This review article summarises the current concepts underlying tolerance and endothelial dysfunction in response to long-term therapy with different nitrates and addresses the question of whether the use of these drugs remains indicated despite these side effects.  The following issues are discussed:

• The haemodynamic effects of nitrates

• Antiaggregant effects of organic nitrates

• Mechanistic insight

• No nitric oxide from glyceryl trinitrate?

• Aldehyde dehydrogenase bioactivates glyceryl trinitrate

• Nitrate tolerance

• Nitrate pseudotolerance

• Does oxidative stress account for nitrate tolerance and cross-tolerance?

• Mechanisms underlying tolerance: impaired biotransformation versus oxidative stress concept

• Unresolved issues

• Clinical implications

• Old and new strategies to prevent the development of tolerance and cross-tolerance

In their summary, the authors comment that “nitrate tolerance is a complex phenomenon caused by abnormalities in the biotransformation and signal transduction of nitrates and by activation of counter-regulatory mechanisms. Although the issue of the clinical implications of nitrate therapy has not been addressed by randomised clinical trials, it is clear that the pharmacology of organic nitrates is also more complex, interesting, and elusive than previously thought.”