An update on nitrate tolerance: can it be avoided?

Organic nitrates have been recognized by physicians as potent vasodilators and effective therapy for angina pectoris for over 100 years."2 Despite the advent of beta-blockers and calcium channel antagonists in the 1960s the organic nitrates remain important antianginal agents and are well-established as the drugs of choice in acute angina. Recently interest in nitrate therapy has increased as a result of the widespread use of intravenous nitrates in coronary care, and in the management of acute heart failure and because of this, their inclusion in the ISIS-4 study. The excellent response to acute nitrate administration led to a search for a method ofgiving nitrate therapy prophylactically. Unfortunately initial attempts were disappointing because, in many instances, chronic dosing with either oral or transcutaneous preparations was associated with the development of tolerance and results in significant attentuation of the antianginal effect. This loss of effect threatened to prevent the successful longterm use ofan apparently effective and safe form of therapy for patients with angina. This review will therefore focus on the evidence for tolerance, the possible mechanisms which cause it and the therapeutic attempts that have been made to circumvent it.