内皮素及其受体拮抗剂与肿瘤

目的分析内皮素系统与肿瘤发生发展的关系,为内皮素受体成为抗肿瘤药物新的作用靶点提供依据,同时为抗肿瘤药物研究提供新思路。方法检索2000—2010年国内外医学期刊中内皮素系统与肿瘤发生发展及内皮素受体拮抗剂与肿瘤治疗的资料,综述内皮素及其受体拮抗剂与肿瘤的关系。结果内皮素受体是抗肿瘤药物新的作用靶点。结论内皮素受体拮抗剂将成为肿瘤治疗中的新型药物。     

内皮素系统与心肌肥厚

心肌肥厚是心脏对神经介质和压力超负荷等应激反应的一种代偿性机制。内皮素(ET)作为一种具有强大血管收缩作用的活性多肽,在心血管系统,特别是血管内皮细胞、平滑肌细胞和心肌细胞,ET对正常功能的调节起着重要的生理作用。局部心肌组织中ET过度生成与心肌肥厚的发生密切相关,心肌组织中的ET-1通过与特异性的受体结合,并与局部组织中其它相关的血管活性物质相互作用,介导了心肌肥厚的发生和发展过程。内皮素通过ETA受体诱导心肌细胞的肥厚和心肌成纤维细胞的增生,ETB受体则在心肌肥厚的发生和发展中均起作用。内皮素受体作为新的药物靶点,已经成为人们研究的热点,相应的受体拮抗剂的研究也取得了很大的进展。     

内皮素受体拮抗剂治疗心血管疾病的研究进展

自从1992年开发了选择型ET(endothelin,ET)受体拮抗剂BQ123,继而开发了选择型ET受体拮抗剂和非选择型ET受体拮抗剂(endothelin receptor antagonist,ETRA).通过应用内皮素受体拮抗剂,对内皮素所具有的生理作用及内皮素系统得到了更多的认识.ET对神经、内分泌、心脏、肾脏、胃肠道、呼吸道和细胞分裂增殖等都有广泛影响,并参与了诸如高血压、心力衰竭、急性心肌梗塞、动脉粥样硬化、脑血管痉挛等心血管疾病的过程[1],因此对内皮素拮抗剂的研究为这些疾病的防治开辟了一条新路径.研究表明内皮素受体拮抗剂可能是治疗心血管疾病的一种有效新药,ETRA的应用可能改变心血管疾病的治疗格局,其前景已经受到重视.     

阿魏酸钠治疗冠心病合并复杂室性心律失常疗效观察

内皮素(ET)为调节性肽类物质,在许多器官系统中都有分布,并且具有较强的生物效能.许多数据显示ET在许多疾病的病理生理学方面起作用,尤其对心血管系统疾病.随着临床医学研究的进一步深入,影响ET受体和ET生物合成的药物开发引起了人们极大的兴趣,期待建立起治疗ET相关疾病的新的方法.内皮素受体拮抗剂(ETRA)用于治疗高血压(EH)、心力衰竭、心肌缺血等方面的临床研究已屡见报道,但用于心律失常的报道少见.本研究旨在观察阿魏酸钠注射液(sodium ferulate for injection)在冠心病(CHD)所致复杂室性心律失常的临床疗效.     

硫芥染毒大鼠肺组织内皮素-1及ETAR转录表达的变化

目的　探讨内皮素 1(ET 1)和内皮素A型受体 (ETAR)在硫芥中毒后病理生理中的作用。方法应用免疫组化及逆转录 聚合酶链反应 (RT PCR)技术 ,观察大鼠硫芥中毒后肺组织ET 1和ETAR各自转录表达变化、相互关系及其与组织损伤程度的关系。结果　硫芥中毒后大鼠肺组织ET的含量明显增加 ,2h达峰值 ,但在 12h后下降到低于正常组 ;中毒后肺组织ET 1及ETAR的mRNA表达均增加 ,ET 1mRNA在 2 4h仍高于正常 ,ETARmRNA在 2 4h低于正常组。结论　ET 1及其受体ETAR在硫芥中毒后肺部病理生理进程中可能起一定作用     

