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Molecular Pharmacology

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Research ArticleArticle

Heterozygous Deficiency of Manganese Superoxide Dismutase in Mice (Mn-SOD+/-): A Novel Approach to Assess the Role of Oxidative Stress for the Development of Nitrate Tolerance

Andreas Daiber, Matthias Oelze, Silke Sulyok, Meike Coldewey, Eberhard Schulz, Nicolai Treiber, Ulrich Hink, Alexander Mülsch, Karin Scharffetter-Kochanek and Thomas Münzel
Molecular Pharmacology September 2005, 68 (3) 579-588; DOI: https://doi.org/10.1124/mol.105.011585
Andreas Daiber
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Matthias Oelze
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Silke Sulyok
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Meike Coldewey
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Eberhard Schulz
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Nicolai Treiber
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Ulrich Hink
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Alexander Mülsch
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Karin Scharffetter-Kochanek
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Thomas Münzel
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Abstract

Nitroglycerin (GTN)-induced tolerance was reported to be associated with increased levels of reactive oxygen species (ROS) in mitochondria. In the present study, we further investigated the role of ROS for the development of nitrate tolerance by using heterozygous manganese superoxide dismutase knock-out mice (Mn-SOD+/-). Mn-SOD is acknowledged as a major sink for mitochondrial superoxide. Vasodilator potency of mouse aorta in response to acetylcholine and GTN was assessed by isometric tension studies. Mitochondrial ROS formation was detected by 8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt (L-012)-enhanced chemiluminescence and mitochondrial aldehyde dehydrogenase (ALDH-2) activity was determined by a high-performance liquid chromatography-based assay. Aortic rings from Mn-SOD+/- mice showed normal endothelial function and vasodilator responses to GTN. In contrast, preincubation of aorta with GTN or long-term GTN infusion caused a marked higher degree of tolerance as well as endothelial dysfunction in Mn-SOD+/- compared with wild type. Basal as well as GTN-stimulated ROS formation was significantly increased in isolated heart mitochondria from Mn-SOD+/- mice, correlating well with a marked decrease in ALDH-2 activity in response to in vitro and in vivo GTN treatment. The data presented indicate that deficiency in Mn-SOD leads to a higher degree of tolerance and endothelial dysfunction associated with increased mitochondrial ROS production in response to in vitro and in vivo GTN challenges. These data further point to a crucial role of ALDH-2 in mediating GTN bioactivation as well as development of GTN tolerance and underline the important contribution of ROS to these processes.

  • Received February 1, 2005.
  • Accepted June 1, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (3)
Molecular Pharmacology
Vol. 68, Issue 3
1 Sep 2005
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Research ArticleArticle

Heterozygous Deficiency of Manganese Superoxide Dismutase in Mice (Mn-SOD+/-): A Novel Approach to Assess the Role of Oxidative Stress for the Development of Nitrate Tolerance

Andreas Daiber, Matthias Oelze, Silke Sulyok, Meike Coldewey, Eberhard Schulz, Nicolai Treiber, Ulrich Hink, Alexander Mülsch, Karin Scharffetter-Kochanek and Thomas Münzel
Molecular Pharmacology September 1, 2005, 68 (3) 579-588; DOI: https://doi.org/10.1124/mol.105.011585

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Research ArticleArticle

Heterozygous Deficiency of Manganese Superoxide Dismutase in Mice (Mn-SOD+/-): A Novel Approach to Assess the Role of Oxidative Stress for the Development of Nitrate Tolerance

Andreas Daiber, Matthias Oelze, Silke Sulyok, Meike Coldewey, Eberhard Schulz, Nicolai Treiber, Ulrich Hink, Alexander Mülsch, Karin Scharffetter-Kochanek and Thomas Münzel
Molecular Pharmacology September 1, 2005, 68 (3) 579-588; DOI: https://doi.org/10.1124/mol.105.011585
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