地塞米松对去甲肾上腺素在孤束核引起的心血管活动的影响

目的：研究糖皮质激素对去甲肾上腺素在孤束核对心血管活动调节的影响。方法：向内侧和中间内侧孤束（ＮＴＳ）微量注射地塞米松（Ｄｅｘ）去甲肾上腺素（ＮＥ）,米非司酮及荷包牡丹碱（Ｂｉｃ）观察它们引起的心血管活动的变化。结果：Ｄｅｘ（０．３９ｍｍｏｌ．Ｌ＾－１,０．１μＬ）可以消除１０ｍｉｎ后在同一区域性注射ＮＥ（８ｍｍｏｌ．Ｌ＾－１,０．１μＬ）所引起的血压下降,心率减慢的效应,这种抑制作用４ｈ内不消失     

去甲肾上腺素在酒依赖发病机制中的作用

<正>酒依赖对人类健康的危害仅次于心脑血管疾病和癌症,列居第三,已成为一个重要的全球性问题[1]。酒依赖对家庭和社会造成了巨大的损害,并产生了严重的安全问题,加重了全球疾病的社会负担[2]。2009年发表在Lancet上关于中国四省(山东省、浙江省、青海省、甘肃省)流行病学调查发现,酒依赖患病率高达5%[3],而一项针对澳大利亚15-45岁人群的调查显示,由饮酒造成的死亡率虽然呈     

人源去甲肾上腺素转运蛋白稳定表达细胞系的构建及其功能鉴定

目的构建人源去甲肾上腺素转运蛋白(h NET)稳定表达细胞系,并对细胞系h NET的结合和重摄取功能进行研究。方法采用脂质体转染法将h NET转染于母细胞-人胚肾(HEK)293细胞(HEK293-h NET);采用RT-PCR和Western蛋白质印迹法在基因和蛋白水平对HEK293-h NET细胞系进行鉴定和稳定性验证;采用放射性配基结合实验检测HEK293-h NET的结合和重摄取功能。并采用三环类抗抑郁药地昔帕明(DIM)和5-羟色胺/去甲肾上腺素双重重摄取抑制剂度洛西汀(DLX),在0~1×10-4mol·L-1浓度梯度范围绘制药物与h NET的结合与重摄取抑制曲线,进一步验证HEK293-h NET细胞系的结合和重摄取功能。结果 RT-PCR和Western蛋白质印迹实验结果表明,所建立的HEK293-h NET细胞系在15代内均稳定表达h NET;放射性配基结合实验表明,HEK293-h NET细胞具有内源性h NET的结合和重摄取功能。并且,DIM和DLX与HEK293-h NET细胞中h NET具有明显的特异性结合(Ki值分别为2.45和3.40 nmol·L-1),并可显著抑制h NET对去甲肾上腺素的重摄取作用(IC50分别为5.78和10.23 nmol·L-1)。结论成功建立的可稳定表达h NET的HEK293-h NET细胞系具有内源性h NET的结合和重摄取功能,可用于h NET靶标药物研究。     

天麻对大鼠脑内去甲肾上腺素含量及释放的影响

本文采用荧光法测定了天麻对大鼠丘脑、皮层、脑干和杏仁核四脑区去甲肾上腺素(NA)含量的影响,结果发现天麻注射液(5 g/kg ip)可使杏仁核的NA含量减少(P<0.01),其它三脑区的NA含量也有降低。在离体脑片孵育法中观察到天麻注射液(2.5g×10~(-3))可使皮层、丘脑、脑干和杏仁核四脑区的人工脑脊液中的NA含量明显增多(P<0.01或0.001)。初步认为天麻的镇静、催眠作用可能与其降低脑内NA的含量有关,而脑内NA含量的降低可能与天麻抑制中枢NA能神经末梢对NA的重摄取和储存有关。     

去甲肾上腺素在全身麻醉中的应用

目的:观察去甲肾上腺素用于全身麻醉是否使血压更平稳及无肾功能损害。方法:选择中山大学孙逸仙纪念医院南院麻醉科2019年5—10月择期全麻手术患者40例,随机分为对照组和观察组,各20例。观察组持续静脉泵注去甲肾上腺素维持血压不低于基础血压20%,对照组使用多巴胺维持血压,比较两组基础和麻醉诱导过程最低心率、平均动脉压,以及术前和术后第一天血尿素氮、肌酐。结果:对照组麻醉诱导过程最低平均动脉压较观察组低(P<0.05),两组术前和术后第一天血尿素氮、肌酐比较无差异(P>0.05)。结论:去甲肾上腺素用于全身麻醉可使患者血压更平稳同时无肾功能损害。     

