Sildenafil Administration in Dogs Heterozygous for a Functional Null Mutation in Pde6a: Suppressed Rod-Mediated ERG Responses and Apparent Retinal Outer Nuclear Layer Thinning

Abstract

This study was designed to assess risk for retinal toxicity associated with administration of high-dose sildenafil citrate to dogs heterozygous for a functionally null mutation in Pde6a over a 4-month period. Three Pde6a +/− dogs were administered 14.3 mg/kg sildenafil per os and two Pde6a +/− dogs placebo once daily for 16 weeks. Three Pde6a +/+ dogs were administered sildenafil for 7 days. Ophthalmic examination, vision testing, and electroretinography (ERG) were regularly performed. At study termination, dogs were euthanized and globes collected. Retinal layer thickness and photoreceptor nuclei counts were determined from plastic sections. In both Pde6a +/− and Pde6a +/+ sildenafil-treated (ST) dogs, elevation of dark-adapted b-wave threshold and unmasking of the scotopic threshold response (STR) were observed. Sildenafil treated Pde6a +/− dogs had significantly thinner ONL (24.90 +/−1.88 μm, p = 0.004) and lower photoreceptor nuclei counts (273.6 +/− 29.3 cells/100 μm, p = 0.008) compared to measurements (35.90 +/− 1.63 μm) and counts (391.5 +/−27.0 cells/100 μm) from archived untreated Pde6a +/− dogs.