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Isosorbide dinitrate
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===Tolerance=== After long-term use for treating chronic conditions, tolerance may develop in patients, reducing its effectiveness. The mechanisms of [[nitrate tolerance]] have been thoroughly investigated in the last 30 years and several hypotheses have been proposed. These include: # Impaired biotransformation of isosorbide dinitrate to its active principle NO (or a NO-related species) # Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II which counteract the vasodilation induced by isosorbide dinitrate # Plasma volume expansion # The oxidative stress hypothesis<ref name="pmid7814613">{{cite journal | vauthors = MΓΌnzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG | title = Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance | journal = The Journal of Clinical Investigation | volume = 95 | issue = 1 | pages = 187β94 | date = January 1995 | pmid = 7814613 | pmc = 295403 | doi = 10.1172/JCI117637 }}</ref> The last hypothesis might represent a unifying hypothesis, and an isosorbide dinitrate-induced inappropriate production of oxygen free radicals might induce a number of abnormalities which include the ones described above. Furthermore, nitrate tolerance is shown to be associated with vascular abnormalities which have the potential to worsen patients prognosis:<ref name="pmid10467211">{{cite journal | vauthors = Nakamura Y, Moss AJ, Brown MW, Kinoshita M, Kawai C | title = Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group | journal = American Heart Journal | volume = 138 | issue = 3 Pt 1 | pages = 577β85 | date = September 1999 | pmid = 10467211 | doi = 10.1016/s0002-8703(99)70163-8 | url = }}</ref> these include endothelial and autonomic dysfunction.<ref name="pmid18634978">{{cite journal | vauthors = Gori T, Parker JD | title = Nitrate-induced toxicity and preconditioning: a rationale for reconsidering the use of these drugs | journal = Journal of the American College of Cardiology | volume = 52 | issue = 4 | pages = 251β4 | date = July 2008 | pmid = 18634978 | doi = 10.1016/j.jacc.2008.04.019 }}</ref>
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