Selective Hcn1 channels inhibition by ivabradine in mouse rod photoreceptors.
OBJECTIVE
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.
Demontis
Gian Carlo
GC
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Pisa, Italy. demontis@farm.unipi.it
Gargini
Claudia
C
Paoli
Timoteo Giacomo
TG
Cervetto
Luigi
L
D000200:Action Potentials; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002586:Cesium / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D000077550:Ivabradine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects* / Q000502:physiology*; D013997:Time Factors
D001552:Benzazepines; D002712:Chlorides; D054815:Cyclic Nucleotide-Gated Cation Channels; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; C489465:Kir2.4 channel; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D002586:Cesium; D000077550:Ivabradine; C028019:cesium chloride