Abstract

Endothelins are endothelial peptides, the properties of which have been investigated for over 25 years. They play a special role in the pathophysiology of many diseases of the cardiovascular system. Endothelin-1, which is the most explored one, is a potent vasoconstrictor. It increases renal water and sodium excretion, augments cell growth and proliferation and has proinflammatory activity, by intensifying the production of reactive oxygen and nitrogen species (ROS and RNS). ET-1 takes part in the progression of such diseases as hypertension, atherosclerosis, heart and renal failure. The physio- and pathological effects of endothelins are mediated through ETA and ETB receptors. Blocking these receptors, in particular the ETA receptor, can prevent negative effects of endothelins. Long-term efforts to create drugs which act like that have brought relevant results. Endothelin receptor antago-nists (ERA) are a new class of medicines, which are indicated in the treatment of pulmonary arterial hypertension. There are also optimistic results of trials with ERA administered in other disorders. On the basis of these data we may conclude that there will be more indications for this group of drugs. This review discusses properties and new research directions of ERA registered in pharmacotherapy.

References

• 1. Corallo C., Pecetti G., Iglarz M., Volpi N., Franci D., Montella A., D’Onofrio F., Nuti R., Giordano N.: Macitentan slows down the dermalfibrotic process in systemic sclerosis: in vitro findings. J. Biol. Regul.Homeost. Agents, 2013; 27: 455-462
  Google Scholar
• 2. Cottin V.: Interstitial lung disease. Eur. Respir. Rev., 2013; 22: 26-32
  Google Scholar
• 3. Davenport A.P.: International Union of Pharmacology. XXIX. Updateon endothelin receptor nomenclature. Pharmacol. Rev., 2002; 54:219-226
  Google Scholar
• 4. Elshaboury S.M., Anderson J.R.: Ambrisentan for the treatment ofpulmonary arterial hypertension: improving outcomes. Patient PreferAdherence, 2013; 7: 401-409
  Google Scholar
• 5. European Medicines Agency. Tracleer: EPAR – Product Information.http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000401/human_med_001100.jsp&mid=WC0b01ac058001d124.htm (07.02.2014)
  Google Scholar
• 6. European Medicines Agency. Volibris: EPAR – Product Information.http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000839/human_med_001151.jsp&mid=WC0b01ac058001d124.htm (07.02.2014)
  Google Scholar
• 7. Fizazi K.S., Higano C.S., Nelson J.B., Gleave M., Miller K., Morris T.,Nathan F.E., McIntosh S., Pemberton K., Moul J.W.: Phase III, randomized,placebo-controlled study of docetaxel in combination with zibotentanin patients with metastatic castration-resistant prostate cancer. J. Clin.Oncol., 2013; 31: 1740-1747
  Google Scholar
• 8. Frumkin L.R.: The pharmacological treatment of pulmonary arterialhypertension. Pharmacol. Rev., 2012; 64: 583-620
  Google Scholar
• 9. Goldenberg M.M.: Pharmaceutical approval update. PharmacyTherapeutics, 2013; 38: 747-754
  Google Scholar
• 10. Gong S., Peng L., Yan B., Dong Q., Seng Z., Wang W., Lv J., He X.:Bosentan reduces neuronal apoptosis following spinal cord ischemicreperfusion injury. Spinal Cord., 2014; 52: 181-185
  Google Scholar
• 11. Grassi G.: Selective endothelin receptor blockade in resistanthypertension: results of the DORADO trial. Expert. Opin. Pharmacother.,2011; 12: 153-155
  Google Scholar
• 12. Haque S.U., Dashwood M.R., Heetun M., Shiwen X., FarooquiN., Ramesh B., Welch H., Savage F.J., Ogunbiyi O., Abraham D.J., LoizidouM.: Efficacy of the specific endothelin A receptor antagonistzibotentan (ZD4054) in colorectal cancer: a preclinical study. Mol.Cancer. Ther., 2013; 12: 1556-1567
