title: Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats.
abstract: BACKGROUND
  In humans, prostate phosphodiesterase type 5 inhibitors (PDE5) expression was prominently localized in the endothelial and smooth muscle cells of the vascular bed, suggesting a possible action of PDE5 inhibitors (PDE5i) on prostate blood flow.
  
  
  OBJECTIVE
  To investigate PDE5 expression in human and rat lower urinary tract (LUT) tissues, including vasculature, and determine the effects of PDE5 inhibition with tadalafil on prostatic blood perfusion.
  
  
  METHODS
  Human vesicular-deferential arteries (which originate from the inferior vesical artery, the main arterial source of blood supply to the bladder and prostate) were analyzed for PDE5 expression and activity. The effects of tadalafil on prostate oxygenation were studied in spontaneously hypertensive rats (SHR), characterized by ischemia/hypoxia of the genitourinary tract.
  
  
  METHODS
  PDE5 expression was evaluated by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. SHR were treated with tadalafil (2 mg/kg/day) for 1, 7, or 28 days and compared with untreated SHR and the unaffected counterpart Wistar-Kyoto (WKY) rats. Prostate oxygenation was detected by Hypoxyprobe-1 and hypoxia markers (hypoxia-inducible factor-1α[HIF-1α] and endothelin-1 type B [ETB]) immunostaining.
  
  
  RESULTS
  Human vesicular-deferential artery expressed high levels of PDE5, similar to corpora cavernosa, immunolocalized in the endothelial and smooth muscle layer. In these arteries, tadalafil inhibited cyclic guanosine monophosphate breakdown (half maximal inhibitory concentration (IC(50) ) in the low nanomolar range, as in corpora cavernosa) and increased the relaxant response to sodium nitroprusside. SHR prostate resulted markedly hypoxic (hypoxyprobe immunopositivity) and positive for HIF-1α and ETB, while tadalafil treatment restored oxygenation to WKY level at each time point. The mRNA expression of the HIF-1α target gene, BCL2/adenovirus E1B 19 kDa interacting protein 3, was significantly increased in SHR prostate and partially restored to WKY level by tadalafil.
  
  
  CONCLUSIONS
  Human vesicular-deferential artery is characterized by a high expression and activity of PDE5, which was inhibited by tadalafil in vitro. In SHR, tadalafil increases prostate tissue oxygenation, thus suggesting a possible mechanism through which PDE5i exert beneficial effects on LUT symptoms.
authors.affiliation: Department of Clinical Physiopathology, Sexual Medicine and Andrology Unit, University of Florence, Florence, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Morelli
authors.forename: Erica
authors.initials: E
authors.lastname: Sarchielli
authors.forename: Paolo
authors.initials: P
authors.lastname: Comeglio
authors.forename: Sandra
authors.initials: S
authors.lastname: Filippi
authors.forename: Rosa
authors.initials: R
authors.lastname: Mancina
authors.forename: Mauro
authors.initials: M
authors.lastname: Gacci
authors.forename: Linda
authors.initials: L
authors.lastname: Vignozzi
authors.forename: Marco
authors.initials: M
authors.lastname: Carini
authors.forename: Gabriella B
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Mario
authors.initials: M
authors.lastname: Maggi
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D000068581:Tadalafil; D001743:Urinary Bladder / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism; D014551:Urinary Tract / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism
chemical_list: D002243:Carbolines; D019332:Endothelin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058986:Phosphodiesterase 5 Inhibitors; D009599:Nitroprusside; D000068581:Tadalafil; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D010100:Oxygen