title: Soluble guanylate cyclase redox state under hypoxia or hypoxia/reoxygenation in isolated monkey coronary arteries.
abstract: Hypoxia or hypoxia/reoxygenation impairs nitric oxide (NO)-mediated relaxation through the increase in superoxide generation in monkey coronary arteries. Soluble guanylate cyclase (sGC), the target enzyme of NO, has been shown to change from the NO-sensitive reduced form to the NO-insensitive oxidized/heme-free form under substantial oxidative stress, so the present study investigated whether hypoxia or hypoxia/reoxygenation influences sGC redox equilibrium. In isolated monkey coronary arteries without endothelium, the relaxation caused by the sGC stimulator BAY 41-2272 (Emax: 93.3% ± 2.2%) was somewhat impaired under hypoxia (Emax: 86.3% ± 2.6%) or hypoxia/reoxygenation (Emax: 86.1% ± 3.2%), whereas that by the sGC activator BAY 60-2770 (Emax: 86.0% ± 3.2%) was significantly augmented under hypoxia (Emax: 94.4% ± 1.3%) or hypoxia/reoxygenation (Emax: 95.5% ± 1.1%). In addition, cGMP formation in response to BAY 41-2272 and BAY 60-2770 was inhibited and stimulated, respectively, under hypoxia or hypoxia/reoxygenation. The effects of hypoxia or hypoxia/reoxygenation on BAY 41-2272- and BAY 60-2770-induced vasorelaxation were completely canceled by the treatment with the superoxide dismutase mimetic tempol. These findings suggest that sGC redox equilibrium in the coronary artery is shifted towards the NO-insensitive form under hypoxia or hypoxia/reoxygenation and that superoxide seems to play an important role in this shift.
authors.affiliation: Department of Pharmacology, Shiga University of Medical Science, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tawa
authors.forename: Ayman
authors.initials: A
authors.lastname: Geddawy
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimosato
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Tomio
authors.initials: T
authors.lastname: Okamura
mesh_terms: D000818:Animals; D001565:Benzoates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003331:Coronary Vessels / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology*; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008251:Macaca; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012995:Solubility; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D006845:Hydrocarbons, Fluorinated; D011720:Pyrazoles; D011725:Pyridines; D013481:Superoxides; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D006162:Guanylate Cyclase; D006152:Cyclic GMP