内皮素受体拮抗剂治疗心血管疾病研究进展

内皮素(ET)家族包括ET-1，ET-2和ET-3。ET-1通过与血管平滑肌细胞上的特异受体结合而产生血管收缩和细胞增殖效应，其异常表达参与了多种心血管疾病如慢性心衰、高血压、肾衰、肺动脉高压、脑血管痉挛等的病理机制。ET受体包括ETA和ETB2种亚型。动物实验和临床研究表明，非选择性ETA/B拮抗剂和选择性ETA拮抗剂对多种心血管疾病有较好的治疗作用。ET及其受体拮抗剂所具有的广泛的生物学效应和独特的作用机制，为临床治疗相关疾病提供了新途径。     

新型内皮素受体拮抗剂CPU0214与正常大鼠心肌ET受体结合特点及对清醒DOCA-盐型高血压大鼠的降压作用

目的　研究新型内皮素受体拮抗剂CPU0 2 1 4与正常大鼠心肌内皮素 (ET)受体结合特点 ,对血管收缩的拮抗作用及对高血压大鼠血压的降低作用。方法　采用放射配体竞争抑制结合法和ET 1引起的胸主动脉环收缩法分别研究CPU0 2 1 4与正常大鼠心肌ET受体结合的特性和对血管收缩功能的拮抗作用 ;采用放射配体结合法观察注射醋酸脱氧皮质酮 (DO CA)和饮用盐水造成的高血压模型大鼠的心肌ET受体的改变及其股动脉平均动脉压的变化 ,研究CPU0 2 1 4的降压作用。结果　CPU0 2 1 4在正常心肌膜上竞争性结合1 2 5I ET1 ,其IC50 为1 6nmol·L-1 ;抑制ET 1所致胸主动脉环收缩。DOCA 盐型高血压大鼠表现内皮素受体的Bmax值和Kd 值升高 ;CPU0 2 1 4使清醒高血压大鼠的平均动脉压明显降低 ,在 6 0～ 90min时最为明显。结论　CPU0 2 1 4在正常大鼠竞争结合内皮素受体、拮抗血管收缩 ,在内皮素异常高血压大鼠可降低其血压 ,表明CPU0 2 1 4对治疗高血压有良好的研究价值     

内皮素受体拮抗剂治疗肺动脉高压的临床应用进展

内皮素（ET）-1是强有力的内源性血管收缩剂，在肺动脉高压的发病机制中发挥重要作用。ET受体分为两种类型：ETA和ETB。本文综述近年来非选择性ET受体拮抗剂和选择性ETA受体拮抗剂治疗肺动脉高压的临床应用进展。证明ET受体拮抗剂可以改善肺动脉高压患者的运动耐量，降低肺血管阻力，增加心输出量，改善心功能。其主要副作用是血清转氨酶增高。     

内皮素受体拮抗剂在肺动脉高压治疗中的作用

肺动脉高压(PAH)是常见的临床疾病,内皮素(ET)在PAH的发生机制中发挥了重要的作用,临床研究显示,ET受体拮抗剂治疗PAH疗效良好,该类药物可能成为治疗PAH的有效药物.     

内皮素受体拮抗剂防治消化性溃疡的研究进展

内皮素(ET)是一种血管张力调节因子,具有极强的血管活性。通过介导ET受体,发挥广泛的生物学活性。然而,ET过度表达将引起胃黏膜组织局部缺血、缺氧、酸中毒等症状,是消化性溃疡形成的重要致病因子之一。因此,ET受体拮抗剂将可能成为治疗消化溃疡的新型药物。现就ET及其受体拮抗剂在消化性溃疡的发生、发展及防治等方面的研究进展进行综述。     