去甲肾上腺素和异丙肾上腺素对猪冠状动脉的舒张作用及机制研究

目的:研究去甲肾上腺素和异丙肾上腺素对冠状动脉环的舒张作用及其可能的作用途径。方法:采用离体实验方法,检测去甲肾上腺素和异丙肾上腺素对静息张力及氯化钾(KCl)预收缩冠状动脉的影响,研究两者对冠状动脉张力的作用及其可能的机制。结果:去甲肾上腺素和异丙肾上腺素对静息张力及KCl(40 mmol.L-1)预收缩冠状动脉环具有浓度依赖性舒张作用。去除内皮,用β受体阻断药普萘洛尔,β1受体抑制药阿替洛尔预处理后,均可明显减弱去甲肾上腺素和异丙肾上腺素诱导的舒张血管作用;用鸟苷酸环化酶抑制药亚甲蓝,一氧化氮合酶抑制药(L-NMMA),β2受体抑制药ICI-118551(10～5 mol.L-1)预处理后,血管舒张作用不能被阻断。α受体阻断药酚妥拉明预处理能增强去甲肾上腺素的舒张作用,对异丙肾上腺素引起的舒张无影响。结论:去甲肾上腺素和异丙肾上腺素是通过激活冠状动脉血管上的β受体(特别是β1受体)产生内皮依赖性的血管舒张作用,与NO-鸟苷酸环化酶途径无关。说明β肾上腺素能受体在猪冠状动脉血管平滑肌和血管内皮上有分布。     

大剂量去甲肾上腺素在重度休克中的应用

目的 探讨去甲肾上腺素抢救休克中的应用方法及疗效。方法 对7例休克患者应用去甲肾上腺素后血压回升情况作回顾性分析。结果 7例经扩容并大量应用去甲肾上腺素生命体征稳定。结论 大剂量去甲肾上腺素能有效地预防重度患者出现心跳骤停，为液体复苏赢得时间。     

地高辛对吗啡戒断大鼠去甲肾上腺素能神经活动的影响

目的:探讨地高辛对吗啡戒断大鼠体内去甲肾上腺素能神经活动的影响。方法:按剂量递增法建立大鼠吗啡依赖模型,给予地高辛(0.05-0.2 mg.kg-1,ig)或等体积溶媒1 h后用纳洛酮催促戒断,参考文献方法对大鼠30 min内戒断症状进行评分。处死大鼠,分离左、右心室和下丘脑,采用酶联免疫吸附法检测去甲肾上腺素(NE)和间羟去甲肾上腺素(NMN)的含量并计算其比率(NMN/NE)。结果:地高辛剂量依赖地减弱纳洛酮催促的大鼠吗啡戒断症状(F=5.264,P<0.01),其中,0.2 mg.kg-1和0.1 mg.kg-1地高辛表现出明显的统计学差异(P<0.01,P<0.05);大剂量地高辛(0.2 mg.kg-1)能明显抑制NMN以及NMN/NE值的升高(P<0.05,P<0.05)。结论:地高辛能够缓解大鼠吗啡戒断症状,其机制可能与抑制去甲肾上腺素能神经活动有关。     

G蛋白信号调节因子在心血管系统中的作用

G蛋白偶联受体（G-Protein-Coupled-Receptors,GPCRs）在体内分布广泛,几乎参与所有生理活动的调节。G蛋白调节因子（Regulator of G protein Signaling,RGS）参与了G蛋白失活的调节。目前研究已证明,参与心血管系统生理和病理活动的很多递质和激素都是通过GPCR信号转导通路发挥作用的。RGS蛋白通过调节GPCR通路信号转导和非GPCR依赖性途径影响多种心血管疾病的发生,其在心脏血管结构和功能中的地位已逐渐引起重视,有望成为相关疾病治疗的新靶点。本文将就RGS蛋白及其在心血管系统中的作用作一综述。     

杏仁核内去甲肾上腺素在应激激素调控记忆保持过程中的作用(英文)

