Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential.
Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential.
复制标题
DOI：
10.1016/j.hrthm.2015.05.027
复制
发表时间：
2015-10
期刊：
影响因子：
5.5
通讯作者：
Burton RA
中科院分区：
文献类型：
--
作者：
Capel RA;Herring N;Kalla M;Yavari A;Mirams GR;Douglas G;Bub G;Channon K;Paterson DJ;Terrar DA;Burton RA
由于心率是心肌耗氧量的重要决定因素，缓速药物对缺血性心脏病和心力衰竭的治疗很有兴趣。本研究的目的是探讨羟氯喹（HCQ）引起心动过缓的倾向。我们评估了HCQ对(1)体外（小鼠）心脏跳动率的影响；(2)离体豚鼠窦房结（SAN）肌细胞的“滑稽”电流（If）（1,3,10µM）；(3)急性大鼠大剂量1 ~ 30mg /kg注射体内心率和血压；(4)进食时血压和心室功能（小鼠100 mg/kg/d，连续2周，尾袖容积脉搏波、麻醉超声心动图）。小鼠心房自发搏动率在3和10µM HCQ下显著降低（分别为9%±3%和15%±2%，n = 7） （P < 0.05）。在豚鼠分离的SAN细胞中，HCQ显著降低自发动作电位放电率（17%±6%，1 μM剂量）和If的剂量依赖性降低（13%±3%，3 μM剂量19%±2%）。3µM时l型钙离子电流（ICaL）降低12%±4%，快速延迟整流钾电流（IKr）降低35%±4%。静脉注射HCQ使麻醉大鼠心率降低（15mg/kg时14.3%±1.1%;n = 6），但平均动脉血压未显著降低。小鼠体内喂养研究显示收缩压和左心室功能没有明显变化。我们已经证明HCQ在SAN细胞、心房制剂和体内作为心动过缓的药物。HCQ通过多通道抑制减缓SAN中自发动作电位放电的速率，包括If的抑制。
Bradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption. The purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia. We assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the “funny” current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 µM); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1–30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography). In mouse atria, spontaneous beating rate was significantly (P < .05) reduced (by 9% ± 3% and 15% ± 2% at 3 and 10 µM HCQ, n = 7). In guinea pig isolated SAN cells, HCQ conferred a significant reduction in spontaneous action potential firing rate (17% ± 6%, 1 μM dose) and a dose-dependent reduction in If (13% ± 3% at 1 µM; 19% ± 2% at 3 µM). Effects were also observed on L-type calcium ion current (ICaL) (12% ± 4% reduction) and rapid delayed rectifier potassium current (IKr) (35% ± 4%) at 3 µM. Intravenous HCQ decreased heart rate in anesthetized rats (14.3% ± 1.1% at 15mg/kg; n = 6) without significantly reducing mean arterial blood pressure. In vivo feeding studies in mice showed no significant change in systolic blood pressure nor left ventricular function. We have shown that HCQ acts as a bradycardic agent in SAN cells, in atrial preparations, and in vivo. HCQ slows the rate of spontaneous action potential firing in the SAN through multichannel inhibition, including that of If.