Endothelin Receptor Antagonists

Chapter
Part of the Respiratory Medicine book series (RM, volume 12)

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen that is secreted by the endothelium. Pulmonary vascular expression of endothelin is increased in pulmonary hypertension and plasma levels correlate with the severity of disease. Several endothelin receptor antagonists (ERAs) have been developed and are available for the treatment of pulmonary arterial hypertension (PAH). These drugs have been shown to be effective at improving functional capacity, decreasing pulmonary vascular resistance and delaying the time to clinical worsening and play an important role in the management of PAH. This chapter briefly reviews how the endothelin signaling pathway modulates pulmonary vascular function and describes its role in the pathogenesis of PAH. The major clinical trials responsible for the currently available ERAs are presented along with their findings and limitations. Recently, adopted treatment guidelines for the use of ERAs in the treatment of pulmonary hypertensive disease are discussed along with potential side effects and adverse reactions associated with the use of these drugs.

Keywords

Endothelin Endothelin-1 Endothelin receptor Endothelin receptor antagonist Pulmonary hypertension Pulmonary arterial hypertension 

Abbreviations

6MWD

6-min Walk distance

CTEPH

Chronic thromboembolic pulmonary hypertension

ERA

Endothelin receptor antagonist

ET-1

Endothelin-1

ET-2

Endothelin-2

ET-3

Endothelin-3

ETA

Endothelin receptor A

ETB

Endothelin receptor B

IPAH

Idiopathic pulmonary arterial hypertension

mPAP

Mean pulmonary artery pressure

NO

Nitric oxide

PAH

Pulmonary arterial hypertension

PPET-1

Preproendothelin

PVR

Pulmonary vascular resistance

TPR

Total pulmonary resistance

This is a preview of subscription content, log in to check access.

