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dc.typeArtigo de periódicopt_BR
dc.titleSoluble Guanylyl Cyclase (sgc) Degradation And Impairment Of Nitric Oxide-mediated Responses In Urethra From Obese Mice: Reversal By The Sgc Activator Bay 60-2770.pt_BR
dc.contributor.authorAlexandre, Eduardo Cpt_BR
dc.contributor.authorLeiria, Luiz Opt_BR
dc.contributor.authorSilva, Fábio Hpt_BR
dc.contributor.authorMendes-Silvério, Camila Bpt_BR
dc.contributor.authorCalmasini, Fabiano Bpt_BR
dc.contributor.authorDavel, Ana Paula Cpt_BR
dc.contributor.authorMónica, Fabíola Zpt_BR
dc.contributor.authorDe Nucci, Gilbertopt_BR
dc.contributor.authorAntunes, Edsonpt_BR
unicamp.authorEduardo C Alexandre, Departments of Pharmacology (E.C.A., L.O.L., F.H.S., C.B.M.S., F.B.C., F.Z.M., G.D.N., E.A.) and Anatomy, Cellular Biology, Physiology, and Biophysics (A.P.C.D.), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.pt_BR O Leiria,ptábio H Silva,pt B Mendes-Silvério,pt B Calmasini,pt Paula C Davel,ptíola Z Mónica,pt De Nucci,pt Antunes,pt
dc.subjectBiphenyl Compoundspt_BR
dc.subjectDose-response Relationship, Drugpt_BR
dc.subjectEnzyme Activationpt_BR
dc.subjectEnzyme Activatorspt_BR
dc.subjectGuanylate Cyclasept_BR
dc.subjectHydrocarbons, Fluorinatedpt_BR
dc.subjectMice, Inbred C57blpt_BR
dc.subjectMuscle Relaxationpt_BR
dc.subjectMuscle Tonuspt_BR
dc.subjectMuscle, Smoothpt_BR
dc.subjectNitric Oxidept_BR
dc.subjectReactive Oxygen Speciespt_BR
dc.subjectReceptors, Cytoplasmic And Nuclearpt_BR
dc.subjectUrinary Bladder, Overactivept_BR
dc.description.abstractObesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 μM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of β1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.en
dc.relation.ispartofThe Journal Of Pharmacology And Experimental Therapeuticspt_BR
dc.relation.ispartofabbreviationJ. Pharmacol. Exp. Ther.pt_BR
dc.identifier.citationThe Journal Of Pharmacology And Experimental Therapeutics. v. 349, n. 1, p. 2-9, 2014-Apr.pt_BR
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