The role of the splanchnic circulation in the regulation of total intravascular volume during alpha adrenergic receptor stimulation

Previous studies have not defined the contribution of the splanchnic circulation to the total intravascular volume change associated with selective alpha adrenergic receptor stimulation. Since the splanchnic circulation is responsible for the total volume changes associated with other types of selective autonomic receptor stimulation, the present study was undertaken to examine the influence of alpha adrenergic receptor stimulation on splanchnic intravascular volume, the hemodynamic mechanism responsible for the splanchnic volume change, and the contribution of the splanchnic volume change to the change in total volume. In 35 anesthetized dogs, blood from the vena cavae was drained into an extracorporeal reservoir and returned to the right atrium at a constant rate so that changes in total intravascular volume could be measured as reciprocal changes in reservoir volume. Phenylephrine infusion (100 g/min) for 20 min in 28 dogs was associated with a decrease in total volume of 64±17 (SEM) ml (P<0.0001). The response was abolished by either alpha adrenergic blockade or evisceration but was not attenuated by beta adrenergic blockade, sinoaortic baroreceptor denervation, ganglionic blockade, or splenectomy. In 5 animals with separate splanchnic perfusion and drainage, total and splanchnic volumes decreased 59±8 ml (P<0.0001) and 317±20 ml (P<0.0001), respectively, while transhepatic vascular resistance increased 17±4 cm H₂O·min/l (P<0.0001). These responses were abolished after alpha adrenergic blockade. Thus, splanchnic volume decreases with alpha adrenergic receptor stimulation, despite an increase in hepatic resistance to splanchnic, venous outflow. The splanchnic volume decrement is entirely responsible for the total volume decrement.The study was supported by NHLBI Grant 1 R23-HL27185, Grant 11-203-812 from the American Heart Association of Greater Hartford, Inc., and the Duberg Cardiovascular Research Fund. Dr. Rutlen was the Duberg Scholar in Cardiovascular Disease when the study was performed.This work was presented in part at the 1982 Scientific Sessions of the American Heart Association (Circ. 66:II-311)     

常压缺氧对大鼠肺组织β和α_1肾上腺能受体数目的影响

本文观察常压缺氧性肺动脉高压对大鼠肺组织β和α_1受体的影响。动物分为对照组、缺氧1天和1、2、4周共5组,以观察不同缺氧时间大鼠肺β和α_1受体的动态变化规律。结果表明缺氧1天组大鼠肺β受体从对照组的299.7±23.4((?)±SD,下同)减少到234.4±73.9fmol/mg蛋白(P<0.05);缺氧1周时增至332.2±21.7(P<0.05);缺氧2、4周再次减少,分别为263.7±39.0,247.4±34.8(均P<0.05),β受体表现为减少、增加、再减少这样一种动态的变化。缺氧时α_1受体的变化与β受体不同。缺氧1天时α_1受体从对照组161.0±49.8增至277.2±24.2fmol/mg蛋白(P<0.01),缺氧1、2周分别为185.0±24.5,167.1±23.6,略高于正常对照组。缺氧4周时明显增加,为246.2±41.4(P<0.01)。α_1受体在缺氧时似乎都倾向于增加的趋势。无论是肺β还是α_1受体,缺氧前后亲和力(Kd)均无明显变化。β受体兴奋使肺血管舒张,α_1受体兴奋使肺血管收缩。缺氧时β受体的减少和α_1受体的增加都能促进肺血管的收缩,故这一变化在缺氧性肺动脉高压的发生、发展中可能具有一定的作用。     

