选择性β肾上腺素受体激动剂对人滑膜细胞增殖能力的影响

目的：观察β-肾上腺素受体( AR)激动药对人成纤维样滑膜细胞( FLS)增殖的作用,探讨β-AR信号对人FLS功能的影响。方法组织块培养法培养人FLS;使用肿瘤坏死因子α( TNF-α)作为刺激剂,MTT法分别检测β1-AR选择性激动剂多巴酚丁胺和β2-AR选择性激动剂沙丁胺醇对人FLS增殖作用的影响,并计算增殖抑制率;使用沙丁胺醇+β2-AR选择性拮抗剂ICI 118551观察其对FLS增殖功能的影响;Western blot法检测人FLSβ-AR、G蛋白偶联受体激酶2(GRK2)和β抑制蛋白2(β-arrestin2)胞膜蛋白的表达水平。结果 TNF-α可以显著促进人FLS的增殖;β2-AR激动剂沙丁胺醇能明显抑制FLS的增殖,其拮抗剂ICI 118551能显著拮抗沙丁胺醇的作用;β1-AR选择性激动剂多巴酚丁胺对FLS的增殖无显著影响;TNF-α和沙丁胺醇均能显著降低β2-AR胞膜表达,上调 GRK2、β-arrestin2的胞膜表达。结论β2-AR信号的激活可以抑制FLS增殖;TNF-α和沙丁胺醇可以使GRK2、β-arrestin2的胞膜表达增加,β2-AR胸膜表达下降。     

鸡Ⅱ型胶原对胶原性关节炎大鼠肠系膜淋巴结β2肾上腺素受体脱敏的影响

目的 研究鸡Ⅱ型胶原(CCⅡ)对胶原性关节炎(CIA)大鼠肠系膜淋巴结(MLNs)中β2肾上腺素受体(β2-AR)、G蛋白偶联受体激酶2(GRK2)、GRK3 和 β-arrestin1、2 表达的影响.方法 SD大鼠随机分成5组:正常组、模型组和CCII(10、20、40μg/kg)3个剂量组,采用CCⅡ皮内注射诱导...     

大鼠内毒素性肺损伤中肺脏肾上腺素能受体的变化及机理研究

采用放射性配基结合分析法,以[~2H]-哌唑嗪和[~3H]-双氢烯丙洛尔测定大鼠肺脏α_1-和β-肾上腺素能受体(α_1-AR和β-AR)。根据Scatchard公式计算受体的最大结合容量(Bmax)和平衡解离常数(K_D)。结果表明,大鼠肺脏含高密度α_1-AR和β-AR。它们具有可饱和性、可逆性、高亲和力和立体专一性。 大鼠静注大肠杆菌内毒素诱导急性肺损伤后,α_1-AR和β-AR的Bmax值分别降低35％和43％。K_D值无变化。该组静注伊文思蓝判定肺微血管通透性指数(PMPI),显著高于对照组和山莨菪碱等组(P<     

心力衰竭大鼠肺脏α_(1A)及β_1、β_2肾上腺素受体表达的改变

目的研究慢性心力衰竭(chronic heart failure,CHF)时肺脏α1A-肾上腺素受体(α1A-AR)和β1、β2肾上腺素受体(β-AR)表达水平的变化。方法结扎Wistar大鼠左冠状动脉前降支制作心肌梗死后心力衰竭模型,模型成功后采用数字表法随机分为正常对照组、假手术组和心力衰竭模型组。取大鼠肺组织,采用蛋白质免疫印迹法(Western blotting)分别测定3组的α1A-AR和β1、β2-AR蛋白表达水平。结果心力衰竭模型组与假手术组相比,α1A-AR、β1-AR的蛋白表达水平显著下调(P<0.01或P<0.05),β2-AR的蛋白表达水平显著上调(P<0.05),正常对照组α1A-AR、β1-AR和β2-AR的蛋白表达水平与假手术组相比差异无统计学意义(P>0.05)。结论 CHF大鼠肺循环淤血,α1A-AR下调,有利于肺血管舒张,抑制平滑肌增生以代偿这种病理改变。肺脏β2-AR表达水平上调可能与β2-AR激动可以舒张血管和支气管平滑肌作用,开放钠离子通道等机制促进肺水肿液的清除、并能改善心力衰竭条件下肺脏微血管的通透性有关。心力衰竭时肺脏β1-AR的下调一方面与CHF时交感肾上腺素系统激活产生的负反馈调节有关,另一面可能与代偿性拮抗β2-AR的上调,维持相对稳定的肺泡液体清除率有关。     

