Functional role of background K+current in pacemaker cells of sinoatrial.node

本项目的目的是表征心肌细胞，特别是窦房结起搏器细胞中的背景K^+电流，以了解其对起搏器活动的可能贡献。得到了以下结果：1)背景K^+电流的种类和区域异质性。在大鼠心房细胞中，背景K^+电流通过增加外部pH值而增加，并被布比卡因或甲胺抑制。此外，氟烷增强了K^+电流。所有这些性质都类似于TASK，它是4tm K^+通道的成员。因此，TASK可能在大鼠心房肌细胞复极中起作用。另一方面，兔窦房结（SAN）细胞的背景K^+电流对甲胺不敏感，并被4-氨基吡啶抑制。猪SAN细胞的背景电流明显小于兔。这些结果表明，K^+电流密度的差异导致了不同哺乳动物的放电频率不同。2)猪窦房结细胞的动作电位。猪SAN细胞的动作电位（AP）持续时间明显长于兔，导致猪心率较慢。我们已经证明，除了缺乏背景K^+电流外，l型Ca^<2+>电流的窗口分量有助于延长AP持续时间。SAN细胞的l型Ca^<2+>通道在动力学和生物学上与心室细胞不同。3)吸入性麻醉剂对延迟整流器K^+电流的影响日本最常用的吸入性麻醉剂氟醚可激活背景K^+电流。此外，麻醉药显示抑制缓慢激活延迟整流器K^+电流。抑制作用发生在临床相关浓度。由此导致的心室复极延长可能部分解释了这些麻醉剂导致QT过度延长的临床观察。

This project was carried out to characterize the background K^+ current in cardiac myocytes, particularly in pacemaker cells of sinoatrial node in relation to its possible contribution to the pacemaker activity. The following results were obtained.1)Species and regional heterogeneity of background K^+ current.In rat atrial cells, the background K^+ current was increased by increasing external pH, and inhibited by bupivacaine or metanandamide. In addition, the K^+ current was enhanced by halothane. All these properties were similar to TASK, a member of 4 TM K^+ channels. Thus, TASK may play a role for repolarization of rat atrial myocytes. On the other hand, the background K^+ current in rabbit sinoatrial node (SAN) cells was insensitive to metanandamide, and was inhibited by 4-aminopyridine. In porcine SAN cells, the background current was significantly smaller than that of rabbit. These findings indicate that the difference in the current density of the K^+ current contributes to different firing frequency among various mammalian species.2)Action potential of porcine sinoatrial node cells.The action potential (AP) duration of porcine SAN cells is significantly longer than that of rabbit, leading to slower heart rate in pigs. We have shown that, in addition to the lack of the background K^+ current, window component of the L-type Ca^<2+> current helps to prolong the AP duration. The L-type Ca^<2+> channel in SAN cells is kinetically and biologically different from that of ventricular cells.3)Effects of inhalational anesthetics on delayer rectifier K^+ currentSevoflurane, a most popular inhalational anesthetics in Japan, activates the background K^+ current. Also the anesthetics is shown to inhibit the slowly activating delayed rectifier K^+ current. The inhibition occurs at clinically relevant concentrations. The resulting prolongation of ventricular repolarization may partly account for the clinical observation of excessive QT prolongation by these anesthetics.