In clinical trials of the erectile dysfunction drug Viagra, it has been observed that high doses can cause transient visual disturbances in otherwise healthy subjects, including blurred vision and photophobia. The active ingredient in Viagra, sildenafil, works by inhibiting phosphodiesterase 5 (PDE5), which in turn leads to vasodilation; however, it can also exert effects on PDE6, an enzyme with a key role in the phototransduction pathway, which could leave some users at risk of potential vision problems. Sildenafil could also potentially exert adverse effects on (heterozygous) carriers of a recessive allele that causes retinitis pigmentosa (RP).
Researchers from Australia and New Zealand decided to investigate how PDE6 inhibition might affect individuals who have preexisting susceptibilities to retinal damage; in this case, heterozygous carriers of genes for retinal dystrophy (1). In the study, mice with a nonsense mutation in a subunit of PDE6 were used to create an animal homology for recessive RP. Mice carrying two of these mutations lose all photoreceptors by six weeks old, whereas carrier mice have lower PDE6 activity, but retain normal retinal structure and function. The mice were each given a single dose of sildenafil – the average dose administered was 29 mg/kg, which is the equivalent of 20 times the recommended dosage for an average human adult. Electroretinograms, dissection and immunohistochemistry were then used to quantify the effects of the drug on normal and carrier mice.
The initial results appear to confirm the researchers’ suspicions. The carrier mice experienced longer and more severe visual disturbances than genetically normal mice, exhibiting ocular changes for two weeks following the dose compared with the normal mice that returned almost entirely to a baseline state within two days. Significantly, the carrier mice also exhibited increased activity of cytochrome c, which can cause apoptosis and is observed in retinal degeneration – implying that sildenafil may trigger cell death in susceptible patients. “These findings are highly significant because about one in 50 people are likely to be carriers of recessive genes which cause retinal disease but are unlikely to know this, because their vision is normal,” says first author Lisa Nivison-Smith, a researcher at the University of New South Wales. “A better understanding of the effect of this family of erectile dysfunction drugs could help scientists and clinicians plan more successful strategies to account for factors such as a patient’s medication and genetic makeup in diseases which cause blindness.”
The current work focuses only on photoreceptors, so further research is needed to understand how sildenafil affects the rest of the retina.
References
- L. Nivison-Smith et al., “Sildenafil alters retinal function in mouse carriers of retinitis pigmentosa”, Exp. Eye Res., 128, 43–56 (2014). doi: 10.1016/j.exer.2014.08.014.
