| The role of lipoic acid in prevention of nitroglycerin tolerance. | |
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MedLine Citation:
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PMID: 18616939 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Besides other organic nitrates, nitroglycerin (glyceryl trinitrate; GTN) has been used to treat acute heart failure particularly due to ischemic heart disease. However, one of serious clinical problems of the GTN therapy, particularly a long-standing medication, is hemodynamic tolerance to GTN, manifested by the decreased therapeutic efficacy of the drug. The most recent studies have suggested that mitochondrial lipoate/dihydrolipoate system-dependent aldehyde dehydrogenase-2 plays a key role in nitric oxide release from GTN. The aldehyde dehydrogenase-2 performs three enzymatic activities of dehydrogenase, esterase and reductase. The reductase activity is responsible for bioactivation of organic nitrates, such as GTN yielding nitrite and dinitrate (1,2-GDN/1,3-GDN, approximately 8:1). In view of a large contribution of dihydrolipoic acid to stabilization and regeneration of thiol groups, necessary for the reductase activity of aldehyde dehydrogenase-2, we conducted studies aimed to determine whether lipoic acid administration to rats is able to prevent GTN tolerance. The studies were conducted on 4 groups of animals: control saline-treated, model GTN-tolerant, GTN + lipoic acid-treated, lipoic acid alone-administered groups. On the 9th day of experiment animals were given i.v. therapeutic dose of GTN. We measured in all animals systolic and diastolic blood pressure before injection of therapeutic dose of GTN into the cadual vein and during 20 min thereafter. Levels of nitric oxide and reactive oxygen species and activities of glutathione peroxidase and superoxide dismutase were assayed in the aorta, plasma and heart of all animals. In addition, levels of malondialdehyde, and non-protein thiols, and activities of glutathione S-transferase and gamma-glutamyl transpeptidase were evaluated in the heart and plasma. The obtained results indicate that treatment of rats with a combination of lipoic acid and GTN can efficiently counteract GTN tolerance. |
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Authors:
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Magdalena Dudek; Marek Bednarski; Anna Bilska; Małgorzata Iciek; Maria Sokołowska-Jezewicz; Barbara Filipek; Lidia Włodek |
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Publication Detail:
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Type: Journal Article Date: 2008-06-27 |
Journal Detail:
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Title: European journal of pharmacology Volume: 591 ISSN: 0014-2999 ISO Abbreviation: Eur. J. Pharmacol. Publication Date: 2008 Sep |
Date Detail:
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Created Date: 2008-08-12 Completed Date: 2008-10-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1254354 Medline TA: Eur J Pharmacol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 203-10 Citation Subset: IM |
Affiliation:
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Laboratory of Pharmacological Screening, Jagiellonian University, Collegium Medicum, 9, Medyczna Street, PL 30-688 Kraków, Poland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antioxidants / pharmacology* Aorta / drug effects, metabolism Blood Pressure / drug effects Drug Tolerance Glutathione Peroxidase / drug effects, metabolism Heart / drug effects Injections, Intravenous Male Nitric Oxide / metabolism Nitroglycerin / administration & dosage, pharmacology* Rats Rats, Wistar Reactive Oxygen Species / metabolism Superoxide Dismutase / drug effects, metabolism Thioctic Acid / pharmacology* Time Factors Vasodilator Agents / administration & dosage, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Antioxidants; 0/Reactive Oxygen Species; 0/Vasodilator Agents; 10102-43-9/Nitric Oxide; 55-63-0/Nitroglycerin; 62-46-4/Thioctic Acid; EC 1.11.1.9/Glutathione Peroxidase; EC 1.15.1.1/Superoxide Dismutase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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