Role of the endothelin axis and its antagonists in the treatment of cancer

The endothelins (ET) are a group of proteins that act through G-protein coupled receptors. Endothelin-1 (ET-1) was initially identified as a potent vasoconstrictor and dysregulation of the ET axis contributes to pathological processes responsible for cardiovascular disease states. More recently, the ET axis, in particular ET-1 acting through the endothelin A receptor (ET(A) ), has been implicated in the development of several cancers through activation of pathways involved in cell proliferation, migration, invasion, epithelial-mesenchymal transition, osteogenesis and angiogenesis. The endothelin B receptor (ET(B) ) may counter tumour progression by promoting apoptosis and clearing ET-1; however, it has recently been implicated in the development of some tumour types including melanomas and oligodendrogliomas. Here, we review emerging preclinical and clinical data outlining the role of the ET axis in cancer, and its antagonism as an attractive and challenging approach to improve clinical cancer management. Clinical data of ET(A) antagonists in patients with prostate cancer are encouraging and provide promise for new ET(A) antagonist-based treatment strategies. Given the unexpected opportunities to affect pleiotrophic tumorigenic signals by targeting ET(A)-mediated pathways in a number of cancers, the evaluation of ET-targeted therapy in cancer warrants further investigation.     

The endothelin axis: a novel target for pharmacotherapy of female malignancies

The endothelin axis (ET axis), comprising the three peptides endothelin (ET)-1, -2, -3 and their receptors ET(A)R and ET(B)R, is expressed in various cells and tissues. The biologically active ET-1 is formed by endothelin-converting enzyme (ECE) from inactive big-ET-1. ET-1 has emerged as an important peptide in a host of biological functions, including development, cellular proliferation, apoptosis and angiogenesis, thereby playing an important physiological and pathophysiological role. As these effects are mediated by ET(A)R, activation of ET(B)R prevents apoptosis, inhibits ECE expression and mediates the clearance of ET-1. Emerging data indicate that the ET axis is involved in tumourigenesis and tumour progression of various cancers. Expression of the ET axis has been demonstrated in a wide range of human tumours. Since most data have been reported for female malignancies, this review will focus on the role of the ET axis in cancers of the ovary, the cervix and the breast. In ovarian cancer, activation of ET(A)R by ET-1 is a key mechanism in the cellular signalling network promoting cancer growth and progression. Similar effects have been shown for cervical and endometrial cancer. In breast cancer, ET-1 via ET(A)R promotes proliferation and invasion, mediates bone metastases and predicts unfavourable response to chemotherapy. The outstanding role of ET-1 and ET(A)R in carcinogenesis and tumour progression has led to an extensive search for interfering agents, resulting in the development of selective ET(A)R antagonists on the one hand and inhibitors of the endothelin-converting enzyme (ECE) on the other. Targeting the ET axis via ET(A)R or ECE blockade seems to be a promising approach in the treatment of female malignancies.     

Targeting endothelin ETA and ETB receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice

Endothelin may contribute to the development of inflammatory events such as leukocyte recruitment and nociception. Herein, we investigated whether endothelin-mediated mechanical hypernociception (decreased nociceptive threshold, evaluated by electronic pressure-meter) and neutrophil migration (myeloperoxidase activity) are inter-dependent in antigen challenge-induced Th1-driven hind-paw inflammation. In antigen challenge-induced inflammation, endothelin (ET) ET(A) and ET(B) receptor antagonism inhibited both hypernociception and neutrophil migration. Interestingly, ET-1 peptide-induced hypernociception was not altered by inhibiting neutrophil migration or endothelin ET(B) receptor antagonism, but rather by endothelin ET(A) receptor antagonism. Furthermore, endothelin ET(A), but not ET(B), receptor antagonism inhibited antigen-induced PGE(2) production, whereas either selective or combined blockade of endothelin ET(A) and/or ET(B) receptors reduced hypernociception and neutrophil recruitment caused by antigen challenge. Concluding, this study advances knowledge into the role for endothelin in inflammatory mechanisms and further supports the potential of endothelin receptor antagonists in controlling inflammation.     

