Mechanisms of nitrate tolerance: a review

With the increased use of long-acting nitroglycerin preparations, there has been greater recognition of the problem of nitrate tolerance. In recent years extensive research has broadened our understanding of the mechanisms of nitroglycerin action and the mechanisms of drug attenuation. This paper reviews the current state of knowledge regarding nitroglycerin tolerance, with an emphasis on the concepts of cellular and neurohumoral mechanisms of drug attenuation. The discussion includes potential approaches to prevent nitrate tolerance, including the introduction of a nitrate-free interval, or concomitant administration of sulfhydryl donors or neurohumoral blocking agents.