title: Mechanism of action of phosphodiesterase type 5 inhibition in metabolic syndrome-associated prostate alterations: an experimental study in the rabbit.
abstract: BACKGROUND
  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).
  
  
  METHODS
  Gene expression was evaluated by quantitative RT-PCR. Prostate morphological changes and oxygenation were evaluated by immunohistochemistry.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our data provide the experimental evidences to support the multiple potentiality of PDE5 inhibitors as a useful therapeutic tool in LUTS.
authors.affiliation: Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Morelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Comeglio
authors.forename: Sandra
authors.initials: S
authors.lastname: Filippi
authors.forename: Erica
authors.initials: E
authors.lastname: Sarchielli
authors.forename: Linda
authors.initials: L
authors.lastname: Vignozzi
authors.forename: Elena
authors.initials: E
authors.lastname: Maneschi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cellai
authors.forename: Mauro
authors.initials: M
authors.lastname: Gacci
authors.forename: Andrea
authors.initials: A
authors.lastname: Lenzi
authors.forename: Gabriella B
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
mesh_terms: D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011817:Rabbits; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5