Pharmacological approach toward the pacemaker mechanism of porcine sinoatrial node cells

猪窦房结细胞起搏机制的药理学研究

• 批准号: 10670080
• 负责人: ONO Kyoichi
• 金额: $ 2.05万
• 依托单位: AKITA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670080/
• 关键词: sinoatrial node; automaticity; pacemaker current; delayed rectifier potassium current; hyperpolarization-activated cation current; chromanol 293B; pig; ion channels; ペースメーカー電流; イオンチャンネル; 心臓自動能; 遅延整流Kチャネル; 持続性内向き電流

This project was carried out to investigate the mechanisms underlying the automaticity of porcine sinoatrial node cells, and the following results were obtained.1. The isolated cells exhibited spontaneous action potentials at a rate of approximately 80 minィイD1-1ィエD1. This value is similar to the heart rate of pigs and slower than that of rabbit sinoatrial node cell (approximately 200 minィイD1-1ィエD1), indicating that the heart rate is determined by intrinsic properties of sinoatrial node cells of various mammalian species.2. In porcine sinoatrial node cells the delayed rectifier KィイD1+ィエD1 current (IィイD2KィエD2) is largely derived from the slowly activating IィイD2KィエD2 (IィイD2KsィエD2). The result suggest that IィイD2KsィエD2 may, in part, account for the relatively slower heart rate of pigs than rabbit in which the rapidly activating IィイD2KィエD2 (IィイD2KrィエD2) is predominant component of IK.3. The hyperpolarization-activated cation current (IィイD2hィエD2) activates at membrane potentials more negative … More than -70 mV. The kinetics and ionic selectivity were essentially similar to IィイD2hィエD2 of rabbit sinoatrial node cells.4. Chromanol derivative 293B blocks IィイD2KsィエD2 selectively. In guinea-pig ventricular cells, block by chromanol 293B of IィイD2KsィエD2 occurred in a time-dependent manner. We conclude that chromanol 293B is an open channel blocker for IィイD2KsィエD2 with a relatively slower blocking rate constant than those reported so far for time- and voltage-dependent blockade of ionic channels.It has been reported that various ionic currents such as IィイD2KィエD2, IィイD2hィエD2, L- and T-type CaィイD12+ィエD1 currents, NaィイD1+ィエD1/KィイD1+ィエD1 pump current, background cation current, muscarinic KィイD1+ィエD1 current and dyhydropyridine-sensitive NaィイD1+ィエD1 current, contribute to the automaticity of sinoatrial node cells. Although we could successfully quantify the properties of IK and Ih in porcine sinoatirial node cells in this project, the characteristics of other ionic currents still remain to be evaluated. Less

本课题旨在探讨猪窦房结细胞自主性的机制，获得以下结果： 1．分离的细胞以大约 80 分钟ィイD1-1ィエD1 的速率表现出自发动作电位。该值与猪心率相似，比兔窦房结细胞慢（约200分钟ィイD1-1ィエD1），表明心率是由各种哺乳动物窦房结细胞的内在特性决定的。 2．在猪窦房结细胞中，延迟整流器KィイD1+ィエD1电流（IィイD2KィエD2）主要源自缓慢激活的IィイD2KィエD2（IィイD2KsィエD2）。结果表明，IィイD2KsィエD2 可能部分解释了猪的心率比兔子慢，其中快速激活的 IィイD2KsィエD2 (IィイD2KrィエD2) 是 IK.3 的主要成分。超极化激活的阳离子电流 (IィイD2hィエD2) 在膜电位更负时激活……超过 -70 mV。动力学和离子选择性与兔窦房结细胞IiiD2hiiD2基本相似。 4．苯并二氢吡喃醇衍生物 293B 选择性阻断 IiiD2KsiiD2。在豚鼠心室细胞中，IiiD2KsiiD2 的 chromanol 293B 阻断以时间依赖性方式发生。我们得出结论，chromanol 293B 是 IiiD2KsiiD2 的开放通道阻断剂，与迄今为止报道的时间和电压依赖性离子通道阻断剂相比，其阻断速率常数相对较慢。据报道，各种离子电流如 IiiD2KsiiD2、IiiD2hiiD2、L- 和 T-型ィイD12+ィエD1 电流、NaィイD1+ィエD1/KィイD1+ィエD1泵电流、背景阳离子电流、毒蕈碱KィイD1+ィエD1电流和二氢吡啶敏感NaィイD1+ィエD1电流有助于窦房结细胞的自动化。尽管我们在该项目中成功量化了猪窦房结细胞中 IK 和 Ih 的特性，但其他离子电流的特性仍有待评估。较少的

项目成果

K. ONO: "Chloride-sensitive nature of the histamine-induced CaィイD12+ィエD1 entry in cultured human aortic endothelial cells."Journal of Physiology. 511. 837-849 (1998)

K. ONO：“培养的人主动脉内皮细胞中组胺诱导的 CaD12+CaD1 进入的氯敏感性。”生理学杂志 511. 837-849 (1998)

M. NAKAO: "Inhibition by antisense oligonucleotides of plasma membrane ATPase in vascular endothelial cells."European Journal of Pharmacology. 387. 273-277 (2000)

M. NAKAO：“反义寡核苷酸对血管内皮细胞质膜 ATP 酶的抑制。”欧洲药理学杂志。

K.Ono,S.Shibata and T.Iijima: "Action potential and membrane currents in porcine sino-atrial node cells." Japamese Journal of Physiology. Suppl 48. S73-S73 (1998)

K.Ono、S.Shibata 和 T.Iijima：“猪窦房结细胞的动作电位和膜电流。”

K. Ono: "Properties of the delayed rectifier potassium current in porcine sino-atrial node cells"Journal of Physiology. (印刷中). (2000)

K. Ono：“猪窦房结细胞延迟整流钾电流的特性”生理学杂志（2000 年出版）。

S. Fujisawa: "Time-dependent block of the slowly activating delayed rectifier K^+ current by chromanol 293B in guinea-pig ventricular cells"British Journal of Pharmacology. (印刷中). (2000)

S. Fujisawa：“豚鼠心室细胞中 chromanol 293B 对缓慢激活的延迟整流 K^+ 电流的时间依赖性阻断”英国药理学杂志（2000 年出版）。