title: Different effects of ascorbate deprivation and classical vascular nitrate tolerance on aldehyde dehydrogenase-catalysed bioactivation of nitroglycerin.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  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
  These results indicate that nitrate tolerance is associated with ALDH2 inactivation, whereas ascorbate deficiency possibly results in down-regulation of ALDH2 expression.
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria.
authors.forename: M V
authors.initials: MV
authors.lastname: Wenzl
authors.forename: G
authors.initials: G
authors.lastname: Wölkart
authors.forename: H
authors.initials: H
authors.lastname: Stessel
authors.forename: M
authors.initials: M
authors.lastname: Beretta
authors.forename: K
authors.initials: K
authors.lastname: Schmidt
authors.forename: B
authors.initials: B
authors.lastname: Mayer
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001205:Ascorbic Acid / Q000097:blood; D001206:Ascorbic Acid Deficiency / Q000201:enzymology* / Q000503:physiopathology; D001711:Biotransformation; D002697:Chloral Hydrate / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004361:Drug Tolerance; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006834:Hydrazines / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D005996:Nitroglycerin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D006834:Hydrazines; D007529:Isoflavones; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; C014509:dinitroglycerol; D009569:Nitric Oxide; D002697:Chloral Hydrate; C013908:daidzin; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin; D001205:Ascorbic Acid