Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina.
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.
Gonzalez
C M
CM
Department of Urology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Bervig
T
T
Podlasek
C
C
Huang
C F
CF
McKenna
K E
KE
McVary
K T
KT
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
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases