内皮素受体及其拮抗剂与肺动脉高压

内皮素及其受体在左向右分流先天性心脏病肺动脉高压的发生与发展过程中起重要的作用,因此内皮素受体拮抗剂可能是一种新的治疗肺动脉高压的有效方法.     

内皮素和内皮素受体在先天性心脏病肺动脉高压发病中的作用

肺动脉高压 (ＰＨ)是肺血流增加的先心病常见的并发症。出生后 ,左向右分流的存在导致了肺血管床的功能异常和结构改变 ,以及肺动脉压的增加。正常的肺血管张力和血管平滑肌增殖或凋亡是由血管内皮细胞局部产生的活性物质及其复杂的相互作用来调节的。继发于肺血流增加和 /或压力增加的内皮损伤干扰了这种机制 ,成为ＰＨ发病的重要始动因素。1988年 ,日本学者Ｙａｎａｇｉｓａｗａ等人从内皮细胞中分离出一种 2 1氨基酸组成的多肽 ,命名为内皮素(ＥＴ) ,有强有力的缩血管和促血管平滑肌增殖的作用 ,心血管系统的内皮素含量居全身各系统组织…     

内皮素受体及其拮抗剂与肺动脉高压

内皮素及其受体在左向右分流先天性心脏病肺动脉高压的发生与发展过程中起重要的作用,因此内皮素受体拮抗剂可能是一种新的治疗肺动脉高压的有效方法.     

内皮素-1在肺动脉高压发病机制中的研究进展

内皮素-1是一种作用强、持续时间长的血管收缩物质.内皮素-1不仅可作用于肺血管的内皮细胞、平滑肌细胞、成纤维细胞,参与肺动脉高压的发生,还可通过参与炎性反应与免疫、线粒体代谢异常等过程,在肺动脉高压的发病机制中发挥重要作用.     

内皮素受体拮抗剂治疗肺动脉高压的研究进展

肺动脉高压（PAH）是一种在中国发病率及病死率都较高的疾病。可根据其病因是否明确而分为特发性和继发性两大类。内皮素（ET）是引起细胞增殖的重要物质,抑制其作用具有控制PAH的作用。现已发现ET有ET-1,ET-2和ET-3三类,肺是ET-1作用和代谢最重要的器官。随着有关ET与PAH关系研究的不断深入,为临床应用内皮素受体拮抗提供了理论基础。理想的内皮素受体拮抗剂应特异性地针对ETA受体,而保留ETB受体的舒张血管和清除ET-1的作用。目前一些内皮素受体拮抗剂已上市或进入Ⅲ期临床试验阶段。所以,ET参与低氧性肺动脉高压和肺血管重构的形成,阻断ET与其受体结合的内皮素拮抗剂对低氧性肺动脉高压具有较好的预防和治疗作用。     

内皮素受体拮抗剂在肺动脉高压中的应用

肺动脉高压是指静息时肺动脉平均压>25 mm Hg(1 mm Hg=0.133 3 kPa)或者运动时肺动脉平均压≥30 mm Hg。随着肺动脉高压发病机制的研究进展,针对细胞增生和血管重塑的治疗大大改善了肺动脉高压的预后。现就内皮素受体拮抗剂在肺动脉高压中的应用进行综述。     

内皮素受体拮抗剂治疗肺动脉高压进展

肺动脉高压是一种以肺血管阻力升高最终导致右心衰竭的严重的症候群.内皮素在其发生、发展过程中起着重要作用,目前已经认识到内皮素受体拈抗剂对治疗肺动脉高压具有一定疗效.但仍需对其疗效和安全性进行进一步研究.本文将对近年内皮素受体拮抗剂治疗肺动脉高压的研究进展作一综述.     

双重内皮素受体拮抗剂在治疗肺动脉高压中的作用

肺动脉高压（pulmonary arterial hypertension,PAH）是指在海平面静息状态下,平均肺动脉压≥25 mm Hg（1 mm Hg=0.133 kPa）,且肺毛细血管楔压≤15 mm Hg的疾病状态。PAH通常为进展性,是严重危害人们健康与生命的疾病。各研究报道PAH发病率的差异很大。     

内皮素受体拮抗剂预防低氧性肺动脉高压的实验研究

内皮细胞合成的内皮素(ＥＴ)具有极强的促肺血管平滑肌细胞收缩和增生的作用。慢性低氧可引起血浆及肺组织匀浆中ＥＴ1水平升高,ＥＴ通过与ＥＴ1选择性受体(ＥＴＡ)或非选择性受体(ＥＴＢ)结合,参与慢性低氧性肺动脉高压的发病过程。为进一步探讨ＥＴ在低氧性肺动脉高压发病中的作用,本研究采用ＥＴＡ受体拮抗剂ＢＱ123进行预防处理,观察其对低氧性肺动脉高压的预防效应。一、材料和方法1动物模型的复制:雄性Ｗｉｓｔａｒ大鼠30只,体重200～220ｇ。分为低氧组、ＢＱ123组和对照组,每组10只。低氧组:将大鼠置于自制常压低氧舱内,向舱内充入氮…     

