| Different effects of ascorbate deprivation and classical vascular nitrate tolerance on aldehyde dehydrogenase-catalysed bioactivation of nitroglycerin. | |
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MedLine Citation:
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PMID: 19254277 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Vascular tolerance to nitroglycerin (GTN) may be caused by impaired GTN bioactivation due to inactivation of mitochondrial aldehyde dehydrogenase (ALDH2). As relaxation to GTN is reduced but still sensitive to ALDH2 inhibitors in ascorbate deficiency, we compared the contribution of ALDH2 inactivation to GTN hyposensitivity in ascorbate deficiency and classical in vivo nitrate tolerance. EXPERIMENTAL APPROACH: Guinea pigs were fed standard or ascorbate-free diet for 2 weeks. Reversibility was tested by feeding ascorbate-deficient animals standard diet for 1 week. Nitrate tolerance was induced by subcutaneous injection of 50 mg x kg(-1) GTN 4 times daily for 3 days. Ascorbate levels were determined in plasma, blood vessels, heart and liver. GTN-induced relaxation was measured as isometric tension of aortic rings; vascular GTN biotransformation was assayed as formation of 1,2- and 1,3-glyceryl dinitrate (GDN). KEY RESULTS: Two weeks of ascorbate deprivation had no effect on relaxation to nitric oxide but reduced the potency of GTN approximately 10-fold in a fully reversible manner. GTN-induced relaxation was similarly reduced in nitrate tolerance but not further attenuated by ALDH inhibitors. Nitrate tolerance reduced ascorbate plasma levels without affecting ascorbate in blood vessels, liver and heart. GTN denitration was significantly diminished in nitrate-tolerant and ascorbate-deficient rings. However, while the approximately 10-fold preferential 1,2-GDN formation, indicative for active ALDH2, had been retained in ascorbate deficiency, selectivity was largely lost in nitrate tolerance. CONCLUSIONS AND IMPLICATIONS: These results indicate that nitrate tolerance is associated with ALDH2 inactivation, whereas ascorbate deficiency possibly results in down-regulation of ALDH2 expression. |
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Authors:
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M V Wenzl; G Wölkart; H Stessel; M Beretta; K Schmidt; B Mayer |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2009-02-27 |
Journal Detail:
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Title: British journal of pharmacology Volume: 156 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-09-15 Completed Date: 2010-01-05 Revised Date: 2011-04-06 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1248-55 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aldehyde Dehydrogenase
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antagonists & inhibitors,
metabolism* Animals Ascorbic Acid / blood Ascorbic Acid Deficiency / enzymology*, physiopathology Biotransformation Chloral Hydrate / pharmacology Disease Models, Animal Dose-Response Relationship, Drug Down-Regulation Drug Tolerance* Enzyme Activation Enzyme Inhibitors / pharmacology Female Guinea Pigs Hydrazines / pharmacology Injections, Subcutaneous Isoflavones / pharmacology Male Nitric Oxide / metabolism Nitric Oxide Donors / pharmacology Nitroglycerin / administration & dosage, analogs & derivatives, metabolism* Time Factors Vasodilation / drug effects* Vasodilator Agents / administration & dosage, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P 20669-B05//Austrian Science Fund FWF; W 901-B12//Austrian Science Fund FWF |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Hydrazines; 0/Isoflavones; 0/Nitric Oxide Donors; 0/Vasodilator Agents; 10102-43-9/Nitric Oxide; 27321-62-6/dinitroglycerol; 302-17-0/Chloral Hydrate; 50-81-7/Ascorbic Acid; 55-63-0/Nitroglycerin; 552-66-9/daidzin; 623-87-0/glyceryl-1,3-dinitrate; 86831-65-4/1,1-diethyl-2-hydroxy-2-nitrosohydrazine; EC 1.2.1.3/Aldehyde Dehydrogenase |
| Comments/Corrections | |
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