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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：
ENDOH Masao
金额：
$ 9.73万
依托单位：
Yamagata University
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

心脏能够通过发达的心脏收缩调节系统立即增加心输出量来维持重要器官广泛适应所需的循环血量。心肌收缩调节是通过心脏内源性和/或外源性调节机制实现的，其中Ca~(2+)~(2+)和GT~(2+)离子起着关键作用。钙离子的调节是通过与肌钙蛋白C结合(中枢机制)、改变钙动员(上游机制)和(或)调节跨桥循环本身(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钙调节过程的选择性或伴随调节水平上。为阐明内皮素-1(ET-1)在不同CA-…患者体循环中释放的调节机制，进行了实验研究。更多的心血管疾病，包括缺血性心脏病和充血性心力衰竭。在小鼠和狗的单个心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)的串扰而产生正性或负性变力作用，其作用取决于去甲肾上腺素的浓度。相反，在小鼠心室肌细胞中，ET-1通过激活Na~+/Ca~(2+)&gt；交换器而产生明显的负性变力作用，该交换器对SEA 0400和PKC抑制剂敏感。因此，对ET-1的变力反应表现出广泛的物种依赖性变化。由于小鼠心脏易于进行基因操作而被用作哺乳动物心脏疾病的病理模型，因此在分析病理结果的病因时，必须考虑到该物种与大型哺乳动物在受体介导的调控方面的差异。采用荷马兜铃素的犬心肌模型，分析了新型强心剂左西孟丹的作用机制。结果发现，在较宽的浓度范围内，左西孟旦通过结合钙动员和肌丝钙敏化而产生正性变力作用。在主要研究人员退休前心血管研究的最后阶段，总结了力-频率关系、PDE-3抑制剂和钙增敏剂等关键调节机制的特点，以及它们与病理生理的关系，以及心血管新药的未来发展方向。较少