Separate or combined treatments with daily sildenafil, molsidomine, or muscle-derived stem cells prevent erectile dysfunction in a rat model of cavernosal nerve damage.

INTRODUCTION: Long-term daily administration of phosphodiesterase type 5 (PDE5) inhibitors in the rat prevents or reverses corporal veno-occlusive dysfunction (CVOD) and smooth muscle cell (CSMC) loss and fibrosis, in both aging and bilateral cavernosal nerve resection (BCNR) models for erectile dysfunction. In the aging rat model, corporal implantation of skeletal muscle-derived stem cells (MDSC) reverses CVOD. Nitric oxide (NO) and cyclic guanosine monophosphate can modulate stem cell lineage. AIM: To investigate in the BCNR model the effects of sildenafil at lower doses, alone or in combination with MDSC or the NO donor molsidomine, on CVOD and the underlying corporal histopathology. MAIN OUTCOMES MEASURES: CVOD, histological, and biochemical markers in rat corporal tissue. Methods. Rats subjected to BCNR were maintained for 45 days either untreated, or received sildenafil in the water or retrolingually at 10, 2.5, and 1.25 mg/kg/day (medium, low, and very low doses), or intraperitoneal molsidomine, or MDSC implantation into the corpora cavernosa separately or in combination. Cavernosometry evaluated CVOD. Histopathology was assessed on penile sections by Masson trichrome, immunohistochemistry for α-smooth muscle actin (ASMA), or immunofluorescence for neuronal nitric oxide synthase (nNOS)/neurofilament 70, and in fresh tissue by Western blot for various markers and picrosirius red for collagen. RESULTS: All treatments normalized erectile function (drop rate), and most increased the CSMC/collagen ratio and ASMA expression in corporal tissue sections, and reduced collagen content in the penile shaft. MDSC also increased nNOS and brain-derived neurotrophic factor. The combination treatment was not superior to MDSC or sildenafil given alone, and upregulated PDE5. CONCLUSIONS: Lowering the dose of a continuous long-term sildenafil administration still maintained the prevention of CVOD in the BCNR rat previously observed, but it was less effective on the underlying histopathology. As in the aging rat model, MDSC also counteracted CVOD, but supplementation with very low-dose sildenafil did not improve the outcome.

Amelioration of diabetes-induced cavernosal fibrosis by antioxidant and anti-transforming growth factor-ß1 therapies in inducible nitric oxide synthase-deficient mice.

OBJECTIVE: • To investigate whether sustained long-term separate treatments of diabetic inducible nitric oxide synthase knockout (iNOSKo) mice with allopurinol, an antioxidant inhibiting xanthine oxidoreductase, decorin, a transforming growth factor-ß1 (TGFß1) -binding antagonist, and molsidomine, a long-life nitric oxide donor, prevent the processes of diabetes-induced cavernosal fibrosis. MATERIALS AND METHODS: • Eight week old male iNOS knock out (iNOSKo) mice were made diabetic by injecting 150 mg/kg B.W Streptozotocin (1P) with were either left untreated or treated with the oral antioxidant allopurinol (40 mg/kg/day), or decoin (50 mg, 1P, twice), as an anti-TGFß1 agent (n = 8/group). • Glycemia and oxidative stress markers were determined in blood and urine. • Paraffin-embedded tissue sections from the penile shaft were subjected to Masson trichrome staining for the smooth muscle (smc)/collagen ratio, and imunostaining for smc content, profibrotic factors, oxidative stress, cell replication and cell death markers followed by quantitative image analysis. RESULTS: • Eight-week treatment with either allopurinol or decorin counteracted the decrease in smooth muscle cells and the increase in apoptosis and local oxidative stress within the corpora tissue. • Decorin but not allopurinol increased the smooth muscle cell/collagen ratio, whereas allopurinol but not decorin inhibited systemic oxidative stress. • Molsidomine was effective in reducing both local and systemic oxidative stress, but did not prevent corporal fibrosis. CONCLUSION: • Both allopurinol and decorin appear as promising approaches either as a single or a combined pharmacological modality for protecting the diabetic corpora from undergoing apoptosis and fibrosis although their functional effects still need to be defined.

The genetic inactivation of inducible nitric oxide synthase (iNOS) intensifies fibrosis and oxidative stress in the penile corpora cavernosa in type 1 diabetes.

INTRODUCTION: Endogenously elicited inducible nitric oxide synthase (iNOS) induction counteracts fibrosis and oxidative stress in penile tissues in rat models of Peyronie's disease and erectile dysfunction. AIM: The current study aimed to determine whether the genetic blockade of iNOS expression in the iNOS knock out (iNOS KO) mouse intensifies fibrosis and oxidative stress in the penile corpora cavernosa, and this is exacerbated by streptozotocin (STZ)-induced diabetes and counteracted by insulin. MAIN OUTCOMES MEASURES: Quantitative assessment of histological and biochemical markers in mouse corporal tissue. METHODS: Male iNOS KO and wild type (WT) mice were left untreated or injected with STZ, with or without insulin treatment. At 8 weeks, glycemia, glucosuria, and proteinuria were determined, and corporal tissue sections were obtained and subjected to Masson trichrome staining for smooth muscle (SM)/collagen ratio, and immunostaining for α-smooth muscle actin (ASMA) for, SM content, proliferating cell nuclear antigen (PCNA) for cell replication, TGFß1 as profibrotic factor, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis, and xanthine oxidoreductase (XOR) for oxidative stress. Collagen was estimated by the hydroxyproline reaction. RESULTS: The corporal SM/collagen ratio and SM content were reduced, and collagen content increased in iNOS KO mice as compared with WT mice, but apoptosis was decreased and cell replication increased, whereas TGFß1 and XOR did not vary. Severe hyperglycemia caused in the WT a reduction of the corporal SM/collagen ratio and SM content and an increase in apoptosis without changes in PCNA, TGFß1, or XOR. In the iNOS KO mouse the hyperglycemia-induced alterations were exacerbated, with additional increases in oxidative stress and TGFß1. Insulin normalized glycemia and partially protected the SM in both the WT and the iNOS KO mice. CONCLUSIONS: The antifibrotic, antioxidative, and SM-protective roles of iNOS in the penile corpora cavernosa were confirmed in the iNOS KO/STZ mouse model. These findings support the importance of endogenously-elicited iNOS induction in protecting the penile corpora cavernosa from the pro-fibrotic effects of hyperglycemia.

Renegotiating masculine identity after prostate cancer treatment.

Because little is known about how low-income Latino and African American men attribute meaning and adapt to prostate cancer treatment-related symptoms relative to masculine identity, in this study we sought to develop a descriptive model of this process. Using qualitative methods, 60 Latino and 35 African American/Black men were interviewed by language- and ethnicity-matched male interviewers using a semistructured guide. Interviews were audiotaped and transcribed verbatim. Spanish transcripts were rigorously translated to produce English transcripts. Analysis using grounded theory techniques found that men constructed masculine identities that were influenced by early experience, challenged by several factors including prostate cancer treatment, and underwent a renegotiation process that resulted in the maintenance of their identity as men. Development and testing of interventions that support this process will facilitate the adaptation process for men in a culturally relevant manner.