Selective Hcn1 Channels Inhibition by Ivabradine in Mouse Rod Photoreceptors
Selective Hcn1 Channels Inhibition by Ivabradine in Mouse Rod Photoreceptors
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DOI：
10.1167/iovs.08-2659
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发表时间：
2009-04-01
影响因子：
4.4
通讯作者：
Cervetto, Luigi
中科院分区：
文献类型：
--
作者：
Demontis, Gian Carlo;Gargini, Claudia;Cervetto, Luigi
目的。目的评价哺乳动物视杆细胞感受器对钾离子选择性通道(KIR 2.4，Kcnj14编码)对超极化激活的环核苷酸脱氢酶(Hcn1)的选择性。伊夫拉定是心脏“有趣”电流(I-f)的选择性抑制剂。结果伊夫拉定可阻断超极化激活电流(I-h)，激活/去激活电压阶跃为-80~-30 mV，最大激活电压为-35 mV。结果在较高浓度(30 MM)时，超极化激活电流(I-h)被完全抑制，3和0.3 mM时抑制作用居中。稳态激活电流和激活动力学与伊夫拉定阻断的电流和氯化铯阻断的电流相似，与伊夫拉定阻断HCN1通道的离子渗透一致。Hcn1的阻断也与在-110 mV的长阶跃过程中缺乏电流再激活相一致。在完全阻断I-h的剂量下，伊夫拉定不影响通过钾选择性Kir 2.4通道的内向整流电流，也不影响从-80 mV到50 mV时诱发的外向电流。在哺乳动物的视杆细胞中，伊夫拉定是Hcn1通道的选择性抑制剂。少数接受伊夫拉定治疗的患者以剂量依赖的方式短暂报道了荧光烯对亮度突然变化的反应，这与视杆中Hcn1的抑制是一致的。(投资眼科VS科学。2009年；50：1948年-1955年)DOI：10.1167/IOVS.08-2659
PURPOSE. To evaluate in mammalian rod photoreceptors the selectivity for hyperpolarization-activated cyclic nucleotidegated (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 mu M), with intermediate effects at 3 and 0.3 mu M. 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. (Invest Ophthalmol Vis Sci. 2009; 50: 1948-1955) DOI: 10.1167/iovs.08-2659