Nitrate tolerance and dependence. A critical assessment.

Tolerance and cross-tolerance to nitrates has been known since 1900 but the actual clinical importance of this phenomenon is unclear. Vasodilator treatment of congestive heart failure has provided an important new role for long-acting nitrates. The advent of high-dose nitrate regimens for both angina and heart failure raises the possibility that nitrate tolerance could be a potential detriment to therapy. A number of older studies have documented the development of tolerance and cross-tolerance to blood pressure and heart rate responses to nitrates as well as the rapid onset of tolerance to nitrate headaches in subjects given nitrates on a regular basis. Animal experiments also confirm the ready appearance of nitrate tachyphylaxis. Needleman has proposed a cellular mechanism for nitrate tolerance based on a chemical alteration of nitrate receptors in the vascular wall. In spite of these studies, there is considerable evidence that clinically relevant tolerance to nitrates is rare. Several recent investigations designed to look at this problem using high-dose isosorbide dinitrate (ISD) failed to demonstrate tachyphylaxis to the anti-anginal or hemodynamic effect of ISD. However, very recent work in patients with angina suggests that tolerance to high dose ISD does occur and may reduce the duration of action of long-acting nitrates. Overall, the bulk of current evidence does not support tolerance to be a major problem in nitrate treatment of cardiac diseases, although attenuated vasodilator responses may occur after several weeks of nitrate therapy.