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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

Texto completo
Autor(es):
Silva, Fabio H. ; Karakus, Serkan ; Musicki, Biljana ; Matsui, Hotaka ; Bivalacqua, Trinity J. ; dos Santos, Jean L. ; Costa, Fernando F. ; Burnett, Arthur L.
Número total de Autores: 8
Tipo de documento: Artigo Científico
Fonte: Journal of Pharmacology and Experimental Therapeutics; v. 359, n. 2, p. 230-237, NOV 1 2016.
Citações Web of Science: 6
Resumo

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 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. (AU)

Processo FAPESP: 13/19781-2 - Terapêutica de prevenção do priapismo em camundongos transgênicos para anemia falciforme com drogas que interferem na via de sinalização NO/GCs/GMPc
Beneficiário:Fábio Henrique da Silva
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 10/12495-6 - Otimização, síntese e avaliação farmacológica de novos candidatos a fármacos para tratamento dos sintomas da anemia falciforme
Beneficiário:Jean Leandro dos Santos
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 14/00984-3 - Doenças dos glóbulos vermelhos: fisiopatologia e novas abordagens terapêuticas
Beneficiário:Fernando Ferreira Costa
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 14/21965-7 - Avaliação farmacológica do composto 4C para prevenir o priapismo em camundongos transgênicos para anemia falciforme
Beneficiário:Fábio Henrique da Silva
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado