Meng Jing, Shi Chenxia, Li Lin, Du Yumin, Xu Yanfang
The Key Laboratory of Neural and Vascular Biology, Ministry of Education; The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Hebei Medical University, Hebei Province, Shijiazhuang 050017, China; Department of Pharmaceutical Chemistry, Hebei Medical University, Shijiazhuang, China.
Eur J Pharmacol. 2013 Oct 15;718(1-3):87-97. doi: 10.1016/j.ejphar.2013.09.011. Epub 2013 Sep 13.
Impaired ventricular repolarization can lead to long QT syndrome (LQT), a proarrhythmic disease with high risk of developing lethal ventricular tachyarrhythmias. The compound ICA-105574 is a recently developed hERG activator and it enhances IKr current with very high potency by removing the channel inactivation. The present study was designed to investigate antiarrhythmic properties of ICA-105574. For comparison, the effects of another compound NS1643 was in-parallel assessed, which also acts primarily to attenuate channel inactivation with moderate potency. We found that both ICA-105574 and NS1643 concentration-dependently shortened action potential duration (APD) in ventricular myocytes, and QT/QTc intervals in isolated guinea-pig hearts. ICA-105574, but not NS1643, completely prevented ventricular arrhythmias in intact guinea-pig hearts caused by IKr and IKs inhibitors, although both ICA-105574 and NS1643 could reverse the drug-induced prolongation of APD in ventricular myocytes. Reversing prolongation of QT/QTc intervals and antagonizing the increases in transmural dispersion of repolarization and instability of the QT interval induced by IKr and IKs inhibitors contributed to antiarrhythmic effect of ICA-105574. Meanwhile, ICA-105574 at higher concentrations showed a potential proarrhythmic risk in normal hearts. Our results suggest that ICA-105574 has more efficient antiarrhythmic activity than NS1643. However, its potential proarrhythmic risk implies that benefits and risks should be seriously taken into consideration for further developing this type of hERG activators.
心室复极受损可导致长QT综合征（LQT），这是一种具有发生致命性室性心律失常高风险的致心律失常疾病。化合物ICA - 105574是一种最近开发的人乙醚 - 去极化相关基因（hERG）激活剂，它通过消除通道失活以非常高的效力增强Ikr电流。本研究旨在探究ICA - 105574的抗心律失常特性。为作比较，同时评估了另一种化合物NS1643的作用，它也主要通过中等效力减弱通道失活起作用。我们发现ICA - 105574和NS1643均浓度依赖性地缩短心室肌细胞的动作电位时程（APD）以及离体豚鼠心脏的QT/QTc间期。ICA - 105574而非NS1643能完全预防完整豚鼠心脏中由Ikr和Iks抑制剂引起的室性心律失常，尽管ICA - 105574和NS1643均可逆转药物诱导的心室肌细胞APD延长。逆转QT/QTc间期延长以及拮抗由Ikr和Iks抑制剂诱导的复极跨壁离散度增加和QT间期不稳定性有助于ICA - 105574的抗心律失常作用。同时，较高浓度的ICA - 105574在正常心脏中显示出潜在的致心律失常风险。我们的结果表明ICA - 105574具有比NS1643更有效的抗心律失常活性。然而，其潜在的致心律失常风险意味着在进一步开发这类hERG激活剂时应认真考虑利弊。