脂多糖诱导急性肺损伤大鼠肺组织GRK2变化的实验研究

目的：探讨脂多糖（LPS）诱导急性肺损伤（ALI）大鼠肺组织G蛋白偶联受体激酶2(GRK2)的变化规律。方法：Wistar大鼠18只，随机分为3组。LPS组自尾静脉注射LPS 8mg/kg，LPS 山莨菪组注射LPS8mg/kg 山莨菪碱10mg/kg，正常对照组注射等量生理盐水。90min放血处死后取肺脏，用Western blot检测各组GRK2的变化。结果：LPS组和LPS 山莨菪碱组GRK2表达较正常对照组显著增加，LPS组和LPS 山莨菪碱组GRK2表达无显著差异。结论：Wistar大鼠肺组织有GRK2表达；LPS诱导的ALI大鼠肺组织GRK2表达显著增加，山莨菪碱对LPS诱导的ALI大鼠肺组织GRK2表达增加无显著抑制作用。     

胆碱能受体和肾上腺素能受体磷酸化的调节作用机制研究

目的：研究受体激活剂或抑制剂影响G蛋白偶联受体激酶2（GRK2）介导的胆碱能m2受体和β2肾上腺素能受体膜蛋白（β2-AR）磷酸化的调节机制。探讨兴奋剂使m2受体和β2-AR受体活化,引发受体磷酸化级联反应,进而影响蛋白激酶催化受体磷酸化的起始机制。方法：制备亲和层析柱;利用亲和层析方法从大鼠脑中纯化毒草碱乙酰胆碱m2受体;分别将纯化的毒蕈碱乙酰胆碱m2受体或β-肾上腺素受体,G蛋白偶联受体激酶-2,[γ-P^32]ATP与受体激活剂或抑制剂共同保温,聚丙烯酰胺凝胶电泳分离蛋白,放射性自显影检测m2受体磷酸化结果。结果：m2受体激活剂氨甲酰胆碱明显增强m2受体的磷酸化,而m2受体抑制剂阿托品或肝素（GRK2抑制剂）完全阻断了m2受体的磷酸化。m2受体的磷酸化是依赖激活剂如氨甲酰胆碱作用发生的,呈明显的剂量依赖关系;β2-AR的激活剂特布他林增强肾上腺素能受体的磷酸化,而肝素可完全阻断β2-AR的磷酸化;并且证实氨甲酰胆碱对mAChR2,特布他林对β2-AR磷酸化的增强作用是选择性的作用结果;HEL299细胞磷酸化实验结果也显示氨甲酰胆碱可以增强HEL299细胞m2受体的磷酸化,阿托品可以抑制HEL299细胞m2受体的磷酸化。结论：实验证实氨甲酰胆碱、特布他林和阿托品等一些m2受体和β2-AR的激活剂及抑制剂对M2受体和β2-AR磷酸化的调节作用。提示激活剂增强m2受体和β2-AR的磷酸化可能是这些受体活化一个重要部分,由此开始加速受体敏感性下调,受体耐受性增强。     

心衰患者的心肌和淋巴细胞GRK2表达硬活性均增高

目的：G蛋白偶联受体激酶-2（GRK2或β-ARKl）调节着心脏β肾上腺素能受体（β-AR）。在心衰（HF）患者中，这种激酶在心脏的表达升高。本文意在探讨已经被用于研究心脏β-AR的白细胞可否用于监测心肌中GRK2的水平和活性。此外，作者亦有意探讨心肌和淋巴细胞的GRK2水平是否与β-AR功能失常和HF严重程度相关。方法和结果：在人心衰心脏外植体的心肌活检标本中，GRK活性与β-AR介导的cAMP生成呈负相关（r^2=0．215，P〈0．05，n=24）。     

