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Pharmacological identification of vascular smooth muscle β-adrenoceptors and clarification. of1heir physiological roles

血管平滑肌β-肾上腺素受体的药理学鉴定及其生理作用的阐明。

基本信息

批准号：
18590242
负责人：
KOIKE Katsuo
金额：
$ 2.34万
依托单位：
Toho University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

β-Adrenoceptors ((β-ARs) are now classified into three subtypes : β1, β2 and (β3. Of these three subtypes, β3-AR was first identified in fat tissue and its distribution and role in smooth muscles were not well known. However, we have recently found that (β3-AR is abundantly present in gastrointestinal smooth muscles and plays the key role in their relaxant responses to endogenous catecholamines. In the present study, we investigated the expression and post-receptor mechanisms of β3-AR as well as non-β3-ARs ((β1- and β2-ARs) in rat aortic smooth muscle for our better understating of the vascular smooth muscle β-ARs, and we obtained the following new findings and/or established experimental conditions.1. We established the evaluation system to detect β-AR-mediated vascular smooth muscle relaxation.2. We found that isoprenaline (ISO)-induced relaxation is mediated through propranolol (Prop)-sensitive β-AR and Prop-insensitive β-AR.3. Based on the rank order of the relaxant potencies of three catecholamines and the pA2 values of subtype-selective β-AR antagonists (atenolol and ICI-118,551) against ISO, we found that Prop-sensitive β-AR is mainly β2-AR in thoracic aorta and it is β1-AR in abdominal aorta.4. Based on the, pA2 value of bupranolol against ISO, we found that Prop-insensitive β3-AR is mainly β3-AR in both thoracic and abdominal aortae.5. We found that mRNAs and receptor proteins corresponding to each β-AR are expressed in the vascular smooth muscles used in the above mechanical studies.6. We found that β3-AR-mediated vascular relaxation is trigged by new molecular mechanisms (cAMP-independent mechanisms and contribution of voltage-dependent potassium channel).

肾上腺素能受体(β-ars，β-AR)分为β1、β2和β3三种亚型。在这三种亚型中，β3-AR最先在脂肪组织中被发现，但其在平滑肌中的分布和作用尚不清楚。然而，我们最近发现(β-3-AR)在胃肠道平滑肌中大量存在，并在其对内源性儿茶酚胺的松弛反应中发挥关键作用。在本研究中，我们研究了β3-AR和非β3-AR((β1-和β2-AR))在大鼠主动脉平滑肌中的表达及其受体后机制，以期更好地了解血管平滑肌β-AR，我们获得了以下新发现和/或建立了实验条件。结论：1.建立了检测β-AR介导的血管平滑肌舒张性的评价体系。我们发现异丙肾上腺素引起的松弛是通过心得安敏感的β-AR和心得安不敏感的β-AR介导的。根据三种儿茶酚胺的舒张效价和选择性β-AR亚型拮抗剂(阿替洛尔和ICI-118,551)的PA2值，我们发现β-AR在胸主动脉以β-2-AR为主，在腹主动脉以β-1-AR为主。根据丁普洛尔对ISO的PA2值，我们发现在胸主动脉和腹主动脉中，对Prop不敏感的β3-AR主要是β3-AR。我们发现与每个β-AR相对应的mRNAs和受体蛋白在上述力学研究中使用的血管平滑肌中都有表达。我们发现β3-AR介导的血管松弛是由新的分子机制(cAMP非依赖性机制和电压依赖性钾通道的贡献)触发的。