title: Effect of soluble guanylyl cyclase activator and stimulator therapy on nitroglycerin-induced nitrate tolerance in rats.
abstract: Chronic nitroglycerin (GTN) anti-ischemic therapy induces side effects such as nitrate tolerance and endothelial dysfunction. Both phenomena could be based on a desensitization/oxidation of the soluble guanylyl cyclase (sGC). Therefore, the present study aims at investigating the effects of the therapy with the sGC activator BAY 60-2770 and the sGC stimulator BAY 41-8543 on side effects induced by chronic nitroglycerin treatment. Male Wistar rats were treated with nitroglycerin (100mg/kg/d for 3.5days, s.c. in ethanol) and BAY 60-2770 (0.5 or 2.5mg/kg/d) or BAY 41-8543 (1 and 5mg/kg/d) for 6days. Therapy with BAY 60-2770 but not with BAY 41-8543 improved nitroglycerin-triggered endothelial dysfunction and nitrate tolerance, corrected the decrease in aortic nitric oxide levels, improved the cGMP dependent activation of protein kinase I in aortic tissue and reduced vascular, cardiac and whole blood oxidative stress (fluorescence and chemiluminescence assays; 3-nitrotyrosine staining). In contrast to BAY 41-8543, the vasodilator potency of BAY 60-2770 was not impaired in isolated aortic ring segments from nitrate tolerant rats. sGC activator therapy improves partially the adverse effects of nitroglycerin therapy whereas sGC stimulation has only minor beneficial effects pointing to a nitroglycerin-dependent sGC oxidation/inactivation mechanism contributing to nitrate tolerance.
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: A
authors: A
authors: Jabs
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: M
authors: M
authors: Oelze
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: Y
authors: Y
authors: Mikhed
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: P
authors: P
authors: Stamm
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: S
authors: S
authors: Kröller-Schön
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: P
authors: P
authors: Welschof
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: T
authors: T
authors: Jansen
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: M
authors: M
authors: Hausding
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: M
authors: M
authors: Kopp
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: S
authors: S
authors: Steven
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: E
authors: E
authors: Schulz
authors: Bayer Pharma AG, Wuppertal, Germany.
authors: J-P
authors: JP
authors: Stasch
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: T
authors: T
authors: Münzel
authors: 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany. Electronic address: daiber@uni-mainz.de.
authors: A
authors: A
authors: Daiber
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; C450679:BAY 41-8543; D001565:Benzoates; D001713:Biphenyl Compounds; D006845:Hydrocarbons, Fluorinated; D009025:Morpholines; D009566:Nitrates; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005996:Nitroglycerin
keywords: 3-nitrotyrosine (PubChem CID: 65124); Endothelial dysfunction; L-012 (PubChem CID: 126741); Nitroglycerin tolerance; Oxidative stress; dihydroethidium (PubChem CID: 128682); nitric oxide (PubChem CID: 145068); nitroglycerin (PubChem CID: 4510); peroxynitrite (PubChem CID: 104806); sGC activator; sGC stimulator; sGC stimulator BAY 41-8543 (PubChem CID: 9953906); superoxide (PubChem CID: 5359597)