• 【牙周炎患者体内内皮素-1浓度的分析。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-020-58585-4 复制DOI
    作者列表:Isola G,Polizzi A,Alibrandi A,Indelicato F,Ferlito S
    BACKGROUND & AIMS: :Endothelin 1 (ET-1) has been shown to have a key role in homeostasis and function of endothelium and maybe fundamental in the relationship between coronary heart disease (CHD) and periodontitis. In this trial, we assessed the influence on serum and salivary ET-1 levels of gingival health, CHD, periodontitis, or a combination of periodontitis-CHD. Clinical and periodontal parameters, were collected from periodontitis patients (n = 34), CHD patients (n = 34), periodontitis + CHD patients (n = 34), and from healthy patients (n = 34) together with saliva and serum samples. The median concentrations of salivary and serum ET-1 were significantly higher in the CHD patients [serum: 1.4(1.1-1.6) pg/ml; saliva 1.2 (0.9-1.6) µmol/g, p < 0.01] and in the periodontitis + CHD patients [serum: 1.7 (1.2-21.8) pg/ml; salivary 1.4(1-1.6) µmol/g, p < 0.001] respect to periodontitis and control patients. Through a univariate regression analysis, c-reactive protein (CRP) and CHD (both p < 0.001) and periodontitis (p = 0.029) were statistically correlated with ET-1 in serum. The multivariate regression analysis demonstrated that only CRP was the statistically predictor of ET-1 in serum(p < 0.001). The multivariate regression analysis in saliva demonstrated that, regarding ET-1 levels the only predictor were CRP (p < 0.001) and total cholesterol (p = 0.042). The present study evidenced that subjects with CHD and periodontitis plus CHD had higher serum and salivary levels of ET-1 compared to subjects with periodontitis and healthy controls. Moreover, only CRP remained a major predictor of increased ET-1 concentrations in both serum and saliva.
    背景与目标: :内皮素1(ET-1)已被证明在体内稳态和内皮功能中具有关键作用,并且可能在冠心病(CHD)与牙周炎之间的关系中具有根本性作用。在该试验中,我们评估了牙龈健康,冠心病,牙周炎或牙周炎-冠心病联合对血清和唾液ET-1水平的影响。从牙周炎患者(n = 34),CHD患者(n = 34),牙周病CHD患者(n = 34)和健康患者(n = 34)以及唾液和血清样本中收集临床和牙周参数。冠心病患者的唾液和血清ET-1的中位数浓度显着较高[血清:1.4(1.1-1.6)pg / ml;唾液1.2(0.9-1.6)µmol / g,p << 0.01]和牙周炎CHD患者[血清:1.7(1.2-21.8)pg / ml;唾液1.4(1-1.6)µmol / g,p <0.001](针对牙周炎和对照患者)。通过单因素回归分析,血清中的ET-1与c-反应蛋白(CRP)和冠心病(p <0.001)和牙周炎(p = 0.029)相关。多元回归分析表明,只有CRP是血清ET-1的统计学预测指标(p <0.001)。唾液的多元回归分析表明,就ET-1水平而言,唯一的预测因素是CRP(p <0.001)和总胆固醇(p = 0.042)。本研究证明,与患有牙周炎和健康对照的受试者相比,患有CHD和牙周炎加CHD的受试者的ET-1血清和唾液水平更高。此外,仅CRP仍是血清和唾液中ET-1浓度增加的主要预测因子。
  • 【白三烯D(4)增强了内皮素1启动的成纤维细胞的功能。】 复制标题 收藏 收藏
    DOI:10.1016/j.clim.2007.05.018 复制DOI
    作者列表:Tokuriki S,Ohshima Y,Yamada A,Ohta N,Tsukahara H,Mayumi M
    BACKGROUND & AIMS: :Airway inflammation is accompanied by structural changes, termed remodeling, that lead to lung dysfunction over the long term. Although both endothelin-1 (ET-1) and cysteinyl leukotrienes (CysLTs) appear to be involved in airway remodeling in several lung diseases, how these molecules interact remains largely unknown. In this study, we examined the effects of leukotriene (LT) D(4) on the function of ET-1-primed fibroblasts. ET-1 at 10(-7) M up-regulated the expression of the CysLT receptors at both the mRNA and protein levels in human lung fibroblasts. LTD(4) enhanced matrix metalloproteinase-2 and pro-collagen production, and alpha-smooth muscle actin expression of ET-1-primed fibroblasts, but had little or no effect on unprimed fibroblasts. The CysLT1 receptor antagonist montelukast completely abrogated the effects of LTD(4). Our data suggested that LTD(4) may act as a precipitating factor during ET-1-mediated airway remodeling and that CysLT1 receptor antagonists may have a role in preventing aberrant extracellular matrix degradation.
    背景与目标: :气道炎症伴随着结构改变,称为重塑,长期导致肺功能障碍。尽管内皮素-1(ET-1)和半胱氨酰白三烯(CysLTs)似乎都参与了几种肺部疾病的气道重塑,但这些分子如何相互作用仍然未知。在这项研究中,我们检查了白三烯(LT)D(4)对ET-1引发的成纤维细胞功能的影响。在10(-7)M处的ET-1在人肺成纤维细胞的mRNA和蛋白水平上均上调了CysLT受体的表达。 LTD(4)增强了基质金属蛋白酶2和促胶原蛋白的产生,以及ET-1启动的成纤维细胞的α平滑肌肌动蛋白表达,但对未启动的成纤维细胞几乎没有影响。 CysLT1受体拮抗剂孟鲁司特完全废除了LTD(4)的作用。我们的数据表明LTD(4)可能在ET-1介导的气道重塑过程中充当沉淀因子,而CysLT1受体拮抗剂可能在防止异常的细胞外基质降解中起作用。
  • 【内皮素-1受体在健康麻醉兔子中的作用。】 复制标题 收藏 收藏
    DOI:10.1046/j.1440-1681.2001.03500.x 复制DOI
    作者列表:Schmitz-Spanke S,Schipke J
    BACKGROUND & AIMS: :1. Many diseases are associated with elevated endothelin (ET)-1 plasma concentrations. In order to understand the consequence of this elevation, in the present study the effects of exogenous ET-1 on the entire organsim were investigated, in particular with respect to the role of ETA and ETB receptors in the cardiovascular system. In open-chest rabbits, left ventricular (LV) pressure (LVPmax, LVPed), dP/dtmax and dP/dtmin were recorded in ejecting and isovolumically beating hearts to determine cardiac function. In addition, heart rate (HR), aortic pressure (AoP) and aortic flow (AoF) were measured. Total peripheral resistance (TPR) was calculated from mean AoP and AoF. 2. In the first series of experiments (n = 11), ET-1 (0.5 nmol/kg; bolus) produced a non-significant reduction in HR. Systolic function, in terms of AoF, LVPmax and dP/dtmax, was improved; for example, LVPmax was increased significantly (69 +/- 10 vs 106 +/- 20 mmHg for control and ET-1, respectively; P < 0.05). Similarly, early relaxation (dP/dtmin) was improved. In parallel, TPR rose significantly (0.25+/-0.07 vs 0.35+/-0.1 mmHg/min per mL for control and ET-1, respectively; P < 0.05). Isovolumic measurements showed corresponding responses. 3. In the second series of experiments (n = 7), animals were pretreated with an ETA receptor antagonist (330 nmol/min per kg FR 139317). After ETA receptor blockade, the administration of ET-1 had no significant effect on cardiac function or vasomotion. 4. In the third series of experiments (n = 6), animals were pretreated with an ETB receptor antagonist (10 nmol/min per kg BQ 788). In this series of experiments, the effects of ET-1 on cardiac function and vasomotion were the same as in the first series of experiments, except for the effect on HR, which decreased by 35% after ET-1. 5. In our experimental model, exogenous ET-1 exerted a clear-cut positive inotropic effect, together with the anticipated peripheral vasoconstriction via ETA receptors.