Pharmacological endothelin receptor interaction does not occur in veins from ET(B) receptor deficient rats

Heterodimerization of G-protein coupled receptors can alter receptor pharmacology. ET A and ET B receptors heterodimerize when co-expressed in heterologous expression lines. We hypothesized that ET A and ET B receptors heterodimerize and pharmacologically interact in vena cava from wild-type (WT) but not ET B receptor deficient (sl/sl) rats. Pharmacological endothelin receptor interaction was assessed by comparing ET-1-induced contraction in rings of rat thoracic aorta and thoracic vena cava from male Sprague Dawley rats under control conditions, ET A receptor blockade (atrasentan, 10 nM), ET B receptor blockade (BQ-788, 100 nM) or ET B receptor desensitization (Sarafotoxin 6c, 100 nM) and ET A plus ET B receptor blockade or ET A receptor blockade plus ET B receptor desensitization. In addition, similar pharmacological ET receptor antagonism experiments were performed in rat thoracic aorta and vena cava from WT and sl/sl rats. ET A but not ET B receptor blockade or ET B receptor desensitization inhibited aortic and venous ET-1-induced contraction. In vena cava but not aorta, when ET B receptors were blocked (BQ-788, 100 nM) or desensitized (S6c, 100 nM), atrasentan caused a greater inhibition of ET-1-induced contraction. Vena cava from WT but not sl/sl rats exhibited similar pharmacological ET receptor interaction. Immunocytochemistry was performed on freshly dissociated aortic and venous vascular smooth muscle cells to determine localization of ET A and ET B receptors. ET A and ET B receptors qualitatively co-localized more strongly to the plasma membrane of aortic compared to venous vascular smooth muscle cells. Our data suggest that pharmacological ET A and ET B receptor interaction may be dependent on the presence of functional ET B receptors and independent of receptor location.     

Intraportal nicotine infusion in rats decreases hepatic blood flow through endothelin-1 and both endothelin A and endothelin B receptors

Smoking has been demonstrated to aggravate liver injury. Nicotine, a major pharmacological component of tobacco smoke, affects a multitude of functions. Smoking and nicotine induce synthesis of endothelin (ET)-1. The effect of intraportal infusion of nicotine on hepatic circulation and an involvement of ET-1 and ET receptor in the action of nicotine were investigated in rats. Nicotine (0-100 microg/kg/h) was infused into the portal vein of urethane-anesthetized rats, and changes of hepatic blood flow were evaluated. Intraportal infusion of nicotine dose-dependently decreased hepatic blood flow and increased portal pressure without any alteration of heart rate or arterial blood pressure. This action of intraportal nicotine was completely abolished by pretreatment of ET-1 antibody. Either BQ485 (ET(A) receptor antagonist) or BQ788 (ET(B) receptor antagonist) partially reversed the effect of nicotine, and combination of BQ788 and BQ485 completely abolished it. These findings suggest that nicotine inhibits hepatic circulation through ET-1, and ET(A) and ET(B) receptor.     

Nonpeptide endothelin antagonists in clinical development

Endothelins (ET-1, ET-2 and ET-3) are 21-amino-acid peptides with two disulfide bonds that belong to the sarafotoxin family. ET-1, ET-2 and ET-3 are produced endogenously from preproendothelin to give big endothelins, which are cleaved by endothelin-converting enzyme (ECE) to yield the active protein. Endothelin has been shown to play important physiological and pathological roles by interacting with its G-protein-coupled receptors. There are two cloned ET receptors: the ET(A) receptor, which is selective for ET-1, and the ET(B) receptor, which binds ET-1, ET-2 and ET-3 with similar affinities. Since the discovery of endothelin, and especially since the availability of peptide ET antagonists such as BQ-123 and BQ-788, and nonpeptide compounds such as bosentan, considerable effort has been spent on better understanding the role of endothelin and its receptor antagonists. As a result, endothelin has been implicated in a variety of serious diseases, such as congestive heart failure, hypertension, pulmonary hypertension and prostate cancer. Research in pharmaceutical and biotechnology laboratories has generated many endothelin antagonists with either sulfonamide or triaryl carboxylic acid scaffolds, and a number of ET(A)-selective or nonselective ET(A)/ET(B) endothelin antagonists have entered clinical trials. This article will review the small-molecule ET(A)-selective and nonselective ET(A)/ET(B) antagonists that are under clinical evaluation, and highlight a member of this group of compounds, sitaxsentan. A summary of the medicinal chemistry that led to the identification of sitaxsentan will be presented, followed by selected animal and human clinical trial data. (c) 2001 Prous Science. All rights reserved.     