哮喘大鼠肺组织中血管紧张素Ⅱ受体和β2肾上腺素能受体表达及缬沙坦的影响

目的:探讨哮喘大鼠肺组织中血管紧张素Ⅱ(AngⅡ)两种受体亚型(AT1R、AT2R)和β2肾上腺素受体(β2-AR)的表达及缬沙坦对两类受体的影响.方法:将50只SPF级Wistar大鼠随机分为正常对照组(A组)、哮喘组(B组)、缬沙坦15 mg/kg组(C1组)、缬沙坦30mg/kg组(C2组)、缬沙坦50 mg/kg组(C3组).用10%鸡卵白蛋白(OVA)致敏和1%OVA激发大鼠建立哮喘模型;分别用逆转录-聚合酶链反应(RT-PCR)和Western blot法检测肺组织中ATR和β2-AR mRNA和蛋白表达.结果:与A组相比,B组的AT1R阳性表达率明显增高(P＜0.05).缬沙坦干预后,C1、C2、C3组的AT1R阳性表达率均明显下降(P均＜0.05);相关性分析提示AT1R的表达与缬沙坦剂量呈负相关(r=-0.96).A组未见AT2R表达,B组AT2R表达明显增加.缬沙坦干预后,C1组无AT2R表达,C2、C3组AT2R表达量低于B组(P均＜0.01).与A组相比,B组的β2-AR阳性表达率明显下调(P＜0.01),缬沙坦干预后,C1、C2、C3组的β2-AR阳性表达率均明显上调(P均＜0.05).结论:大鼠肺组织中存在血管紧张素Ⅱ受体,并在哮喘发作时被活化,可能参与哮喘发病的病理生理过程.ATR与β2-AR的变化可能存在相关性.哮喘大鼠肺组织中AT1R和AT2R表达增加,β2-AR表达下调.AT1R拮抗剂缬沙坦能抑制AT1R表达,上调β2-AR表达.     

肝复乐对肝纤维化大鼠神经递质受体表达的调节作用

目的 研究中药肝复乐对肝纤维化大鼠肝细胞神经递质受体表达的调节作用,探讨其抗肝纤维化的机制.方法 将40只Wistar大鼠分为3组:正常对照组10只、肝复乐组15只及模型组15只.用CCl4皮下注射制备大鼠肝纤维化模型,采用光镜及电镜观察肝组织病理学改变;运用半自动生化分析仪测定谷丙转氨酶(ALT)、谷草转氨酶(AST)、血清7谷丙转氨酶(GGT),放射免疫法测定血清层黏连蛋白(LN)、Ⅲ型前胶原(PC-Ⅲ)、Ⅳ型胶原(Ⅳ-C)、透明质酸(HA)的含量,免疫组织化学SP法检测各组肝组织M1、N型胆碱能受体(M1-AChR、N-AChR),α1、β2型肾上腺素能受体(α1-AR、β2-AR)的表达水平.结果 肝复乐组病理改变较模型组明显改善;肝复乐组Mt-AChR、N-AChR的表达较模型组显著降低(均P<0.05),而α1-AR、β2-AR的表达较模型组显著升高(均P<0.05).结论 肝复乐能通过抑制肝组织M1-AChR、N-AChR的表达,促进α1-AR、β2-AR的表达,从而调节神经递质在肝纤维化中的作用.     

Do beta-adrenoceptor blocking drugs cause retroperitoneal fibrosis?

The aetiology of retroperitoneal fibrosis is unknown. From time to time different drugs have been suggested as a cause, including beta adrenoceptor blocking agents. The notes of 100 hospital inpatients in whom retroperitoneal fibrosis had been diagnosed were surveyed to identify the date of onset of symptoms, the drugs prescribed before then, and the blood pressures on admission. Seventy one patients had diastolic pressures on admission of 90 mm Hg or more and 53 of these had pressures of at least 100 mm Hg despite 14 of the patients taking anti-hypertensive drugs at the time. Six patients had received beta-adrenoceptor blocking agents before the onset of symptoms and a further 24 received them subsequently. In particular, three patients continued treatment for at least six years after the diagnosis was made and surgery performed, without suffering a recurrence of retroperitoneal fibrosis. Besides beta-adrenoceptor drugs, diuretics and other hypotensive drugs were taken in amounts reflecting the pattern of drug use among hypertensive patients generally. Rather than being causal agents, the antihypertensive drugs were probably being used to treat hypertension associated with the retroperitoneal fibrosis, and our findings suggest that beta-adrenoceptor blocking agents do not cause retroperitoneal fibrosis.     