C57BL/6哮喘小鼠细胞内镁含量与肺组织β2受体mRNA表达的相关性研究

目的：探讨细胞内镁含量对C57BL/6哮喘小鼠肺组织β₂受体mRNA表达的影响。方法:健康4－6周龄清洁级雌性C57BL/6小鼠96只，体重(12±2)g，随机数字表法分为A、B、C、D 4组，每组各24只。应用鸡卵蛋白(OVA)建立哮喘小鼠模型。A、B组予低镁饲料喂食，C、D组予正常镁饲料喂食。B、D组腹腔内注射沙丁胺醇诱导β₂受体低调节，A、C组腹腔内注射生理盐水作对照。第1 d、21 d、34 d各组分别随机抽取8只检测血浆Mg2+、红细胞内Mg2+、肺组织β₂受体mRNA及蛋白表达。 结果:1 d血浆Mg2+、红细胞内Mg2+、肺组织β₂AR mRNA及蛋白表达各组间差异无显著（均P>0.05）。21 d、34 d C组血浆Mg2+、红细胞内Mg2+、肺组织β₂AR mRNA及蛋白表达均显著高于A组［21 d：(0.84±0.09)mmol/L vs （0.57±0.10)mmol/L、(2.39±0.14)mmol/L vs （2.11±0.08)mmol/L、(0.75±0.09)mmol/L vs （0.59±0.06)pmol/g、（88.50±8.50)pmol/g vs （60.10±7.70)pmol/g，均P<0.05；34 d：(0.67±0.10)mmol/L vs (0.51±0.09)mmol/L、(2.17±0.08)mmol/L vs (2.05±0.09)mmol/L、(0.61±0.05)pmol/g vs (0.53±0.06)pmol/g、(76.60±7.10)pmol/g vs (58.00±7.60)pmol/g，均P<0.05］；21 d、34 d D组血浆Mg2+、红细胞内Mg2+、肺组织β₂AR mRNA及蛋白表达亦显著高于B组［21 d：(0.95±0.33)mmol/L vs (0.46±0.09)mmol/L、(2.32±0.18)mmol/L vs (1.87±0.14)mmol/L、(0.73±0.10)pmol/g vs (0.43±0.07)pmol/g、(96.90±8.00)pmol/g vs (47.90±4.90)pmol/g，均P<0.05；34 d：(0.71±0.10)mmol/L vs (0.31±0.08)mmol/L、(1.66±0.13)mmol/L vs (1.45±0.16)mmol/L、(0.40±0.07)pmol/g vs (0.33±0.05)pmol/g、(61.50±3.20)pmol/g vs (35.30±7.10)pmol/g，均P<0.05］。结论:细胞内镁缺乏的C57BL/6哮喘小鼠肺组织β₂受体表达减少，在激动剂作用下更易发生β₂受体低调节。     

beta2-adrenergic receptor gene polymorphisms in myasthenia gravis (MG)

The beta2-adrenergic receptor (beta2-AR) belongs to the group of G-protein coupled receptors and is present mainly on skeletal and cardiac muscle cells and lymphocytes. The gene encoding beta2-AR (ADRB2) displays a moderate degree of heterogeneity in the human population. The distribution of polymorphisms at amino acid positions 16, 27 and 164 is changed in asthma, hypertension and obesity. We have earlier reported a decreased density of the beta2-AR on peripheral blood mononuclear cells and the presence of beta2-AR antibodies in patients with MG. Since certain polymorphisms affect the function of the beta2-AR, it was of interest to analyse these in MG. Using allele-specific polymerase chain reaction amplification, we revealed an over-representation of homozygosity for Arg16 and a lower prevalence of homozygosity for Gly16 in MG patients compared with healthy individuals. The increased frequency of homozygosity for Arg16 was due to a contribution from patients with generalized MG but not from patients with only ocular disease. Homozygosity for Glu27 was negatively associated with both the presence of beta2-AR antibodies and severity of disease. Moreover, acetylcholine receptor (AChR) antibodies were more often present in patients being homozygous for Gln27. Our results imply that homozygosity for Arg16 confers susceptibility to generalized MG, and that certain polymorphisms at amino acid position 27 are associated with subgroups of patients.     

Interaction of the pesticide chlordimeform with adrenergic receptors in mouse brain: an in vitro study

Chlordimeform (N'(4-chloro-o-tolyl)-N, N-dimethylformamidine; CDM) is a formamidine insecticide/acaricide whose major active metabolite is its N-monomethyl analog, desmethylchlordimeform, (DCDM). While their pesticidal action in invertebrates appears to be related to activation of octopamine receptors, their mechanism of action in mammals has not been established. Because of similarities between octopamine and adrenergic receptors and suggestions of CDM and DCDM action on adrenoceptors, the in vitro interactions of CDM and DCDM with adrenoceptors were studied. In mouse brain membrane preparations CDM inhibited the binding of [³H]-clonidine to alpha₂- adrenoceptors and of [³H]-WB4101 to alpha₁-adrenoceptors with IC₅₀ values of 18.2 and 87 M, respectively. DCDM was a much more potent inhibitor, with IC₅₀ values toward alpha_2–, and alpha₁-adrenoceptors of 44 nM and 1 M, respectively. Both compounds were only weak inhibitors of the binding of [³H]-dihydroalprenolol to beta-adrenoceptors and of [³H]-quinuclidinyl benzilate to muscarinic receptors and were inactive toward benzodiazepines and gamma aminobutyric acid (GABA_A) receptors. Inhibition of [³H]-clonidine binding by both compounds was competitive, as indicated by a decreased receptor affinity without changes in receptor density. Interaction of CDM and DCDM with [³H]-WB4101 binding, on the other hand, was more complex, and not of the competitive type. These results show that CDM and its metabolite DCDM can interact directly in vitro with alpha-adrenergic receptors, suggesting that these receptors could mediate some of the effects of CDM and DCDM in vivo.     

