More answers to the still unresolved question of nitrate tolerance.

Organic nitrates are traditionally felt to be a safe adjuvant in the chronic therapy of patients with coronary artery disease. Despite their long use, progress in the understanding of the pharmacology and mechanism of action of these drugs has been achieved only in the last two decades, with the identification of the role of oxidative stress in the pathophysiology of nitrate tolerance, with, the discovery of the ancillary effects of nitrates, and with the demonstration that nitrate therapy has important chronic side effects that might modify patients' prognosis. These advances are however mostly confined to the molecular level or to studies in healthy volunteers, and the true impact of organic nitrates on clinical outcome remains unknown. Complicating this issue, evidence supports the existence of important differences among the different drugs belonging to the group, and there are reasons to believe that the nitrates should not be treated as a homogeneous class. As well, the understanding of the effects of alternative nitric oxide (NO) donors is currently being developed, and future studies will need to test whether the properties of these new medications may compensate and prevent the abnormalities imposed by chronic nitrate therapy. Intermittent therapy with nitroglycerin and isosorbide mononitrate is now established in clinical practice, but they should neither be considered a definitive solution to the problem of nitrate tolerance. Both these strategies are not deprived of complications, and should currently be seen as a compromise rather than a way fully to exploit the benefits of NO donor therapy.