There is extensive evidence indicating that the noradrenergic system of the amygdala, particularly the baso-lateral nucleus of the amygdala (BLA), is involved in memory consolidation. This article reviews the central hypothesis that stress hormones released during emotionally arousing experiences activate noradrenergic mechanisms in the BLA, resulting in enhanced memory for those events. Findings from experiments using rats have shown that the memory-modulatory effects of the adreno-cortical stress hormones epinephrine and glucocorticoids involve activation of β-adrenoceptors in the BLA. In addition, both behavioral and microdialysis studies have shown that the noradrenergic system of the BLA also mediates the influences of other neuromodulatory systems such as opioid peptidergic and GABAergic systems on memory storage. Other findings indicate that this stress hormone-induced activation of noradrenergic mechanisms in the BLA regulates memory storage in other brain regions.     

Central cardiovascular and antidiuretic action of adrenergic drugs

Central noradrenergic mechanisms are reportedly involved in blood pressure and fluid balance regulating mechanisms. The results of the present experiments suggest that, in unanaesthetized water-loaded rats. intracranial injections of norepinephrine and tyramine will produce presser and antidiuretic effects by the release of antidiuretic hormone (ADH). These responses are blocked by central α-adrenergic blockade but not by peripheral ganglionic blockade with hexamelhonium. Longer latency depressor responses were also seen with α-adrenergic stimulation. Central injections of clonidine, an α-adrenergic agonist, produced depressor effects, but no antidiuresis. Clonidine also inhibited the antidiuretic effects of central angiotensin II stimulation. These results suggest that central α-adrenergic stimulation can produce pressor and depressor effects. ADH release or inhibition of that release. These seemingly conflicting effects may be resolved by pharmocological characterization of central α-adrenergic receptors or isolation of separate sites of action within the brain.     

Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS

Rationale In cell culture systems, agonists can promote the phosphorylation and internalization of receptors coupled to G proteins (GPCR), leading to their desensitization. However, in the CNS opioid agonists promote a profound desensitization of their analgesic effects without diminishing the presence of their receptors in the neuronal membrane. Recent studies have indicated that CNS proteins of the RGS family, specific regulators of G protein signalling, may be involved in mu-opioid receptor desensitization in vivo.Objective In this work we review the role played by RGS proteins in the intensity and duration of the effects of mu-opioid receptor agonists, and how they influence the delayed tolerance that develops in response to specific doses of opioids.Results RGS proteins are GTPase-activating proteins (GAP) that accelerate the hydrolysis of GGTP to terminate signalling at effectors. The GAP activity of RGS-R4 and RGS-Rz proteins restricts the amplitude of opioid analgesia, and the efficient deactivation of GzGTP subunits by RGS-Rz proteins prevents mu receptor desensitization. However, RGS-R7 proteins antagonize effectors by binding to and sequestering mu receptor-activated Gi/o/z subunits. Thus, they reduce the pool of receptor-regulated G proteins and hence, the effects of agonists. The delayed tolerance observed following morphine administration correlates with the transfer of G subunits from mu receptors to RGS-R7 proteins and the subsequent stabilization of this association.Conclusion In the CNS, the RGS proteins control the activity of mu opioid receptors through GAP-dependent (RGS-R4 and RGS-Rz) as well as by GAP-independent mechanisms (RGS-R7). As a result, they can both antagonize effectors and desensitize receptors under certain circumstances.     

Effect of prolonged treatment with adrenergic neuron blocking drugs on sympathoadrenal reactivity in rats

The effects of repeated high doses of the adrenergic neuron blocking drug guanethidine or a hexahydropyrazinoindole compound (2-guanyl-1,2,3,10,10a, hexahydro-1,2,a-pyrazinoindole, EMD 21192) (30 mg/kg i.p., 21.5 mg/kg i.p. respectively, equimolar doses) on sympathoadrenal activity were investigated in normotensive adult rats. During treatment for 5 weeks with either guanethidine or EMD 21192 the systemic blood pressure fell steadily. Noradrenaline content in the heart and vas deferens were decreased markedly by guanethidine and to a much less degree by EMD 21192. EMD 21192 markedly lowers the catecholamine content of the adrenal medulla, presumably as a result of inhibition of dopamine-beta-hydroxylase. The plasma catecholamine concentrations reflected the different sites of action of the drugs in the sympathoadrenal system, i.e. guanethidine mainly reduced circulating norepinephrine and dopamine-beta-hydroxylase by more than 50%, whereas EMD 21192 decreased considerably by the total catecholamines (mainly epinephrine) without altering significantly in the plasma norepinephrine. Disappearance or reduction of fluorescent nerve endings in the iris and the heart and a decrease of the intensity of fluorescence in chromaffin cells of the adrenal gland caused by the drugs were consistent with the biochemical alteration. Whereas the repeated doses of guanethidine caused degeneration of sympathetic nerves, destruction of adrenergic neurons was not found after prolonged treatment with EMD 21192.     