    背景与目标: :1。许多疾病与内皮素(ET)-1血浆浓度升高有关。为了了解这种升高的后果,在本研究中,研究了外源性ET-1对整个器官的影响,特别是关于ETA和ETB受体在心血管系统中的作用。在开胸的兔子中,在跳动和等容跳动的心脏中记录左心室(LV)压力(LVPmax,LVPed),dP / dtmax和dP / dtmin,以确定心脏功能。此外,还测量了心率(HR),主动脉压(AoP)和主动脉血流(AoF)。从平均AoP和AoF计算总外周电阻(TPR)。 2.在第一个系列实验(n = 11)中,ET-1(0.5 nmol / kg;推注)导致HR无明显降低。在AoF,LVPmax和dP / dtmax方面的收缩功能得到改善;例如,对照组和ET-1的LVPmax显着增加(分别为69 /-10 vs 106 /-20 mmHg; P <0.05)。同样,早期放松(dP / dtmin)也得到了改善。同时,TPR显着上升(对照和ET-1分别为每毫升0.25 /-0.07和0.35 /-0.1 mmHg / min; P <0.05)。等容测量显示相应的响应。 3.在第二系列实验(n = 7)中,动物用ETA受体拮抗剂(330 nmol / min / kg FR 139317)进行预处理。 ETA受体阻滞后,ET-1的使用对心功能或血管舒张作用无明显影响。 4.在第三组实验(n = 6)中,动物用ETB受体拮抗剂(每千克BQ 788每分钟10 nmol / min)进行预处理。在这一系列实验中,除了对HR的影响(在ET-1之后降低了35%)外,ET-1对心功能和血管舒张的影响与第一系列实验相同。 5.在我们的实验模型中,外源性ET-1发挥了明确的正性肌力作用,并预期通过ETA受体引起外周血管收缩。
  • 【内皮素受体拮抗剂波生坦对大鼠骨骼肌缺血/再灌注损伤的影响。】 复制标题 收藏 收藏
    DOI:10.1016/s0014-2999(01)01133-5 复制DOI
    作者列表:Herbert KJ,Hickey MJ,Lepore DA,Knight KR,Morrison WA,Stewart AG
    BACKGROUND & AIMS: :We examined the role of endothelin in ischaemia/reperfusion injury in skeletal muscle, using the endothelin receptor antagonist Bosentan. In the rat hindlimb tourniquet ischaemia model, one hindlimb was rendered ischaemic for 2 h at 36 degrees C, then blood flow was re-established for either 24 h to assess muscle survival or 1.5 h for a study of capillary perfusion. In the first set of rats, the gastrocnemius muscle was removed from the postischaemic limb and assessed for viability histochemically using the nitro blue tetrazolium stain. Tissue water content (a measure of oedema) and myeloperoxidase activity (a measure of neutrophil accumulation) were also assessed in the ischaemic muscle, the contralateral non-ischaemic muscle and the lungs. In the second set of rats, the hind limb was infused with India ink after 2-h ischaemia and 1.5-h reperfusion and the muscle was harvested, fixed and cleared. In control rats, muscle viability was 17+/-2% (S.E.M.). In rats treated with Bosentan (10 mg/kg, i.p.) 30 min before release of the tourniquet, muscle viability (48+/-7%) was significantly increased compared to the control group (P<0.01). Bosentan treatment had no significant effect on tissue water content or myeloperoxidase activity in the ischaemic muscle, the contralateral non-ischaemic muscle or the lung. Immunoreactive endothelin levels in serum increased to a peak at 90 min of reperfusion and returned to control levels by 24-h reperfusion. India ink studies demonstrated a significantly increased functional capillary density in postischaemic Bosentan-treated muscles compared with postischaemic control muscles (P<0.05). These results suggest that endothelin plays an important role in the necrosis which results from a period of ischaemia and reperfusion in skeletal muscle, by mediating a decrease in postischaemic microvascular perfusion.
    背景与目标: :我们使用内皮素受体拮抗剂波生坦研究了内皮素在骨骼肌缺血/再灌注损伤中的作用。在大鼠后肢止血带缺血模型中,将一只后肢在36摄氏度下缺血2小时,然后重新建立血流24小时以评估肌肉存活率或1.5小时以进行毛细血管灌注研究。在第一组大鼠中,将腓肠肌从缺血后肢中移出,并使用硝基蓝四唑染色法进行组织化学活力评估。还测定了局部缺血肌肉,对侧非局部缺血肌肉和肺中的组织含水量(水肿的量度)和髓过氧化物酶活性(中性粒细胞积聚的量度)。在第二组大鼠中,缺血2小时和再灌注1.5小时后,向后肢注入印度墨水,并收集,固定和清理肌肉。在对照大鼠中,肌肉活力为17%/-2%(S.E.M。)。在释放止血带前30分钟用波生坦(10 mg / kg,腹腔内)治疗的大鼠中,肌肉活力(48 / -7%)与对照组相比显着增加(P <0.01)。波生坦治疗对缺血性肌肉,对侧非缺血性肌肉或肺的组织含水量或髓过氧化物酶活性无明显影响。血清中的免疫反应性内皮素水平在再灌注90分钟时增加至峰值,并在24小时再灌注时恢复至对照水平。印度墨水研究表明,与缺血后对照肌肉相比,波森坦治疗后的肌肉的功能性毛细血管密度显着增加(P <0.05)。这些结果表明,通过介导缺血后微血管灌注的减少,内皮素在由局部缺血和骨骼肌再灌注引起的坏死中起重要作用。
  • 【内皮素-1对大鼠心肌细胞C型利尿钠肽作用的相反作用。】 复制标题 收藏 收藏
    DOI:10.1016/s0014-2999(01)01094-9 复制DOI
    作者列表:Fixler R,Hasin Y,Eilam Y,Zhang DF,Nir A
    BACKGROUND & AIMS: :C-type natriuretic peptide (CNP) and Endothelin-1 are paracrine peptides with opposing vascular and mitogenic actions. In cardiac myocytes, CNP reduced contractility and induced accumulation of cyclic guanosine monophosphate (cGMP). Endothelin-1 caused an increase in contractile amplitude, abolished the negative inotropic effect of CNP, reduced the negative inotropic effect of a membrane permeable cGMP, and inhibited cGMP accumulation induced by CNP. We conclude that endothelin-1 abolishes the negative inotropic effect of CNP. This effect may be mediated by inhibition of the negative inotropic actions of cGMP as well as by reduction of cGMP levels.
