Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment

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dc.contributor.authorSilva, Fabio H.
dc.contributor.authorKarakus, Serkan
dc.contributor.authorMusicki, Biljana
dc.contributor.authorMatsui, Hotaka
dc.contributor.authorBivalacqua, Trinity J.
dc.contributor.authorSantos, Jean L. dos [UNESP]
dc.contributor.authorCosta, Fernando F.
dc.contributor.authorBurnett, Arthur L.
dc.contributor.institutionJohns Hopkins Sch Med
dc.contributor.institutionUniversidade Estadual de Campinas (UNICAMP)
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.date.accessioned2018-11-26T17:13:49Z
dc.date.available2018-11-26T17:13:49Z
dc.date.issued2016-11-01
dc.description.abstractPatients with sickle cell disease (SCD) display priapism, and dysregulated nitric oxide (NO) pathway may contribute to this condition. However, current therapies offered for the prevention of priapism in SCD are few. The 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate (compound 4C) was synthesized through molecular hybridization of hydroxyurea and thalidomide, which displays an NO-donor property. This study aimed to evaluate the effects of compound 4C on functional and molecular alterations of erectile function in murine models that display low NO bioavailability, SCD transgenic mice, and endothelial NO synthase and neuronal NO synthase double gene-deficient (dNOS(-/)) mice, focusing on the dysregulated NO-cGMP-phosphodiesterase type 5 (PDE5) pathway and oxidative stress in erectile tissue. Wild-type, SCD, and dNOS(-/-) mice were treated with compound 4C (100 mu mol/kg/d, 3 weeks). Intracavernosal pressure in anesthetized mice was evaluated. Corpus cavernosum tissue was dissected free and mounted in organ baths. SCD and dNOS(-/-) mice displayed a priapism phenotype, which was reversed by compound 4C treatment. Increased corpus cavernosum relaxant responses to acetylcholine and electrical-field stimulation were reduced by 4C in SCD mice. Likewise, increased sodium nitroprusside-induced relaxant responses were reduced by 4C in cavernosal tissue from SCD and dNOS(-/-) mice. Compound 4C reversed PDE5 protein expression and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91(phox), and 3-nitrotyrosine in penises from SCD and dNOS(-/-) mice. In conclusion, 3-week therapy with the NO donor 4C reversed the priapism in murine models that display lower NO bioavailability. NO donor compounds may constitute an additional strategy to prevent priapism in SCD.en
dc.description.affiliationJohns Hopkins Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD USA
dc.description.affiliationJohns Hopkins Sch Med, Dept Urol, Baltimore, MD USA
dc.description.affiliationUniv Estadual Campinas, Hematol & Hemotherapy Ctr, Rua Carlos Chagas,480,Cidade Univ, BR-13083970 Campinas, SP, Brazil
dc.description.affiliationUniv Estadual Paulista, Fac Ciencias Farmaceut, Lab Pesquisa & Desenvolvimento Farmacos, Araraquara, SP, Brazil
dc.description.affiliationUnespUniv Estadual Paulista, Fac Ciencias Farmaceut, Lab Pesquisa & Desenvolvimento Farmacos, Araraquara, SP, Brazil
dc.description.sponsorshipNational Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIdNational Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases: R01DK067223
dc.description.sponsorshipIdFAPESP: 2010/12495-6
dc.description.sponsorshipIdFAPESP: 2013/19781-2
dc.description.sponsorshipIdFAPESP: 2014/21965-7
dc.description.sponsorshipIdFAPESP: 2014/00984-3
dc.format.extent230-237
dc.identifierhttp://dx.doi.org/10.1124/jpet.116.235473
dc.identifier.citationJournal Of Pharmacology And Experimental Therapeutics. Bethesda: Amer Soc Pharmacology Experimental Therapeutics, v. 359, n. 2, p. 230-237, 2016.
dc.identifier.doi10.1124/jpet.116.235473
dc.identifier.issn0022-3565
dc.identifier.urihttp://hdl.handle.net/11449/162238
dc.identifier.wosWOS:000389605500001
dc.language.isoeng
dc.publisherAmer Soc Pharmacology Experimental Therapeutics
dc.relation.ispartofJournal Of Pharmacology And Experimental Therapeutics
dc.relation.ispartofsjr1,586
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.titleBeneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatmenten
dc.typeArtigo
dcterms.rightsHolderAmer Soc Pharmacology Experimental Therapeutics

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