The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles.

Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0007-1188 (Print) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.

Biotransformation*; Drug Tolerance/*physiology ; Nitrates/*adverse effects ; Nitroglycerin/*pharmacology; Nitrates/pharmacology ; Nitroglycerin/adverse effects ; Nitroglycerin/metabolism ; Nitroglycerin/therapeutic use ; Animals ; Humans ; United States

Nitroglycerin (glyceryl trinitrate; GTN) is the most prominent representative of the organic nitrates or nitrovasodilators, a class of compounds that have been used clinically since the late nineteenth century for the treatment of coronary artery disease (angina pectoris), congestive heart failure and myocardial infarction. Medline lists more than 15 000 publications on GTN and other organic nitrates, but the mode of action of these drugs is still largely a mystery. In the first part of this article, we give an overview on the molecular mechanisms of GTN biotransformation resulting in vascular cyclic GMP accumulation and vasodilation with focus on the role of mitochondrial aldehyde dehydrogenase (ALDH2) and the link between the ALDH2 reaction and activation of vascular soluble guanylate cyclase (sGC). In particular, we address the identity of the bioactive species that activates sGC and the potential involvement of nitrite as an intermediate, describe our recent findings suggesting that ALDH2 catalyses direct 3-electron reduction of GTN to NO and discuss possible reaction mechanisms. In the second part, we discuss contingent processes leading to markedly reduced sensitivity of blood vessels to GTN, referred to as vascular nitrate tolerance. Again, we focus on ALDH2 and describe the current controversy on the role of ALDH2 inactivation in tolerance development. Finally, we emphasize some of the most intriguing, in our opinion, unresolved puzzles of GTN pharmacology that urgently need to be addressed in future studies.

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P 20669 Austria FWF_ Austrian Science Fund FWF; W 901 Austria FWF_ Austrian Science Fund FWF

0 (Nitrates)
G59M7S0WS3 (Nitroglycerin)

Date Created: 20080625 Date Completed: 20081008 Latest Revision: 20250529

20260130

PMC2538691

10.1038/bjp.2008.263

18574453