The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes

Summary The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of -adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (¹²⁵I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (¹²⁵I)-hydroxybenzylpindolol (predrug) at 2 h (r_s=0.72), 4 h (r_s=0.84) and 6 h (r_s=0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.     

Relationship between the Mutation of IRS-1 Gene and β_3-adrenergic Receptor Gene

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心肌细胞β_1和β_2 肾上腺素能信号传导系统的区别(英文)

尽管 β1和β2 亚型肾上腺素能受体在结构和功能上十分相似 ,作者最近的研究显示这两种受体亚型在心肌细胞上的信号传递机制有很大的不同。β1受体激活后 ,启动经典的刺激性G蛋白 -腺苷酸环化酶 -环磷酸腺苷 -蛋白激酶A的线性信号传导途径 ;而 β2 受体除与刺激性G蛋白耦联外 ,还与抑制性G蛋白 ,Gi2 和Gi3 ,耦联。β2 受体与抑制性G蛋白的耦联在很大程度上决定了 β受体亚型在心脏钙调控、收缩力、环磷酸腺苷水平和蛋白磷酸化上的不同作用。β2 受体激活所引起的细胞内钙和收缩力的增加与细胞内环磷酸腺苷的增加和胞浆蛋白磷酸化有明显的脱节。这主要由于抑制性G蛋白激活的蛋白脱磷酸酶可以使 β2 受体诱导的环磷酸腺苷 -蛋白激酶A的作用局限于细胞质膜上。这种格局化作用 ,使公用的第二信使 ,环磷酸腺苷 ,在不同的 β受体亚型激活时 ,选择性地执行不同的功能。新的证据表明 ,β受体亚型不仅在激动剂激活时表现不同 ,而且自发激活的能力也不同。另外 ,自发激活的 β2 受体和激动剂激活的 β2 受体在细胞内信号传递和靶蛋白的特异性上都不同。这些发现不仅进一步揭示了 β受体亚型在信号传递上的多样性和特异性 ,而且为理解 β受体亚型在健康和疾病状态下的调节和功能提供了新的线索。     

抗心脏β_1和M_2受体自身抗体与老年扩张型心肌病(英文)

目的　观测抗心脏 β1和M2 受体的自身抗体和老年扩张型心肌病 (EDCM)的相关性。方法　分别以 β1和M2 受体细胞外第二环 197- 2 2 2和 16 9- 173氨基酸序列的合成肽作为抗原 ,来检测老年扩张型心肌病患者的血清 (EDCM组 ,n =32 ) ,以健康人血清为正常对照 (NC组 ,n =2 0 )。结果　EDCM组抗 β1受体自身抗体的阳性率为 37.5 % (12 / 32 ) ,NC组为 5 .0 %(1/ 2 0 ) (P <0 .0 5 ) ;EDCM组抗M2 受体自身抗体的阳性率为 40 .6 % (13/ 32 ) ,NC组为 10 .0 % (2 / 2 0 ) (P <0 .0 5 ) ;心功能II-III级患者两种受体的阳性率是心功能IV级的 2倍或以上。结论　抗心脏 β1与M2 受体自身抗体的产生与老年EDCM有关 ,推测这两种自身抗体可能参与老年EDCM患者心肌重构和 /或心力衰竭的病理生理过程。     

胺碘酮合用小剂量β受体阻滞剂治疗老年阵发房颤临床观察

目的 比较胺碘酮与小剂量β受体阻滞剂合用对老年阵发性房颤的疗效。方法 回顾分析30名老年阵发房颤患者,根据房颤复律后维持用药的不同,分为3组：单用胺碘酮组（n=11);单用β阻滞剂组（n=9);胺碘酮与小剂量β阻滞剂合用组（n=10)。比较3组患者用药后12个月中房颤控制情况及心室率、心脏传导情况。结果 单用胺碘酮组显效率54．5％,有效率45．5％,无效率0％;单用β受体阻滞剂组显效率22．2％,有效率44．5％,无效率33．3％;胺碘酮与小剂量β受体阻滞剂合用治疗房颤,显效率90％,有效率10％,其疗效明显优于单用胺碘酮（P＜0．05）或单用β阻滞剂（P＜0．01）组,且未见明显副作用：3组间心室率未见显著差别。结论 胺碘酮与小剂β受体阻滞剂合用可有效地控制老年阵发性心房纤颤的发作。