    背景与目标: :C型利钠肽(CNP)和内皮素-1是旁分泌肽,具有相反的血管和促有丝分裂作用。在心肌细胞中,CNP降低了收缩力并诱导了环鸟苷单磷酸(cGMP)的积累。内皮素-1引起收缩幅度增加,消除了CNP的负性肌力作用,降低了膜可渗透性cGMP的负性肌力作用,并抑制了CNP诱导的cGMP积累。我们得出的结论是,内皮素-1消除了CNP的负性变力作用。可以通过抑制cGMP的负性肌力作用以及降低cGMP水平来介导这种作用。
  • 【内皮素-1对大鼠心肌钾通道TASK-1的抑制作用是由磷脂酶C介导的。】 复制标题 收藏 收藏
    DOI:10.1093/cvr/cvs285 复制DOI
    作者列表:Schiekel J,Lindner M,Hetzel A,Wemhöner K,Renigunta V,Schlichthörl G,Decher N,Oliver D,Daut J
    BACKGROUND & AIMS: AIMS:The two-pore-domain potassium channel TASK-1 is robustly inhibited by the activation of receptors coupled to the Gα(q) subgroup of G-proteins, but the signal transduction pathway is still unclear. We have studied the mechanisms by which endothelin receptors inhibit the current carried by TASK-1 channels (I(TASK)) in cardiomyocytes. METHODS AND RESULTS:Patch-clamp measurements were carried out in isolated rat cardiomyocytes. I(TASK) was identified by extracellular acidification to pH 6.0 and by the application of the TASK-1 blockers A293 and A1899. Endothelin-1 completely inhibited I(TASK) with an EC(50) of <10 nM; this effect was mainly mediated by endothelin-A receptors. Application of 20 nM endothelin-1 caused a significant increase in action potential duration under control conditions; this was significantly reduced after pre-incubation of the cardiomyocytes with 200 nM A1899. The inhibition of I(TASK) by endothelin-1 was not affected by inhibitors of protein kinase C or rho kinase, but was strongly reduced by U73122, an inhibitor of phospholipase C (PLC). The ability of endothelin-1 to activate PLC-mediated signalling pathways was examined in mammalian cells transfected with TASK-1 and the endothelin-A receptor using patch-clamp measurements and total internal reflection microscopy. U73122 prevented the inhibition of I(TASK) by endothelin-1 and blocked PLC-mediated signalling, as verified with a fluorescent probe for phosphatidylinositol-(4,5)-bisphosphate hydrolysis. CONCLUSION:Our results show that I(TASK) in rat cardiomyocytes is controlled by endothelin-1 and suggest that the inhibition of TASK-1 via endothelin receptors is mediated by the activation of PLC. The prolongation of the action potential observed with 20 nM endothelin-1 was mainly due to the inhibition of I(TASK).
    背景与目标: 目的:两孔结构域钾通道TASK-1被与G蛋白的Gα(q)亚基偶联的受体激活强烈抑制,但信号转导途径尚不清楚。我们已经研究了内皮素受体抑制心肌细胞中TASK-1通道(I(TASK))携带的电流的机制。
    方法和结果:在分离的大鼠心肌细胞中进行膜片钳测量。通过细胞外酸化至pH 6.0和应用TASK-1阻滞剂A293和A1899来鉴定I(TASK)。内皮素-1完全抑制I(TASK),EC(50)<10 nM;这种作用主要是由内皮素A受体介导的。在控制条件下,应用20 nM内皮素-1导致动作电位持续时间显着增加。在将心肌细胞与200 nM A1899预温育后,这显着降低。内皮素-1对I(TASK)的抑制作用不受蛋白激酶C或rho激酶抑制剂的影响,但被磷脂酶C(PLC)抑制剂U73122强烈抑制。使用膜片钳测量和全内反射显微镜检查了用TASK-1和内皮素A受体转染的哺乳动物细胞中内皮素1激活PLC介导的信号通路的能力。 U73122阻止了内皮素-1对I(TASK)的抑制,并阻断了PLC介导的信号传导,这一点已通过磷脂酰肌醇-(4,5)-二磷酸水解的荧光探针验证。
    结论:我们的结果表明,大鼠心肌细胞中的I(TASK)受内皮素1控制,并表明内皮素受体对TASK-1的抑制作用是由PLC的激活介导的。用20 nM内皮素-1观察到的动作电位的延长主要归因于I(TASK)的抑制。
  • 【内皮素受体下调介导的配体调节机制可防止大鼠血管内皮细胞细胞缺氧性损伤。】 复制标题 收藏 收藏
    DOI:10.1159/000453196 复制DOI
    作者列表:Li L,Hu M,Zheng L,Zhang C,Li J,Rong R,Zhu T,Jia Y
    BACKGROUND & AIMS: OBJECTIVE:Investigation of the effect of endothelin receptor A (ETaR)-targeting small interfering RNA (siRNA) on rat vascular endothelial cellular hypoxia injury, as well as its underlying mechanism. METHODS:An in vitro rat vascular smooth muscle cells - endothelial cells co-culture model was established and transfected with ETaR siRNA before hypoxia treatment. Cell culture supernatant, cellular protein and RNA were collected and examined at 0.5hrs, 1hrs, 2hrs, 4hrs, 8hrs, 16hrs, 24hrs and 48hrs of hypoxia with 1% oxygen. The time point at which the best silencing effect was achieved was chosen, eNOS inhibitor L-NAME was added, and post hypoxia cell culture supernatant, cellular protein and RNA was collected for further examination. RESULTS:After hypoxic treatment, endothelial-1 (ET-1) and ETaR expression levels gradually increased as oxygen deprivation extended. ET-1 and ETaR expression levels were significantly lower in the ETaR siRNA group compared with the Hypoxia group (P<0.001). Such difference peaked at 4hrs of hypoxia. ELISA examination of cell culture supernatant revealed that the amount of ET-1 and TGF-βin the ETaR siRNA group were significantly lower compared to the Hypoxia group at all times, while the amount of NO and eNOS was higher. After 4 hrs of hypoxia, Smad2, Smad3, HIF-1, TNF-α, IFN-γ, IL-6, MCP-1, NF-κb, ET-1 and ANG II mRNA expression in endothelial cells and ETaR mRNA expression in A-10 cells of the ETaR siRNA group were lower than those of the Hypoxia siRNA group, while such results were much higher in the L-NAME group. Western Blot results showed lower expression of ETaR in the ETaR siRNA group compared with the hypoxia and negative siRNA groups, as well as significantly higher ETaR expression in the L-NAME group compared with the ETaR siRNA group. PI3K and p-AKT expression levels were mildly elevated after mild oxygen deprivation, and ETaR siRNA was able to enhance such elevation induced by hypoxia. In the L-NAME group, PI3K and p-AKT expression was much higher than the ETaR siRNA group. PKG and sGC expression levels significantly descended after mild oxygen deprivation. While such levels were higher in the ETaR siRNA group, compared with the hypoxia and negative siRNA groups, the L-NAME group had lower levels of PKG and sGC compared with the ETaR siRNA group. CONCLUSION:ETaR siRNA is capable of down-regulating the expression of inflammatory and transcription factors among endothelial cells treated with hypoxia. Down-regulation of ET-1 is triggered by altered nucleus transcription factor activity through the sGC/PKG signal pathway, and results in enhanced eNOS activity through the PI3K/Akt signal pathway. We suspect this to be the mechanism of the protective effect of ETaR siRNA.
