Purpose Priapism is a vasculopathy occurring in approximately 40% of patients with SCD. Mouse models have suggested that dysregulated NOS and RhoA/ROCK signaling as well as increased oxidative stress may contribute to mechanisms of SCD-associated priapism. We examined changes in protein expressions of NOS and ROCK signaling pathways and a source of oxidative stress, NADPH oxidase, in penile erectile tissue from patients with priapism histories, etiologically related and unrelated to SCD. Materials and Methods Human penile erectile tissue was obtained from patients with SCD-associated priapism (SCD, n=5) and priapism of other etiologies (non-SCD, n=6) during non-emergent penile prosthesis surgery for ED or priapism management and urethroplasty, and from control patients without priapism histories (Control, n=5) during penectomy for penile cancer. Samples were collected, immediately placed in cold buffer and then frozen in liquid nitrogen. Expressions of PDE5, eNOS, nNOS, iNOS, RhoA, ROCK1, ROCK2, p47phox, p67phox, gp91phox and β-actin were determined by Western blot analysis and NO amount was measured using the Griess reaction. Results In the SCD group, PDE5 (p<0.05), eNOS (p<0.01) and RhoA (p<0.01) expressions were significantly decreased while gp91phox (p<0.05) expression was significantly increased compared to Control group values. In the non-SCD group, eNOS (p<0.05), ROCK1 (p<0.05) and p47phox (p<0.05) expressions were significantly decreased compared to Control group values. Total NO levels were not significantly different across study groups. Conclusions The mechanisms of SCD-associated priapism in the human penis may involve dysfunctional NOS and ROCK signaling and increased oxidative stress associated with NADPH oxidase-mediated signaling.

We evaluated the therapeutic potential of a sustained nitric oxide (NO)-releasing compound to correct the molecular hallmarks and pathophysiology of priapism, an important but poorly characterized erectile disorder. 1,5-Bis-(dihexyl-N-nitrosoamino)-2,4-dinitrobenzene (C6') and an inactive form of the compound [1,5-bis-(dihexylamino)-2,4-dinitrobenzene (C6)] were tested in neuronal cell cultures and penile lysates for NO release (Griess assay) and biological activity (cGMP production). The effect of local depot C6' or C6 was evaluated in mice with a priapic phenotype due to double neuronal and endothelial NO synthase deletion (dNOS(-/-)) or human sickle hemoglobin transgenic expression (Sickle). Changes in NO signaling molecules and reactive oxygen species (ROS) surrogates were assessed by Western blot. The physiological response after C6' treatment was assessed using an established model of electrically stimulated penile erection. C6' generated NO, increased cGMP, and dose dependently increased NO metabolites. C6' treatment reversed abnormalities in key penile erection signaling molecules, including phosphodiesterase type 5, phosphorylated endothelial nitric oxide synthase, and phosphorylated vasodilator-stimulated phosphoprotein. In Sickle mice, C6' also attenuated the increased ROS markers gp91(phox), 4-hydroxynonenal, and 3-nitrotyrosine. Finally, C6' corrected the excessive priapic erection response of dNOS(-/-) mice. Exogenous sustained NO release from C6' corrects pathological erectile signaling in mouse models of priapism and suggests novel approaches to human therapy.

Combined inflatable penile prosthesis-artificial urinary sphincter implantation and staged prosthesis implantation are feasible without an increased risk of adverse outcomes compared to implantation of a single prosthesis. Patients with concomitant erectile dysfunction and stress urinary incontinence should be counseled about the possible advantages of this surgical option, which include a single anesthesia event and faster resumption of sexual activity and urinary control.

Straightening maneuvers (SM), including manual penile modeling, tunical relaxing incisions and corporal reconstruction using grafting techniques, are occasionally required during inflatable penile prosthesis (IPP) implantation to ensure functional penile straightness. The aim of this study was to compare the outcomes of men undergoing SM employed during IPP implantation compared with those wherein these maneuvers were not required. A retrospective review of 391 patients undergoing IPP implantation at the Johns Hopkins Hospital from January 2000 to December 2011 was performed. Patients in whom some SM was employed (SM, n=93, 23.9% of the overall cohort) were compared with those for whom SM was not required (IPP group, n=298). Seven patients were excluded from final analysis (6 patients with IPPs inserted in neophalli (SM group), and 1 patient with incomplete data (IPP group). Patients in whom a SM was used were younger (55.4 vs 62.3 years), more likely to have Peyronie's disease, and less likely to have prostate cancer, radical prostatectomy or to have previously used erectile aids (all P<0.05). Mean operating room time in the SM group was longer (173.8 vs 152.9 min, P=0.003). Within the SM group, modeling was performed in 40 (43%), tunical relaxing incisions in 37 (39.8%) and tunical reconstruction in 16 (17.2%) (most commonly using allograft dermis or pericardium, or synthetic gore-tex grafts). There were no significant differences in terms of device infection (P=0.15), mechanical failure (P=0.23) or erosion (P=0.96). Although limited in size, this cohort study suggests that IPP implantation in men with penile deformity requiring complex reconstruction to achieve straightening may be done proficiently and without increased adverse outcome risk.

Objective To characterize transforming growth factor beta1 (TGFβ1) and related signaling pathway proteins in a large cohort of human penile tissue (HPT) samples. Methods HPT was collected from patients undergoing penile prosthesis implantation (PPI) for erectile dysfunction (ED) and divided into 2 groups: post-radical prostatectomy ED (RP-ED; n=57) or organic ED (O-ED; n=30). HPT from patients undergoing partial penectomy without ED was used as controls (CON; n=6). Western blot analysis was performed to investigate the protein expressions of TGFβ1, thrombospondin 1 (TSP1; an activator of TGFβ1), fibronectin (FN; an extracellular matrix glycoprotein induced by TGFβ1) and a family of transcriptional factors activated by TGFβ1 [Smad2, phospho-Smad2-serine-465/467 (pSmad2), Smad3, phospho-Smad3-serine-423/425 (pSmad3)]. Results Expressions of TGFβ1 and TSP1 were significantly higher in both RP-ED (p<0.05) and O-ED (p<0.05) groups compared to that of the CON group, and were not different between either ED groups. Expressions of Smad2, pSmad2, Smad3, pSmad3 and FN were similar among all groups. Within the RP-ED group, a subgroup analysis showed that time from RP to PPI was related to increased expression of pSmad2 (p<0.05) and previous history of intracavernosal injection was related to increased expression of TGFβ1 (p<0.05) . Conclusion Our results demonstrate that TSP1 and TGFβ1-dependent fibrotic changes occur in penile tissue in patients with ED regardless of etiology. The unchanged expression of the Smad transcriptional factors may be reconciled by a Smad-independent downstream signaling pathway transmitting TGFβ1 signals.