Hancox Jules C, James Andrew F, Marrion Neil V, Zhang Henggui, Thomas Dierk
a School of Physiology, Pharmacology and Neuroscience , University Walk , Bristol , UK.
b Biological Physics Group, School of Physics and Astronomy , University of Manchester , Manchester , United Kingdom.
Expert Opin Ther Targets. 2016 Aug;20(8):947-58. doi: 10.1517/14728222.2016.1159300. Epub 2016 Mar 17.
Atrial fibrillation (AF) is the most common arrhythmia in humans. It is progressive and the development of electrical and structural remodeling makes early intervention desirable. Existing antiarrhythmic pharmacological approaches are not always effective and can produce unwanted side effects. Additional atrial-selective antiarrhythmic strategies are therefore desirable.
Evidence for three novel ion channel atrial-selective therapeutic targets is evaluated: atrial-selective fast sodium channel current (INa) inhibition; small conductance calcium-activated potassium (SK) channels; and two-pore (K2P) potassium channels.
Data from animal models support atrial-ventricular differences in INa kinetics and also suggest atrial-ventricular differences in sodium channel β subunit expression. Further work is required to determine whether intrinsic atrial-ventricular differences in human INa exist or whether functional differences occur due to distinct atrial and ventricular action and resting potentials. SK and K2P channels (particularly K2P 3.1) offer potentially attractive atrial-selective targets. Work is needed to identify the underlying basis of SK current that contributes to (patho)physiological atrial repolarization and settings in which SK inhibition is anti- versus pro-arrhythmic. Although K2P3.1 appears to be a promising target with comparatively selective drugs for experimental use, a lack of selective pharmacology hinders evaluation of other K2P channels as potential atrial-selective targets.
心房颤动（AF）是人类最常见的心律失常。它是进行性的，电重构和结构重构的发展使得早期干预成为必要。现有的抗心律失常药物方法并不总是有效，并且可能产生不良副作用。因此，需要额外的心房选择性抗心律失常策略。
评估了三种新型离子通道心房选择性治疗靶点的证据：心房选择性快速钠通道电流（INa）抑制；小电导钙激活钾（SK）通道；以及双孔（K2P）钾通道。
动物模型的数据支持INa动力学的房室差异，也提示钠通道β亚基表达的房室差异。需要进一步研究来确定人类INa是否存在内在的房室差异，或者功能差异是否由于不同的心房和心室动作电位及静息电位而产生。SK和K2P通道（特别是K2P 3.1）提供了潜在有吸引力的心房选择性靶点。需要开展工作来确定促成（病理）生理性心房复极的SK电流的潜在基础，以及SK抑制具有抗心律失常或促心律失常作用的情况。尽管K2P3.1似乎是一个有前景的靶点，有相对选择性的药物用于实验，但缺乏选择性药理学阻碍了将其他K2P通道评估为潜在的心房选择性靶点。
