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S.M. Szabo, M.J. Potter; Effect of Sildenafil in the rd Mouse Model of Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3563.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Retinitis pigmentosa (RP) can be caused by mutations in the genes encoding phosphodiesterase 6 (PDE6). High doses of sildenafil (Viagra(R)) have previously been shown to cause severely decreased retinal function on electroretinography (ERG) in Pdegtm1+/- mice, heterozygous for a mutation in the gene encoding the γ-subunit of PDE6. The rd mouse is another more widely-studied model of human RP, that has a mutation in the gene for the PDE6 ß-subunit. The purpose of this study is to examine the effect of high-dose sildenafil on the ERG of rd+/- mice. Methods: ERG was performed according to a standard protocol. All mice were dark-adapted for > 8 h prior to recordings. Baseline ERGs were recorded from wild-type (+/+; C57BL/6; n=5) and rd+/- heterozygous mice (n=10). All mice were then exposed to an intraperitoneal injection of high-dose (10X the maximal human daily dose equivalent by weight; 14.3 mg/kg) sildenafil, followed by ERG recording forty-five minutes later. ERGs were also obtained 48 h following treatment with sildenafil to evaluate the reversibility of changes in retinal function. Results: ERGs of rd+/- mice treated with sildenafil showed no significant difference in a-wave and b-wave amplitudes or implicit time at the two brightest flash intensities (8 and 0 dB), compared to recordings from the same mice without sildenafil. At the brightest intensity (0 db), neither mean a-wave values (sildenafil-treated (S) =309 µV; untreated (U) =302 µV; p>0.05) nor b-wave values (S=1062 µV; U=1020 µV; p>0.05) were significantly different under either treatment condition. Similarly, a-wave (S=17.6 msec; U=17.7 msec; p>0.05) and b-wave (S=64.5; U=65.8; p>0.05) implicit times also did not show any significant difference. However, at all intensities less than 8 dB, b-wave amplitudes and implicit times were significantly reduced following sildenafil treatment, compared to the no-treatment condition (p<0.05). A-wave and b-wave amplitudes and implicit times were unaffected in wild-type mice by high-dose sildenafil administration, as demonstrated previously. Conclusions: At low light intensities, high-dose sildenafil administration has a significant impact on the ERG of rd+/- mice. However, as light intensity is increased, sildenafil inhibition is overcome, and no significant differences exist between a-wave and b-wave amplitudes and implicit times. It would seem unlikely that decreases observed under low light intensities would be clinically significant. Since the most common PDE6 mutation in human RP is in the ß-subunit, we would therefore expect carriers to be unaffected by sildenafil.
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