SSI Prize Essay for Male Erectile Dysfunction—Research ‘Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina‘

Abstract

Objectives: Some authors have advocated the daily use of sildena®l for prophylaxis against, or treatment of, erectile dysfunction. However, no information has been published to support such a dosage regimen. The safety pro®le of uninterrupted use of sildena®l 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 sildena®l doses affect the expression of an enzyme important in the normal phototransduction cascade. Methods: Sustained-release sildena®l pellets were implanted in 120-day-old male rats with concentrations from 1 ± 200 mg. 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 5 mg (P`0.02). Signi®cant downregulation of PDE type 6 expression was ®rst noted with high dose sildena®l 14 days after implantation (P`0.02). Expression of PDE type 6 was signi®cantly and profoundly downregulated 29 days after implantation for all pellet formulations ! !10 mg (P`0.01). Conclusions: Sildena®l downregulates PDE type 6 expression in a dose-and time-dependent fashion. These ®ndings support the explanation that PDE type 6 inhibition causes the dosedependent clinical effects of visual disturbance in men taking sildena®l. Implications for longterm, daily use of sildena®l in men are not clear.

Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects

“…PDE6 is intensely localized at the rod and cone cells and has an important role in the phototransduction cascade. [17][18][19][20] PDE5 inhibitors show a PDE5 affinity only 10 times greater than PDE6, so some recent studies hypothesized that visual side effects of these drugs may be related to their cross-reactivity with PDE6.…”

Sildenafil alters retinal function in mouse carriers of Retinitis Pigmentosa

“…Acosta et al (2010) showed accelerated photoreceptor death in a rat model of RP (P23H rat) after a single dose of sildenafil. Sildenafil also decreased PDE6 expression in normal rats after long-term administration (Gonzalez et al, 1999). Thus, in retinal tissue where photoreceptors are under metabolic stress, sildenafil usage may push photoreceptors beyond the threshold of normal function and trigger dysfunction.…”

Phosphodiesterase type 5 inhibitors, visual changes, and nonarteritic anterior ischemic optic neuropathy: Is there a link?

“…These abnormalities, which are usually mild and transient, include color tinge to vision, predominantly, and increased sensitivity to light or blurred vision. It is believed to be secondary to transient inhibition of phosphodiesterase type 6 (PDE6) when higher doses are used [4][5][6]. This cross-reactivity with PDE6 explains why these abnormalities are associated mainly with sildenafil and to a lesser extent with vardenafil, but not with tadalafil.…”