Explaining the Phenomenon of Nitrate Tolerance

Münzel, Thomas; Daiber, Andreas; Mülsch, Alexander

doi:10.1161/01.res.0000184694.03262.6d

Cited by 424Nitric Oxide and Endothelin EffectsEicosanoids and Hypertension PharmacologyCardiovascular Health and Disease Prevention

Explaining the Phenomenon of Nitrate Tolerance

Münzel, Thomas, Daiber, Andreas, Mülsch, Alexander·2005·Circulation Research

DOI 10.1161/01.res.0000184694.03262.6d

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Abstract

During the last century, nitroglycerin has been the most commonly used antiischemic and antianginal agent. Unfortunately, after continuous application, its therapeutic efficacy rapidly vanishes. Neurohormonal activation of vasoconstrictor signals and intravascular volume expansion constitute early counter-regulatory responses (pseudotolerance), whereas long-term treatment induces intrinsic vascular changes, eg, a loss of nitrovasodilator-responsiveness (vascular tolerance). This is caused by increased vascular superoxide production and a supersensitivity to vasoconstrictors secondary to a tonic activation of protein kinase C. NADPH oxidase(s) and uncoupled endothelial nitric oxide synthase have been proposed as superoxide sources. Superoxide and vascular NO rapidly form peroxynitrite, which aggravates tolerance by promoting NO synthase uncoupling and inhibition of soluble guanylyl cyclase and prostacyclin synthase. This oxidative stress concept may explain why radical scavengers and substances, which reduce oxidative stress indirectly, are able to relieve tolerance and endothelial dysfunction. Recent work has defined a new tolerance mechanism, ie, an inhibition of mitochondrial aldehyde dehydrogenase, the enzyme that accomplishes bioactivation of nitroglycerin, and has identified mitochondria as an additional source of reactive oxygen species. Nitroglycerin-induced reactive oxygen species inhibit the bioactivation of nitroglycerin by thiol oxidation of aldehyde dehydrogenase. Both mechanisms, increased oxidative stress and impaired bioactivation of nitroglycerin, can be joined to provide a new concept for nitroglycerin tolerance and cross-tolerance. The consequences of these processes for the nitroglycerin downstream targets soluble guanylyl cyclase, cGMP-dependent protein kinase, cGMP-degrading phosphodiesterases, and toxic side effects contributing to endothelial dysfunction, such as inhibition of prostacyclin synthase, are discussed in this review.

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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 [141]

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Authors: Münzel, T., Daiber, A., & Mülsch, A.
Affiliations: From the Johannes Gutenberg Universität, II. Medizinische Klinik und Poliklinik, Kardiologie, Mainz, Germany.
Johannes Gutenberg University Mainz (DE)
ORCID: Daiber, Andreas
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2005-09-30
Volume: 97
Issue: 7
Pages: 618-628
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/01.res.0000184694.03262.6d
OpenAlex: W2116403540
Cited by: 424
References: 186
Citations by year: 2026: 7 · 2025: 4 · 2024: 12 · 2023: 13 · 2022: 13 · 2021: 14 · 2020: 19 · 2019: 9 · 2018: 18 · 2017: 22 · 2016: 32 · 2015: 21 · 2014: 16 · 2013: 23 · 2012: 35
FWCI: 3.18
Type: journal article
Language: en
Open access: closed
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords: nitroglycerin tolerance, nitrate tolerance, nitrate
MeSH terms: Aldehyde Dehydrogenase, Mitochondrial, Aldehyde Dehydrogenase, Animals, Biotransformation, Drug Tolerance, Endothelium, Vascular, Nitroglycerin, Humans, Nitric Oxide, Phosphoric Diester Hydrolases, Superoxides, Vasoconstriction, Vasodilation, Vasodilator Agents, Signal Transduction, Reactive Oxygen Species, Cyclic GMP-Dependent Protein Kinases, Oxidative Stress, Peroxynitrous Acid, Cyclic Nucleotide Phosphodiesterases, Type 1

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Explaining the Phenomenon of Nitrate Tolerance

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