Effects of HCN channel blockade on the intensity-response function of electroretinographic ON and OFF responses in dark adapted frogs

Abstract

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are well expressed in the vertebrate retina. Their role in formation of electroretinographic (ERG) responses to stimulus onset (b-wave) and stimulus offset (d-wave) are largely unknown. In this study we investigated the effects of pharmacological blockade of HCN channels (with ZD7288 or ivabradine) on the ERG band d-waves in dark adapted frog eyecup preparations. Initially, the dose-response relationship of ZD7288 effects on the band d-waves was investigated. Afterwards, the effects of 75 μM ZD7288 on the stimulus-response function of the ERG band d-waves were explored over a wide intensity range (10 log units). Finally, the effects of 30 μM ivabradine on the same function were studied. Perfusion with 75 μM ZD7288 did not change the absolute and relative sensitivity of the ERG ON and OFF responses. It caused an enhancement of the d-wave amplitude at all suprathreshold stimulus intensities, while the b-wave amplitude was slightly enhanced only in the range of higher intensities. As a result of the greater blocker effect on the OFF response amplitude, the b/d amplitude ratio was significantly decreased over the whole intensity range. ZD7288 caused a prolongation of the b-wave half-width duration, but a shortening of the d-wave half-width duration at higher intensities. Similar results were obtained when 30 μM ivabradine was used for HCN channel blockade. Our results clearly demonstrate that the blockade of retinal HCN channels changes the balance between the ON and OFF responses in the distal frog retina. This ON/OFF imbalance may be one of the causes for visual disturbances reported in ivabradine treated patients.

Characterization of Inhibitory Capability on Hyperpolarization-Activated Cation Current Caused by Lutein (β,ε-Carotene-3,3′-Diol), a Dietary Xanthophyll Carotenoid

“…The HCN channels, another family of ionic channels gated by cyclic nucleotides, have been previously demonstrated to be linked to phototransduction in photosensitive retinal ganglion cells [47]. Its activity was found to alter the electroretinographic ON and OFF responses or to delay photoreceptor degeneration [19,[68][69][70]. To what extent do lutein-mediated changes in magnitude, gating kinetics and Hys (V) behavior of I h presented herein engage in lutein-mediated action on age-related diseases (e.g., macular degeneration or retinitis pigmentosa) [8,19,[71][72][73][74] still needs to be further delineated.…”

Effective Perturbations by Small-Molecule Modulators on Voltage-Dependent Hysteresis of Transmembrane Ionic Currents

“…Additionally, HCN channels have been previously demonstrated to be linked to phototransduction in photosensitive retinal ganglion cells [ 39 ]. Its activity was found either to alter the electroretinographic ON and OFF responses or to delay photoreceptor degeneration [ 40 ]. To what extent lutein-mediated changes in Hys (V) behavior of I h is associated with its action on age-related diseases (e.g., macular degeneration) [ 41 ] still needs to be further determined.…”