Endothelin-1 as a target for therapeutic intervention in prostate cancer

The endothelins, a family of potentvasoconstricting peptides, have beenimplicated in the pathophysiology ofadvanced prostate cancer. Two endothelinreceptors, ET-A and ET-B are found innormal prostate tissue. Malignant prostatecells are notable for the loss of ET-Breceptors and increased levels ofendothelin-1 [ET-1]; this distortion of theendothelin system may be a significantfactor in the progression of prostatecancer. Proposed roles for endothelin inprostate cancer include growth promotion,apoptosis inhibition, bone formation, andstimulation of nociceptive receptors. ET-1can act alone as a mitogen, but its effectsare greatest as a comitogen with a varietyof growth factors, including basicfibroblast growth factor, insulin-likegrowth factors, and platelet derived growthfactor. Although their exact functions areunclear, ET-1, in conjunction with vascularendothelial growth factor, appears to playa major role in tumor angiogenesis. By avariety of methods, ET-1 alters the balanceof osteoblast and osteoclasts to the favornew bone formation that is characteristicof metastatic disease. Several studiesindicate that the refractory pain ofmetastatic cancer is related to the directnociceptive effects ET-1. These findingssuggest that ET receptors are promisingtherapeutic targets for pharmacologicintervention. Early clinical trialsindicate that the ET-A receptor antagonistused in prostate cancer is reasonably welltolerated with mild but pervasive symptomsrelated to ET-1's vasoconstrictive effects. Results of ongoing clinical trials areeagerly awaited in order to see if thehypothetical promise of ET antagonism willresult in clinical success.     

Interaction and inhibitory cross-talk between endothelin and ErbB receptors in the adult heart

Endothelin-1 (ET-1) regulates contractility and growth of the mammalian heart by binding endothelin receptor type A (ET(A)) and endothelin receptor type B (ET(B)) G-protein-coupled receptors. To identify growth signaling pathways associated with ET-1 receptors in adult myocardium, a combined immunoprecipitation/proteomic analysis was performed. Signaling proteins believed to function downstream of ET(A) such as Galpha(q), phospholipase C-beta1, protein kinase C (PKC) epsilon, and PKCdelta were identified in immunoprecipitates of ET(A) by matrix-assisted laser desorption ionization/time of flight mass spectrometry. Also prominent were the growth factor receptor tyrosine kinases erbB2 and erbB4 and their downstream growth signaling effectors phosphoinositide-3 kinase (PI3 kinase), Akt, Raf-1, mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (Erk). Western blot analysis confirmed coimmunoprecipitation of erbB2/4, PI3 kinase, and Akt with ET(A), and confocal microscopy revealed their colocalization in cardiac transverse tubules (T-tubules). The erbB4 receptor ligand neuregulin-1beta (NRG1beta) promoted erbB2/4 tryosine phosphorylation and Akt serine phosphorylation in ventricular myocytes, whereas treatment with ET-1 did not. This observation argues against ET-1 growth signaling occurring via erbB2/4 transactivation in adult myocardium. ET-1 did, however, stimulate Erk1/2 phosphorylation and substantially blunted several NRG1beta-mediated actions, including erbB2/4 phosphorylation, serine phosphorylation of Akt, and negative inotropy. This inhibitory cross-talk between ET(A) and erbB2/4-Akt pathways was mimicked by a phorbol ester and blocked by pharmacological inhibition of PKC or MEK/Erk. The proteomic analysis and subsequent investigation of receptor cross-talk indicate that growth signaling between ET(A) and erbB pathways is fundamentally different in adult versus neonatal cardiac myocytes. The results may be relevant to cardiomyopathies associated with 1) prolonged exposure to ET-1; 2) degeneration of T-tubules; and 3) therapies targeted at erbB2 inhibition.     