    背景与目标: 目的:研究靶向内皮素受体A(ETaR)的小干扰RNA(siRNA)对大鼠血管内皮细胞缺氧性损伤的作用及其潜在机制。
    方法:建立体外大鼠血管平滑肌细胞-内皮细胞共培养模型,并在缺氧治疗前用ETaR siRNA转染。收集细胞培养上清液,细胞蛋白和RNA,并在含1%氧气的缺氧状态下分别于0.5小时,1小时,2小时,4小时,8小时,16小时,24小时和48小时检查。选择达到最佳沉默效果的时间点,添加eNOS抑制剂L-NAME,缺氧后细胞培养上清液,细胞蛋白和RNA收集用于进一步检查。
    结果:低氧治疗后,随着缺氧时间的延长,内皮1(ET-1)和ETaR的表达水平逐渐升高。与缺氧组相比,ETaR siRNA组的ET-1和ETaR表达水平显着降低(P <0.001)。这种差异在缺氧的4小时达到顶峰。 ELISA检查细胞培养上清液显示,ETaR siRNA组中的ET-1和TGF-β的含量始终低于缺氧组,而NO和eNOS的含量则较高。缺氧4小时后,内皮细胞中Smad2,Smad3,HIF-1,TNF-α,IFN-γ,IL-6,MCP-1,NF-κb,ET-1和ANG II mRNA表达及ETaR mRNA表达ETaR siRNA组的A-10细胞低于低氧siRNA组的细胞,而L-NAME组则更高。 Western Blot结果显示,与低氧和阴性siRNA组相比,ETaR siRNA组中的ETaR表达较低,与ETaR siRNA组相比,L-NAME组中的ETaR表达显着较高。轻度缺氧后,PI3K和p-AKT表达水平轻度升高,ETaR siRNA能够增强这种由缺氧引起的升高。在L-NAME组中,PI3K和p-AKT表达远高于ETaR siRNA组。轻度缺氧后,PKG和sGC表达水平显着下降。尽管ETaR siRNA组的这种水平较高,但与缺氧和阴性siRNA组相比,L-NAME组的PKG和sGC水平低于ETaR siRNA组。
    结论:ETaR siRNA能够下调低氧处理的内皮细胞中炎性因子和转录因子的表达。 ET-1的下调是通过sGC / PKG信号途径的核转录因子活性改变触发的,并通过PI3K / Akt信号途径导致eNOS活性增强。我们怀疑这是ETaR siRNA保护作用的机制。
  • 【一氧化氮和内皮素-1在单芥子碱诱导的大鼠肺动脉高压中的作用。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Mathew R,Zeballos GA,Tun H,Gewitz MH
    BACKGROUND & AIMS: OBJECTIVE:Nitric oxide (NO) and endothelin-1 (ET-1) have both been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, we examined NO-related relaxation and ET-1 levels in rat hilar pulmonary arteries (PA) during the progression of monocrotaline (MCT)-induced PH. METHODS:Rats were studied 1 and 2 weeks after a single subcutaneous injection of MCT (80 mg/kg). Pulmonary artery pressure (PAP), right ventricular hypertrophy (RVH), NO-related relaxation and tissue ET-1 levels in PA were evaluated and compared with control (C). RESULTS:One week post-MCT, endothelium (E)-dependent relaxation to 10(-5) M adenosine diphosphate (ADP), 10(-5) M A23187 and 10(-5) M acetylcholine (ACh) and tissue ET-1 levels in PA were normal. Rats in this group did not develop PH or RVH. Two weeks post-MCT, E-dependent relaxation was impaired (ADP, 7 +/- 3% VS. c, 62 +/- 5%; A23187, 2 +/- 7% vs. C, 58 +/- 2%; ACh, 33 +/- 7% vs. C, 86 +/- 2%; P < 0.05) and ET-1 levels were elevated (1925 +/- 244 pg/g wwt vs. C, 469 +/- 59 pg/g wwt, P < 0.05), In addition, significant PH and RVH were present (PAP 33 +/- 4 mmHg vs. C 18 +/- 0.8 mmHg, P < 0.05; RVH index 0.40 +/- 0.006 vs. C, 0.25 +/- 0.01, P < 0.05). Incubation with 10 microM indomethacin, 150 U/ml superoxide dismutase or 300 microM L-arginine failed to restore impaired relaxation to ACh. In E-intact rings, relaxation to 10(-6) M glyceryl trinitrate (GTN) was inhibited at 1 week post-MCT (72 +/- 2% vs. C, 87 +/- 3%, P < 0.05) with further inhibition at 2 weeks (39 +/- 4%). Response to GTN in E-denuded rings was normal in MCT groups. CONCLUSIONS:These results indicate that MCT injection in rats results in delayed but progressive endothelial injury and PH. Despite mild endothelial dysfunction 1 week post-MCT, NO-related relaxation and ET-1 levels are normal. At 2 weeks post-MCT, inhibition of E-dependent NO-related relaxation and elevation of ET-1 levels are associated with PH and RVH. Thus inhibition of NO production associated with elevated ET-1 levels may play an important role in the pathophysiology of MCT-induced PH.