  Google Scholar
• 13. Hynynen M.M., Khalil R.A.: The vascular endothelin systemin hypertension – recent patents and discoveries. Recent Pat. Cardiovasc.Drug Discov., 2006; 1: 95-108
  Google Scholar
• 14. Iglarz M., Binkert C., Morrison K., Fischli W., Gatfield J., TreiberA., Weller T., Bolli M.H., Boss C., Buchmann S., Capeleto B., HessP., Qiu C., Clozel M.: Pharmacology of macitentan, an orally activetissue-targeting dual endothelin receptor antagonist. J. Pharmacol.Exp. Ther., 2008; 327: 736-745
  Google Scholar
• 15. Imhof A.K., Glück L., Gajda M., Bräuer R., Schaible H.G., SchulzS.: Potent anti-inflammatory and antinociceptive activity of theendothelin receptor antagonist bosentan in monoarthritic mice.Arthritis Res. Ther., 2011; 13: R97
  Google Scholar
• 16. Kawanabe Y., Nauli S.M.: Endothelin. Cell Mol. Life Sci., 2011;68: 195-203
  Google Scholar
• 17. Kim S.J., Kim J.S., Kim S.W., Brantley E., Yun S.J., He J., Maya M.,Zhang F., Wu Q., Lehembre F., Regenass U., Fidler I.J.: Macitentan(ACT-064992), a tissue-targeting endothelin receptor antagonist,enhances therapeutic efficacy of paclitaxel by modulating survivalpathways in orthotopic models of metastatic human ovarian cancer.Neoplasia, 2011; 13: 167-179
  Google Scholar
• 18. Kim S.J., Kim J.S., Kim S.W., Yun S.J., He J., Brantley E., FanD., Strickner P., Lehembre F., Regenass U., Fidler I.J.: Antivasculartherapy for multidrug-resistant ovarian tumors by macitentan,a dual endothelin receptor antagonist. Transl. Oncol., 2012; 5: 39-47
  Google Scholar
• 19. Kohan D.E.: Endothelin, hypertension and chronic kidneydisease: new insights. Curr. Opin. Nephrol. Hypertens., 2010; 19:134-139
  Google Scholar
• 20. Kohan D.E., Pollock D.M.: Endothelin antagonists for diabeticand non-diabetic chronic kidney disease. Br. J. Clin. Pharmacol.,2013; 76: 573-579
  Google Scholar
• 21. Konieczka K., Meyer P., Schoetzau A., Neutzner A., MozaffariehM., Flammer J.: Effect of avosentan (SPP-301) in porcine ciliary arteries.Curr. Eye Res., 2011; 36: 118-124
  Google Scholar
• 22. Lima V.V., Giachini F.R., Hardy D.M., Webb R.C., Tostes R.C.:O-GlcNAcylation: a novel pathway contributing to the effects ofendothelin in the vasculature. Am. J. Physiol. Regul. Integr. Comp.Physiol., 2011; 300: R236-R250
  Google Scholar
• 23. Maron B.A., Waxman A.B., Opotowsky A.R., Gillies H., Blair C.,Aghamohammadzadeh R., Loscalzo J., Leopold J.A.: Effectivenessof spironolactone plus ambrisentan for treatment of pulmonaryarterial hypertension (from the [ARIES] study 1 and 2 trials). Am.J. Cardiol., 2013; 112: 720-725
  Google Scholar
• 24. Mazzuca M.Q., Khalil R.A.: Vascular endothelin receptor typeB: structure, function and dysregulation in vascular disease. Biochem.Pharmacol., 2012; 84: 147-162
  Google Scholar
• 25. Montani D., Günther S., Dorfmüller P., Perros F., Girerd B.,Garcia G., Jais X., Savale L., Artaud-Macari E., Price L.C., HumbertM., Simonneau G., Sitbon O.: Pulmonary arterial hypertension.Orphanet J. Rare Dis., 2013; 8: 97
  Google Scholar
• 26. Motte S., McEntee K., Naeije R.: Endothelin receptor antagonists.Pharmacol. Ther., 2006; 110: 386-414
  Google Scholar
• 27. Nelson J.B., Fizazi K., Miller K., Higano C., Moul J.W., Akaza H., MorrisT., McIntosh S., Pemberton K., Gleave M.: Phase 3, randomized, placebocontrolledstudy of zibotentan (ZD4054) in patients with castration-resistantprostate cancer metastatic to bone. Cancer, 2012; 118: 5709-5718