两种脱敏剂在复合树脂充填治疗楔状缺损的疗效观察

目的:比较Gluma与Single Bond脱敏剂在复合树脂充填治疗楔状缺损时的临床疗效.方法:选择本院口腔内科就诊的楔状缺损患者67例,共186颗前牙,按就诊顺序排列随机分为3组:治疗组(T1组):Gluma脱敏剂脱敏后光固化复合树脂充填楔状缺损;治疗组(T2组):Single Bond脱敏剂脱敏后光固化复合树脂充填;对照组:用光固化复合树脂直接充填,统一临床检查标准下对有效率(术后即刻,3个月和6个月复查)进行统计分析.结果:各治疗组与对照组之间差异有统计学意义(P＜0.05),但两治疗组组间差异无统计学意义(P＞0.05).结论:用复合树脂充填治疗楔状缺损前使用Gluma或Single Bond脱敏剂脱敏治疗均可有效减少充填术后牙齿敏感症状的出现.     

脱敏治疗对变应性鼻炎患者嗜碱粒细胞释放能力的影响

本文应用逆向嗜碱粒细胞脱颗粒实验的方法,探讨脱敏治疗对变应性鼻炎患者嗜碱粒细胞释放能力的影响。实验显示:脱敏治疗一年能显著降低变应性鼻炎患者的嗜碱粒细胞释放能力(t=5.755,P<0.01);血清总 IgE 水平虽有一定程度的降低,但没有显著性差异(t=1.161,P>0.05)。提示:脱敏治疗对于稳定嗜碱粒细胞的功能起到重要作用。     

Rapid heterologous desensitization of antinociceptive activity between mu or delta opioid receptors and chemokine receptors in rats

Previous studies have shown pretreatment with chemokines CCL5/RANTES (100 ng) or CXCL12/SDF-1alpha (100 ng) injected into the periaqueductal grey (PAG) region of the brain, 30 min before the mu opioid agonist DAMGO (400 ng), blocked the antinociception induced by DAMGO in the in vivo cold water tail-flick (CWT) antinociceptive test in rats. In the present experiments, we tested whether the action of other agonists at mu and delta opioid receptors is blocked when CCL5/RANTES or CXCL12/SDF-1alpha is administered into the PAG 30 min before, or co-administered with, opioid agonists in the CWT assay. The results showed that: (1) CXCL12/SDF-1alpha (100 ng, PAG) or CCL5/RANTES (100 ng, PAG), given 30 min before the opioid agonist morphine, or selective delta opioid receptor agonist DPDPE, blocked the antinociceptive effect of these drugs; (2) CXCL12/SDF-1alpha (100 ng, PAG) or CCL5/RANTES (100 ng, PAG), injected at the same time as DAMGO or DPDPE, significantly reduced the antinociceptive effect induced by these drugs. These results demonstrate that the heterologous desensitization is rapid between the mu or delta opioid receptors and either CCL5/RANTES receptor CCR5 or CXCL12/SDF-1alpha receptor CXCR4 in vivo, but the effect is greater if the chemokine is administered before the opioid.     

Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins

GPCRs represent the largest family of integral membrane proteins and were first identified as receptor proteins that couple via heterotrimeric G-proteins to regulate a vast variety of effector proteins to modulate cellular function. It is now recognized that GPCRs interact with a myriad of proteins that not only function to attenuate their signalling but also function to couple these receptors to heterotrimeric G-protein-independent signalling pathways. In addition, intracellular and transmembrane proteins associate with GPCRs and regulate their processing in the endoplasmic reticulum, trafficking to the cell surface, compartmentalization to plasma membrane microdomains, endocytosis and trafficking between intracellular membrane compartments. The present review will overview the functional consequence of β-arrestin, receptor activity-modifying proteins (RAMPS), regulators of G-protein signalling (RGS), GPCR-associated sorting proteins (GASPs), Homer, small GTPases, PSD95/Disc Large/Zona Occludens (PDZ), spinophilin, protein phosphatases, calmodulin, optineurin and Src homology 3 (SH3) containing protein interactions with GPCRs.     

