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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

心肌α_1-肾上腺素受体激活后的信号转导过程由于α_、α_和α_亚型的发现而变得更加复杂<1A><1B>，<1C>而α_在心脏功能中的功能作用<1C>目前还不清楚。本研究旨在阐明心脏α_1-肾上腺素能受体介导的细胞内过程。实验结果如下：（1）在兔心室肌中。α_1肾上腺素能受体中有60%属于α_1<1B>亚型，它与正性肌力作用（PIE）和PI水解作用相偶联，能被二乙基可乐定（CEC）有效拮抗。CEC在0.1-10 μ M浓度范围内抑制由α_1-肾上腺素能受体介导的苯肾上腺素PIE。(2)In兔心室Ca. 40%的α_1受体属于α_<1A>亚型。该亚型中似乎还有两个亚类：（1）WB 4101敏感型，与PI水解和PIE偶联;（2）（+）-尼古地平敏感型，与PIE偶联，但不加速PI水解。地诺帕明和HV 723（低浓度）选择性抑制（+）-尼古地平敏感亚型。（3）激活内皮素和血管紧张素受体可促进PI水解，其作用与α_1刺激相似。本研究发现，这些受体的激活反应在以下几个方面具有明显的相似性：（1）PIE与等长收缩的延长有关，（2）PIE和PI水解反应的浓度和时间依赖性变化具有良好的相关性;（3）激活蛋白激酶C的佛波醇12，13-二丁酸酯可持续抑制通过这些受体引起的PIE和PI水解。这些发现强烈地表明PI水解可能介导了由激活