Pharmacological Profile of the Bradycardic Agent Ivabradine on Human Cardiac Ion Channels.
Pharmacological Profile of the Bradycardic Agent Ivabradine on Human Cardiac Ion Channels.
复制标题
DOI：
10.33594/000000119
复制
发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Koenig, Xaver
中科院分区：
文献类型：
--
作者：
Haechl, Nicholas;Ebner, Janine;Koenig, Xaver
背景/目的：伊伐布雷定通过抑制介导窦房结“滑稽”起搏器电流的超极化激活环核苷酸门控（HCN）通道来降低心率。临床批准用于治疗心力衰竭和心绞痛。由于其对心律失常的高选择性，伊伐布雷定的应用与其他降心率药物应用后常见的副作用无关。然而，最近的证据表明，伊伐布雷定对Kv11.1（醚-a-go-go相关基因，ERG）钾通道具有显著的亲和力。尽管伊伐布雷定抑制了Kv11.1通道，但人心电图（ECG）的心动作电位（AP）持续时间和心率校正QT间期（QTc）并未延长。因此，我们推测代偿机制可能会抵消药物对Kv11.1的抑制作用。方法：采用全细胞膜片钳技术，采用电压箝位方式研究伊伐布雷定对人tsA-201细胞异种表达的Kv11.1、Kv7.1钾、Cav1.2钙、Nav1.5钠通道的影响。此外，采用电流箝法研究了伊伐布雷定对人诱导多能干细胞（iPSC）心肌细胞动作电位参数的影响。结果：我们发现伊伐布雷定对心脏离子通道有明显的亲和力，而不是对HCN。我们首次证明了在治疗相关浓度下抑制人类电压门控Nav1.5钠通道。在这项研究中，我们也证实了最近的研究结果，即低浓度的伊伐布雷定对人Kv11.1的抑制作用，并观察到iPSCs衍生的心肌细胞的心室样APs没有延长。结论：我们的研究结果解释了为什么尽管伊伐布雷定对Kv11.1通道有亲和力，但它并没有延长心脏AP和QTc间期。此外，我们的研究结果表明，抑制电压门控的Nav1.5钠通道是最近观察到的房室传导减慢的基础，在给予伊伐布雷定后，心房-他束间隔增加。
BACKGROUND/AIMS: Ivabradine lowers the heart rate by inhibition of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels mediating the 'funny' pacemaker current If in the sinoatrial node. It is clinically approved for the treatment of heart failure and angina pectoris. Due to its proposed high selectivity for If administration of ivabradine is not associated with the side effects commonly observed following the application of other heart rate lowering agents. Recent evidence, however, has shown significant affinity of ivabradine towards Kv11.1 (ether-a-go-go related gene, ERG) potassium channels. Despite the inhibition of Kv11.1 channels by ivabradine, cardiac action potential (AP) duration and heart rate corrected QT interval (QTc) of the human electrocardiogram (ECG) were not prolonged. We thus surmised that compensatory mechanisms might counteract the drug's inhibitory action on Kv11.1.METHODS: The effects of ivabradine on human Kv11.1 and Kv7.1 potassium, Cav1.2 calcium, and Nav1.5 sodium channels, heterologously expressed in tsA-201 cells, were studied in the voltage-clamp mode of the whole cell patch clamp technique. In addition, changes in action potential parameters of human induced pluripotent stem cell (iPSC) derived cardiomyocytes upon application of ivabradine were studied with current-clamp experiments.RESULTS: Here we show that ivabradine exhibits significant affinity towards cardiac ion channels other than HCN. We demonstrate for the first time inhibition of human voltage-gated Nav1.5 sodium channels at therapeutically relevant concentrations. Within this study we also confirm recent findings of human Kv11.1 inhibition by low M concentrations of ivabradine and observed no prolongation of ventricular-like APs in cardiomyocytes derived from iPSCs.CONCLUSION: Our results provide an explanation why ivabradine, despite its affinity for Kv11.1 channels, does not prolong the cardiac AP and QTc interval. Furthermore, our results suggest the inhibition of voltage-gated Nav1.5 sodium channels to underlie the recent observations of slowed atrioventricular conduction by increased atrial-His bundle intervals upon administration of ivabradine.