Carbachol-induced nonspecific desensitization in guinea-pig ileum

Summary The effects of repeated stimulation by carbachol on force development have been examined in smooth muscle of the longitudinal layer of the guinea-pig ileum. Carbachol was applied at 20°C for 5 min. Each application was followed by a 25-min washout period and the desensitization was expressed by the decline of the maximal force development. Three hours after the first carbachol-induced contraction the peak amplitude was about 40% of the initial value. Increasing the frequency of application, thereby decreasing the washout time, enhanced the desensitization, while the presence of the competitive blocker atropine reduced the phenomenon. At 35°C no desensitization could be observed. Blocking the Na⁺/K⁺ pump by ouabain or by K⁺-free solution reduced the force development to less than 20%. Increasing [K⁺]₀ in the washout solution at 20°C reduced the desensitization phenomenon, while decreasing [K⁺]₀ resulted in an enhanced desensitization as expressed by a decline of the force development.The total cellular Na⁺ content after various stimulation sequences was determined at 20° and 35°C from the ²²Na⁺ effluxes. At 35°C the cellular Na⁺ content did not change significantly during stimulation for 10 min with 10^–4 mol/l carbachol. At 20°C the resting Na⁺ content was significantly increased, and it doubled during carbachol stimulation for 10 min. Furthermore, the recovery of the cellular Na⁺ content after washout proceeded extremely slowly at that temperature. The appearance of desensitization was increased by 10 mol/l ryanodine, while it was reduced by adding the Ca²⁺ agonist Bay K 8644. Also the presence of pertussis toxin reduced the desensitization. The desensitizing effects of other agonists as histamine and substance P were less pronounced but also frequency dependent. The nonspecific nature of the carbachol desensitization was confirmed by the reduced response to histamine after stimulations with carbachol.We conclude that nonspecific desensitization is an agonist-, time- and temperature-dependent phenomenon. This desensitization could be the result of a G-protein-mediated inactivation of voltage-gated Ca²⁺ currents, which would thereby reduce the amount of [Ca²⁺]_i mobilized during repeated stimulation. Send offprint requests to: B. Himpens at the above address     

Role of G12 proteins in oncogenesis and metastasis

The G12 subfamily of heterotrimeric guanine nucleotide-binding proteins consists of two α subunits, Gα12 and Gα13. These proteins mediate signalling via G protein-coupled receptors and have been implicated in various physiological and pathophysiological processes. A number of direct and indirect effectors of Gα12 and Gα13 have been identified that mediate, or have been proposed to mediate, the diverse cellular responses accompanying activation of G12 proteins. This review describes the signalling pathways and cellular events stimulated by G12 proteins, with a particular emphasis on processes that are important in regulating cell migration and invasion, and could potentially be involved in the pathophysiology of cancer metastasis. Experimental findings directly implicating G12 proteins in the spread of metastatic disease are also summarized, indicating the importance of targeted inhibition of G12 signalling as a potential therapeutic option for locally advanced and metastatic disease.     

异丙肾上腺素导致的心肌损伤大鼠心肌牛磺酸转运障碍和牛磺酸防治作用

目的:观察异丙肾上腺素(ISO)导致心肌损伤大鼠的心肌组织牛磺酸跨膜转运功能及牛磺酸转运体(TAUT)和半胱氨酸亚磺酸脱羧酶(CSD)的改变.方法:用[~3H]标记的牛磺酸测定心肌牛磺酸转运及其与心肌浆膜结合功能;竞争性RT-PCR测定TAUT和CSD mRNA的含量.结果:ISO组与对照组比,心肌[~3H]-牛磺酸摄入减少,释放量增加,心肌浆膜最大结合速率(B_(max))减少,TAUT和CSD mRNA水平减少.牛磺酸治疗组与ISO组比,心肌牛磺酸摄入量明显增加,释放量减少,B_(max)值增加,TAUT和CSDmRNA含量增加,各组间K_d值无明显差异.结论:ISO诱导的心肌损伤存在牛磺酸转运障碍及TAUT和CSD基因的下调,外源性给予牛磺酸对心肌损伤有明显防治作用.