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

Autor(es)

Silva, Fabio H. ; Karakus, Serkan ; Musicki, Biljana ; Matsui, Hotaka ; Bivalacqua, Trinity J. ; dos Santos, Jean L. ; Costa, Fernando F. ; Burnett, Arthur L.

• 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: 4

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: 14/00984-3 - Doenças dos glóbulos vermelhos: fisiopatologia e novas abordagens terapêuticas
• Beneficiário: Fernando Ferreira Costa
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• 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
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• 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
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• 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
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado