The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes
The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes
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DOI：
10.1016/j.ejphar.2006.09.023
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发表时间：
2006-12-28
影响因子：
5
通讯作者：
Cinca, Juan
中科院分区：
文献类型：
--
作者：
Hove-Madsen, Leif;Llach, Anna;Cinca, Juan
心肌细胞肌浆网的自发钙释放在心律失常的发生中起着重要作用。因此，干扰细胞内钙处理的用于治疗的化合物可能具有不受欢迎的心律失常潜在性。在这里，我们使用分离的人心房肌细胞来比较促心律失常的抗组胺药物特非那定与非致心律失常的抗组胺药物非索非那定和鲁帕他定对细胞内钙稳态的影响。穿孔膜片钳技术用于测量离子电流和检测肌浆网的自发钙释放。结果表明，复方特非那定具有致心律失常作用，当细胞受到1.0赫兹刺激时，其抑制L钙电流的IC50值为185 nM。0.3 mU特非那定的抑制作用由0.2 Hz时的194%增加到2.0 Hz时的63+/-6%。此外，特非那定还增加了肌浆网的自发钙释放。特非那定在1 mU M时可使自发钠钙交换电流频率从0.48+/-0.25显著增加到1.93+/-0.67 S(-1)。而非索非那定和卢帕他定对自发性I-NCX频率和ICa无明显影响。我们得出结论，促心律失常的抗组胺药物特非那定改变了分离的人心房肌细胞内钙离子的处理。这一实验模型可能适用于筛选用于治疗的化合物潜在的致心律失常副作用。(C)2006爱思唯尔B.V.保留所有权利。
Spontaneous calcium release from the sarcoplasmic reticulum in cardiac myocytes plays a central role in cardiac arrhythmogenesis. Compounds intended for therapeutical use that interfere with intracellular calcium handling may therefore have an undesired proarrhythmic potential. Here we have used isolated human atrial myocytes to compare the effect of the proarrhythmic antihistaminic drug terfenadine with the non-proarrhythmic antihistaminic drugs fexofenadine and rupatadine on intracellular calcium homeostasis. Perforated patch-clamp technique was used to measure ionic currents and to detect spontaneous calcium release from the sarcoplasmic reticulum. Our results show that the compound terfenadine, with known arrhythmogenic effects, inhibits L-type calcium current (I-Ca) with an IC50 of 185 nM when cells are stimulated at 1.0 Hz. The inhibitory effect of 0.3 mu M terfenadine increased from 19 4% at stimulation frequency of 0.2 Hz to 63 +/- 6% at 2.0 Hz. Moreover, terfenadine also increased spontaneous calcium release from the sarcoplasmic reticulum. At a concentration of 1 mu M, terfenadine significantly increased the spontaneous Na-Ca exchange current (I-NCX) frequency from 0.48 +/- 0.25 to 1.93 +/- 0.67 s(-1). In contrast, fexofenadine and rupatadine did not change I-Ca or the frequency of spontaneous I-NCX. We conclude that the proarrhythmic antihistaminic drug terfenadine alters intracellular calcium handling in isolated human atrial myocytes. This experimental model may be suitable to screen for potential arrhythmogenic side-effects of compounds intended for therapeutical use. (c) 2006 Elsevier B.V. All rights reserved.