心力衰竭病人β受体信号转导系统相关基因表达水平的变化

目的 探讨慢性充血性心力衰竭时,β肾上腺素受体信号转导系统相关基因表达水平的变化。方法 以淋巴细胞为研究模型,采用逆转录聚合酶链反应技术定量检测了β２肾上腺素受体,腺苷酸环化酶,β受体激酶,β－ａｒｒｅｓｔｉｎ和ｃＡＭＰ反应元素结合蛋白基因的ｍＲＮＡ水平,在１６例正常人体和３０例心力衰竭患者中比较了β受体信号转导系统相关基因的变化。     

β-受体阻断剂治疗血管迷走性晕厥的Meta分析

目的:通过Meta分析的方法综合评价β-肾上腺素能受体阻断剂(简称β-受体阻断剂)治疗血管迷走性晕厥的治疗效果,为临床应用提供可参考的循证医学证据.方法:制定纳入及筛选文献的标准,从PubMed(1968至2007年)、EMBASE(1991至2007年)、Ovid(1990至2007年)、Elsevier(1990至2007年)和中国期刊伞文数据库(CNKI,1990至2007)中筛选符合标准的文献,用Juni量表进行质量评估,采用Review Manager 4.2分析软件进行定向综合分析.疗效判定指标为随访期限内是否出现复发或者直立试验(head-up tilt teat,HUT)是否转阴.结果以相对危险度(relative risk,RR)或比值比(odd ratio,OR)及其95%可信区间(confidence interval,Ct)表示,P<0.05为差异有统计学意义.结果:数据库中共筛选出符合要求的文献13篇,中文文献均来自CNKI,英文文献中有5篇来自于PubMed,2篇来自于Elsevier,这7篇中的2篇同时来自于EMBASE.经过漏斗图分析,可能存在发表偏倚.Meta分析结果显示:(1)综合分析11项β-受体阻断剂治疗血管迷走性晕厥的随机对照试验(randomized controlledtrials,RCT),治疗组(460例)晕厥的复发率低于对照组(371例),RR=0.61,95%CI为0.39～0.96,P=0.03;(2)综合分析7项β-受体阻断剂治疗血管迷走性晕厥RCT表明,治疗组(166例)在随访结束时HUT的转阴率高于对照组(163例),OR=9.15,95%CI为3.75～22.31,P<0.01.结论:本研究结果支持β-受体阻断剂可能是治疗血管迷走性晕厥的有效药物,有待更大规模、设计更精确严格、多中心的随机对照试验进一步分析并研究其疗效.     

Role of β- adrenoceptor at different stages of bronchial asthma

Objective To investigate the changes of β- adrenergic receptor (βAR) in peripheral lymph ocytes and β (2)AR mRNA levels at different stages of bronchial asthma. Methods β (2)AR density and β (2)AR mRNA level in peripheral lymphocytes, cAMP and cGMP levels in blood plasma were estimated by radioligand binding assay, radioimmunoa ssay and RT- PCR. Results (1) Maximum bound volume (Bmax) and equilibrium dissociation constant (Kd) of β (2)AR of lymphocyte in asthma patients at remission stage were markedly higher t han that in normal subjects, while cAMP levels in blood plasma showed no differe nce. Bmax of β (2)AR and cAMP levels in asthma patients at acute exacerbation s tage were significantly lower than that in normal subjects, and Kds between thes e two groups were not much different. (2) Expression of β (2)ARmRNA in peripher al lymphocytes of asthmatics at remission stage was not significantly different compared with that in normals. Conclusions Amount and function of βAR and β (2)ARmRNA levels are related to asthmatic cond itions. Changes of βAR and β (2)ARmRNA in asthma might rather be a pathologica l change accompanied by the course of the disease than a primary defect.     

Age-dependent changes in β-adrenoceptor function in human detrusors and possible mechanisms

Objective To study age-dependent changes in β-adrenergic responsiveness and their possible mechanisms. Methods Responsiveness to the β-adrenergic agonists isoprenaline, BRL37344, forskolin, and dibutyryl cyclic AMP (DBcAMP) was examined in samples from 10 older patients by using a cellular function test. A radioligand binding assay was performed using the non-selective β-adrenergic receptor ligand ［3H］- dihydroalprenolol (［3H］-DHA). Specimens from 10 young men were used as controls. Results There were no age-dependent changes in contractile response to KCl. The relaxation responses to isoprenaline, BRL37344, and forskolin decreased in the aged group by 15.0%, 17.6%, and 12.6%, respectively （P&lt;0.001）. The pD2 values for isoprenaline and BRL37344 also declined significantly. There was no difference in the responsiveness to dibutyryl cyclic AMP (DBcAMP) between the two groups; the maximum binding site decreased significantly with increasing age, but the equilibrium-dissociation constant did not change. Conclusions There is an age-related decline in β-adrenergic responsiveness which might be one of the causative factors of reduced bladder compliance in the elderly. A decrease in cAMP level caused by reduced receptor density and adenylyl cyclase activity might be the underlying molecular mechanism of the changes in β-adrenergic responsiveness.     

