Sildenafil-mediated reduction in retinal function in heterozygous mice lacking the gamma-subunit of phosphodiesterase.
OBJECTIVE
Retinitis pigmentosa (RP) is a common inherited degenerative retinal disease that has many causes including mutations in the genes coding for cyclic guanosine monophosphate (cGMP) phosphodiesterase 6 (PDE6). Sildenafil (Viagra; Pfizer Pharmaceuticals, New York, NY), a widely used medication for erectile dysfunction, is a specific inhibitor of PDE, with the potential to affect PDE6 in the retina. The purpose of this study was to investigate the retinal effects of sildenafil on knockout mice heterozygous for a mutation causing absence of the gamma subunit of rod PDE6 (PDEG:(tm1)/+).


METHODS
Wild-type mice and PDEG:(tm1)/+ mice were subjected to electroretinography (ERG) 1 hour after exposure to one of three treatments: 1) no drug, 2) an intraperitoneal injection of sildenafil at 2 times the equivalent maximal daily recommended dosage for humans, or 3) 10 times this dosage. Control ERGs were also obtained to evaluate the reversibility of changes in retinal function after sildenafil treatment. A minimum of 48 hours elapsed between electroretinogram (ERG) recordings for drug washout and animal recovery.


RESULTS
ERGs of the PDEG:(tm1)/+ mice treated with sildenafil showed a reversible, dose-dependent decrease in a- and b-wave amplitudes. Wild-type mice treated with sildenafil did not show significant differences in either a- or b-wave amplitudes compared with untreated control animals.


CONCLUSIONS
These findings suggest that sildenafil has a significant impact on retinal function in PDEG:(tm1)/+ mice and may have implications in human carriers of RP. In addition, extension of these results in other model systems could be useful in understanding the mechanisms of RP and other forms of retinal degeneration.
Behn
D
D
Department of Ophthalmology, University of British Columbia, Vancouver, British Columbia, Canada.
Potter
M J
MJ
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000172:deficiency; D000818:Animals; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D012174:Retinitis Pigmentosa / Q000503:physiopathology; D000068677:Sildenafil Citrate; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human; C517438:Pde6b protein, mouse; C517444:Pde6g protein, mouse