endothelin receptors


Summary: Cell surface proteins that bind ENDOTHELINS with high affinity and trigger intracellular changes which influence the behavior of cells.

Top Publications

  1. Huang L, He J, Yuan B, Cao Y. Lipid soluble smoke particles upregulate endothelin receptors in rat basilar artery. Toxicol Lett. 2010;197:243-55 pubmed publisher
    ..Additionally, the p38 pathway seems to be involved in the feedback regulation of the ET(A) receptor...
  2. Takaoka S, Faul J, Doyle R. Current therapies for pulmonary arterial hypertension. Semin Cardiothorac Vasc Anesth. 2007;11:137-48 pubmed
    ..The authors review this topic and provide an outline of the general pathophysiology of RHF and an approach to its management. ..
  3. Kohan D. Biology of endothelin receptors in the collecting duct. Kidney Int. 2009;76:481-6 pubmed publisher
    ..This brief review will describe our current state of knowledge about this complex regulatory system in the collecting duct, and will identify clinically relevant issues that need addressing. ..
  4. Li N, Jia N, Dai D, Dai Y. Endothelin receptor antagonist CPU0213 and vitamin E reverse downregulation of FKBP12.6 and SERCA2a: a role of hyperphosphorylation of PKCepsilon. Eur J Pharmacol. 2008;591:211-8 pubmed publisher
    ..Thus by testing with biomarkers FKBP12.6 and SERCA2a, we have shown that the endothelin receptor antagonist CPU0213 and the antioxidant vitamin E may relieve risk of lethal arrhythmias and heart failure by suppressing PKCvarepsilon. ..
  5. McGoon M, Frost A, Oudiz R, Badesch D, Galie N, Olschewski H, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest. 2009;135:122-129 pubmed publisher
    ..Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities. Clinicaltrials.gov Identifier NCT00423592. ..
  6. Khimji A, Rockey D. Endothelin--biology and disease. Cell Signal. 2010;22:1615-25 pubmed publisher
    ..Here, we review the cell and molecular biology as well as the prominent pathophysiological aspects of the endothelin system. ..
  7. Dupuis J, Hoeper M. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J. 2008;31:407-15 pubmed publisher
  8. Feng Y, Tang X, Dai D, Dai Y. Reversal of isoproterenol-induced downregulation of phospholamban and FKBP12.6 by CPU0213-mediated antagonism of endothelin receptors. Acta Pharmacol Sin. 2007;28:1746-54 pubmed
    ..This study demonstrates a role of ET in mediating the downregulation of the cardiac Ca2+-handling protein by ISO. ..
  9. Galie N, Olschewski H, Oudiz R, Torres F, Frost A, Ghofrani H, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117:3010-9 pubmed publisher
    ..Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities. ..

More Information


  1. Antus B, Sebe A, Fillinger J, Jeney C, Horvath I. Effects of blockade of the renin-angiotensin and endothelin systems on experimental bronchiolitis obliterans. J Heart Lung Transplant. 2006;25:1324-9 pubmed
    ..Interruption of both pathways provides superior graft protection as compared with single-system blockade. ..
  2. Mano Y, Usui T, Kamimura H. Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2. Biopharm Drug Dispos. 2007;28:13-8 pubmed
    ..Collectively, these results suggest that bosentan inhibits BSEP in humans with a similar potency to rats, and that increased bile salt-independent flow in rats by bosentan is at least partly attributable to the activation of Mrp2...
  3. Adriaenssens T, Delcroix M, Van Deyk K, Budts W. Advanced therapy may delay the need for transplantation in patients with the Eisenmenger syndrome. Eur Heart J. 2006;27:1472-7 pubmed
    ..However, we might suggest with these data that the need for heart-lung transplantation can be substantially delayed with new drugs. ..
  4. Opitz C, Ewert R, Kirch W, Pittrow D. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter?. Eur Heart J. 2008;29:1936-48 pubmed publisher
    ..These characteristics bear more relation to the chemical or pharmacological properties of the drugs than to receptor selectivity itself. ..
