title: Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina.
abstract: OBJECTIVE
  Some authors have advocated the daily use of sildenafil for prophylaxis against, or treatment of, erectile dysfunction. However, no information has been published to support such a dosage regimen. The safety profile of uninterrupted use of sildenafil has not been evaluated as it pertains to alteration of PDE type 6 in the retina. In the present study we investigated whether short- or long-term exposure to a variety of sildenafil doses affect the expression of an enzyme important in the normal phototransduction cascade.
  
  
  METHODS
  Sustained-release sildenafil pellets were implanted in 120-day-old male rats with concentrations from 1-200mg. Rat retinal tissue was harvested 7, 14, and 29 days after implantation. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using GAPDH as an endogenous internal standard was used to quantitate PDE type 6 gene expression.
  
  
  RESULTS
  Expression of PDE type 6 was upregulated after 7 days with dosages < or =5 mg (P<0.02). Significant downregulation of PDE type 6 expression was first noted with high dose sildenafil 14 days after implantation (P<0.02). Expression of PDE type 6 was significantly and profoundly downregulated 29 days after implantation for all pellet formulations > or =10 mg (P<0.01).
  
  
  CONCLUSIONS
  Sildenafil downregulates PDE type 6 expression in a dose- and time-dependent fashion. These findings support the explanation that PDE type 6 inhibition causes the dose-dependent clinical effects of visual disturbance in men taking sildenafil. Implications for long-term, daily use of sildenafil in men are not clear.
authors.affiliation: Department of Urology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Gonzalez
authors.forename: T
authors.initials: T
authors.lastname: Bervig
authors.forename: C
authors.initials: C
authors.lastname: Podlasek
authors.forename: C F
authors.initials: CF
authors.lastname: Huang
authors.forename: K E
authors.initials: KE
authors.lastname: McKenna
authors.forename: K T
authors.initials: KT
authors.lastname: McVary
mesh_terms: D000818:Animals; D007172:Erectile Dysfunction / Q000188:drug therapy; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology*; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones
chemical_list: D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases