PT  - JOURNAL ARTICLE
AU  - Andreas Daiber
AU  - Matthias Oelze
AU  - Silke Sulyok
AU  - Meike Coldewey
AU  - Eberhard Schulz
AU  - Nicolai Treiber
AU  - Ulrich Hink
AU  - Alexander Mülsch
AU  - Karin Scharffetter-Kochanek
AU  - Thomas Münzel
TI  - Heterozygous Deficiency of Manganese Superoxide Dismutase in Mice (Mn-SOD<sup>+/-</sup>): A Novel Approach to Assess the Role of Oxidative Stress for the Development of Nitrate Tolerance
AID  - 10.1124/mol.105.011585
DP  - 2005 Sep 01
TA  - Molecular Pharmacology
PG  - 579--588
VI  - 68
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/68/3/579.short
4100  - http://molpharm.aspetjournals.org/content/68/3/579.full
SO  - Mol Pharmacol2005 Sep 01; 68
AB  - 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.