title: Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates.
abstract: OBJECTIVE
  Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance.
  
  
  RESULTS
  Wistar rats were treated with PETN or GTN (10.5 or 6.6 microg/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assessed by isometric tension recordings in isolated aortic rings. Vascular protein and mRNA expression of HO-1 and ferritin were increased in response to PETN but not GTN. In contrast to GTN therapy, NO signaling, ROS formation, and the activity of ALDH-2 (as assessed by an high-performance liquid chromatography-based method) were not significantly influenced by PETN. Inhibition of HO-1 expression by apigenin induced "tolerance" to PETN whereas HO-1 gene induction by hemin prevented tolerance in GTN treated rats.
  
  
  CONCLUSIONS
  HO-1 expression and activity appear to play a key role in the development of nitrate tolerance and might represent an intrinsic antioxidative mechanism of therapeutic interest.
authors.affiliation: II. Medizinische Klinik, Johannes-Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Meike
authors.initials: M
authors.lastname: Coldewey
authors.forename: Marcus
authors.initials: M
authors.lastname: Hortmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Seeling
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hink
authors.forename: Hanke
authors.initials: H
authors.lastname: Mollnau
authors.forename: Dirk
authors.initials: D
authors.lastname: Stalleicken
authors.forename: Henry
authors.initials: H
authors.lastname: Weiner
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.forename: Huige
authors.initials: H
authors.lastname: Li
authors.forename: Ulrich
authors.initials: U
authors.lastname: Förstermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects; D016166:Free Radical Scavengers; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology*; D010417:Pentaerythritol Tetranitrate / Q000378:metabolism / Q000494:pharmacology*; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D012016:Reference Values; D012680:Sensitivity and Specificity
chemical_list: D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D010417:Pentaerythritol Tetranitrate; D051547:Heme Oxygenase-1; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin; D006152:Cyclic GMP