Ko C M, Ducic I, Fan J, Shuba Y M, Morad M
Department of Pharmacology and Institute for Cardiovascular Sciences, Georgetown University Medical Center, Washington, D.C. 20007, USA.
J Pharmacol Exp Ther. 1997 Apr;281(1):233-44.
Nonsedating H1 receptor (H1-R) antagonists exert variable effects on QT interval, most likely mediated through modulation of cardiac K+ channels. We examined the effects of a novel H1-R antagonist, ebastine, on a family of K+ currents in isolated rat and guinea pig ventricular cardiomyocytes as well as on HERG-induced rapidly delayed rectifier K+ current (I(Kr)) in Xenopus laevis oocytes. The effect of ebastine was compared with that of two other H1-R antagonists, terfenadine and loratadine, with and without reported cardiotoxicity, respectively. In guinea pig ventricular myocytes, ebastine at concentrations approximating those found in plasma under certain conditions suppressed in a voltage-independent manner the I(Kr) (Kd = 0.14 microM, maximum block 74%) more effectively than the slowly delayed rectifier K+ current (I(Ks)) (Kd = 0.8 microM, maximum block 60%). Ebastine also suppressed I(Kr) in HERG-expressing X. laevis oocytes with the Kd value of 0.3 microM and a maximal block of 46% at 3 microM. The block of the rapidly activating delayed rectifier channel in rat myocytes (Iped) (Kd = 1.7 microM, maximum block 58%) had a small voltage dependence. Ebastine only minimally suppressed rat transient K+ current (Ito) (Kd = 1.1 microM, maximum block 10%). The drug was also not a very potent blocker of the inwardly rectifier K+ current (I(K1)) of rat and guinea pig (15 +/- 3% block at 3 microM). At concentrations of <100 nM, ebastine produced negligible effect on all K+ currents. We conclude that ebastine blocks various cardiac K+ channels with different potencies. The group of delayed rectifier K+ currents appeared to be most susceptible to ebastine with the order of sensitivity of I(Kr) > I(Ks) > Iped. Ebastine-induced inhibition of all K+ current types was always weaker than that observed with similar concentrations of terfenadine.
非镇静性H1受体（H1-R）拮抗剂对QT间期有不同影响，很可能是通过调节心脏钾通道介导的。我们研究了新型H1-R拮抗剂依巴斯汀对分离的大鼠和豚鼠心室心肌细胞中一系列钾电流的影响，以及对非洲爪蟾卵母细胞中HERG诱导的快速延迟整流钾电流（I(Kr)）的影响。将依巴斯汀的作用与另外两种H1-R拮抗剂特非那定和氯雷他定的作用进行比较，特非那定和氯雷他定分别有和没有报道的心脏毒性。在豚鼠心室肌细胞中，在某些条件下接近血浆中浓度的依巴斯汀以电压非依赖性方式抑制I(Kr)（解离常数Kd = 0.14微摩尔，最大阻断率74%）比缓慢延迟整流钾电流（I(Ks)）（Kd = 0.8微摩尔，最大阻断率60%）更有效。依巴斯汀也抑制表达HERG的非洲爪蟾卵母细胞中的I(Kr)，Kd值为0.3微摩尔，在3微摩尔时最大阻断率为46%。大鼠心肌细胞中快速激活延迟整流通道（Iped）的阻断（Kd = 1.7微摩尔，最大阻断率58%）有较小的电压依赖性。依巴斯汀仅轻微抑制大鼠瞬时钾电流（Ito）（Kd = 1.1微摩尔，最大阻断率10%）。该药物对大鼠和豚鼠的内向整流钾电流（I(K1)）也不是非常有效的阻断剂（在3微摩尔时阻断15±3%）。在浓度<100纳摩尔时，依巴斯汀对所有钾电流产生的影响可忽略不计。我们得出结论，依巴斯汀以不同效力阻断各种心脏钾通道。延迟整流钾电流组似乎对依巴斯汀最敏感，敏感性顺序为I(Kr)>I(Ks)>Iped。依巴斯汀诱导的对所有钾电流类型的抑制总是弱于用相似浓度特非那定观察到的抑制。
