Phosphodiesterase-5 Expression and Function in the Lower Urinary Tract: A Critical Review

Lin, Chen; Albersen, Maarten; Xin, Zhongcheng; Namiki, Mikio; Müller, Dieter; Lue, Tom F.

doi:10.1016/j.urology.2012.11.028

Cited by 19 publications

(8 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These changes include overactivity of the autonomic nervous system, pelvic ischemia, a decrease in pelvic nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling, atherosclerosis, and elevated Rho-kinase activity (which results in control of myosin phosphatase activity and, therefore, facilitates smooth prostatic muscle contractions) [3]. Several research studies suggest an elevated expression of phosphodiesterase type 5 (PDE5) to be present in the lower part of the urinary tract and the supporting vasculature [4][5][6][7][8]. Furthermore, inhibition of PDE5 has been observed to decrease the proliferation of prostate cells, while also decreasing the number of smooth muscle cells (SMCs) in the prostate, bladder, neck, and supporting vasculature.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Attenuation of Benign Prostatic Hyperplasia by Optimized Tadalafil Loaded Pumpkin Seed Oil-Based Self Nanoemulsion: In Vitro and In Vivo Evaluation

2019

View full text Add to dashboard Cite

The FDA has approved tadalafil (TDL) for the treatment of benign prostatic hyperplasia (BPH)-associated symptoms. Pumpkin seed oil (PSO) has shown promise for the relief of prostatitis-related lower urinary tract symptoms. The aim was to improve TDL delivery to the prostate and assess the combined effect of TDL with a PSO-based formula in the management of BPH. PSO, Tween 80, and polyethylene glycol 200 were selected for the optimization of self nano-emulsified drug delivery system (SNEDDS). The formed vesicles were assessed for their globule size and zeta potential. A rat in vivo study was carried out to investigate prostate weight and index, histopathology, and pharmacokinetics. The average globule size for the optimized TDL-PSO SNEDDS was 204.8 ± 18.76 nm, with a zeta-potential value of 7.86 ± 1.21 mV. TDL-PSO SNEDDS produced a marked drop in prostate weight by 35.51% and prostate index by 36.71% compared to the testosterone-only group. Pharmacokinetic data revealed a 2.3-fold increase of TDL concentration, from optimized TDL-PSO SNEDDS, in the prostate compared with the raw TDL group. This study indicated that the combination of TDL and PSO in an optimized TDL PSO SNEDDS formula improved the efficacy of TDL in the management of BPH.Pharmaceutics 2019, 11, 640 2 of 13 PDE5 also elevates the amount of blood reaching the lower urinary tract, while influencing the afferent nerve activity of the bladder [5,9,10]. Moreover, bladder performance can be impacted by functional and structural variations in the prostate, bladder, and the vasculature supporting such structures [11]. This elevation in cGMP concentration results in an efflux of calcium and relaxation of the SMCs. Several processes may aid in the alleviation of lower urinary tract symptoms (LUTS) and can be facilitated by PDE5 isoenzyme inhibition in the lower part of the urinary tract [4]. Altogether, the administration of 5 mg of tadalafil (TDL) in a daily manner led to significantly better results compared to the placebo. The safety profile of TDL was promising, and TDL was found to be well-tolerated [1,12]. Thus, the findings of these studies supported administering TDL 5 mg once a day as a treatment for benign LUTS suggestive of BPH [1,12,13]. TDL (5 mg) was approved by the FDA to be taken once a day for the treatment of LUTS symptoms linked to BPH. A randomized, double-blind, placebo-controlled, parallel design study using 2.5 mg of TDL over 12 weeks indicated improvements in the international prostate symptom score (IPSS) [14]. TDL increased pelvic perfusion by up-regulating NO and cGMP, which reduced the prostatic ischemia and improved the blood circulation.Pumpkin seed oil (PSO) is a part of the Cucurbitaceae family that has demonstrated excellent potential for the treatment of nocturia, urinary incontinence, and the frequency of urination in clinical trials [9]. PSO's chemical composition includes fatty acids, tocopherols, and phytosterols, in addition to squalene (triterpene). The main fatty acids that constitute about 90% of PSOs are palmitic aci...

show abstract

Section: Introductionmentioning

confidence: 99%

RETRACTED: Attenuation of Benign Prostatic Hyperplasia by Optimized Tadalafil Loaded Pumpkin Seed Oil-Based Self Nanoemulsion: In Vitro and In Vivo Evaluation

