PURPOSE: To evaluate in mammalian rod photoreceptors the selectivity for hyperpolarization-activated cyclic nucleotide-gated (Hcn1, coded by Hcn1) over potassium-selective (Kir 2.4, coded by Kcnj14) channels of ivabradine, a selective inhibitor of the cardiac "funny" current (I(f)). METHODS: Rods were isolated from the mouse retina and voltage clamped by the perforated-patch technique. The hyperpolarization-activated current (I(h)) was blocked by ivabradine during repetitive stimulation with activating/deactivating voltage steps from -80 to -30 mV, from a holding of -35 mV. RESULTS: Full inhibition was observed at a high concentration of ivabradine (30 microM), with intermediate effects at 3 and 0.3 microM. Steady state activation and activation kinetics of the ivabradine- and CsCl-blocked currents were similar, consistent with the block by ivabradine of ion permeation through Hcn1 channels. Hcn1 blockade was also consistent with the lack of current reactivation during long steps at -110 mV. At doses that fully block I(h), ivabradine does not affect the inward rectifier current through potassium-selective Kir 2.4 channels or the outward currents evoked by stepping up from -80 to 50 mV. CONCLUSIONS: In mammalian rods, ivabradine is a selective inhibitor of Hcn1 channels. Phosphenes perception in response to abrupt changes in luminance, which has been transiently reported in a dose-dependent way by few patients treated with ivabradine, was consistent with Hcn1 inhibition in rods.
PURPOSE: To evaluate in mammalian rod photoreceptors the selectivity for hyperpolarization-activated cyclic nucleotide-gated (Hcn1, coded by Hcn1) over potassium-selective (Kir 2.4, coded by Kcnj14) channels of ivabradine, a selective inhibitor of the cardiac "funny" current (I(f)). METHODS: Rods were isolated from the mouse retina and voltage clamped by the perforated-patch technique. The hyperpolarization-activated current (I(h)) was blocked by ivabradine during repetitive stimulation with activating/deactivating voltage steps from -80 to -30 mV, from a holding of -35 mV. RESULTS: Full inhibition was observed at a high concentration of ivabradine (30 microM), with intermediate effects at 3 and 0.3 microM. Steady state activation and activation kinetics of the ivabradine- and CsCl-blocked currents were similar, consistent with the block by ivabradine of ion permeation through Hcn1 channels. Hcn1 blockade was also consistent with the lack of current reactivation during long steps at -110 mV. At doses that fully block I(h), ivabradine does not affect the inward rectifier current through potassium-selective Kir 2.4 channels or the outward currents evoked by stepping up from -80 to 50 mV. CONCLUSIONS: In mammalian rods, ivabradine is a selective inhibitor of Hcn1 channels. Phosphenes perception in response to abrupt changes in luminance, which has been transiently reported in a dose-dependent way by few patients treated with ivabradine, was consistent with Hcn1 inhibition in rods.
Authors: Mathias W Seeliger; Arne Brombas; Reto Weiler; Peter Humphries; Gabriel Knop; Naoyuki Tanimoto; Frank Müller Journal: Nat Commun Date: 2011-11-08 Impact factor: 14.919
Authors: Luca Della Santina; Ilaria Piano; Lorenzo Cangiano; Antonella Caputo; Andreas Ludwig; Luigi Cervetto; Claudia Gargini Journal: PLoS One Date: 2012-01-18 Impact factor: 3.240
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