  5. Galie N, Brundage B, Ghofrani H, Oudiz R, Simonneau G, Safdar Z, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-903 pubmed publisher
    ..In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening. ..
  6. Benza R, Barst R, Galie N, Frost A, Girgis R, Highland K, et al. Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival. Chest. 2008;134:775-82 pubmed publisher
    ..At 1 year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy. ..
  7. Cheng Y, Dai D, Dai Y. Stress-induced cardiac insufficiency relating to abnormal leptin and FKBP12.6 is ameliorated by CPU0213, an endothelin receptor antagonist, which is not affected by the CYP3A suppressing effect of erythromycin. J Pharm Pharmacol. 2009;61:569-76 pubmed publisher
    ..CPU0213 improved isoprenaline-induced cardiomyopathy by modulating ETA, leptin and FKBP12.6. However, erythromycin increased plasma levels but did not change its effects. ..
  8. Barst R. A review of pulmonary arterial hypertension: role of ambrisentan. Vasc Health Risk Manag. 2007;3:11-22 pubmed
    ..The demonstration of clinical efficacy, low incidence of acute hepatic toxicity, and low risk of drug-drug interactions support the role of ambrisentan for the treatment of PAH. ..
  9. Opitz C, Ewert R. Dual ET(A)/ET(B) vs. selective ET(A) endothelin receptor antagonism in patients with pulmonary hypertension. Eur J Clin Invest. 2006;36 Suppl 3:1-9 pubmed
    ..When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ET(A) receptor antagonism. ..
  10. Benza R, Mehta S, Keogh A, Lawrence E, Oudiz R, Barst R. Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan. J Heart Lung Transplant. 2007;26:63-9 pubmed
    ..Overall, sitaxsentan was well tolerated. Sitaxsentan may represent a safe and efficacious alternative endothelin receptor antagonist for patients discontinuing bosentan. ..
  11. Liu C, Chen J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev. 2006;:CD004434 pubmed
    ..Additional assessment of this outcome is important in order to establish whether there is evidence that ERAs have an impact on the risk of death. Longer studies are required. ..
  12. Peng H, Dai D, Ji H, Dai Y. The separate roles of endothelin receptors participate in remodeling of matrix metalloproteinase and connexin 43 of cardiac fibroblasts in maladaptive response to isoproterenol. Eur J Pharmacol. 2010;634:101-6 pubmed publisher
    ..RT-PCR and Western blotting were conducted. Upregulation of the two endothelin receptors, MMP-2/9 and NADPH oxidase subunits (p22phox and p47phox), and downregulation of connexin 43 in cardiac ..
  13. Battistini B, Berthiaume N, Kelland N, Webb D, Kohan D. Profile of past and current clinical trials involving endothelin receptor antagonists: the novel "-sentan" class of drug. Exp Biol Med (Maywood). 2006;231:653-95 pubmed
    ..This review is intended to provide a useful reference for those interested in the current state of clinical trials involving ERAs, and to identify lessons that might apply to the design of future trials. ..
  14. Hiramoto Y, Shioyama W, Kuroda T, Masaki M, Sugiyama S, Okamoto K, et al. Effect of bosentan on plasma endothelin-1 concentration in patients with pulmonary arterial hypertension. Circ J. 2007;71:367-9 pubmed
    ..The present study is the first study to show that bosentan administration increases plasma ET-1 in patients with PAH. The response of plasma ET-1 to bosentan administration might be useful for determining the severity of PAH. ..
  15. Khodorova A, Montmayeur J, Strichartz G. Endothelin receptors and pain. J Pain. 2009;10:4-28 pubmed publisher
    ..that mimic neuropathic and inflammatory pain and are all reduced by local administration of antagonists of endothelin receptors. Many effects of endogenously released endothelin are simulated by acute, local subcutaneous administration ..
  16. Feng Y, Dai D, Na T, Cui B, Wang T, Zhang Y, et al. Endothelin receptor antagonist CPU0213 suppresses ventricular fibrillation in L-thyroxin induced cardiomyopathy. Pharmacol Rep. 2007;59:306-14 pubmed
    ..In conclusion, an activated ET receptor signaling plays a role in the progression of augmented VF in association with abnormal expression of ion channels in both sarcolemma and sarcoplasmic reticulum in the CM. ..
