Effect of β-adrenoceptor blockers on Human Ether-a-go-go-Related gene (HERG) potassium channels
Effect of β-adrenoceptor blockers on Human Ether-a-go-go-Related gene (HERG) potassium channels
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DOI：
10.1111/j.1742-7843.2005.pto960206.x
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发表时间：
2005-02-01
影响因子：
3.1
通讯作者：
Olesen, SP
中科院分区：
文献类型：
--
作者：
Dupuis, DS;Klaerke, DA;Olesen, SP
先天性长QT综合征患者可在交感神经张力增高的情况下发生心律失常。我们已经讨论了一些通常用于预防这些心律失常发展的β -肾上腺素受体阻滞剂是否可以本身阻断心脏HERG（人类以太-a-go-go- go相关基因）钾通道，这将是最不希望的副作用。HERG钾通道在爪蟾卵母细胞中异种表达，并通过双电极电压箝位技术测量电流。心得安对HERG电流的抑制呈浓度依赖性，在-10 mV下的IC50值为81 muM。当HERG与附属亚基KCNE2共表达时，IC50值为52 muM。心得安的阻断作用是电压依赖性的，但不改变HERG通道失活动力学。普萘洛尔类似物ICI118551(（+/-)-1-[2,3-（二氢-7-甲基- 1h -吲哚-4-基）氧]-3-[（1-甲基乙基）氨基]-2-丁醇盐酸盐）以相似的亲和力阻断HERG通道，而β 1受体拮抗剂美托洛尔和阿替洛尔的作用较弱。此外，这四种化合物阻断了HERG通道在哺乳动物HEK293细胞系中的表达。这些数据表明，β -肾上腺素能受体阻滞剂对HERG的阻断仅发生在高微摩尔浓度下，这一浓度明显高于最近确定的100的安全范围（Redfern等，2003年）。
Patients with congenital long QT syndrome may develop arrhythmias under conditions of increased sympathetic tone. We have addressed whether some of the beta-adrenoceptor blockers commonly used to prevent the development of these arrhythmias could per se block the cardiac HERG (Human Ether-a-go-go-Related Gene) potassium channels, which would be a most unwanted side effect. HERG potassium channels were heterologously expressed in Xenopus oocytes and the currents measured by two-electrode-voltage-clamp technique. Propranolol caused a concentration-dependent inhibition of HERG current with an IC50 value of 81 muM at -10 mV. When HERG was co-expressed with the accessory subunit KCNE2, an IC50 value of 52 muM was determined. The block by propranolol was voltage-dependent, but it did not change the HERG channel deactivation kinetics. The propranolol analogue ICI118551 ((+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) blocked the HERG channel with similar affinity, whereas the beta1-receptor antagonists metoprolol and atenolol showed weak effects. Further, the four compounds blocked HERG channels expressed in a mammalian HEK293 cell line. These data showed that HERG blockade by beta-adrenoceptor blockers occurred only at high micromolar concentrations, which are significantly above the recently established safe margin of 100 (Redfern et al., 2003).