ArticleThe Journal of clinical investigation2004
Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance.
Article in The Journal of clinical investigation, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers.
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Who cites it
108 citing papers in PubMed, 273 citations in OpenAlex.
- Oxidative stress and enhanced sympathetic vasoconstriction in contracting muscles of nitrate-tolerant rats and humans.The Journal of physiology · 2012Trial
- Nitric oxide-induced headache may arise from extracerebral arteries as judged from tolerance to isosorbide-5-mononitrate.The journal of headache and pain · 2008Trial
- Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight.British journal of clinical pharmacology · 2007Trial
- Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease.Free radical biology & medicine · 2005Trial
- Preservation of platelet responsiveness to nitroglycerine despite development of vascular nitrate tolerance.British journal of clinical pharmacology · 2005Trial
- The Regulatory Role ofAntioxidants (Basel, Switzerland) · 2025Article
- Nitric oxide releasing graphene for next-generation therapeutics.Advanced drug delivery reviews · 2025Review
- Insights into Active Site Cysteine Residues inInternational journal of molecular sciences · 2025Review
- Advances in Factors Affecting ALDH2 Activity and its Mechanisms.Cardiovascular toxicology · 2024Review
- Recent advances on the role of monoamine oxidases in cardiac pathophysiology.Basic research in cardiology · 2023Article
- The role of aldehyde dehydrogenase 2 in cardiovascular disease.Nature reviews. Cardiology · 2023Review
- Vascular Redox Signaling, Endothelial Nitric Oxide Synthase Uncoupling, and Endothelial Dysfunction in the Setting of Transportation Noise Exposure or Chronic Treatment with Organic Nitrates.Antioxidants & redox signaling · 2023Review
- Article
- Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Approach to Overcome Nitrates Tolerance, an Ex Vivo Study.Antioxidants (Basel, Switzerland) · 2022Article
- Study of ALDH fromCells · 2021Article
- The Application of Nitric Oxide for Ocular Hypertension Treatment.Molecules (Basel, Switzerland) · 2021Review
- Treating Acute Decompensated Heart Failure in Patients with COVID-19 Using Intravenous Nitroglycerin in 5% Glutathione.American journal of cardiovascular drugs : drugs, devices, and other interventions · 2021Article
- NO donors and NO delivery methods for controlling biofilms in chronic lung infections.Applied microbiology and biotechnology · 2021Review
- The NO-cGMP-PKG pathway in skeletal remodeling.Annals of the New York Academy of Sciences · 2021Review
- Insights into Aldehyde Dehydrogenase Enzymes: A Structural Perspective.Frontiers in molecular biosciences · 2021Review
48 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 (rho(0) 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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.