  17. Macchia A, Marchioli R, Marfisi R, Scarano M, Levantesi G, Tavazzi L, et al. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am Heart J. 2007;153:1037-47 pubmed
    ..Although confirming the limited benefits in clinical end points documented by each trial, the overview fails to support a significant survival advantage and does not support the predictive power of surrogate end points. ..
  18. Galie N, Beghetti M, Gatzoulis M, Granton J, Berger R, Lauer A, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114:48-54 pubmed
    ..In this first placebo-controlled trial in patients with Eisenmenger syndrome, bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation. ..
  19. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-36 pubmed
  20. Sitbon O, Badesch D, Channick R, Frost A, Robbins I, Simonneau G, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. 2003;124:247-54 pubmed
    ..Overall, bosentan treatment was well tolerated. No patient underwent transplantation or died. Long-term treatment with bosentan is safe and has sustained benefits on exercise capacity and hemodynamics in patients with PAH. ..
  21. Kuklin V, Kirov M, Evgenov O, Sovershaev M, Sjöberg J, Kirova S, et al. Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep. Crit Care Med. 2004;32:766-73 pubmed
    ..To evaluate the cardiopulmonary effects of the novel endothelin receptor antagonist tezosentan in endotoxin-induced lung injury in sheep and to assess the dose response to tezosentan and endothelin-1 in healthy sheep...
  22. Frost A, Langleben D, Oudiz R, Hill N, Horn E, McLaughlin V, et al. The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect. Vascul Pharmacol. 2005;43:36-9 pubmed
    ..The magnitude of the treatment effect and statistical power when using 6MW as the endpoint. Comparisons between PAH trials that do not adjust for the effects of differing enrollment criteria require caution. ..
  23. Teerlink J. The development of new medical treatments for acute decompensated heart failure. Heart Fail Monit. 2002;2:129-37 pubmed
    ..These three agents represent a new generation of therapeutics for this important medical problem and may provide the means not only to treat symptoms, but also to improve longer-term clinical outcomes. ..
  24. Widlitz A, Barst R, Horn E. Sitaxsentan: a novel endothelin-A receptor antagonist for pulmonary arterial hypertension. Expert Rev Cardiovasc Ther. 2005;3:985-91 pubmed
    ..Initial studies using the selective oral endothelin-A receptor antagonist sitaxsentan in pulmonary arterial hypertension patients have revealed a favorable risk-benefit therapeutic profile with the 100 mg once-daily dose. ..
  25. Sitbon O, Gressin V, Speich R, Macdonald P, Opravil M, Cooper D, et al. Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;170:1212-7 pubmed
  26. Black S, Mata Greenwood E, Dettman R, Ovadia B, Fitzgerald R, Reinhartz O, et al. Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow. Circulation. 2003;108:1646-54 pubmed
    ..These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow. ..
  27. Wilkins M, Paul G, Strange J, Tunariu N, Gin Sing W, Banya W, et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292-7 pubmed
    ..008). Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained. ..
  28. Boivin B, Chevalier D, Villeneuve L, Rousseau E, Allen B. Functional endothelin receptors are present on nuclei in cardiac ventricular myocytes. J Biol Chem. 2003;278:29153-63 pubmed
    ..Western blot analysis of nuclei isolated from the heart indicated the presence of endothelin receptors: both ETAR and ETBR copurified with nucleoporin 62, whereas markers of endoplasmic reticulum and Golgi ..
  29. Nohria A, Garrett L, Johnson W, Kinlay S, Ganz P, Creager M. Endothelin-1 and vascular tone in subjects with atherogenic risk factors. Hypertension. 2003;42:43-8 pubmed
    ..These results indicate that ET-1 contributes more to the pathophysiology of hypertension than of other risk factors in subjects without overt atherosclerosis. ..
