Molecular pharmacological research for regulation and disorder of cardiac myocytes

心肌细胞调控与紊乱的分子药理学研究

基本信息

  • 批准号:
    16390064
  • 负责人:
  • 金额:
    $ 9.73万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    2004
  • 资助国家:
    日本
  • 起止时间:
    2004 至 2006
  • 项目状态:
    已结题

项目摘要

The heart is able to maintain circulating blood volume required for wide range of adaptation of vital organs by an immediate increase in cardiac output by means of well-developed regulatory systems of cardiac contractility. Contractile regulation is achieved by cardiac intrinsic and/or external regulatory mechanisms, in both of which Ca^<2+> ions play a pivotal role. The regulation by Ca^<2+> is achieved by Ca^<2+> binding to troponin C (central mechanism), alteration of Ca^<2+> mobilization (upstream mechanism), and thin filament regulation of cross-bridge cycling and/or regulation of cross-bridge cycling itself (downstream mechanism). Regulation and disorder of cardiac excitation-contraction coupling occur at the level of selective or concomitant modulation of these Ca^<2+> regulatory processes. Experiments were carried out to elucidate the regulatory mechanisms of action of endothelin-1 (ET-1) that has been shown to be released in the systemic circulation of patients with various ca … More rdiovascular diseases including ischemic heart disease and congestive heart failure. Cell shortening and indo-1 fluorescent signals were detected simultaneously in mouse and dog single ventricular myocytes. In the dog, ET-1 induced a positive or negative inotropic effect by cross-talk with norepinephrine (NE) depending on the NE concentration. By contrast, in the mouse ventricular myocytes, ET-1 elicited a pronounced negative inotropic effect through the activation of Na^+/Ca^<2+> exchanger, which is susceptible to SEA 0400 and PKC inhibitors. Thus the inotropic response to ET-1 show a wide range of species-dependent variation. Since the mouse heart is employed as pathological models of mammalian heart diseases because of its ease for genetic manipulation, the difference in receptor-mediated regulation in this species from larger mammalian species has to be taken into consideration in analysis the etiology underlying the pathological outcome. The mechanism of action of a novel cardiotonic agent levosimendan was analyzed by means of aequorin-loaded dog ventricular myocardium. It was found that over a wide range of levosimendan concentration, it elicited a positive inotropic effect by combination of Ca^<2+> mobilization and myofilament Ca^<2+> sensitization. In the final stage of cardiovascular research of the main investigator before retirement the characteristics of crucial regulatory mechanisms, such as force-frequency relationship, PDE 3 inhibitors, and Ca^<2+> sensitizers are summarized in relation to their pathophysiological relevance, and the future direction of development of novel cardiovascular drugs. Less
心脏能够通过借助于发达的心脏收缩性调节系统立即增加心输出量来维持重要器官的广泛适应所需的循环血容量。收缩调节是通过心脏的内在和/或外在调节机制实现的,其中Ca^2+离子起关键作用。Ca^2+的调节是通过Ca^2+与肌钙蛋白C的结合(中枢机制)、Ca^2+动员的改变(上游机制)和跨桥循环的细丝调节和/或跨桥循环本身的调节(下游机制)来实现的。心脏兴奋-收缩偶联的调节和紊乱发生在这些Ca^2+调节过程的选择性或伴随性调节水平上。本实验旨在阐明内皮素-1(ET-1)的调节作用机制,ET-1已被证明在各种癌症患者的体循环中释放。 ...更多信息 心血管疾病包括缺血性心脏病和充血性心力衰竭。在小鼠和狗单个心室肌细胞中同时检测到细胞缩短和indo-1荧光信号。在狗中,ET-1通过与去甲肾上腺素(NE)的相互作用诱导正性或负性肌力作用,这取决于NE的浓度。与此相反,在小鼠心室肌细胞中,ET-1通过激活Na^+/Ca^2+交换体引起显著的负性肌力作用,而Na^+/Ca^2+交换体对SEA 0400和PKC抑制剂敏感。因此,对ET-1的变力性反应表现出广泛的种属依赖性变化。由于小鼠心脏因其易于遗传操作而被用作哺乳动物心脏病的病理模型,因此在分析病理结果的病因学时必须考虑该物种中受体介导的调节与较大哺乳动物物种的差异。本文用水母发光蛋白负载犬心室肌,分析了新型强心药左西孟旦的作用机制。研究发现,在很宽的左西孟旦浓度范围内,它通过Ca^<2+>动员和肌丝Ca^<2+>增敏的结合引起正性肌力作用。在主要研究者退休前的心血管研究的最后阶段,总结了力-频关系、PDE 3抑制剂和Ca^2+增敏剂等关键调节机制的特点及其与心血管疾病的病理生理相关性,并展望了心血管新药的发展方向。少

项目成果

期刊论文数量(49)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Na+ channel agonist: a potential cardiotonic agent with a novel mechanism?
Ca^<2+>チャネルとCa^<2+>拮抗薬~その薬理学の新しい展開~
Ca^<2+>通道和Ca^<2+>拮抗剂~药理学新进展~
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Endoh;M.;遠藤 政夫
  • 通讯作者:
    遠藤 政夫
Episodes in development of anti-hypertensive drugs : Ca^<2+> antagonists.
抗高血压药物开发中的事件:Ca ^ 2 拮抗剂。
Differential inhibition by TAK-044 of the inotorpic effects of endothelin-1 and endothelin-3.
TAK-044 对内皮素 1 和内皮素 3 的正性肌力作用的差异抑制。
Differential action of a protein tyrosine kinase inhibitor, genistein, on the positive inotropic effect of endothelin‐1 and norepinephrine in canine ventricular myocardium
  • DOI:
    10.1038/sj.bjp.0706097
  • 发表时间:
    2005-02
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    L. Chu;Jian-xin Zhang;I. Norota;M. Endoh
  • 通讯作者:
    L. Chu;Jian-xin Zhang;I. Norota;M. Endoh
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ENDOH Masao其他文献

ENDOH Masao的其他文献

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{{ truncateString('ENDOH Masao', 18)}}的其他基金

Basic research for regulation and disorder of cardiac Ca signal
心脏Ca信号调控与紊乱的基础研究
  • 批准号:
    14370778
  • 财政年份:
    2002
  • 资助金额:
    $ 9.73万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
MORECULAR PHARMACOLOGICAL STUDY OF SIGNAL TRANSDUCTION
信号转导的更常规药理学研究
  • 批准号:
    11470021
  • 财政年份:
    1999
  • 资助金额:
    $ 9.73万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of Novel Therapeutic Agents for Treatment of Congestive Heart Failure by Means of Model Animals
通过模型动物开发治疗充血性心力衰竭的新型治疗剂
  • 批准号:
    11557203
  • 财政年份:
    1999
  • 资助金额:
    $ 9.73万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of new drugs for the treatment of congestive heart failure
治疗充血性心力衰竭新药的开发
  • 批准号:
    07557193
  • 财政年份:
    1995
  • 资助金额:
    $ 9.73万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Development of novel cardiotonic agents
新型强心剂的开发
  • 批准号:
    04557009
  • 财政年份:
    1992
  • 资助金额:
    $ 9.73万
  • 项目类别:
    Grant-in-Aid for Developmental Scientific Research (B)
A Molecular Mechanism, of Myocardial alpha-Adrenoceptor-mediated Signaltransductio
心肌α-肾上腺素受体介导的信号转导的分子机制
  • 批准号:
    03454142
  • 财政年份:
    1991
  • 资助金额:
    $ 9.73万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
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