Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance
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Recent studies suggest that mitochondrial aldehyde dehydrogenase (ALDH-2) plays a central role in the process of nitroglycerin (glyceryl trinitrate, GTN) biotransformation in vivo and that its inhibition accounts for mechanism-based tolerance in vitro. The extent to which ALDH-2 contributes to GTN tolerance (impaired relaxation to GTN) and cross-tolerance (impaired endothelium-dependent relaxation) in vivo remain to be elucidated. Rats were treated for three days with GTN. Infusions were accompanied by decreases in vascular ALDH-2 activity, GTN biotransformation, and cGMP-dependent kinase (cGK-I) activity. Further, whereas in control vessels, multiple inhibitors and substrates of ALDH-2 reduced both GTN-stimulation of cGKI and GTN-induced vasodilation, these agents had little effect on tolerant vessels. A state of functional tolerance (in the GTN/cGMP pathway) was recapitulated in cultured endothelial cells by knocking down mitochondrial DNA (ρ0 cells). In addition, GTN increased the production of reactive oxygen species (ROS) by mitochondria, and these increases were associated with impaired relaxation to acetylcholine. Finally, antioxidants/reductants decreased mitochondrial ROS production and restored ALDH-2 activity. These observations suggest that nitrate tolerance is mediated, at least in significant part, by inhibition of vascular ALDH-2 and that mitochondrial ROS contribute to this inhibition. Thus, GTN tolerance may be viewed as a metabolic syndrome characterized by mitochondrial dysfunction.
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Prolonged nitroglycerin use often causes nitrate tolerance because reactive oxygen species oxidize the thiol group of mtALDH and cause enzyme dysfunction.
“However, patients often develop nitrate tolerance (tachyphylaxis) after prolonged use because the reactive oxygen species generated by nitroglycerin can oxidize the thiol group of the mtALDH and result in enzyme dysfunction.111,141–143”
From Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO) (2016) · cites this paper as [142]
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- Authors
- Sydow, K., Daiber, A., Oelze, M., Chen, Z., August, M., Wendt, M., Ullrich, V., Mülsch, A., Schulz, E., Keaney, J. F., Stamler, J. S., & Münzel, T.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- Howard Hughes Medical Institute (US)
- University of Konstanz (DE)
- Goethe University Frankfurt (DE)
- Boston University (US)
- Corresponding author
- Münzel, Thomas
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2004-02-01
- Volume
- 113
- Issue
- 3
- Pages
- 482-489
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2172008520
- Cited by
- 300
- References
- 38
- Citations by year
- 2025: 5 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 10 · 2017: 17 · 2016: 11 · 2015: 11 · 2014: 12 · 2013: 7 · 2012: 18
- FWCI
- 18.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- nitroglycerin tolerance, nitrate tolerance, mitochondrial aldehyde dehydrogenase, reactive oxygen species, endothelium-dependent relaxation, mitochondrial dysfunction, antioxidants, acetylcholine-induced relaxation, vascular smooth muscle
- MeSH terms
- Aldehyde Dehydrogenase, Animals, Aorta, Drug Tolerance, Nitroglycerin, Cyclic GMP, Mitochondria, Myocardium, Vasodilator Agents, Rats, Wistar, Reactive Oxygen Species, Models, Animal, Rats
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