  30. Langleben D, Hirsch A, Shalit E, Lesenko L, Barst R. Sustained symptomatic, functional, and hemodynamic benefit with the selective endothelin-A receptor antagonist, sitaxsentan, in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. 2004;126:1377-81 pubmed
    ..Long-term selective ET-A blockade with sitaxsentan sodium is safe and may improve exercise capacity, functional class, and hemodynamics in patients with PAH. ..
  31. Oudiz R, Barst R, Hansen J, Sun X, Garofano R, Wu X, et al. Cardiopulmonary exercise testing and six-minute walk correlations in pulmonary arterial hypertension. Am J Cardiol. 2006;97:123-6 pubmed
    ..Weight adjustment of the 6MW improved its correlation with peak VO2. In conclusion, in future multicenter trials, CPET expertise should be validated at all sites before subject enrollment. ..
  32. Hoeper M, Dinh Xuan A. Combination therapy for pulmonary arterial hypertension: still more questions than answers. Eur Respir J. 2004;24:339-40 pubmed
  33. Hubloue I, Biarent D, Abdel Kafi S, Bejjani G, Melot C, Naeije R, et al. Endothelin receptor blockade in canine oleic acid-induced lung injury. Intensive Care Med. 2003;29:1003-1006 pubmed publisher
  34. Sharma S, Kashour T, Philipp R. Secondary pulmonary arterial hypertension: treated with endothelin receptor blockade. Tex Heart Inst J. 2005;32:405-10 pubmed
    ..This case series suggests a role for endothelin receptor blockade therapy in SPAH and should generate further interest in pharmacologic management of SPAH. A prospective controlled clinical trial of bosentan in SPAH is urgently needed. ..
  35. Cheng J. Tezosentan in the management of decompensated heart failure. Cardiol Rev. 2005;13:28-34 pubmed
    ..Clinical studies demonstrated mixed results for tezosentan regarding its efficacy and tolerability in the management of decompensated heart failure. The role or tezosentan in treating heart failure is yet to be defined. ..
  36. Shirai N, Naruko T, Ohsawa M, Ikura Y, Sugama Y, Hirayama M, et al. Expression of endothelin-converting enzyme, endothelin-1 and endothelin receptors at the site of percutaneous coronary intervention in humans. J Hypertens. 2006;24:711-21 pubmed
    ..The increased expression of the ET system may contribute to SMC proliferation/migration and vasoconstriction in human post-PCI coronary lesions. ..
  37. Cernacek P, Stewart D, Monge J, Rouleau J. The endothelin system and its role in acute myocardial infarction. Can J Physiol Pharmacol. 2003;81:598-606 pubmed
    ..Acute use of short-acting ET receptor antagonists in patients with AMI complicated by an acute heart failure is an attractive possibility that also remains to be investigated. ..
  38. Dingemanse J, van Giersbergen P. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43:1089-115 pubmed
    ..In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan. ..
  39. Barst R, Langleben D, Frost A, Horn E, Oudiz R, Shapiro S, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:441-7 pubmed
    ..02 for each parameter at both doses). The incidence of elevated aminotransferase values (> three times normal) was 3% for the placebo group, 0% for the 100-mg group, and 10% for the 300-mg group. ..
  40. Bonderman D, Nowotny R, Skoro Sajer N, Jakowitsch J, Adlbrecht C, Klepetko W, et al. Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest. 2005;128:2599-603 pubmed
    ..Our study suggests a beneficial effect of the oral dual ET receptor antagonist bosentan in patients with inoperable CTEPH, urging the need for a randomized, placebo-controlled trial. ..
  41. Clozel M, Salloukh H. Role of endothelin in fibrosis and anti-fibrotic potential of bosentan. Ann Med. 2005;37:2-12 pubmed
    ..dual endothelin receptor antagonist, which competitively antagonizes the binding of endothelin to both endothelin receptors ETA and ETB...
