ORIGINAL RESEARCHPhosphodiesterase Type 5 Expression in Human and Rat Lower Urinary Tract Tissues and the Effect of Tadalafil on Prostate Gland Oxygenation in Spontaneously Hypertensive Rats
Introduction
In the last few years, phosphodiesterase type 5 (PDE5) inhibitors (PDE5i)—the approved, gold standard, therapy for erectile dysfunction (ED)—have gained much interest in urology research for the treatment of lower urinary tract (LUT) symptoms (LUTS), secondary to benign prostatic hyperplasia (BPH), another common condition affecting the aging male. Accordingly, several clinical studies showed a clear effect of all the three PDE5i (vardenafil, sildenafil, and tadalafil) in improving LUTS in men with or without ED 1, 2, 3, 4, 5, 6, 7, 8, 9
It is well known that PDE5 inhibition improves erectile function through the amplification of the relaxing pathway mediated by nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in penile musculature. However, the mechanism of action of PDE5i in LUT remains to be fully elucidated. Several evidences have been collected in different species, including humans, about a physiological role of NO/cGMP in LUT, regulating smooth muscle tone of bladder, prostate, and prostatic urethra, as well as prostate glandular secretion, and local blood flow 10, 11, 12. Indeed, the cGMP hydrolyzing activity of PDE5 strongly limits relaxation in bladder musculature [11], most probably by decreasing the activity of the RAS homologue of small G‐protein A (RhoA)/Rho‐kinase contractile signaling through a cGMP‐protein kinase (PKG)‐dependent phosphorylation of RhoA, which remains docked into the cytoplasm in an inactive state [13]. Moreover, it has been demonstrated that in human LUT and penis, PDE5 is present not only in the muscular wall but also in the endothelial and smooth muscle cells of the vascular bed 11, 12, 14. When PDE5 expression and activity were analyzed in human smooth muscle cells isolated from LUT tissues, it was found that prostate exhibited the lowest amount and functional activity in comparison with bladder and urethra [12]. In human prostate, PDE5 expression was predominantly localized in the endothelial cells of vascular bed [12], thus suggesting a possible action of PDE5i on prostate blood flow. The functional significance of PDE5 expression in prostate vasculature is still unclear.
The spontaneous hypertensive rat (SHR) is a rat strain characterized by an excessive neuroendocrine activity (sympathetic overactivity) and a commonly used model to study both LUT (such as BPH and overactive bladder) and EDs 15, 16, 17, 18, 19. This genetically selected rat strain is characterized by a reduced pelvic blood flow to the genitourinary tract, when compared with its control strain, Wistar‐Kyoto (WKY) rats [20]. In SHR, ischemia/hypoxia in the LUT leads to morphological/structural alterations, such as prostate and bladder fibrosis, increased prostate and bladder contractions, and an increase in urethral resistance 21, 22. Accordingly, we recently demonstrated in SHR the presence of bladder hypoxia that was ameliorated by acute treatment with the PDE5i vardenafil, administered 90 minutes before the sacrifice [23]. We also previously demonstrated the ability of both short‐ (1, 5, and 10 days) and long‐term (12 weeks) PDE5 inhibition (sildenafil and tadalafil, respectively) in improving penile oxygenation in a rat model of penile hypoxia induced by bilateral cavernous neurotomy 24, 25, 26. Hence, it is possible that PDE5 inhibition might lead to increased blood supply and oxygenation also in other vascular districts.
The present study had two main objectives: (i) to investigate the expression and activity of PDE5 in human and rat LUT tissues, including the supporting vasculature, and (ii) to determine the effect of PDE5 inhibition with tadalafil on prostate oxygenation in SHR.
Section snippets
Human Tissues
Human tissues, including bladder, corpora cavernosa (CC), urethra, prostate, epididymis, testis, and vas deferens, were collected during surgery for benign diseases, after signed informed consent. In particular, bladder, urethra, and prostate samples were collected during open transvesical simple prostatectomy for large BPH, CC during penile surgery for Peyronie's disease, while testis, epididymis, and vas deferens during post‐traumatic orchiectomy.
The main arterial supply to the LUT, including
PDE5 Expression and Activity in Human Vesicular‐Deferential Artery and Other LUT Tissues
Figure1 shows the absolute expression of PDE5 mRNA in a panel of tissues from the human urogenital tract, using a previously validated quantitativeRT‐PCR method [14]. In vesicular‐deferential artery, the PDE5 mRNA was expressed similarly to CC (29 ± 9 × 106 and 22 ± 5 × 106 molecules/µg total RNA, respectively). CC is known to be the human tissue expressing the highest amount of PDE5 [14]. A lower PDE5 abundance was found in other portions of the male urogenital tract, including bladder
Discussion
In this report, we confirm [12] that human prostate expresses PDE5 mostly in the vascular bed and show for the first time that human vesicular‐deferential artery (one of the small arterial branches arising from the main artery that provides blood flow to prostate gland and bladder) expresses high levels of PDE5 (as in CC), which is immunolocalized in the endothelial cells and smooth muscle layer. Accordingly, human vesicular‐deferential artery homogenates catabolyzes cGMP, as CC does. In
Acknowledgment
This study was funded by Eli Lilly and Company.
Conflict of Interest
None.
Category 1
- (a)
Conception and Design
Annamaria Morelli; Sandra Filippi; Mauro Gacci; Mario Maggi
- (b)
Acquisition of Data
Annamaria Morelli; Erica Sarchielli; Paolo Comeglio; Sandra Filippi; Rosa Mancina; Gabriella B. Vannelli
- (c)
Analysis and Interpretation of Data
Annamaria Morelli; Erica Sarchielli; Paolo Comeglio; Sandra Filippi; Rosa Mancina; Linda Vignozzi; Marco Carini; Gabriella B. Vannelli; Mario Maggi
Category 2
- (a)
Drafting the Article
Annamaria Morelli; Erica Sarchielli; Paolo Comeglio; Sandra Filippi; Rosa Mancina; Mario Maggi
- (b)
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2021, Life SciencesCitation Excerpt :Tadalafil, a PDE5 inhibitor, has been approved for the treatment of urinary symptoms associated with benign prostatic hyperplasia. PDE5 inhibitors increase the levels cGMP produced by activation by NO-dependent pathways, by inhibiting the cGMP breakdown [17]. Because the sGC used in this study increases cGMP in an NO-independent manner, we could expect a bigger therapeutic effect of sGC treatment [18] in disease conditions such as DM, in which NO synthase activity is reduced [3,15].
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