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

心肌α _1-肾上腺素受体激活后的信号转导过程因α _<1A>、α _<1B>和α _<1C>亚型的发现而进一步复杂化，而α _<1C>在心功能中的功能作用目前尚不清楚。本研究旨在阐明心脏α _1-肾上腺素受体介导的细胞内过程。结果表明：(1)家兔脑室中约60%的α _1-肾上腺素受体属于α _<1B>亚型，该亚型与正性肌力作用（PIE）和PI水解相结合，可被氯乙基氯定（CEC）有效拮抗。0.1 ~ 10 μ m CEC对α _1-肾上腺素受体介导的苯肾上腺素PIE呈浓度依赖性抑制。(2)在兔脑室中，约40%的α _1受体属于α _<1A>亚型。该亚型似乎还有两个亚类：(1)WB 4101敏感型，与PI水解和PIE偶联；(2)(+)-尼古地平敏感，偶联于PIE，不加速PI水解。去多巴胺和HV723（低浓度）选择性抑制(+)-尼古地平敏感亚型。(3)兔心脏内皮素和血管紧张素受体的激活与α _1刺激一样，加速了PI的水解。在本研究中，我们发现这些受体对激活的反应在以下方面表现出显著的相似性：(1)PIE与等距抽动收缩的延长有关；(2) PIE和PI水解随受体激活的浓度和时间变化表现出良好的相关性；(3)激活蛋白激酶C的12,13-二丁酸phorbol持续抑制通过这些受体诱导的PIE和PI水解。这些结果有力地表明，PI水解可能介导了活化诱导的PIE

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