  42. Apostolopoulou S, Rammos S. Sitaxsentan in pulmonary arterial hypertension. Chest. 2003;123:1772; author reply 1772-3 pubmed
  43. Minchenko A, Stevens M, White L, Abatan O, Komjati K, Pacher P, et al. Diabetes-induced overexpression of endothelin-1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP-ribose) polymerase activation. FASEB J. 2003;17:1514-6 pubmed
    ..PARP inhibitors could provide a novel therapeutic approach for diabetic complications including nephropathy, and other diseases that involve the endothelin system. ..
  44. Torre Amione G, Young J, Colucci W, Lewis B, Pratt C, Cotter G, et al. Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2003;42:140-7 pubmed
    ..The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is <50 mg/h. ..
  45. Suleman N, Frost A. Transition from epoprostenol and treprostinil to the oral endothelin receptor antagonist bosentan in patients with pulmonary hypertension. Chest. 2004;126:808-15 pubmed
    ..No long-term adverse events were associated with failed transition attempts. Further studies need to be carried out to determine which patients are more likely to undergo the transition successfully. ..
  46. Yang L, Gros R, Kabir M, Sadi A, Gotlieb A, Husain M, et al. Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice. Circulation. 2004;109:255-61 pubmed
    ..These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death. ..
  47. Rossi P, Wanecek M, Konrad D, Oldner A. Tezosentan counteracts endotoxin-induced pulmonary edema and improves gas exchange. Shock. 2004;21:543-8 pubmed
    ..These results suggest that endothelin is involved in endotoxin-induced lung injury and the development of pulmonary edema. Dual endothelin receptor antagonism may be of value in the treatment of sepsis-related acute lung injury. ..
  48. Johnström P, Fryer T, Richards H, Harris N, Barret O, Clark J, et al. Positron emission tomography using 18F-labelled endothelin-1 reveals prevention of binding to cardiac receptors owing to tissue-specific clearance by ET B receptors in vivo. Br J Pharmacol. 2005;144:115-22 pubmed
    ..Under conditions of ET(B) receptor blockade, the heart could be visualised by microPET imaging.These results suggest that clearance by ET(B) receptors in the lung and kidney prevents binding of ET-1 to receptors in the heart. ..
  49. Teerlink J, McMurray J, Bourge R, Cleland J, Cotter G, Jondeau G, et al. Tezosentan in patients with acute heart failure: design of the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Study (VERITAS). Am Heart J. 2005;150:46-53 pubmed
    ..Thus, the VERITAS program will provide valuable insights into the effect of tezosentan on clinical outcomes in patients with AHF, as well as hemodynamics and clinical symptoms. ..
  50. Adur J, Takizawa S, Quan J, Uchide T, Saida K. Increased gene expression and production of murine endothelin receptors after birth. Biochem Biophys Res Commun. 2003;305:700-6 pubmed
    ..These findings were corroborated through observation of the correlation between the gene expression and (poly)peptide production of the ET system in normal skin before and after parturition. ..
  51. Torbidoni V, Iribarne M, Ogawa L, Prasanna G, Suburo A. Endothelin-1 and endothelin receptors in light-induced retinal degeneration. Exp Eye Res. 2005;81:265-75 pubmed
    ..After light-induced degeneration of photoreceptors, endothelinergic molecules were overexpressed at the RPE and astrocytes, but mostly disappeared from the OPL. ..
  52. Southwood M, Mackenzie Ross R, Kuc R, Hagan G, Sheares K, Jenkins D, et al. Endothelin ETA receptors predominate in chronic thromboembolic pulmonary hypertension. Life Sci. 2016;159:104-110 pubmed publisher
    ..Our aim in this study was to identify the presence of endothelin receptors in patients with CTEPH by analysing tissue removed at pulmonary endarterectomy...
  53. Jesmin S, Maeda S, Mowa C, Zaedi S, Togashi H, Prodhan S, et al. Antagonism of endothelin action normalizes altered levels of VEGF and its signaling in the brain of stroke-prone spontaneously hypertensive rat. Eur J Pharmacol. 2007;574:158-71 pubmed
    ..Endothelin receptor blocker might be important to prevent the progression in the defect in VEGF and its angiogenic signaling cascade in the pathogenesis of hypertension-induced vascular remodeling in frontal cortex of SHRSP rats. ..