References

  1. 1.
    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation. 2000;102(19):2434–40.CrossRefPubMedGoogle Scholar
  3. 3.
    Firth JD, Ratcliffe PJ. Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. J Clin Invest. 1992;90(3):1023–31.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Masaki T, Kimura S, Yanagisawa M, Goto K. Molecular and cellular mechanism of endothelin regulation. implications for vascular function. Circulation. 1991;84(4):1457–68.CrossRefPubMedGoogle Scholar
  5. 5.
    Markewitz BA, Farrukh IS, Chen Y, Li Y, Michael JR. Regulation of endothelin-1 synthesis in human pulmonary arterial smooth muscle cells. Effects of transforming growth factor-beta and hypoxia. Cardiovasc Res. 2001;49(1):200–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Shi-Wen X, Chen Y, Denton CP, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell. 2004;15(6):2707–19.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Dupuis J, Stewart DJ, Cernacek P, Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin-1. Circulation. 1996;94(7):1578–84.CrossRefPubMedGoogle Scholar
  8. 8.
    Wagner OF, Christ G, Wojta J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem. 1992;267(23):16066–8.PubMedGoogle Scholar
  9. 9.
    Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J. 2008;31(2):407–15.CrossRefPubMedGoogle Scholar
  10. 10.
    Boulanger C, Luscher TF. Release of endothelin from the porcine aorta. inhibition by endothelium-derived nitric oxide. J Clin Invest. 1990;85(2):587–90.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Morey AK, Razandi M, Pedram A, Hu RM, Prins BA, Levin ER. Oestrogen and progesterone inhibit the stimulated production of endothelin-1. Biochem J. 1998;330(Pt 3):1097–105.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Davie N, Haleen SJ, Upton PD, et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med. 2002;165(3):398–405.CrossRefPubMedGoogle Scholar
  13. 13.
    Chua BH, Krebs CJ, Chua CC, Diglio CA. Endothelin stimulates protein synthesis in smooth muscle cells. Am J Physiol. 1992;262(4 Pt 1):E412–6.PubMedGoogle Scholar
  14. 14.
    Hofman FM, Chen P, Jeyaseelan R, Incardona F, Fisher M, Zidovetzki R. Endothelin-1 induces production of the neutrophil chemotactic factor interleukin-8 by human brain-derived endothelial cells. Blood. 1998;92(9):3064–72.PubMedGoogle Scholar
  15. 15.
    Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358(9288):1119–23.CrossRefPubMedGoogle Scholar
  16. 16.
    Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896–903.CrossRefPubMedGoogle Scholar
  17. 17.
    Galie N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371(9630):2093–100.CrossRefPubMedGoogle Scholar
  18. 18.
    Sitbon O, Badesch DB, Channick RN, 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(1):247–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Sitbon O, Gressin V, Speich R, et al. Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;170(11):1212–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Galie N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114(1):48–54.CrossRefPubMedGoogle Scholar
  21. 21.
    Berger RM, Beghetti M, Galie N, et al. Atrial septal defects versus ventricular septal defects in BREATHE-5, a placebo-controlled study of pulmonary arterial hypertension related to Eisenmenger’s syndrome: a subgroup analysis. Int J Cardiol. 2010;144(3):373–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Jais X, D’Armini AM, Jansa P, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (bosentan effects in iNopErable forms of chronIc thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008;52(25):2127–34.CrossRefPubMedGoogle Scholar
  23. 23.
    Galie N, Badesch D, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46(3):529–35.CrossRefPubMedGoogle Scholar
  24. 24.
    Galie N, Olschewski H, Oudiz RJ, 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(23):3010–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Bolli MH, Boss C, Binkert C, et al. The discovery of a N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an orally active, potent, dual endothelin receptor antagonist. J Med Chem. 2012;55(17):7849–61.CrossRefPubMedGoogle Scholar
  26. 26.
    Gatfield J, Grandjean CM, Sasse T, Clozel M, Nayler O. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012;7(10):1–11.CrossRefGoogle Scholar
  27. 27.
    Giersbergen PL, Dingemanse J. Safety, tolerability, pharmacokinetics and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple dose study in healthy subjects. J Clin Pharmacol. 2013;53(11):1131–8.PubMedGoogle Scholar
  28. 28.
    Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–18.CrossRefPubMedGoogle Scholar
  29. 29.
    Wilkins MR, Paul GA, Strange JW, et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171(11):1292–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Sitbon O, McLaughlin VV, Badesch DB, et al. Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol. Thorax. 2005;60(12):1025–30.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Steiner MK, Preston IR, Klinger JR, et al. Conversion to bosentan from prostacyclin infusion therapy in pulmonary arterial hypertension: a pilot study. Chest. 2006;130(5):1471–80.CrossRefPubMedGoogle Scholar
  32. 32.
    Galiè N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC, Klepetko W, McGoon MD, McLaughlin VV, Preston IR, Rubin LJ, Sandoval J, Seeger W, Keogh A. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60–72.CrossRefPubMedGoogle Scholar
  33. 33.
    Hoeper MM, Taha N, Bekjarova A, Gatzke R, Spiekerkoetter E. Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. Eur Respir J. 2003;22(2):330–4.CrossRefPubMedGoogle Scholar
  34. 34.
    Akagi S, Matsubara H, Miyaji K, et al. Additional effects of bosentan in patients with idiopathic pulmonary arterial hypertension already treated with high-dose epoprostenol. Circ J. 2008;72(7):1142–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Benza RL, Rayburn BK, Tallaj JA, Pamboukian SV, Bourge RC. Treprostinil-based therapy in the treatment of moderate-to-severe pulmonary arterial hypertension: long-term efficacy and combination with bosentan. Chest. 2008;134(1):139–45.CrossRefPubMedGoogle Scholar
  36. 36.
    Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24(3):353–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, Palevsky HI, Rich S, Sood N, Rosenzweig EB, Trow TK, Yung R, Elliott CG, Badesch DB. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest. 2014;146(2):449–75.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Pulmonary and Critical Care Division, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations