Characterization and Functional Role of Androgen-Dependent PDE5 Activity in the Bladder

Abstract

Benign prostate hyperplasia is the most common disease in the aging male, often comorbid with erectile dysfunction. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) decrease lower urinary tract symptoms in patients with erectile dysfunction and BPH. We studied PDE5 expression and activity in the human bladder and PDE5i effects both in vitro (human and rat) and in vivo (rat). PDE5 is highly expressed in rat and human bladder and immunolocalized in vascular endothelium and muscle fibers. Sildenafil, tadalafil, and vardenafil blocked 70% of the total cGMP-catabolizing activity; vardenafil was the most potent (IC(50) = 0.3 nm). In human bladder cells and in rat strips, a PDE-resistant cGMP analog, SP-8-Br-PET-cGMPS, induced, respectively, a consistent antiproliferative and relaxant effect. In contrast, the nitric oxide donor sodium nitroprusside (SNP) was almost ineffective. However, blocking PDE5 with vardenafil increased SNP antiproliferative and relaxant activity up to the level observed with SP-8-Br-PET-cGMPS. We also found that castration decreased, and T supplementation restored, PDE5 gene expression in rat bladder. Accordingly, bladder strips from castrated rats were more sensitive to SNP-induced relaxation than strips from control or T-replaced rats, whereas in the presence of vardenafil, all groups showed the same SNP sensitivity. To discover whether vardenafil affects bladder activity in vivo, the rat bladder outlet obstruction model was used. Chronic treatment with 10 mg/kg.d vardenafil significantly reduced nonvoiding contractions (47%, P < 0.05 vs. placebo) up to tamsulosin level (51%). Overall, these results demonstrate that PDE5 regulates bladder smooth muscle tone, strongly limiting the nitric oxide/cGMP signaling, and that vardenafil, by blocking PDE5, may be a possible therapeutic option for bladder dysfunction by ameliorating irritative lower urinary tract symptoms.

Influence of serum testosterone on urinary continence and sexual activity in patients undergoing radical prostatectomy for clinically localized prostate cancer

“…This finding is in line with our published studies: as we previously showed in an in vitro study on the human bladder, PDE5 is expressed not only in the smooth muscle cells of the bladder wall but also in the endothelial and smooth muscle cells of the vessels. 28 We also showed that the continence recovery after nerve-sparing prostatectomy for PCa was strictly correlated with recovery of SF: thus, we concluded that PDE5 inhibitors can exhibit an activity in the lower urinary tract, even in the absence of the prostatic gland, by a pathway not including prostate. 29 Therefore, the androgen-dependent PDE5 activity of the bladder wall can explain the significant correlation between erectile function and urinary symptoms exclusively in patients with adequate T. In our experience, this activity can be provided both by the relaxation of the smooth muscle and by the improvement in perfusion of the bladder wall.…”

Association of lower urinary tract symptoms and erectile dysfunction: pathophysiological aspects and implications for clinical management

“…In rats, PDE5 expression is highest in the bladder, where it is expressed approximately 10-fold more than in the rat corpus cavernosum. 23 In an in vivo BOO model in which rat urethras were narrowed with a silk ligature was used, chronic treatment with 10 mg kg -1 per day of vardenafil significantly reduced bladder nonvoiding contractions by 47% compared with placebo. Tamsulosin demonstrated a comparable 51% reduction in nonvoiding contractions.…”

“…The same study demonstrated inhibition of human prostate stromal cell proliferation with vardenafil in vivo. 23 Tinel et al 24 utilized a rat model that demonstrated a PDE-inhibitor dosedependent reduction in smooth muscle contraction of bladder, urethral and prostate strips. A reduction in bladder nonvoiding contractions was noted in the rat BOO model after administration of sildenafil and vardenafil.…”

PDE5 inhibitors for LUTS

“…93 Experimental models, in human and rat tissue, have shown that PDE5 inhibitors decrease nonvoiding bladder contractions. 94,83 In addition, PDE5 inhibitors have been shown to improve urodynamic parameters in SCI patients. 82 PDE5 inhibitors offer an opportunity to treat ED and LUTS concurrently.…”

“…Thus, PDE5 inhibitors may act at an alternative site of action, separate from a-blockers. 83 Their effects may be secondary to relaxation of smooth muscle present in the prostate, urethra, and bladder neck, as well as their vascular supply. [84][85][86][87] In vitro studies have also shown that NO donor drugs and PDE5 inhibitors may stimulate anti-proliferative or apoptotic effects in the prostate, improved pelvic blood flow, and effects on afferent nerves from the prostate or bladder, resulting in their improvement of LUTS symptoms.…”