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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 359; no. 2; p. 230
• Main Authors: Silva, Fábio H, Karakus, Serkan, Musicki, Biljana, Matsui, Hotaka, Bivalacqua, Trinity J, Dos Santos, Jean L, Costa, Fernando F, Burnett, Arthur L
• Format: Journal Article
• Language: English
• Published: United States 01-11-2016
• Subjects: Acetylcholine - pharmacology; Anemia, Sickle Cell - complications; Animals; Cell Adhesion Molecules - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Dose-Response Relationship, Drug; Electric Stimulation; Gene Expression Regulation, Enzymologic - drug effects; Humans; Isoindoles - pharmacology; Isoindoles - therapeutic use; Male; Membrane Glycoproteins - metabolism; Mice; Microfilament Proteins - metabolism; NADPH Oxidase 2; NADPH Oxidases - metabolism; Nitrates - pharmacology; Nitrates - therapeutic use; Nitric Oxide Donors - pharmacology; Nitric Oxide Donors - therapeutic use; Nitroprusside - pharmacology; Oxidative Stress - drug effects; Penis - drug effects; Penis - metabolism; Phosphoproteins - metabolism; Phosphorylation - drug effects; Phthalimides - pharmacology; Phthalimides - therapeutic use; Priapism - complications; Priapism - drug therapy; Priapism - enzymology; Priapism - metabolism; Reactive Nitrogen Species - metabolism; Time Factors; Tyrosine - analogs & derivatives; Tyrosine - metabolism
• ISSN: 1521-0103
• DOI: 10.1124/jpet.116.235473

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 gp91
, 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.