肺动脉高压的发病机制探讨

正常肺循环是一种低压、高容量循环。肺血管阻抗被氧分压、钾离子通道和一系列的局部及循环血管活性物质(如：内皮素、一氧化氮及血管内皮细胞生长因子等)调节。这些系统的混乱将导致肺动脉高压发生。原发性肺动脉高压是一种威胁生命的疾病，伴有进展性右心衰竭。继发性肺动脉高压继发于各种心肺疾患，目前是危害人类健康的主要疾病之一。本文综述了近年来对于肺动脉高压发病机制的新观点、新进展，并对肺血管和体血管进行比较研究，有助于深入理解肺动脉高压发病机制，指导临床治疗。     

血管内皮生长因子和内皮素在低氧性肺血管重建中的作用

目的探讨血管内皮生长因子(VEGF)和内皮素(ET)-1在低氧性肺动脉高压(HPH)及其肺血管重建中的作用,并观察钾通道开放剂(pinacidil)对HPH的防治作用及对VEGF和ET-1的影响.方法Wister大鼠46只,随机分为3组,对照组15只,低氧组16只,治疗组15只.缺氧组和治疗组大鼠缺氧[氧浓度为(10.0±0.5)%]4周,每天缺氧8h,其中治疗组大鼠于每天缺氧前腹腔注射pinacidil3mg/kg.缺氧4周后测定各组大鼠血清VEGF和血浆ET-1水平、平均肺动脉压(mPAP)、右心室(RV)/[左心室(LV)+室间隔(S)]比值及肺小动脉病理及其形态计量学.结果(1)缺氧组大鼠血清VEGF[(118.73±55.40)ng/L]和血浆ET-1[(221.2±56.2)ng/L]水平明显高于对照组(P＜0.01);缺氧组较对照组mPAP升高,RV/(LV+S)比值增高,肺小动脉血管壁显著增厚,管腔明显狭窄.(2)治疗组大鼠血清VEGF[(78.20±16.45)ng/L]和血浆ET-1[(181.6±30.5)ng/L]水平明显低于缺氧组(P＜0.01);治疗组较缺氧组mPAP下降(P＜0.01),肺小动脉血管壁增厚、管腔狭窄等明显减轻,但治疗组上述各指标仍未完全恢复到对照组水平.结论VEGF和ET-1在HPH及其肺血管重建中发挥重要作用,钾通道开放剂对HPH及其肺血管重建具有一定的逆转作用.     

Etiology-specific endothelin-1 clearance in human precapillary pulmonary hypertension

STUDY OBJECTIVES: Endothelin (ET)-1 is a mediator of vascular remodeling seen in human pulmonary hypertension (PH), and it is normally cleared via endothelial ET-B receptors. Increased levels of ET-1 are found in precapillary PH, partly from increased synthesis. We hypothesized that the endothelial dysfunction and vascular remodeling seen in human precapillary PH would also reduce ET-1 clearance. DESIGN AND SETTING: Case series from a single institutional PH center. PATIENTS: Thirty-four patients with pulmonary arterial hypertension (PAH; idiopathic [IPAH], n = 19; connective tissue disease [CTD], n = 15) and 11 patients with chronic thromboembolic PH were studied. MEASUREMENTS AND RESULTS: Using indicator dilution methods, the first-pass extraction of radiolabeled ET-1 through the pulmonary circulation, and permeability surface (PS) area, an index of functional microvascular surface available for ET-1 clearance, were determined. Mean extraction for IPAH and thromboembolic PH groups was normal, but it was reduced in PAH from CTD; 69% of all patients studied had normal extraction. The mean PS product was reduced significantly for all three etiologies as compared to normal, but 58% of IPAH patients and 40% of CTD-related PAH patients had normal PS products. CONCLUSIONS: Receptor-mediated ET-1 extraction and functional vascular surface area for clearance vary between etiologies of PAH. However, contrary to our hypothesis, endothelial ET-B receptor-mediated extraction is preserved in many patients. The scientifically significant finding of our study is that high ET-1 levels seen in patients with PAH must be predominantly due to excess synthesis rather than reduced clearance. The finding that endothelial ET-B receptors are still present and functional in PAH may also be of relevance to the choice of selective vs nonselective ET receptor antagonists.     

Analysis of endothelin-1 and endothelin-1 receptor A gene polymorphisms in patients with pulmonary arterial hypertension

This study analyses the frequency and the potential role of two polymorphisms, the +134del/insA, located in the gene encoding for Endothelin-1 (EDN1), and the His323His in the gene encoding for Endothelin receptor type A (EDNRA) in a cohort of 98 consecutive patients with pulmonary arterial hypertension from two different Cardiology Units (Mid-South of Italy), and in 100 healthy Caucasian subjects randomly recruited from the same area. Cardiac anatomy and function were analysed by non invasive diagnostic imaging techniques (Echocardiography standard m-mode, 2D, colour-Doppler) and by invasive studies (cardiac catheterization). Molecular screening of the region of interest was performed by automated sequencing. At univariate analysis, patients with the His323His TT genotype show a lower cardiac index (2 ± 0.6 vs. 2.3 ± 0.6; p = 0.05) and a higher indexed pulmonary vascular resistance (18.8 ± 9.6 vs. 14.2 ± 6.9; p = 0.01) at cardiac catheterization. A logistic multivariate model shows idiopathic disease (p = 0.01; OR = 3.8; CI = 1.3-11) and indexed pulmonary vascular resistances (p = 0.01; OR = 1.1; CI = 1-1.2) as independent predictors of TT genotype. Our findings may suggest a potential link between specific genotypes in the EDNRA gene and susceptibility for PAH.     

Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension.

STUDY OBJECTIVES: Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology that is characterized by a poor prognosis. This study was undertaken to investigate possible correlations between endothelin (ET)-1 and big ET-1 plasma levels and the severity of PPH. PATIENTS: Sixteen consecutive patients with PPH were included. INTERVENTIONS: Hemodynamics of patients with PPH were measured by right-heart catheterization, and a 6-min walk test was performed. MEASUREMENTS: Plasma levels of the biologically active peptide ET-1 and its precursor big ET-1 were determined in blood samples from the pulmonary artery, peripheral artery, and peripheral vein by radioimmunoassay. RESULTS: A strong correlation was shown between pulmonary vascular resistance, mean pulmonary artery pressure, cardiac output, cardiac index, 6-min walk data, and elevated plasma levels of big ET-1 as well as mature ET-1 plasma levels at all sites of blood sampling (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: Levels of circulating ET-1 might become a prognostic marker for patients with PPH and serve as a tool for the selection of patients who may benefit from treatment with ET-receptor antagonists.     

Netrin-1及其受体在脑缺血中的作用

以netrin-1为代表的netrin家族是目前最受关注的轴突导向因子之一.在胚胎发育期,netrin-1通过吸引/排斥的双重机制对轴突生长和细胞迁移发挥导向作用.同时,netrin-1也在成年神经系统中广泛表达,并参与成年神经系统损伤后的结构和功能重塑.文章综述了netrin-1在缺血性脑损伤中的作用.     

The role of endothelin-1 in human hypertension

Endothelin-1 (ET-1) is a powerful vasoconstrictor and mitogen that contributes to blood pressure elevation and related vascular remodeling and target organ damage. ET-1 also influences salt and water homeostasis through effects on the renin-angiotensin-aldosterone system and vasopressin, thus elevating blood pressure and increasing vascular tone. Circulating ET-1 levels are elevated in a variety of animal models of hypertension, particularly those that are salt-dependent, and in a subset of human hypertensives, i.e. African-Americans and those with renal dysfunction. ET type B receptors, which normally have vasodilator functions, mediate vasoconstriction in some hypertensives, and hypertensive African-American patients may have increased numbers of vasoconstrictor ET-B receptors in their vascular smooth muscle. Whether selective ET-A or combined ET-A/ET-B receptor antagonists are more efficacious in treating hypertension and related cardiovascular disease is controversial. ET antagonists have only modest BP lowering effects in the general population of essential hypertensives, but show promise in patients with severe, treatment resistant hypertension.     

Hemodynamic and clinical correlates of endothelin-1 in chronic thromboembolic pulmonary hypertension.

BACKGROUND: In non-thromboembolic pulmonary hypertension, endothelin (ET)-1 levels are increased and correlate with the hemodynamic severity of the disease. Whether such correlations exist in chronic thromboembolic pulmonary hypertension (CTEPH) is unknown, nor whether ET-1 levels correlate with hemodynamic outcome after pulmonary endarterectomy (PEA). METHODS AND RESULTS: ET-1 levels were determined by ELISA. ET-levels were increased in 35 CTEPH patients (1.62+/-0.21 pg/ml) compared with healthy controls (n=11: 0.75+/-0.06 pg/ml, p<0.02). ET-1 levels correlated (all p<0.0001) with mean pulmonary artery pressure (mPAP) (r=0.70), cardiac index (r=-0.76), total pulmonary resistance (r=0.72), mixed venous oxygen saturation (r=-0.87), and the distance walked in the 6-min walk test (r=-0.59; p<0.005; n=23). Three months after PEA, ET-1 levels had decreased (p<0.002), and were similar between patients with and without residual pulmonary hypertension (p=0.4). Preoperative ET-1 levels, however, were higher in patients with bad postoperative outcome; that is, patients who either died because of persistent pulmonary hypertension or had residual pulmonary hypertension after PEA (2.68+/-0.48 pg/ml, and 1.13+/-0.15 pg/ml, respectively; p<0.002). The levels also correlated with hemodynamic outcome after PEA (mPAP: r=0.67, p<0.0001). By receiver-operator characteristic curve analysis, ET-1>1.77 pg/ml detected a bad postoperative outcome with a sensitivity and specificity of 79% and 85%, respectively, and a likelihood ratio of 5.2. CONCLUSION: ET-1 levels in CTEPH closely correlated with the hemodynamic and clinical severity of disease in a large cohort of patients. Preoperative ET-1 levels may be useful for better identification of patients at risk for persistent pulmonary hypertension after PEA.