After long term use for treating chronic conditions, tolerance may develop in a patient 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 ISDN 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 ISDN
Plasma volume expansion
The oxidative stress hypothesis (proposed by Munzel et al. in 1995).
Recent evidence suggests that the last hypothesis might represent a unifying hypothesis, and an ISDN-induced inappropriate production of oxygen free radicals might induce a number of abnormalities which include the ones described above. Furthermore, studies have shown that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients prognosis (Nakamura et al.): these include endothelial and autonomic dysfunction (Gori et al.). In the short run, ISDN can cause severe headaches, necessitating analgesic (very rarely up to morphine) administration for relief of pain as well as severe hypotension, and, in certain cases, bradycardia. This makes some physicians nervous and should prompt caution when starting nitrate administration.