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

基本信息

批准号：
03454142
负责人：
ENDOH Masao
金额：
$ 4.16万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1993
项目状态：
已结题

项目摘要

The signal transduction process subsequent to activation of myocardial alpha_1-adrenoceptors has been further complicated by the discovery of subtypes, alpha_<1A>, alpha_<1B> and alpha_<1C> whereas the functional role of alpha _<1C> in cardiac function is unknown at the moment. The present study was carried out to elucidate intracellular process mediated by cardiac alpha_1-adrenoceptors. Results obtained can be summarized as follows : (1)In the rabbit ventricle ca. 60% of alpha_1-adrenoceptors belong to alpha_<1B> subtype, which is coupled to the positive inotropic effect (PIE) and PI hydrolysis and is effectively antagonized by chlorethylclonidine (CEC). CEC at 0.1-10 uM inhibited the PIE of phenylephrine mediated by alpha_1-adrenoceptors in a concentration-dependent manner. (2)In the rabbit ventricle ca. 40% of alpha_1-receptors belong to alpha_<1A> subtype. There appear to be further two subclasses in this subtype : (1)WB 4101-sensitive one, coupled to PI hydrolysis and PIE ; (2) (+)-niguldipine-sensitive one, coupled to PIE without acceleration of PI hydrolysis. Denopamine and HV723 (in low concentration) inhibit selectively the (+)-niguldipine-sensitive subtype. (3)Activation of endothelin and angiotensin receptor in rabbit heart accelerates PI hydrolysis as alpha_1 stimulation does. In the present study it was found that the response to activation of these receptors showed a remarkable similarity to each other in following respects : (1) the PIE was associated with prolongation of isometric twitch contractions ; (2) the concentration-and time-dependent change in PIE and PI hydrolysis in response to receptor activation showed an excellent correlation ; (3) phorbol 12,13-dibutyrate that activates protein kinase C consistently inhibited the PIE and PI hydrolyis elicited through these receptors. These findings strongly indicate that PI hydrolysis may mediated the PIE induced by activation of

通过发现亚型，alpha_ <1a>，alpha_ <1b>和alpha_ <1c>激活心肌alpha_1-肾上腺素受体激活后的信号转导过程，而心脏_ <1c> <1c> alpha_ <1b>> <1c>当时心脏功能的功能在当时尚不清楚。本研究是为了阐明由心脏α_1-肾上腺素受体介导的细胞内过程。获得的结果可以总结如下：（1）在兔子心室中。 60％的alpha_1-肾上腺素受体属于Alpha_ <1b>亚型，该α_<1b>亚型与阳性肌瘤效应（PIE）和PI水解耦合，并通过氯乙基氯苯烷（CEC）有效地拮抗。 CEC在0.1-10的UM下抑制了由α_1-肾上腺素受体介导的苯肾上腺素的馅饼，以浓度依赖性方式。（2）在兔子心室中。 40％的alpha_1受体属于Alpha_ <1A>子类型。该亚型中似乎还有两个亚类：（1）WB 4101敏感的一个，与PI水解和馅饼耦合；（2）（+） - niguldipine敏感的敏感性，与PIE结合而无需加速PI水解。非洲异构指南和HV723（低浓度）选择性抑制（+） - 尼古丁敏感的亚型。（3）兔心脏中内皮素和血管紧张素受体的激活像alpha_1刺激一样加速PI水解。在本研究中，发现对这些受体的激活的反应在以下方面表现出显着的相似性：（1）pie与等距抽搐收缩的延长有关；（2）响应受体激活的PIE和PI水解的浓度和时间依赖性变化显示出极好的相关性；（3）激活蛋白激酶C的佛波尔12,13-二丁酸酯始终抑制通过这些受体引起的PIE和PI水解。这些发现强烈表明，PI水解可能通过激活的激活介导