2019

View full text Add to dashboard Cite

show abstract

“…Note that the evaluation of PDE5 expression in the prostate has been highly controversial, with levels ranging from extremely low to highly abundant, and this discrepancy also occurs between western blot and immunostaining analyses within this article. 54 One common denominator shared by all of the abovementioned androgen-for-PDE5-regulation papers is the lack of smooth muscle control. It is well known that castration causes reduction of cavernous and prostatic smooth muscles.…”

Section: Resultsmentioning

confidence: 99%

“…69 This finding also contradicts the notion that androgen is a positive regulator for PDE5 expression because PDE5 inhibitors have been rather consistently shown to improve lower urinary tract symptoms. 54 Thus, direct positive androgen regulation of PDE5 expression is inconsistent with clinical findings whether in ED or lower urinary tract symptoms.…”

Section: Resultsmentioning

confidence: 99%

Direct androgen regulation of PDE5 gene or the lack thereof

et al. 2013

View full text Add to dashboard Cite

Inhibition of phosphodiesterase-5 (PDE5) is a well-known mechanism for the effective treatment of erectile dysfunction (ED). Androgen supplementation has also been prescribed for treating ED. However, it has been widely accepted that androgen can upregulate PDE5 expression, and thus creating a paradox in which a positive regulator of erectile function (androgen) could possibly increase the level of a negative regulator (PDE5). To solve this paradox, we conducted a systematic search of the PubMed and a non-systematic search of the Internet using PDE5, erectile, penis, testosterone and androgen as keywords. The retrieved papers were analyzed for data concerning the expression and regulation of PDE5 by androgens. Human and rat PDE5A gene sequences were retrieved from GenBank and computer-analyzed. The results showed that a putative androgen-response element (ARE) was reported in a study of human PDE5A gene promoter, and this prompted a separate study on whether androgen regulates PDE5 expression. The positive outcome in the latter study has since been cited in 17 review and editorial articles as the underlying mechanism for androgen's therapeutic effects on ED. In addition, five other research studies also reached the same conclusion. On the other hand, two independent studies on the genome-wide searches for androgen-regulated genes did not find PDE5A as a candidate. Sequence analysis conducted in this study also failed to find ARE in rat PDE5A gene. Two independent studies on Leydig cells also failed to find positive regulation of PDE5 expression by androgen. Two other studies found concomitant reduction of cavernous smooth muscle and PDE5 expression in castrated rats. One of these studies also found no effect of androgen on PDE5 expression in cultured cavernous smooth muscle cells. Thus, it appears that reduced PDE5 expression in castrated animals is due to reduced smooth muscle content and that PDE5A gene is not directly regulated by androgens.

show abstract

“…However, the involvement of changes in the production and efficacy of NO in urethral dysfunction due to diabetes has been little documented in the literature. These recently studies demonstrated the impact of sildenafil on micturition behavior and urethral tone, and that irrespective of the hormonal status, sildenafil decreased leak point pressure by a nNOS-mediated mechanism [15][16][17] .…”

Section: Urethral Pressure During Detrusor Contraction (Upc)mentioning

confidence: 97%

Urethral dysfunction due to alloxan-induced diabetes. Urodynamic evaluation and action of sildenafil citrate

Pegorare

Gonçalves²,

Oliveira³

et al. 2014

Acta Cir. Bras.

View full text Add to dashboard Cite

Brazil. Design the protocol, final approval of the version to be published. ABSTRACT PURPOSE:To evaluate the effect of diabetes mellitus and of sildenafil citrate on female urethral function. METHODS:Twenty nine female rats were divided into four groups: G1 -(n=9), normal rats; G2 -(n=6), normal rats treated with sildenafil citrate; G3 -(n=9) rats with alloxan-induced diabetes; G4 -(n=5) rats with alloxan-induced diabetes treated with sildenafil citrate. Under anesthesia, urodynamic evaluation was performed by cystometry and urethral pressure simultaneously. RESULTS:A significant increase in urethral pressure was observed during micturition. CONCLUSION:Sildenafil citrate can partially reduced urethral pressure in diabetic female rats.

show abstract

Phosphodiesterase-5 Expression and Function in the Lower Urinary Tract: A Critical Review

Cited by 19 publications

References 47 publications

RETRACTED: Attenuation of Benign Prostatic Hyperplasia by Optimized Tadalafil Loaded Pumpkin Seed Oil-Based Self Nanoemulsion: In Vitro and In Vivo Evaluation

RETRACTED: Attenuation of Benign Prostatic Hyperplasia by Optimized Tadalafil Loaded Pumpkin Seed Oil-Based Self Nanoemulsion: In Vitro and In Vivo Evaluation

Direct androgen regulation of PDE5 gene or the lack thereof

Urethral dysfunction due to alloxan-induced diabetes. Urodynamic evaluation and action of sildenafil citrate

Contact Info

Product

Resources

About