Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina

Objectives: Some authors have advocated the daily use of sildenafil for pro phylaxis against, or treatment of, erectile dysfunction, However, no inform ation has been published to support such a dosage regimen. The safety profi le 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 investi gated whether short- or long-term exposure to a variety of sildenafil doses affect the expression of an enzyme important in the normal phototransducti on cascade. Methods: Sustained-release sildenafil pellets were implanted in 120-day-old male rats with concentrations from 1-200mg. Rat retinal tissue was harvest ed 7, 14, and 29 days after implantation. Quantitative reverse transcriptas e-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 less than or equal to 5 mg (P<0.02). Significant downregulation of PDE typ e 6 expression was first noted with high dose sildenafil 14 days after impl antation (P<0.02). Expression of PDE type 6 was significantly and profoundl y downregulated 29 days after implantation for all pellet formulations grea ter than or equal to 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 typ e 6 inhibition causes the dose-dependent clinical effects of visual disturb ance in men taking sildenafil. Implications for longterm, daily use of sild enafil in men are not clear.