Effect of a long acting beta-adrenoceptor blocker on diurnal variation of cardiac dysrhythmias

To investigate circadian variation of cardiac arrhythmias ambulatory electrocardiogram monitoring was carried out before and after one week's treatment with a long acting beta-adrenoceptor blocker, nadolol, in 26 patients who presented with symptoms attributable to arrhythmias. Analysis of the 24 hour profile of premature ventricular contractions showed a significantly (P less than 0.05) higher frequency during midday to midnight than between midnight and midday. The frequency of supraventricular tachycardia was significantly (P less than 0.05) higher during the periods from 12.00 hours to 16.00 hours (11.0 +/- 12) and 16.00 hours to 20.00 hours (11.3 +/- 11) than during the periods of 00.00 hours to 04.00 hours (3.6 +/- 3) and 04.00 hours to 08.00 hours (6.0 +/- 8). The period of the highest incidence of all arrhythmias was between 16.00 hours to 24.00 hours, and that of lowest during the period between 04.00 hours to 12.00 hours (P less than 0.01). After one week's treatment with nadolol the frequency of all arrhythmias was strikingly reduced but their pattern of occurrence remained unchanged. These studies suggest that patients who present with symptoms attributable to arrhythmias tend to have these more frequently during the physical and mental activities of the day and evening presumably due to the accompanying sympathetic overactivity.     

Effects of the systemic beta-adrenoceptor antagonist nebivolol on ocular hemodynamics in glaucoma patients

BACKGROUND: Systemic antihypertensive treatment in glaucoma patients with hypertension carries the potential risk of an additional deterioration in ocular hemodynamics due to the reduction in ocular perfusion pressure. Nebivolol is a beta1-selective adrenoceptor antagonist with known peripheral vasodilatory effects due to NO-releasing properties. The effect of a switch in systemic beta-blocker treatment to nebivolol on retrobulbar hemodynamics in glaucoma patients with arterial hypertension was therefore investigated. MATERIAL/METHODS: Peak systolic (PSV) and end-diastolic (EDV) velocity in the short and long posterior ciliary arteries (SPCA, LPCA), central retinal artery (CRA), and ophthalmic artery (OA) were recorded by color Doppler imaging (CDI) in 23 glaucoma patients with arterial hypertension using their primary systemic beta-blocker medication and four weeks after a switch to nebivolol. RESULTS: Compared with the first recording under the primary antihypertensive medication, the CDI measurements after four weeks of nebivolol treatment revealed a significant acceleration of the PSV in the SPCA and LPCA and the EDV in the SPCA and CRA. No significant differences in flow velocities were found for the OA. Intraocular pressure and systemic blood pressure remained unchanged. CONCLUSIONS: Switching blood pressure treatment to nebivolol in glaucoma patients with hypertension leads to accelerated blood flow in the small retrobulbar vessels. A stabilization of ocular perfusion might be of particular importance in this group of co-morbid patients.     

奈比洛尔对冠心病人内皮勃起功能及C反应蛋白的影响

目的观察第三代倍他受体阻滞剂奈比洛尔及第二代倍他受体阻滞剂美托洛尔对稳定型冠心病病人内皮功能、勃起功能及炎症指标的影响。方法本研究采用随机、对照的方法。80名35～67岁稳定型冠心病病人。符合入选条件者随机分为奈比洛尔和美托洛尔组。服药12周后比较两组病人血液中血管内皮功能变化及炎症的相关指标及勃起功能的变化。结果奈比洛尔组内皮功能相关指标一氧化氮（NO）水平、血流介导的血管扩张（FMD）明显高于服药前,而血管性血友病因子（vWF）水平、CRP（C反应蛋白）明显低于服药前。两组之间经过独立样本的t检验差异有显著性意义（P〈0．01）,勃起功能明显好转。美托洛尔组内皮功能变化及炎症指标及勃起功能无显著性变化。结论第三代倍他受体阻滞剂奈比洛尔对稳定型冠心病病人具有改善血管内皮功能、勃起功能及炎症反应作用。