New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance.
Organic nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with organic nitrates, however, results in a rapid development of nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for organic nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various organic nitrates. Finally, we would like to draw the reader's attention to the protective properties of the organic nitrate pentaerithrityl tetranitrate (PETN), which, in contrast to all other organic nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.
Daiber
A
A
Klinikum der Johannes-Gutenberg-Universität Mainz, II. Medizinische Klinik, Labor für Molekulare Kardiologie, Verfügungsgebäude für Forschung und Entwicklung - Raum 00349, 55101, Mainz, Germany. daiber@uni-mainz.de
Wenzel
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P
Oelze
M
M
Münzel
T
T
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D004361:Drug Tolerance; D006331:Heart Diseases / Q000188:drug therapy*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D009566:Nitrates / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010417:Pentaerythritol Tetranitrate / Q000008:administration & dosage / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
D009566:Nitrates; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D010417:Pentaerythritol Tetranitrate; D000444:Aldehyde Dehydrogenase