Journal of Clinical Investigation, volume 113: For more detail information.
Organic nitrates have been used widely in the treatment of both coronary artery disease and congestive heart failure. The most commonly used organic nitrates are nitroglycerin, isosorbide dinitrate, and isosorbide-5-mononitrate (1). The organic nitrates are prodrugs, undergoing a biotransformation process that is generally believed to yield NO or some NO adjunct as their vasoactive metabolite. Despite clear benefits when given acutely, the organic nitrates rapidly lose their hemodynamic and clinical effectiveness when used as sustained therapy, a phenomenon known as nitrate tolerance. The mechanism of nitrate tolerance has been the subject of numerous investigations and much debate. Initially, it was hypothesized that tolerance was caused by abnormalities in the nitrate biotransformation process (termed mechanism-based or classical tolerance); however, those studies were limited by our lack of understanding of the biochemical processes involved. Many other theories have been proposed, including reflex hormonal and neurochemical mechanisms (termed pseudotolerance), although a clear cause-and-effect relationship could not be established.....