Identification of the Enzymatic Mechanism of Nitroglycerin Bioactivation

Nitroglycerin (glyceryl trinitrate, GTN), originally manufactured by Alfred Nobel, has been used to treat angina and heart failure for over 130 years. However, the molecular mechanism of GTN biotransformation has remained a mystery and it is not well understood why "tolerance" (i.e., loss...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-06, Vol.99 (12), p.8306-8311
Main Authors: Chen, Zhiqiang, Zhang, Jian, Stamler, Jonathan S.
Format: Article
Language:English
Subjects:
Aldehyde Dehydrogenase - metabolism
Animals
Aorta, Thoracic - drug effects
Aorta, Thoracic - physiology
Biological Sciences
Biotransformation
Blood vessels
Cell Line
Cell lines
Dehydrogenases
Drug therapy
Enzymes
Hydrates
In Vitro Techniques
Kinetics
Macrophages
Medical research
Metabolism
Mice
Mitochondria - enzymology
Muscle Contraction - drug effects
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - physiology
NAD - metabolism
Nitrates
Nitrites
Nitroglycerin - pharmacokinetics
Nitroglycerin - pharmacology
Rabbits
Thiols
Vasodilation
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Summary:Nitroglycerin (glyceryl trinitrate, GTN), originally manufactured by Alfred Nobel, has been used to treat angina and heart failure for over 130 years. However, the molecular mechanism of GTN biotransformation has remained a mystery and it is not well understood why "tolerance" (i.e., loss of clinical efficacy) manifests over time. Here we purify a nitrate reductase that specifically catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from GTN, leading to production of cGMP and relaxation of vascular smooth muscle both in vitro and in vivo, and we identify it as mitochondrial aldehyde dehydrogenase (mtALDH). We also show that mtALDH is inhibited in blood vessels made tolerant by GTN. These results demonstrate that the biotransformation of GTN occurs predominantly in mitochondria through a novel reductase action of mtALDH and suggest that nitrite is an obligate intermediate in generation of NO bioactivity. The data also indicate that attenuated biotransformation of GTN by mtALDH underlies the induction of nitrate tolerance. More generally, our studies provide new insights into subcellular processing of NO metabolites and suggest new approaches to generating NO bioactivity and overcoming nitrate tolerance.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.122225199