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

β-肾上腺素能受体（β-AR）分为β1、β2和β3三种亚型。在这三种亚型中，β3-AR首先在脂肪组织中被鉴定，其在平滑肌中的分布和作用尚不清楚。然而，我们最近发现β3-AR大量存在于胃肠平滑肌中，并在其对内源性儿茶酚胺的舒张反应中起关键作用。为了更好地了解血管平滑肌β-AR的功能，本研究对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进行了研究，并获得了以下新的发现和/或建立了实验条件.建立了β-AR介导的血管平滑肌舒张反应的评价体系.我们发现异丙肾上腺素（ISO）的舒张作用是通过普萘洛尔（Prop）敏感的β-AR和不敏感的β-AR介导的.根据三种儿茶酚胺类药物舒张作用的强弱顺序和亚型选择性β-AR拮抗剂（阿替洛尔和ICI-118，551）对ISO的pA 2值，我们发现在胸主动脉中，Prop敏感的β-AR主要是β2-AR，在腹主动脉中主要是β1-AR.根据布萘洛尔对ISO的pA 2值，我们发现在胸、腹主动脉中，对Prop不敏感的β3-AR主要是β3-AR.我们发现，在上述力学研究中使用的血管平滑肌中，对应于每种β-AR的mRNA和受体蛋白均有表达.我们发现β3-AR介导的血管舒张作用受到新的分子机制（cAMP非依赖性机制和电压依赖性钾通道的作用）的影响。

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).