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

背景钾电流在窦房结起搏细胞中的功能作用

基本信息

批准号：
15590182
负责人：
ONO Kyouichi
金额：
$ 2.24万
依托单位：
Akita University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590182/
关键词：
sinoatrial node Pacemaker mechanism background K^+ current TASK Ca^<2+> channel delayed rectifier K^+ current QT prolongation 外向き電流カルシウム電流イオンチャネル自動能

项目摘要

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.

本项目旨在研究心肌细胞，特别是窦房结起搏细胞的背景K^+电流对起搏活动的影响。结果表明：1）背景钾电流的物种和区域异质性：在大鼠心房肌细胞中，背景钾电流随外界pH值的升高而增加，布比卡因和间雄胺可抑制背景钾电流。此外，氟烷还能增强K^+电流。所有这些特性都与4个TM K^+通道中的一个成员--ASK相似。因此，ASK可能在大鼠心房肌细胞复极中起作用。另一方面，兔窦房结细胞的背景K^+电流对间花生四烯酸不敏感，并可被4-氨基吡啶抑制。猪窦房结细胞的背景电流明显小于兔窦房结细胞。2）猪窦房结细胞动作电位：猪窦房结细胞动作电位时程明显长于家兔，导致猪心率减慢。我们已经证明，除了缺乏背景K^+电流外，L型Ca^<2+>电流的窗口成分有助于延长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肌细胞的不同。3）吸入麻醉药对延迟整流钾电流的影响七氟醚是日本最常用的吸入麻醉药，它激活背景钾电流。麻醉剂也能抑制缓慢激活的延迟整流钾电流。在临床相关浓度下发生抑制。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的QT间期过度延长的临床观察结果。