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Pentaerythritol tetranitrate improves angiotensin II-induced vascular dysfunction via induction of heme oxygenase-1.

Abstract
The organic nitrate pentaerythritol tetranitrate is devoid of nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetranitrate can improve angiotensin II-induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 mononitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetranitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase), as assessed by dihydroethidine staining, lucigenin-enhanced chemiluminescence, and quantification of dihydroethidine oxidation products in angiotensin II (1 mg/kg per day for 7 days)-treated rats. The antioxidant features of pentaerythritol tetranitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1 protein expression, pentaerythritol tetranitrate but not isosorbide-5 mononitrate normalized vascular reactive oxygen species formation and augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase I and dihydrofolate reductase in angiotensin II-treated rats, thereby preventing endothelial NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of pentaerythritol tetranitrate in angiotensin II-treated mice, whereas HO-1 induction by hemin (25 mg/kg) mimicked the effect of pentaerythritol tetranitrate. Improvement of vascular function in this particular model of arterial hypertension by pentaerythritol tetranitrate largely depends on the induction of the antioxidant enzyme HO-1 and identifies pentaerythritol tetranitrate, in contrast to isosorbide-5 mononitrate, as an organic nitrate able to improve rather than to worsen endothelial function.
AuthorsSwenja Schuhmacher, Philip Wenzel, Eberhard Schulz, Matthias Oelze, Christian Mang, Jens Kamuf, Tommaso Gori, Thomas Jansen, Maike Knorr, Susanne Karbach, Marcus Hortmann, Falk Mäthner, Aruni Bhatnagar, Ulrich Förstermann, Huige Li, Thomas Münzel, Andreas Daiber
JournalHypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 55 Issue 4 Pg. 897-904 (Apr 2010) ISSN: 1524-4563 [Electronic] United States
PMID20157049 (Publication Type: Journal Article)
Chemical References
  • Reactive Oxygen Species
  • Vasodilator Agents
  • Pentaerythritol Tetranitrate
  • Angiotensin II
  • Hemin
  • Nitric Oxide Synthase Type III
  • Heme Oxygenase-1
Topics
  • Analysis of Variance
  • Angiotensin II (pharmacology)
  • Animals
  • Blotting, Western
  • Endothelium, Vascular (drug effects, metabolism)
  • Fluorescent Antibody Technique
  • Heme Oxygenase-1 (metabolism)
  • Hemin (pharmacology)
  • Mitochondria (drug effects, metabolism)
  • Nitric Oxide Synthase Type III (metabolism)
  • Oxidative Stress (drug effects)
  • Pentaerythritol Tetranitrate (pharmacology)
  • Rats
  • Rats, Inbred SHR
  • Reactive Oxygen Species (metabolism)
  • Vasodilator Agents (pharmacology)

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