    背景与目标: 目的:一氧化氮(NO)和内皮素-1(ET-1)均与肺动脉高压(PH)的发病有关。因此,我们检查了单芥子碱(MCT)诱导的PH进程中大鼠肺门肺动脉(PA)中NO相关的松弛和ET-1水平。
    方法:皮下注射MCT(80 mg / kg)1周和2周后,对大鼠进行研究。评价肺动脉压(PAP),右心室肥大(RVH),NO相关舒张和PA中组织ET-1的水平,并将其与对照组(C)进行比较。
    结果:MCT后一周,内皮(E)依赖松弛至10(-5)M磷酸二腺苷(ADP),10(-5)M A23187和10(-5)M乙酰胆碱(ACh)和组织ET- PA中1个水平正常。该组中的大鼠未出现PH或RVH。 MCT后两周,E依赖的放松受到损害(ADP,7 /-3%VS. c,62 /-5%; A23187,2 /-7%vs. C,58 /-2%; ACh,33 /-相对于C为7%,86 /-2%; P <0.05)和ET-1水平升高(1925 /-244 pg / g wwt对C,469 /-59 pg / g wwt,P <0.05 ),此外,存在明显的PH和RVH(PAP 33 /-4 mmHg vs.C 18 /-0.8 mmHg,P <0.05; RVH指数0.40 /-0.006 vs.C,0.25 /-0.01,P <0.05) 。与10 microM消炎痛,150 U / ml超氧化物歧化酶或300 microM L-精氨酸一起孵育无法恢复ACh的受损松弛。在E型完整环中,MCT后1周抑制到10(-6)M三硝酸甘油酯(GTN)的松弛(72 /-2%vs. C,87 /-3%,P <0.05),并进一步抑制在2周时(39 /-4%)。在MCT组中,E剥脱环对GTN的反应是正常的。
    结论:这些结果表明,在大鼠中进行MCT注射可导致延迟但进行性的内皮损伤和PH。尽管在MCT后1周出现了轻度的内皮功能障碍,但NO相关的舒张和ET-1水平是正常的。 MCT后2周,抑制E依赖的NO相关松弛和ET-1水平升高与PH和RVH有关。因此,抑制与NO-1升高相关的NO产生可能在MCT诱导的PH的病理生理中起重要作用。
  • 【肾功能障碍一氧化氮合酶作为盐敏感性高血压的决定因素:肾动脉内皮功能障碍的机制以及内皮素在血管肥大和肾小球硬化中的作用。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Barton M,Vos I,Shaw S,Boer P,D'Uscio LV,Gröne HJ,Rabelink TJ,Lattmann T,Moreau P,Lüscher TF
    BACKGROUND & AIMS: :This study investigated the role of renal nitric oxide synthase (NOS), endothelin, and possible mechanisms of renovascular dysfunction in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated for 8 wk with high salt diet (4% NaCl) alone or in combination with the ET(A) receptor antagonist LU135252 (60 mg/kg per d). Salt loading markedly increased NOS activity (pmol citrulline/mg protein per min) in renal cortex and medulla in DR but not in DS rats by 270 and 246%, respectively. Hypertension in DS rats was associated with renal artery hypertrophy, increased vascular and renal endothelin-1 (ET-1) protein content, and glomerulosclerosis. In the renal artery but not in the aorta of hypertensive DS rats, endothelium-dependent relaxation to acetylcholine was unchanged; however, endothelial dysfunction due to enhanced prostanoid-mediated, endothelium-dependent contractions and attenuation of basal nitric oxide release was present. Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-1 without affecting ET-3 levels. This was associated with a slight increase of renal NOS activity, normalization of endothelial dysfunction and renal artery hypertrophy, and marked attenuation of glomerulosclerosis. Thus, DS rats fail to increase NOS activity in response to salt loading. This abnormality may predispose to activation of the tissue ET-1 system, abnormal renal vasoconstriction, and renal injury. Chronic ET(A) receptor blockade normalized salt-induced changes in the renal artery and reduced glomerular injury, suggesting therapeutic potential for ET antagonists in salt-sensitive forms of hypertension.
    背景与目标: :本研究调查了盐敏感型高血压中肾一氧化氮合酶(NOS),内皮素的作用以及肾血管功能障碍的可能机制。盐敏感性(DS)和抗盐(DR)的Dahl大鼠单独或与ET(A)受体拮抗剂LU135252(60 mg / kg / d)高盐饮食(4%NaCl)一起治疗8周。盐负荷显着增加了DR大鼠的肾皮质和髓质中的NOS活性(pmol瓜氨酸/ mg蛋白/分钟),而DS大鼠中的NOS活性则没有分别增加270和246%。 DS大鼠的高血压与肾动脉肥大,血管和肾脏内皮素1(ET-1)蛋白含量增加以及肾小球硬化有关。在高血压DS大鼠的肾动脉而非主动脉中,对乙酰胆碱的内皮依赖性舒张作用没有改变。然而,由于前列腺素介导的内皮依赖性收缩增强和基底一氧化氮释放减弱而引起的内皮功能障碍。 LU135252的治疗可以部分减轻高血压,但完全可以阻止ET-1组织的活化,而不会影响ET-3的水平。这与肾NOS活性略有增加,内皮功能障碍和肾动脉肥大正常化以及肾小球硬化明显减轻有关。因此,DS大鼠不能响应盐负荷而增加NOS活性。这种异常可能导致组织ET-1系统激活,异常的肾血管收缩和肾脏损伤。慢性ET(A)受体阻滞了盐引起的肾动脉变化的正常化,并减少了肾小球损伤,这表明ET拮抗剂在盐敏感性形式的高血压中具有治疗潜力。
  • 【副流感1呼吸道病毒感染对小鼠和大鼠气管平滑肌中内皮素受体效应系统的影响。】 复制标题 收藏 收藏
    DOI:10.1111/j.1476-5381.1996.tb15984.x 复制DOI
    作者列表:Knott PG,Henry PJ,McWilliam AS,Rigby PJ,Fernandes LB,Goldie RG
    BACKGROUND & AIMS: 1. In this study we have compared the effects of parainfluenza-1 respiratory tract viral infection on the density and function of ETA and ETB receptors in rat and mouse tracheal airway smooth muscle. 2. The bronchoconstrictor effect of inhaled methacholine was significantly enhanced in virus-infected rats, at both 4 and 12 days post-inoculation. That is, the concentration of methacholine causing an increase in resistance of 100% (PC100 methacholine) was significantly lower in virus-infected animals at both 4 and 12 days post-inoculation (n = 6-8; P < 0.05). 3. Total specific binding of [125I]-endothelin-1 and the relative proportions of ETA and ETB binding sites for [125I]-endothelin-1 were assessed in tracheal airway smooth muscle in parainfluenza-1-infected rats and mice at days 2, 4 and 12 post-inoculation using the ligands BQ-123 (1 microM; ETA receptor-selective) and sarafotoxin S6c (100 nM; ETB receptor-selective). Total specific binding in mice was significantly reduced at day 2 post-inoculation (n = 5; P < 0.05) but not at days 4 and 12 post-inoculation (n = 5). In control mice, the proportions of ETA and ETB binding sites were 53%11% at day 4 (P < 0.05). By day 12 post-inoculation, the proportion of ETA and ETB binding sites in tracheal smooth muscle from mice infected with parainfluenza-1 was not significantly different from control.

