Activators of soluble guanylyl cyclase are of potential interest as treatment for cardiovascular diseases but to our knowledge they have never been proposed to treat overactive bladder. We evaluated the effects of the soluble guanylyl cyclase activator BAY 60-2270 on voiding dysfunction and detrusor overactivity in a mouse model of obesity associated overactive bladder. C57BL/6 male mice fed for 10 weeks with standard chow or a high fat diet were treated with 1 mg/kg BAY 60-2770 per day for 2 weeks via gavage. Cystometric evaluations were done and responses to contractile agents in isolated bladders were determined. Obese mice showed an irregular micturition pattern characterized by significant increases in voiding and nonvoiding contractions, which were normalized by BAY 60-2770. Carbachol, KCl and CaCl2 produced concentration dependent contractions in isolated bladder strips, which were markedly greater in obese than in lean mice. BAY 60-2770 normalized bladder contractions in the obese group. A 78% increase in reactive oxygen species generation in the bladder tissue of obese mice was observed, which was unaffected by BAY 60-2770. Treatment with BAY 60-2770 generated a tenfold increase in cyclic guanosine monophosphate in the bladders of obese mice without affecting the nucleotide level in the lean group. Protein expression of the soluble guanylyl cyclase α1 and β1 subunits was decreased 40% in the bladder tissue of obese mice but restored by BAY 60-2770. Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase α1 and β1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction.

Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 μM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of β1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.

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^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.