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

本研究旨在研究心肌细胞，特别是窦房结起搏细胞的背景钾电流及其对起搏器活动的可能贡献。结果表明：1)背景K~+电流的种类和区域异质性：在大鼠心房细胞上，背景K~+电流随外加pH的升高而增加，并被布比卡因或偏安非他明抑制。此外，氟烷对K~(++)电流有增强作用。所有这些特性都与4个TM K^+通道成员TASK相似。因此，TASK可能对大鼠心房肌细胞的复极起作用。另一方面，兔窦房结细胞的背景钾电流对偏安非他明不敏感，可被4-氨基吡啶抑制。猪窦房结细胞的背景电流明显小于兔的背景电流。这些结果表明，K~+电流密度的不同是导致不同哺乳动物放电频率不同的原因。2)猪窦房结细胞的动作电位，猪窦房结细胞的动作电位时程明显长于兔，导致猪心率减慢。结果表明，除了缺乏背景K^+电流外，L型钙电流的窗口成分有助于延长AP的持续时间。窦房结细胞的L型钙通道在动力学和生物学上不同于心室肌细胞的钙通道。3)吸入麻醉药对延迟整流性K^+电流的影响日本最流行的吸入麻醉药七氟醚激活背景K^+电流。麻醉药还能抑制慢激活的延迟整流钾电流。这种抑制作用发生在临床相关的浓度。由此导致的心室复极延长可能是临床观察到这些麻醉药过度延长QT的部分原因。

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.