Hove-Madsen Leif, Llach Anna, Molina Cristina E, Prat-Vidal Cristina, Farré Jordi, Roura Santiago, Cinca Juan
Cell Physiology Laboratory, Cardiology Department, Institut Catalá de Ciencies Cardiovasculars, Hospital de la Santa Creu i Sant Pau, St Antoni M(a) Claret 167, 08025 Barcelona, Spain.
Eur J Pharmacol. 2006 Dec 28;553(1-3):215-21. doi: 10.1016/j.ejphar.2006.09.023. Epub 2006 Sep 23.
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 IC(50) of 185 nM when cells are stimulated at 1.0 Hz. The inhibitory effect of 0.3 muM 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 muM, 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.
心肌细胞肌浆网的自发性钙释放在心律失常的发生中起核心作用。因此，用于治疗的干扰细胞内钙处理的化合物可能具有不良的促心律失常潜力。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促心律失常的抗组胺药物非索非那定和卢帕他定对细胞内钙稳态的影响。采用穿孔膜片钳技术测量离子电流，并检测肌浆网的自发性钙释放。我们的结果表明，已知有致心律失常作用的化合物特非那定，当以1.0 Hz刺激细胞时，以185 nM的IC(50)抑制L型钙电流（I(Ca)）。0.3 μM特非那定的抑制作用从0.2 Hz刺激频率下的19±4%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性钙释放。在1 μM浓度下，特非那定显著增加自发性钠钙交换电流（I(NCX)）频率，从0.48±0.25增加到1.93±0.67 s(-1)。相比之下，非索非那定和卢帕他定没有改变I(Ca)或自发性I(NCX)的频率。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的钙处理。该实验模型可能适合筛选用于治疗的化合物潜在的致心律失常副作用。
