals, University of Toronto, Toronto, Canada.

Correspondence to John D. Parker, MD, FRCP(C), Division of Cardiology, Department of Medicine, Mount Sinai Hospital, 600 University Ave, Suite 1609, Toronto, Ontario, Canada M5G 1X5. E-mail jdp@inforamp.net

Key Words: acetylcholine • nitroglycerin • endothelium • nitric oxide synthase • blood flow

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The first part of this review provided a synopsis of the recent literature about superoxide anion (·O₂^-) 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^- 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^- generation is proposed.

Plasma Volume Expansion During Nitrate Therapy

Several studies reported that nitrate therapy causes plasma volume expansion, as demonstrated by a decreased hematocrit during nitrate therapy both in healthy volunteers⁵ and patients with congestive heart failure . . . [Full Text of this Article]

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