Inhibition of hyperpolarization-activated cyclic nucleotide-gated channels by β-blocker carvedilol
Inhibition of hyperpolarization-activated cyclic nucleotide-gated channels by β-blocker carvedilol
复制标题
β-受体阻滞剂卡维地洛对超极化激活的环核苷酸门控通道的抑制
DOI：
10.1111/bph.14469
复制
发表时间：
2018-10-01
影响因子：
7.3
通讯作者：
Zhou, Pingzheng
中科院分区：
文献类型：
--
作者：
Cao, Ying;Chen, Shujun;Zhou, Pingzheng
背景和结论卡维地洛是一种临床上有效的β受体阻滞剂，广泛用于治疗充血性心力衰竭（CHF），多项临床试验表明，与其他受体阻滞剂相比，卡维地洛对CHF患者显示出良好的疗效。与其他β受体阻滞剂相比，卡维地洛这种有益作用的机制尚不清楚。除了β-受体阻滞剂之外，超极化激活的环核苷酸（HCN）门控通道的抑制剂（其在心脏中的自发节律活动中起关键作用）也已被提出为用于降低心率的合适药物，并且因此有益于治疗CHF。在本研究中，我们研究了卡维地洛对HCN通道的影响。实验方法：全细胞膜片钳记录被用来评估卡维地洛对CHO细胞表达的野生型和突变型HCN 1，HCN 2和HCN 4通道电流的影响。关键词卡维地洛是唯一一种对主要的窦房HCN通道亚型HCN 4显示抑制作用的β受体阻滞剂。卡维地洛以浓度依赖性方式抑制HCN 4，EC 50为4.4 μ M。卡维地洛对HCN 1和HCN 2通道也有抑制作用。卡维地洛通过减慢通道激活速率和增加通道失活速率阻断HCN通道，并使通道激活的电压依赖性左移。我们的数据还表明，卡维地洛，不像该通道的其他抑制剂（伊伐布雷定和ZD 7288），不是HCN 4的“开放通道”抑制剂。结论和意义卡维地洛是HCN通道的负门控调节剂。它代表了未来HCN通道抑制剂药物设计的新结构。
BACKGROUND AND PURPOSECarvedilol is a clinically effective beta-blocker broadly used for treating congestive heart failure (CHF), and several clinical trials have demonstrated that it shows a favourable effect compared with other-blockers in patients with CHF. The mechanism underlying this beneficial effect of carvedilol compared to other beta-blockers is not clearly understood. In addition to beta-blockers, inhibitors of hyperpolarization-activated cyclic nucleotide (HCN)-gated channels, which play a critical role in spontaneous rhythmic activity in the heart, have also been proposed to be suitable drugs for reducing heart rate and, therefore, beneficial for treating CHF. In the present study, we investigated the effect of carvedilol on HCN channels.EXPERIMENTAL APPROACHWhole-cell patch-clamp recordings were used to assess the effect of carvedilol on currents from wild-type and mutant HCN1, HCN2 and HCN4 channels expressed in CHO cells.KEY RESULTSCarvedilol was the only beta-blocker tested that showed inhibitory effects on the major sinoatrial HCN channel isoform HCN4. Carvedilol inhibited HCN4 in a concentration-dependent manner with an EC50 of 4.4 mu M. In addition, carvedilol also inhibited HCN1 and HCN2 channels. Carvedilol blocked HCN channels by decelerating the rate of channel activation and increasing that of deactivation, and shifted the voltage-dependence of activation leftwards. Our data also showed that carvedilol, unlike other inhibitors of this channel (ivabradine and ZD7288), is not an 'open-channel' inhibitor of HCN4.CONCLUSIONS AND IMPLICATIONSCarvedilol is a negative gating modulator of HCN channels. It represents a novel structure for future drug design of HCN channel inhibitors.