    In rat tracheal airway smooth muscle, neither total specific binding nor the ETA and ETB binding site ratio (64%36%) were significantly altered in virus-inoculated rats at days 2, 4 or 12 post-inoculation (n = 5). 4. Parainfluenza-1 infection in mice had no effect on the sensitivity or maximal contractile effect of endothelin-1 in tracheal smooth muscle at days 2, 4 or 12 post-inoculation (n = 4). In contrast, contraction in response to the ETB receptor-selective agonist sarafotoxin S6c was attenuated by 39% at day 2 and by 93% at day 4 post-inoculation (P < 0.05). However, by day 12 post-inoculation, contractions to sarafotoxin S6c were not significantly different between control and virus-infected mice. In parainfluenza-1-infected rats, there were small but significant reductions in the sensitivity to carbachol, endothelin-1 and sarafotoxin S6c whilst the maximal responses to the highest concentrations of these agonists were not significantly altered by virus infection (n = 8). 5. BQ-123 (3 microM) had no significant effect on cumulative concentration-effect curves to endothelin-1 in tracheal preparations from control mice (n = 4) or parainfluenza-1-infected rats (n = 8). In contrast, in tissues taken from virus-infected mice at day 4 post-inoculation, BQ-123 caused a marked 9.6 fold rightward shift in the concentration-effect curve to endothelin-1 (n = 4). 6. In summary, we have demonstrated that parainfluenza-1 infection in mice transiently reduced the density of tracheal airway smooth muscle ETB receptors and this was reflected in reduced responsiveness to the ETB receptor-selective agonist sarafotoxin S6c. In contrast, whilst parainfluenza-1 infection in rats was associated with the pathological features and bronchial hyperresponsiveness common to respiratory tract viral infection, there was no selective down-regulation of ETB receptor expression or functional activity. The reasons for these species differences are not clear, but may relate to differences in the airway inflammatory response to parainfluenza-1 virus.

    背景与目标: 1.在这项研究中,我们比较了副流感1呼吸道病毒感染对大鼠和小鼠气管气道平滑肌中ETA和ETB受体的密度和功能的影响。 2.在感染后的第4天和第12天,吸入乙酰甲胆碱在病毒感染的大鼠中的支气管收缩作用显着增强。也就是说,在接种病毒后的第4天和第12天,引起病毒感染的动物中,引起100%耐药性增加的乙酰甲胆碱(PC100乙酰甲胆碱)的浓度显着降低(n = 6-8; P <0.05)。 3.在第2天,在副流感-1感染的大鼠和小鼠的气管气道平滑肌中评估[125I]-内皮素-1的总特异性结合以及[125I]-内皮素-1的ETA和ETB结合位点的相对比例。 ,接种后第4和第12个,使用的是配体BQ-123(1 microM;对ETA受体具有选择性)和sarafotoxin S6c(100 nM;对ETB受体具有选择性)。接种后第2天(n = 5; P <0.05),小鼠的总特异性结合显着降低,但接种后第4和12天(n = 5)则没有。在对照小鼠中,第4天ETA和ETB结合位点的比例为53%(P <0.05)。接种后第12天,副流感1感染小鼠气管平滑肌中ETA和ETB结合位点的比例与对照组无显着性差异。

    在大鼠气管气道平滑肌中,两者均没有特异性结合在接种后第2、4或12天(n = 5),用病毒接种的大鼠中的ETA和ETB结合位点比例(646%)也没有明显改变。 4.小鼠副流感1感染在接种后第2、4或12天(n = 4)对气管平滑肌中内皮素1的敏感性或最大收缩作用没有影响。相反,接种后第2天对ETB受体选择性激动剂sarafotoxin S6c的响应收缩减弱了39%,在第4天减弱了93%(P <0.05)。然而,到接种后第12天,对照小鼠和病毒感染的小鼠对sarafotoxin S6c的收缩没有显着差异。在感染副流感1的大鼠中,对卡巴胆碱,内皮素1和sarafotoxin S6c的敏感性有较小但显着的降低,而对这些激动剂的最高浓度的最大反应并未因病毒感染而明显改变(n = 8)。 5. BQ-123(3 microM)对对照小鼠(n = 4)或副流感1感染大鼠(n = 8)的气管制剂中内皮素1的累积浓度效应曲线没有显着影响。相反,在接种后第4天从感染病毒的小鼠中获取的组织中,BQ-123在向内皮素1的浓度效应曲线中引起了明显的9.6倍向右移位(n = 4)。 6.总之,我们已经证明小鼠副流感1感染会暂时降低气管气道平滑肌ETB受体的密度,这反映在对ETB受体选择性激动剂sarafotoxin S6c的反应性降低。相比之下,虽然大鼠副流感1感染与呼吸道病毒感染常见的病理特征和支气管高反应性有关,但没有选择性下调ETB受体的表达或功能活性。这些物种差异的原因尚不清楚,但可能与对副流感1病毒的气道炎症反应差异有关。

  • 【难治性内皮素-1在猪睫状动脉中的作用。】 复制标题 收藏 收藏
    DOI:10.1089/jop.2012.0060 复制DOI
    作者列表:Konieczka K,Flammer AJ,Neutzner A,Schoetzau A,Binggeli T,Flammer J
    BACKGROUND & AIMS: PURPOSE:Endothelin-1 (ET) is an important molecule in vascular physiology. After an acute stimulation with ET, vessels are to some extent temporarily refractory to further stimulation. However, few details are known about this phenomenon. The aim of our study was to verify the existence of refractoriness in ophthalmic ciliary arteries and, if present, to analyze its time course. METHODS:Twenty freshly isolated porcine ciliary arteries were placed in a myograph system to measure isometric forces. Each vessel was stimulated with 10(-7) M ET twice. The experiment was performed in 5 groups of vessels, which differed in the time interval between the initial and the second stimulation with ET. The intervals were 15 min, 30 min, 1 h, 2 h, and 4 h, respectively. RESULTS:The vasoconstrictive response to re-exposure to ET was time-dependently reduced. The response was lowest after 15 min (22% of baseline response), and then the sensitivity slowly recovered and was finally normal again after 4 h. CONCLUSIONS:Our experiment with isolated porcine ophthalmic ciliary arteries revealed a refractoriness phase to ET after an acute stimulation with ET. This refractoriness was transient and disappeared after 4 h. The lowest response was observed in the group of vessels re-exposed 15 min after the first stimulation.
