Mechanism of action of phosphodiesterase type 5 inhibition in metabolic syndrome‐associated prostate alterations: An experimental study in the rabbit

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Phosphodiesterase type 5 (PDE5) inhibitors improve benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS), often associated with metabolic syndrome (MetS). This study investigated the effects of PDE5 inhibition in the prostate of rabbits fed a high fat diet (HFD) for 12 weeks. HFD-rabbits develop the most important features of human MetS (glucose intolerance, dyslipidemia, increased abdominal adiposity, and hypertension), along with hypogonadism and LUT abnormalities (prostate and bladder inflammation/tissue remodeling). Gene expression was evaluated by quantitative RT-PCR. Prostate morphological changes and oxygenation were evaluated by immunohistochemistry. HFD prostates showed increased PDE5 expression, suggesting a peculiar sensitivity of prostate to the action of PDE5 inhibitors during MetS. Accordingly, prostate PDE5 mRNA was negatively associated to plasma testosterone/estradiol ratio, whose reduction characterizes MetS, and positively with the expression in prostate of several genes exploring pathogenetic processes for BPH/LUTS, such as inflammation, leukocyte infiltration, and fibrosis/myofibroblast activation. Most of these genes was up-regulated by HFD, and significantly reduced by PDE5 inhibition, through either chronic (12 weeks) or, at a lower extent, acute (1-week) tadalafil dosing. Tadalafil was also able to reduce blood pressure and visceral fat in HFD rabbits, without changing any other MetS parameter. Interestingly, 1-week tadalafil administration to HFD rabbits, significantly blunted prostate inflammation (increased CD45 immunopositivity), fibrosis (reduced muscle/fiber ratio) and hypo-oxygenation, thus suggesting a potential curative effect of PDE5 inhibition on MetS-related prostate alterations. Our data provide the experimental evidences to support the multiple potentiality of PDE5 inhibitors as a useful therapeutic tool in LUTS.