Stimulation of soluble guanylate cyclase by superoxide dismutase is mediated by NO.
Soluble guanylate cyclase (sGC), which is found in many cells and tissues, represents the receptor for the intra- and intercellular messenger molecule NO. Superoxide dismutase (SOD), an enzyme involved in the degradation of toxic superoxide radicals, has been proposed as a non-NO activator of sGC. Here we show that SOD stimulated sGC purified from bovine lung up to 10-fold. Activation by SOD was not influenced by the hydroxyl radical scavengers mannitol and DMSO. In contrast, the presence of the NO scavengers oxyhaemoglobin and 2-(4-carboxyphenyl)-4,4,5, 5-tetramethylimidazoline-1-oxyl-3-oxide, as well as the O2(-)-generating system xanthine oxidase/hypoxanthine, led to inhibition of SOD-stimulated cGMP production. NO-insensitive sGC mutants were not influenced either by SOD or by xanthine oxidase. We have previously shown that sGC was stimulated by NO present in the normal atmosphere. Here we show that the SOD effect depended on the NO concentration from the atmosphere, as the stimulation of sGC by defined NO gases (0, 120, 330 and 1000 parts per billion NO) was potentiated by SOD. NO stimulation of sGC and its potentiation by SOD were inhibited by oxyhaemoglobin to identical levels. We conclude that the SOD-mediated stimulation of sGC is due to the elimination of superoxide, thereby preventing its reaction with NO to form peroxynitrite.
Friebe
A
A
Institut für Pharmakologie, Freie Universität Berlin, D-14195 Berlin, Germany.
Schultz
G
G
Koesling
D
D
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002417:Cattle; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006834:Hydrazines / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D008353:Mannitol / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology* / Q000502:physiology; D009589:Nitrogen Oxides; D010108:Oxyhemoglobins / Q000494:pharmacology / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism*
D001565:Benzoates; D016166:Free Radical Scavengers; D006834:Hydrazines; D007093:Imidazoles; D009589:Nitrogen Oxides; D010108:Oxyhemoglobins; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D008353:Mannitol; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D013482:Superoxide Dismutase; D006162:Guanylate Cyclase