    背景与目标: 目的:内皮素-1(ET)是血管生理中的重要分子。在用ET进行急性刺激后,血管在某种程度上暂时难于进一步刺激。但是,有关此现象的细节知之甚少。我们研究的目的是验证眼睫状动脉是否存在难治性,并分析其时间进程。
    方法:将二十个新鲜分离的猪睫状动脉放置在肌电图仪系统中,以测量等轴测力。每个容器用10(-7)M ET刺激两次。实验是在5组血管中进行的,它们在ET的初始刺激和第二次刺激之间的时间间隔有所不同。间隔分别为15分钟,30分钟,1 h,2 h和4 h。
    结果:再次暴露于ET的血管收缩反应呈时间依赖性降低。 15分钟后反应最低(占基线反应的22%),然后敏感性缓慢恢复,并在4小时后再次恢复正常。
    结论:我们用分离的猪眼睫状动脉进行的实验显示,在用ET急性刺激后,ET出现了难治性阶段。这种耐火度是短暂的,并在4小时后消失。在第一次刺激后15分钟再次暴露的血管组中观察到最低的反应。
  • 【内皮素和BQ123对健康受试者眼部血流参数的影响。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Polak K,Petternel V,Luksch A,Krohn J,Findl O,Polska E,Schmetterer L
    BACKGROUND & AIMS: PURPOSE:To characterize the role of the endothelin system in the blood flow control of the optic nerve head and of the choroid in humans. METHODS:Two studies were performed in healthy subjects. Study 1 was a randomized, placebo-controlled, double-masked, balanced, two-way crossover design and study 2 a three way-way crossover design. In study 1 twelve healthy male subjects received endothelin (ET)-1 in stepwise increasing doses of 1.25, 2.5, and 5 ng/kg x min (each infusion step occurred over 20 minutes) coinfused with BQ123 (60 microg/kg x min) or placebo on two different study days. In study 2 twelve healthy male subjects received two doses of BQ123 (60 or 120 microg/kg x min over 60 minutes) or placebo on three different study days. Measurements of optic nerve head blood flow (ONHBF) and choroidal blood flow (ChBF) were performed with laser Doppler flowmetry in both studies. In study 2 mean flow velocity (MFV) of the ophthalmic artery was assessed with Doppler sonography. RESULTS:In study 1, ET-1 significantly decreased ONHBF (-22.8% +/- 4.3% at 5 ng/kg x min, P = 0.003 versus baseline) and ChBF (-21.7% +/- 3.2% at 5 ng/kg x min, P = 0.0001 versus baseline). The effect of the highest administered dose of exogenous ET-1 on ONHBF was significantly attenuated (P = 0.04, ANOVA) by coinfusion of BQ123. Effects of exogenous ET-1 on blood flow (2.5 ng/kg x min ET-1 or higher) also were attenuated in the choroid by coinfusion of BQ123 (ChBF: P = 0.03, ANOVA). In study 2, both dosages of BQ123 significantly increased MFV in the ophthalmic artery (60 microg/kg x min, 12.5% +/- 7.3%; 120 microg/kg x min, 17.2% +/- 9.2%, versus baseline; P = 0.001), but did not change blood flow in the ONH or the choroid. CONCLUSIONS:BQ123 antagonizes the effects of exogenously administered ET-1 on blood flow in the ONH and the choroid. The data indicate, however, that ET-1 does not substantially contribute to the regulation of basal vascular tone in these tissues.
    背景与目标: 目的:表征内皮素系统在人类视神经乳头和脉络膜的血流控制中的作用。
    方法:在健康受试者中进行了两项研究。研究1是随机的,安慰剂对照,双掩蔽,平衡的两向交叉设计,而研究2是三向交叉设计。在研究1中,十二名健康男性受试者分别以1.25、2.5和5 ng / kg x min的剂量逐步增加剂量接受内皮素(ET)-1(每个输注步骤发生在20分钟之内),并与BQ123(60 microg / kg x min)混合或在两个不同的学习日服用安慰剂。在研究2中,十二位健康的男性受试者在三个不同的研究日接受了两剂BQ123(60分钟内60或120 microg / kg x分钟)或安慰剂。在这两项研究中,均使用激光多普勒血流仪对视神经乳头血流量(ONHBF)和脉络膜血流量(ChBF)进行了测量。在研究2中,用多普勒超声检查评估了眼动脉的平均流速(MFV)。
    结果:在研究1中,ET-1显着降低了ONHBF(5 ng / kg x min时为-22.8%/-4.3%,相对于基线P = 0.003)和ChBF(5 ng / kg x时为-21.7%/-3.2%)最小值,相对于基线,P = 0.0001)。 BQ123的共融合显着减轻了最高剂量的外源ET-1对ONHBF的影响(P = 0.04,ANOVA)。 BQ123的共融合也减轻了脉络膜中外源性ET-1对血流的影响(2.5 ng / kg x min ET-1或更高)(ChBF:P = 0.03,ANOVA)。在研究2中,两种BQ123剂量均显着增加了眼动脉中的MFV(与基线相比,分别为60微克/千克x分钟,12.5%/-7.3%; 120微克/千克x分钟,17.2%/-9.2%; P = 0.001 ),但没有改变ONH或脉络膜中的血流。
    结论:BQ123拮抗外源性ET-1对ONH和脉络膜中血流的影响。然而,数据表明,ET-1在这些组织中基本无助于调节基础血管张力。
  • 【通过肾脏生物标记物N-乙酰基-β-D-氨基葡萄糖苷酶和内皮素比较等渗性和低渗性造影剂的肾脏安全性。】 复制标题 收藏 收藏
    DOI:10.1177/0003319712469094 复制DOI
    作者列表:Semerci T,Cuhadar S,Akçay FA,Aydin TK,Atay A,Köseoglu M,Bayata S
    BACKGROUND & AIMS: :Iodixanol and iopamidol are commonly used contrast agents in coronary angiography. We evaluated the nephrotoxic effects of both contrast media in relation to renal biomarkers. A total of 38 low-risk patients who underwent coronary angiography were enrolled. Patients were randomized to receive either low-osmolar nonionic monomer or isoosmolar nonionic dimer contrast medium. N-Acetyl-β-d-glucosaminidase (NAG), endothelin, blood urea nitrogen, and urine and serum creatinine (SCr) levels were measured before  the procedure (T0), at 6 hours (T6), and at 1 year after the procedure. Plasma endothelin, urine NAG/creatinine, and SCr were higher; accordingly, the urine creatinine values were lower in both the groups when comparing T0 versus T6. The groups were similar with each other when comparing T0 and T6 values. Both the contrast agents may be safely used at a low volume for coronary angiography in low-risk patients. Endothelin and NAG are sensitive to acute renal changes in function. There is a need for further prospective investigations with more patients.
