Soluble Guanylyl Cyclase (sGC) Degradation and Impairment of Nitric Oxide-Mediated Responses in Urethra from Obese Mice: Reversal by the sGC Activator BAY 60-2770

dc.creatorAlexandre, EC
dc.creatorLeiria, LO
dc.creatorSilva, FH
dc.creatorMendes-Silverio, CB
dc.creatorCalmasini, FB
dc.creatorDavel, APC
dc.creatorMonica, FZ
dc.creatorDe Nucci, G
dc.creatorAntunes, E
dc.date2014
dc.dateAPR
dc.date2014-07-30T18:43:14Z
dc.date2015-11-26T16:49:25Z
dc.date2014-07-30T18:43:14Z
dc.date2015-11-26T16:49:25Z
dc.date.accessioned2018-03-28T23:36:10Z
dc.date.available2018-03-28T23:36:10Z
dc.identifierJournal Of Pharmacology And Experimental Therapeutics. Amer Soc Pharmacology Experimental Therapeutics, v. 349, n. 1, n. 2, n. 9, 2014.
dc.identifier0022-3565
dc.identifier1521-0103
dc.identifierWOS:000333179900001
dc.identifier10.1124/jpet.113.211029
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/71838
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/71838
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1275456
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionObesity 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-(5fluoro-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 mM) 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. Reactiveoxygen species (ROS) production was enhanced, but protein expression of beta 1 second guanylate cyclase subunit was reduced in USM from obesemice, 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.
dc.description349
dc.description1
dc.description2
dc.description9
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.languageen
dc.publisherAmer Soc Pharmacology Experimental Therapeutics
dc.publisherBethesda
dc.publisherEUA
dc.relationJournal Of Pharmacology And Experimental Therapeutics
dc.relationJ. Pharmacol. Exp. Ther.
dc.rightsfechado
dc.sourceWeb of Science
dc.subjectSpontaneously Hypertensive-rats
dc.subjectLower Urinary-tract
dc.subjectSmooth-muscle
dc.subjectHyperlipidemic Rat
dc.subjectMetabolic Syndrome
dc.subjectOxidative Stress
dc.subjectS-nitrosylation
dc.subjectNeural-control
dc.subjectAnimal-model
dc.subjectNo
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
dc.typeArtículos de revistas


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