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

最近，已经认识到引起房颤的第二种不同机制;通常位于肺静脉（PV）内或附近的快速放电病灶（病灶）。从PV记录的动作电位的形态学来看，缓慢的舒张期去极化似乎参与了自发活动的产生。超极化激活的内向电流I_h或I_f在心肌细胞的起搏活动中起重要作用。最近克隆了一个新的超极化激活的环状核苷酸阳离子通道家族（HCN 1，2，3，4）。HCN 4似乎是心脏组织中的主要亚型之一。本研究的第一个目的是通过免疫组织化学染色确定HCN 4通道是否分布在大鼠肺静脉与心房组织的连接处。本研究的第二个目的是观察几种抗心律失常药物对哺乳动物（HEK 293）细胞表达的HCN 4通道电流和肺静脉心房组织自发活动的影响。HCN 4通道在HEK 293细胞中稳定表达，用膜片钳技术检测了不同药物对电流的影响。扎替雷定、胺碘酮和苄普地尔可显著抑制HCN 4通道电流。其他抗癫痫药物如奎尼丁、利多卡因、阿帕林定和氟卡尼也抑制HCN 4通道电流，尽管它们的效力低于胺碘酮或苄普地尔。异丙肾上腺素可加速大鼠肺静脉-心房的自发活动，扎替雷定或抗心律失常药物可抑制其自发活动，抗心律失常药物抑制HCN通道可预防肺静脉-心房交界处异位灶诱发的阵发性心房颤动。

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.