    背景与目标: :碘克沙醇和碘帕醇是冠状动脉造影中常用的造影剂。我们评估了两种造影剂相对于肾脏生物标志物的肾毒性作用。共有38例接受冠状动脉造影的低危患者入组。患者被随机分配接受低渗性非离子单体或等渗性非离子二聚体造影剂。在手术前(T0),术后6小时(T6)和术后1年测量N-乙酰基-β-d-氨基葡萄糖苷酶(NAG),内皮素,血尿素氮,尿液和血清肌酐(SCr)的水平程序。血浆内皮素,尿液NAG /肌酐和SCr较高。因此,当比较T0与T6时,两组的尿肌酐值均较低。比较T0和T6值时,两组彼此相似。在低危患者中,两种造影剂均可安全地以小剂量安全地用于冠状动脉造影。内皮素和NAG对急性肾功能改变敏感。有必要对更多的患者进行进一步的前瞻性研究。
  • 【IL-33 / ST2信号传导有助于角叉菜胶诱导的先天性炎症和炎症性疼痛:细胞因子,内皮素-1和前列腺素E2的作用。】 复制标题 收藏 收藏
    DOI:10.1111/bph.12110 复制DOI
    作者列表:Zarpelon AC,Cunha TM,Alves-Filho JC,Pinto LG,Ferreira SH,McInnes IB,Xu D,Liew FY,Cunha FQ,Verri WA Jr
    BACKGROUND & AIMS: BACKGROUND AND PURPOSE:IL-33 signals through ST2 receptors and induces adaptive and innate inflammation. IL-33/ST2 is involved in adaptive inflammation-induced pain. Here, we have investigated the contribution of IL-33/ST2-triggered mechanisms to carrageenin-induced innate inflammation. EXPERIMENTAL APPROACH:Carrageenin- and IL-33-induced inflammatory responses were assessed in BALB/c- (WT) and ST2-deficient ((-/-) ) mice as follows: oedema (plethysmometer), myeloperoxidase activity (colorimetric assay), mechanical hyperalgesia (electronic version of von Frey filaments), cytokine levels (ELISA), PGE2 (RIA), mRNA expression (quantitative PCR), drug treatments targeting leukocyte recruitment (fucoidin), TNF-α (infliximab), CXCL1 (antibody to CXCL1), IL-1 (IL-1ra), endothelin ETA (clazosentan) and ETB (BQ788) receptors and COX (indomethacin). KEY RESULTS:Carrageenin injection increased ST2 and IL-33 mRNA expression and IL-33 production in paw skin samples. Carrageenin-induced paw oedema, hyperalgesia and myeloperoxidase activity were reduced in ST2(-/-) compared with WT mice, effects mimicked by IL-33 injection in the paw. Furthermore, IL-33-induced hyperalgesia was reduced by fucoidin suggesting a role for recruited leukocytes in its hyperalgesic effect. IL-33-induced hyperalgesia in naïve mice was reduced by treatments targeting TNF, CXCL1, IL-1, endothelin receptors and COX while carrageenin-induced ST2-dependent TNF-α, CXCL1, IL-1β, IL-10 and PGE2 production and preproET-1 mRNA expression. Combining IL-33 and carrageenin at doses that were ineffective as single treatment induced significant hyperalgesia, oedema, myeloperoxidase activity and cytokine production in a ST2-dependent manner. CONCLUSIONS AND IMPLICATIONS:IL-33/ST2 signalling triggers the production of inflammatory mediators contributing to carrageenin-induced inflammation. These data reinforces the importance of IL-33/ST2 signalling as a target in innate inflammation and inflammatory pain.
    背景与目标: 背景与目的:IL-33通过ST2受体发出信号,并诱导适应性和先天性炎症。 IL-33 / ST2与适应性炎症引起的疼痛有关。在这里,我们调查了IL-33 / ST2触发机制对角叉菜胶诱导的先天性炎症的贡献。
    实验方法:角叉菜胶和IL-33诱导的炎症反应在BALB / c-(WT)和ST2缺乏((-/-))小鼠中进行了如下评估:水肿(体积描记器),髓过氧化物酶活性(比色测定),机械性痛觉过敏(von Frey细丝的电子版本),细胞因子水平(ELISA),PGE2(RIA),mRNA表达(定量PCR),靶向白细胞募集的药物(岩藻糖蛋白),TNF-α(英夫利昔单抗),CXCL1(CXCL1抗体) ),IL-1(IL-1ra),内皮素ETA(clazosentan)和ETB(BQ788)受体以及COX(吲哚美辛)。
    关键结果:角叉菜胶注射液可增加爪皮肤样品中ST2和IL-33 mRNA的表达以及IL-33的产生。与野生型小鼠相比,角叉菜胶诱导的爪水肿,痛觉过敏和髓过氧化物酶活性在ST2(-/-)中降低,这种作用与在爪中注射IL-33相似。此外,岩藻糖苷可降低IL-33诱导的痛觉过敏,提示募集的白细胞在其痛觉过敏作用中起作用。通过针对TNF,CXCL1,IL-1,内皮素受体和COX的治疗,IL-33诱导的单纯性痛觉过敏减少,而角叉菜胶诱导的ST2依赖性TNF-α,CXCL1,IL-1β,IL-10和PGE2的产生以及preproET-1 mRNA表达。以单次治疗无效的剂量将IL-33和角叉菜胶组合以ST2依赖性方式诱导明显的痛觉过敏,水肿,髓过氧化物酶活性和细胞因子产生。
    结论和意义:IL-33 / ST2信号会触发炎症介质的产生,从而导致角叉菜胶引起的炎症。这些数据加强了IL-33 / ST2信号作为先天性炎症和炎性疼痛中靶标的重要性。
  • 【长期内皮素受体拮抗作用减弱了早期动脉粥样硬化患者的冠状动脉斑块进展。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijcard.2012.12.001 复制DOI
    作者列表:Yoon MH,Reriani M,Mario G,Rihal C,Gulati R,Lennon R,Tilford JM,Lerman LO,Lerman A
    BACKGROUND & AIMS: AIM:The purpose of the current study was to determine if long term treatment with an endothelin-A (ETA) receptor antagonist attenuates the progression of coronary plaques in patients with coronary endothelial dysfunction. METHODS:Thirty-five patients with non-obstructive coronary disease and coronary endothelial dysfunction were randomized in a double blind manner to treatment with placebo or ETA receptor antagonist Atrasentan (10 mg) for six months. Endothelial function was assessed by the change in coronary blood flow and coronary artery diameter in response to intracoronary acetylcholine. Normalized mean total atheroma volume (TAVMEAN), percent atheroma volume (PAV) and changes of atheroma volume were assessed by intravascular ultrasound (IVUS) at baseline and 6-month follow-up. RESULTS:In segments with coronary endothelial dysfunction, there was a significant decrease in normalized TAVMEAN and PAV at six months from baseline in the Atrasentan group compared to the placebo group median (IQR) -2.00 mm(3) (-7.28, 2.53.) vs 9.11 mm(3) (1.23, 14.05), p=0.0024 and 0.955% (-3.43, 1.70) vs 3.85% (-0.39, 14.59) p=0.010. There was no change in normalized TAV or PAV in the segments with normal endothelial function. CONCLUSION:This study demonstrates that 6-month treatment with Atrasentan attenuates progression of coronary plaque in segments with endothelial dysfunction.
    背景与目标: 目的:本研究的目的是确定长期使用内皮素-A(ETA)受体拮抗剂治疗是否能减轻冠状动脉内皮功能障碍患者的冠状动脉斑块进展。
    方法:将35例非阻塞性冠心病和冠状动脉内皮功能障碍的患者以双盲方式随机分配接受安慰剂或ETA受体拮抗剂阿曲生坦(10 mg)治疗六个月。通过响应冠状动脉内乙酰胆碱引起的冠状动脉血流量和冠状动脉直径的变化来评估内皮功能。在基线和6个月的随访中,通过血管内超声(IVUS)评估标准化平均总动脉粥样硬化体积(TAVMEAN),动脉粥样硬化体积百分比(PAV)和动脉粥样硬化体积变化。
    结果:与安慰剂组中位数(IQR)-2.00 mm(3)相比,在Atrasentan组中从基线开始六个月的冠状动脉内皮功能障碍的正常化TAVMEAN和PAV显着降低(-7.28,2.53。) vs 9.11 mm(3)(1.23,14.05),p = 0.0024和0.955%(-3.43,1.70)vs 3.85%(-0.39,14.59)p = 0.010。具有正常内皮功能的节段中的标准化TAV或PAV没有变化。
    结论:这项研究表明,阿特拉森坦治疗6个月可减轻具有内皮功能障碍的部分中冠状动脉斑块的进展。

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