  Google Scholar
• 28. Ohkita M., Tawa M., Kitada K., Matsumura Y.: Pathophysiologicalroles of endothelin receptors in cardiovascular diseases. J. Pharmacol.Sci., 2012; 119: 302-313
  Google Scholar
• 29. Opsumit (macitentan). Full Prescribing Information. http://opsumit.com(07.02.2014)
  Google Scholar
• 30. Patel T., McKeage K.: Macitentan: first global approval. Drugs, 2014;74: 127-133
  Google Scholar
• 31. Pinho-Ribeiro F.A., Borghi S.M., Staurengo-Ferrari L., FilgueirasG.B., Estanislau C., Verri W.A. Jr.: Bosentan, a mixed endothelin receptorantagonist, induces antidepressant-like activity in mice. Neurosci.Lett., 2014; 560: 57-61
  Google Scholar
• 32. Raghu G., Behr J., Brown K.K., Egan J.J., Kawut S.M., FlahertyK.R., Martinez F.J., Nathan S.D., Wells A.U., Collard H.R., Costabel U.,Richeldi.L, de Andrade J., Khalil N., Morrison L.D., et al.: Treatment ofidiopathic pulmonary fibrosis with ambrisentan: a parallel, randomizedtrial. Ann. Intern. Med., 2013; 158: 641-649
  Google Scholar
• 33. Reriani M., Raichlin E., Prasad A., Mathew V., Pumper G.M., NelsonR.E., Lennon R., Rihal C., Lerman L.O., Lerman A.: Long-term administrationof endothelin receptor antagonist improves coronary endothelialfunction in patients with early atherosclerosis. Circulation, 2010;122: 958-966
  Google Scholar
• 34. Rodriguez M.R., Soria L.R., Ventimiglia M.S., Najenson A.C., Di MaríaA., Dabas P., Fellet A., Marinelli R.A., Vatta M.S., Bianciotti L.G.: Endothelin-1and -3 induce choleresis in the rat through ETB receptors coupledto nitric oxide and vagovagal reflexes. Clin. Sci., 2013; 125: 521-532
  Google Scholar
• 35. Sachidanandam K., Portik-Dobos V., Kelly-Cobbs A.I., Ergul A.: Dualendothelin receptor antagonism prevents remodeling of resistance arteriesin diabetes. Can. J. Physiol. Pharmacol., 2010; 88: 616-621
  Google Scholar
• 36. Sen S., Chen S., Feng B., Iglarz M., Chakrabarti S.: Renal, retinal andcardiac changes in type 2 diabetes are attenuated by macitentan, a dualendothelin receptor antagonist. Life Sci., 2012; 91: 658-668
  Google Scholar
• 37. Sengul O., Ferah I., Polat B., Halici Z., Bayir Y., Yilmaz M., Kilic N.,Keles O.N.: Blockade of endothelin receptors with bosentan limits ischaemia/reperfusion-inducedinjury in rat ovaries. Eur. J. Obstet. Gynecol.Reprod. Biol., 2013; 170: 458-463
  Google Scholar
• 38. Sidharta P.N., van Giersbergen P.L., Dingemanse J.: Safety, tolerability,pharmacokinetics, and pharmacodynamics of macitentan, anendothelin receptor antagonist, in an ascending multiple-dose studyin healthy subjects. J. Clin. Pharmacol., 2013; 53: 1131-1138
  Google Scholar
• 39. Takatsuki S., Rosenzweig E.B., Zuckerman W., Brady D., CalderbankM., Ivy D.D.: Clinical safety, pharmacokinetics, and efficacy of ambrisentantherapy in children with pulmonary arterial hypertension. Pediatr.Pulmonol., 2013; 48: 27-34
  Google Scholar
• 40. Wang R.F., Podos S.M., Serle J.B., Baltatu O.C.: Effect of SPP 301, anendothelin antagonist, on intraocular pressure in glaucomatous monkeyeyes. Curr. Eye Res., 2011; 36: 41-46
  Google Scholar
• 41. Yoon M.H., Reriani M., Mario G., Rihal C., Gulati R., Lennon R., TilfordJ.M., Lerman L.O., Lerman A.: Long-term endothelin receptor antagonismattenuates coronary plaque progression in patients with earlyatherosclerosis. Int. J. Cardiol., 2013; 168: 1316-1321
  Google Scholar
• 42. Zhang Z., Jian X., Zhang W., Wang J., Zhou Q.: Using bosentan totreat paraquat poisoning-induced acute lung injury in rats. PLoS One,2013; 8: e75943
  Google Scholar

Full text