title: 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.
abstract: Patients 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 μmol/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 gp91phox, 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.
authors.affiliation: James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland (F.H.S., S.K., B.M., H.M., T.J.B., A.L.B.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.H.S., F.F.C.); and Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil (J.L.S.) fabiohsilva87@gmail.com.
authors.forename: Fábio H
authors.initials: FH
authors.lastname: Silva
authors.affiliation: James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland (F.H.S., S.K., B.M., H.M., T.J.B., A.L.B.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.H.S., F.F.C.); and Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil (J.L.S.).
authors.forename: Serkan
authors.initials: S
authors.lastname: Karakus
authors.affiliation: James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland (F.H.S., S.K., B.M., H.M., T.J.B., A.L.B.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.H.S., F.F.C.); and Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil (J.L.S.).
authors.forename: Biljana
authors.initials: B
authors.lastname: Musicki
authors.affiliation: James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland (F.H.S., S.K., B.M., H.M., T.J.B., A.L.B.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.H.S., F.F.C.); and Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil (J.L.S.).
authors.forename: Hotaka
authors.initials: H
authors.lastname: Matsui
authors.affiliation: James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland (F.H.S., S.K., B.M., H.M., T.J.B., A.L.B.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.H.S., F.F.C.); and Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil (J.L.S.).
authors.forename: Trinity J
authors.initials: TJ
authors.lastname: Bivalacqua
authors.affiliation: James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland (F.H.S., S.K., B.M., H.M., T.J.B., A.L.B.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.H.S., F.F.C.); and Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil (J.L.S.).
authors.forename: Jean L
authors.initials: JL
authors.lastname: Dos Santos
authors.affiliation: James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland (F.H.S., S.K., B.M., H.M., T.J.B., A.L.B.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.H.S., F.F.C.); and Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil (J.L.S.).
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
authors.affiliation: James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland (F.H.S., S.K., B.M., H.M., T.J.B., A.L.B.); Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil (F.H.S., F.F.C.); and Laboratório de Pesquisa e Desenvolvimento de Fármacos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brazil (J.L.S.).
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Burnett
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000150:complications; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009566:Nitrates / Q000494:pharmacology* / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010413:Penis / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010797:Phthalimides / Q000494:pharmacology* / Q000627:therapeutic use; D011317:Priapism / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C000619419:3-(1,3-dioxoisoindolin-2-yl)benzyl nitrate; D015815:Cell Adhesion Molecules; D054833:Isoindoles; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009566:Nitrates; D020030:Nitric Oxide Donors; D010750:Phosphoproteins; D010797:Phthalimides; D026361:Reactive Nitrogen Species; D000098662:Vasodilator-Stimulated Phosphoprotein; D009599:Nitroprusside; C002744:3-nitrotyrosine; D014443:Tyrosine; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D000109:Acetylcholine