Introduction An important mechanism suggested to be responsible for diabetes-associated erectile dysfunction (ED) involves increased apoptosis, increased collagen deposition, and reduced smooth muscle content in the corpus cavernosum. Aim To determine whether the activation of the pro-apoptotic poly(adenosine diphosphate ribose) polymerase (PARP) pathway is involved in the induction of corporal apoptosis, and whether the administration of 3-aminobenzamide (3-AB), a specific PARP inhibitor, could ameliorate ED in diabetic rats. Methods Male Sprague-Dawley rats (8-weeks-old) were randomly divided into three groups: age-matched controls (C), diabetic controls (DM), and 3-AB-treated diabetic group (DM + 3-AB). Diabetes was induced by intraperitoneal (ip) injection of streptozotocin (50 mg/kg). Eight weeks after the induction of diabetes, DM + 3-AB group treated with 3-AB (30 mg/kg/day, ip) for 4 weeks. Main Outcome Measures At 12 weeks after diabetes induction, erectile function was assessed by cavernous nerve stimulation. Penile tissue was assessed for apoptosis, Masson’s trichrome stain and immunohistochemical analysis for smooth muscle alpha actin. Expression of poly(ADP-ribose), phospho-protein kinase B (Akt), phospho-Bcl-2-associated death promoter (Bad), B-cell leukemia/lymphoma 2 (Bcl-2), Bcl-2-associated X Protein (Bax), and apoptosis-inducing factor (AIF) were evaluated by Western blot. Caspase-3 activity and malondialdehyde (MDA), adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NAD+) concentrations were also determined. Results DM group showed impaired erectile function, increased PARP activity and corporal apoptosis, and decreased smooth muscle contents. Expression of phospho-Akt, phospho-Bad, Bcl-2, and concentrations of ATP and NAD+ were decreased in the DM group, whereas concentrations of MDA, expression of Bax, nuclear translocation of AIF, and caspase-3 activity were increased. Treatment with 3-AB restored erectile function and significantly reversed all molecular and histological alterations except for the increased MDA. Conclusions Over-activation of penile PARP pathway in diabetic rats enhances corporal apoptosis via energy depletion, suppression of Akt phosphorylation, and activation of the mitochondrial apoptotic pathway, which results in ED; these event could be prevented by treatment with 3-AB.

These results indicate that bladder apoptosis is involved in diabetic cystopathy via activation of the PARP/JNK/mitochondrial apoptotic pathway. These findings may be used to develop novel therapies for patients with diabetic bladder dysfunction.

Introduction Patients with diabetes exhibit more severe erectile dysfunction (ED) and are less responsive to first-line oral phosphodiesterase type 5 inhibitor (PDE5i). It has been suggested that increased collagen deposition and reduced smooth muscle content in the corpus cavernosum are important mechanisms for diabetes-associated ED and that transforming growth factor-β1 (TGF-β1) is a potent fibrotic factor responsible for the structural alterations in the corpus cavernosum. Aims The aims of this study are to determine whether activation of TGF-β1 and its downstream pathways is responsible for the reduced efficacy of the PDE5is in diabetic ED via abnormalities in cavernosal structures and to investigate the synergistic effects of the TGF-β1 antagonist P144 and sildenafil on erectile response. Methods Six weeks after inducting diabetes with streptozotocin in male Sprague-Dawley rats, age-matched control and diabetic rats were treated with vehicle, sildenafil, or P144 alone or in combination for 4 weeks, respectively. Main Outcome Measures Intracavernous pressure, dynamic infusion cavernosometry, and histological and molecular alterations of the corpus cavernosum were analyzed. Results Diabetic rats exhibited a decreased erectile response, severe corporal veno-occlusive dysfunction (CVOD), and structural alterations including cavernosal fibrosis and decreased smooth muscle content. Expression and activation of TGF-β1 and its downstream Smad and non-Smad pathways increased in diabetic rats. Treatment with sildenafil showed modest effect on erectile response and a less suppressive effect on CVOD, cavernosal fibrosis, and molecular alterations. Treatment with P144 had lower effect on erectile response, even greatly improved the histological and molecular alterations and CVOD than sildenafil. The combined treatment with P144 and sildenafil effectively restored erectile response, CVOD, and histological and molecular alterations. Conclusion An insufficient suppressive effect of sildenafil on cavernosal fibrosis, severe CVOD, and TGF-β1 pathways was implicated in reduced efficacy of the PDE5i in diabetic ED. Treatment with P144 synergized sildenafil and significantly increased erectile response by the potential antifibrotic activity.

Background/Aims: Transforming growth factor-β1 (TGF-β1) plays important roles in penile corporal fibrosis and veno-occlusive dysfunction (CVOD). Angiotensin II (Ang II) is critically involved in erectile dysfunction, and blocking of Ang II is more important than inhibition of TGF-β in non-penile tissue fibrosis. However, the role of Ang II in corporal fbrosis and CVOD in a diabetic condition has not been investigated. Methods: Diabetic rats were treated with sildenafil or losartan (an Ang II antagonist) alone or in combination. Intracavernosal pressure, dynamic infusion cavernosometry, and histological and molecular alterations of the corpus cavernosum were examined. Results: Diabetic rats exhibited decreases in erectile response, severe CVOD, apoptosis, fibrosis, and activation of the TGF-β1 pathway. Treatment with sildenafil had a modest effect on erectile response and an insignificant suppressive effect on CVOD, apoptosis, fibrosis, and the TGF-β1 pathway. Although losartan greatly improved the histological and molecular changes and CVOD as compared with sildenafil, its effect on erectile response was low. The combination of sildenafil and losartan had superior effects on these parameters than did either compound alone. Conclusion: Ang II activation may be involved in apoptosis and fibrosis of the corpus cavernosum through Smad and non-Smad pathways, resulting in CVOD and ED. The low efficacy of sildenafil in a diabetic ED rat model was at least partly due to its inadequate effects on apoptosis, fibrosis, and CVOD.

It has been demonstrated that increases in poly(ADP-ribose) polymerase (PARP) activity causes damage to several organs under ischemia/reperfusion (I/R) conditions. The aims of this study were to investigate whether inhibition of PARP could suppress apoptosis in the bladder following acute urinary retention (AUR) and subsequent bladder emptying. Twelve-week-old male Sprague Dawley rats were divided into a control group, saline treated group, and 3-aminobenzamide (3-AB, a specific PARP inhibitor)-treated group. Sixty minutes after the administration of saline and 3-AB, the saline and 3-AB-treated groups had 60 min of over-distension and followed by 2 h of drainage. The degree of bladder apoptosis, levels of malondialdehyde (MDA), ATP and nicotinamide adenine dinucleotide (NAD+); expression of poly(ADP-ribose) (PAR), phosphorylation of protein kinase B (Akt); and levels of Bcl-2, Bax, and caspase 3 activity in the bladder were determined. Molecular and histological analyses showed that bladder apoptosis was associated with increases in the amount of PAR and decreases in ATP and NAD+ levels in the saline treated group. In addition, phosphorylated Akt and Bcl-2/Bax ratio were significantly decreased. The activity of caspase 3 was significantly increased in the saline treated group. Inhibition of PARP significantly increased the levels of ATP and NAD+, phosphorylation of Akt, and Bcl-2/Bax ratio, and significantly reduced the activation of caspase 3. As a result, apoptosis in the bladder was attenuated. These results indicate that PARP activation may be involved in apoptosis in the bladder induced by AUR and subsequent emptying via energy depletion and suppression of Akt activity.