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

Author(s)

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

• Document type: Journal article
• Source: Journal of Pharmacology and Experimental Therapeutics; v. 359, n. 2, p. 230-237, NOV 1 2016.
• Web of Science Citations: 4

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 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)

• FAPESP's process: 14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches
• Grantee: Fernando Ferreira Costa
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/12495-6 - Optimization, synthesis and pharmacological evaluation of new drug candidates to treat the symptoms of sickle cell disease
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/19781-2 - Therapeutic prevention of priapism in transgenic sickle cell mice with drugs that interfere on the NO/sGC/cGMP signaling pathway.
• Grantee: Fábio Henrique da Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/21965-7 - Pharmacological evaluation of compound 4C to prevent priapism in transgenic sickle cell mice
• Grantee: Fábio Henrique da Silva
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor