Retinal ON- and OFF-pathway dysfunction due to HCN channel inhibition evaluated using dark and light adapted flicker electroretinograms in rats.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitors that induce visual abnormalities such as phosphenes in humans are believed to disrupt the feedback mechanisms of retinal photoreceptor cells and cause dysfunction of the ON and OFF pathways in the retina. However, this hypothesis is based mainly on studies using HCN channel-knockout mice. In this study, we evaluated whether the retinal ON and OFF pathway defects could be detected in animals treated with HCN channel inhibitors by dark-adapted and light-adapted flicker electroretinography (ERG). Ivabradine, an HCN channel inhibitor, was administered subcutaneously to Long-Evans rats at 4-40 mg/kg as a single dose, and dark- and light-adapted flicker ERGs were measured at frequencies ranging from 1 to 30 Hz. In dark-adapted flicker ERGs, waveforms including rod photoreceptor components in the low frequency range and rod ON pathway and cone ON and OFF pathway components in the intermediate- and high-frequency range were changed, and the amplitude of the waveforms were attenuated. These inhibitions of cone ON and OFF pathways were considered, based on the results of the light-adapted flicker ERGs, to have been influenced by interference with rod-driven signals via gap junctions. This study is the first report to demonstrate inhibition of ON and OFF pathway signaling in animals treated with an HCN channel inhibitor. Our findings also suggest that dark- and light-adapted flicker ERGs across a range of frequencies may be a useful tool for detecting retinal dysfunction caused by compounds inducing visual abnormalities.