A Molecular Mechanism, of Myocardial alpha-Adrenoceptor-mediated Signaltransductio

心肌α_1-肾上腺素能受体激活后的信号转导过程因α_1受体亚型的发现而变得更加复杂。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。结果如下：(1)在兔脑室，约60%的α_1肾上腺素能受体属于α_1受体亚型，该亚型与正性变力作用(PIE)和PI水解性有关，可被氯乙基可乐定(CEC)有效拮抗。0.1-10um的CEC以浓度依赖的方式抑制α_1-肾上腺素受体介导的苯肾上腺素PIE。(2)兔脑室约40%的α_1受体属于α_1亚型。在这个亚型中似乎还有两个亚类：(1)WB 4101敏感亚类，与PI水解和PIE结合；(2)(+)-尼古地平敏感亚类，与PIE结合而不加速PI水解。地诺帕明和HV723(低浓度)选择性地抑制(+)-尼古地平敏感亚型。(3)激活兔心脏的内皮素和血管紧张素受体可加速PI的降解，与α_1刺激一样。在本研究中发现，这些受体的激活反应在以下几个方面表现出显著的相似性：(1)PIE与等长收缩有关；(2)PIE的浓度和时间依赖的变化与PI对受体激活的反应具有很好的相关性；(3)激活蛋白激酶C的佛波醇12，13-二丁酸酯持续抑制PIE，PI水解物是通过这些受体引起的。这些发现有力地表明，PI的水解可能介导了PIE的激活

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