A new strategy for the prevention of atrial fibrillation : HCN channel blockers

点击翻译按钮获取中文摘要

Recently a second distinct mechanism causing atrial fibrillation has been recognized ; a rapidly firing focus (foci), usually located in or near the pulmonary veins (PVs). From the morphology of the action potential recorded from PV, a slow diastolic depolarization appears to be involved in the generation of the spontaneous activity. It is acknowledged that the hyperpolarization-activated inward current called I_h or I_f plays an important role in the pacemaker activity of cardiac cells. Recently a new family of the hyperpolarization-activated cyclic-nucleotide cation channels has been cloned (HCN1, 2, 3, 4). HCN4 appears to be a dominant one among the isoforms in cardiac tissues. The first aim of the present study was to determine whether HCN4 channels distribute in the junction of PVs and atrial tissues of rat by immunohistochemical staining. The second aim of this study was to examine several antiarrhythmic drugs on the HCN4 channel current expressed in mammalian (HEK293) cells and spontaneous activity of PV atriai preparations.Immunohistochemical staining with ant-HCN4 antibody was observed at the boundary of PV and atrial tissues. HCN4 channels were stably expressed in HEK293 cells and effects of various drugs on the current were examined by using patch clamp techniques. The HCN4 channel current was significantly inhibited by zatebradine, amiodarone and bepridil. Other antiarrhythmic drugs such as quinidine, lidocaine, aprindine and flecainide also inhibited the HCN4 channel current although they were less potent than amiodarone or bepridil. Spontaneous activity in isolated PV-atrial preparations of the rat was accelerated by isoproterenol and suppressed by zatebradine or antiarrhythmic drugs.The inhibition of the HCN channels by antiarrhythmic drugs may lead to the prevention of paroxysmal atrial fibrillation triggered by ectopic foci at the boundary of PV and atrial tissues.