Agonist-dependent modulation of arterial endothelinA receptor function

BACKGROUND AND PURPOSE Endothelin-1 (ET-1) causes long-lasting vasoconstrictions. These can be prevented by ET(A) receptor antagonists but are only poorly reversed by these drugs. We tested the hypothesis that endothelin ET(A) receptors are susceptible to allosteric modulation by endogenous agonists and exogenous ligands. EXPERIMENTAL APPROACH Rat isolated mesenteric resistance arteries were pretreated with capsaicin and studied in wire myographs, in the presence of L-NAME and indomethacin to concentrate on arterial smooth muscle responses. KEY RESULTS Endothelins caused contractions with equal maximum but differing potency (ET-1 = ET-2 > ET-3). ET-1(1-15) neither mimicked nor antagonized these effects in the absence and presence of ET(16-21). 4(Ala) ET-1 (ET(B) agonist) and BQ788 (ET(B) antagonist) were without effects. BQ123 (peptide ET(A) antagonist) reduced the sensitivity and relaxed the contractile responses to endothelins. Both effects depended on the agonist (pK(B): ET-3 = ET-1 > ET-2; % relaxation: ET-3 = ET-2 > ET-1). Also, with PD156707 (non-peptide ET(A) antagonist) agonist-dependence and a discrepancy between preventive and inhibitory effects were observed. The latter was even more marked with bulky analogues of BQ123 and PD156707. CONCLUSIONS AND IMPLICATIONS These findings indicate allosteric modulation of arterial smooth muscle ET(A) receptor function by endogenous agonists and by exogenous endothelin receptor antagonists. This may have consequences for the diagnosis and pharmacotherapy of diseases involving endothelins.     

BQ-788, a selective endothelin ET(B) receptor antagonist

We describe characteristics of a selective endothelin (ET) ET(B) receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine], which is widely used to demonstrate the role of endogenous or exogenous ETs in vitro and in vivo. In vitro, BQ-788 potently and competitively inhibited (125)I-labeled ET-1 binding to ET(B) receptors in human Girrardi heart cells (hGH) with an IC(50) of 1.2 nM, but only poorly inhibited the binding to ET A receptors in human neuroblastoma cell line SK-N-MC cells (IC(50), 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 showed no agonistic activity up to 10 microM and competitively inhibited the vasoconstriction induced by an ET(B)-selective agonist (pA(2), 8.4). BQ-788 also inhibited several bioactivities of ET-1, such as bronchoconstriction, cell proliferation, and clearance of perfused ET-1. Thus, it is confirmed that BQ-788 is a potent, selective ET(B) receptor antagonist. In vivo, in conscious rats, BQ-788, 3 mg/kg/h, i.v., completely inhibited a pharmacological dose of ET-1- or sarafotoxin6c (S6c) (0.5 nmol/kg, i.v.)-induced ET(B) receptor-mediated depressor, but not pressor responses. Furthermore, BQ-788 markedly increased the plasma concentration of ET-1, which is considered an index of potential ET(B) receptor blockade in vivo. In Dahl salt-sensitive hypertensive (DS) rats, BQ-788, 3 mg/kg/h, i.v., increased blood pressure by about 20 mm Hg. It is reported that BQ-788 also inhibited ET-1-induced bronchoconstriction, tumor growth and lipopolysaccharide-induced organ failure. These data suggest that BQ-788 is a good tool for demonstrating the role of ET-1 and ET(B) receptor subtypes in physiological and/or pathophysiological conditions.