title: Vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetranitrate but not isosorbide-5-mononitrate therapy.
abstract: OBJECTIVE
  Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetranitrate (PETN) is an organic nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes.
  
  
  METHODS
  After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-mononitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was determined by isometric tension recordings, protein expression was measured by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was determined by luciferase assays.
  
  
  RESULTS
  PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both organic nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S-glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2.
  
  
  CONCLUSIONS
  In contrast to ISMN, the organic nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes.
authors.affiliation: 2nd Medical Clinic, Department of Cardiology, Medical Centerof the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Swenja
authors.initials: S
authors.lastname: Schuhmacher
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Franziska
authors.initials: F
authors.lastname: Bollmann
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kleinert
authors.forename: Christian
authors.initials: C
authors.lastname: Otto
authors.forename: Tjebo
authors.initials: T
authors.lastname: Heeren
authors.forename: Sebastian
authors.initials: S
authors.lastname: Steven
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.forename: Andrea
authors.initials: A
authors.lastname: Pautz
authors.forename: Kurt
authors.initials: K
authors.lastname: Reifenberg
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gori
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010417:Pentaerythritol Tetranitrate / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D015430:Weight Gain; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D010417:Pentaerythritol Tetranitrate; D051547:Heme Oxygenase-1; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D006136:GTP Cyclohydrolase; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate