Respiratory Medicine
Volume 103, Issue 7 , Pages 951-962 , July 2009

Endothelin receptor blockade in the management of pulmonary arterial hypertension: Selective and dual antagonism

  • Terence K. Trow

      Affiliations

    • Yale University School of Medicine, Division of Internal Medicine, Section of Pulmonary and Critical Care Medicine, Yale Pulmonary Hypertension Center, 333 Cedar Street, LCI 105D, P.O. Box 208057, New Haven, CT 06520-8057, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 203 785 4196; fax: +1 203 785 3634.
  • ,
  • Darren B. Taichman

      Affiliations

    • Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

Received 8 December 2008 ,Accepted 19 February 2009.

References 

  1. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114(13):1417–1431
  2. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–415
  3. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328(24):1732–1739
  4. Morelli S, Ferri C, Polettini E, et al. Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis. Am J Med. 1995;99(3):255–260
  5. Li H, Elton TS, Chen YF, et al. Increased endothelin receptor gene expression in hypoxic rat lung. Am J Physiol. 1994;266(5 Pt 1):L553–L560
  6. Clozel M, Clozel JP. Effects of endothelin on regional blood flows in squirrel monkeys. J Pharmacol Exp Ther. 1989;250(3):1125–1131
  7. Yang ZH, Buhler FR, Diederich D, et al. Different effects of endothelin-1 on cAMP- and cGMP-mediated vascular relaxation in human arteries and veins: comparison with norepinephrine. J Cardiovasc Pharmacol. 1989;13(Suppl. 5):S129–S131
  8. Ito H, Hirata Y, Hiroe M, et al. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res. 1991;69(1):209–215
  9. Simonson MS, Wann S, Mene P, et al. Endothelin stimulates phospholipase C, Na+/H+ exchange, c-fos expression, and mitogenesis in rat mesangial cells. J Clin Invest. 1989;83(2):708–712
  10. Yang Z, Krasnici N, Luscher TF. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Circulation. 1999;100(1):5–8
  11. Muldoon LL, Pribnow D, Rodland KD, et al. Endothelin-1 stimulates DNA synthesis and anchorage-independent growth of Rat-1 fibroblasts through a protein kinase C-dependent mechanism. Cell Regul. 1990;1(4):379–390
  12. Cambrey AD, Harrison NK, Dawes KE, et al. Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol. 1994;11(4):439–445
  13. Helset E, Lindal S, Olsen R, et al. Endothelin-1 causes sequential trapping of platelets and neutrophils in pulmonary microcirculation in rats. Am J Physiol. 1996;271(4 Pt 1):L538–L546
  14. Browatzki M, Schmidt J, Kubler W, et al. Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells. Basic Res Cardiol. 2000;95(2):98–105
  15. Filep JG, Fournier A, Foldes-Filep E. Acute pro-inflammatory actions of endothelin-1 in the guinea-pig lung: involvement of ETA and ETB receptors. Br J Pharmacol. 1995;115(2):227–236
  16. Loesch A. Localisation of endothelin-1 and its receptors in vascular tissue as seen at the electron microscopic level. Curr Vasc Pharmacol. 2005;3(4):381–392
  17. 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
  18. Abraham DJ, Vancheeswaran R, Dashwood MR, et al. Increased levels of endothelin-1 and differential endothelin type A and B receptor expression in scleroderma-associated fibrotic lung disease. Am J Pathol. 1997;151(3):831–841
  19. Lutz J, Gorenflo M, Habighorst M, et al. Endothelin-1- and endothelin-receptors in lung biopsies of patients with pulmonary hypertension due to congenital heart disease. Clin Chem Lab Med. 1999;37(4):423–428
  20. Bauer M, Wilkens H, Langer F, et al. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation. 2002;105(9):1034–1036
  21. Dupuis J, Goresky CA, Fournier A. Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors. J Appl Physiol. 1996;81(4):1510–1515
  22. Hirata Y, Emori T, Eguchi S, et al. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest. 1993;91(4):1367–1373
  23. Shichiri M, Kato H, Marumo F, et al. Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells. Hypertension. 1997;30(5):1198–1203
  24. Clozel M, Breu V, Gray GA, et al. In vivo pharmacology of Ro 46-2005, the first synthetic nonpeptide endothelin receptor antagonist: implications for endothelin physiology. J Cardiovasc Pharmacol. 1993;22(Suppl. 8):S377–S379
  25. Iglarz M, Clozel M. Mechanisms of ET-1-induced endothelial dysfunction. J Cardiovasc Pharmacol. 2007;50(6):621–628
  26. Juergens UR, Racke K, Uen S, et al. Inflammatory responses after endothelin B (ET(B)) receptor activation in human monocytes: new evidence for beneficial anti-inflammatory potency of ET(B)-receptor antagonism. Pulm Pharmacol Ther. 2008;
  27. Cardozo AM, D'Orleans-Juste P, Yano M, et al. Influence of endothelin ET(A) and ET(B) receptor antagonists on endothelin-induced contractions of the guinea pig isolated gall bladder. Regul Pept. 1997;69(1):15–23
  28. Fukuroda T, Ozaki S, Ihara M, et al. Synergistic inhibition by BQ-123 and BQ-788 of endothelin-1-induced contractions of the rabbit pulmonary artery. Br J Pharmacol. 1994;113(2):336–338
  29. Liu JJ, Chen JR, Buxton BF. Unique response of human arteries to endothelin B receptor agonist and antagonist. Clin Sci (Lond). 1996;90(2):91–96
  30. Lagerstrom MC, Schioth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov. 2008;7(4):339–357
  31. Ng GY, Clark J, Coulombe N, et al. Identification of a GABAB receptor subunit, gb2, required for functional GABAB receptor activity. J Biol Chem. 1999;274(12):7607–7610
  32. Prinster SC, Hague C, Hall RA. Heterodimerization of G protein-coupled receptors: specificity and functional significance. Pharmacol Rev. 2005;57(3):289–298
  33. Rozenfeld R, Decaillot FM, IJzerman AP, et al. Heterodimers of G protein-coupled receptors as novel and distinct drug targets. Drug Discov Today Ther Strateg. 2006;3(4):437–443
  34. Clozel M, Gray GA. Are there different ETB receptors mediating constriction and relaxation?. J Cardiovasc Pharmacol. 1995;26(Suppl. 3):S262–S264
  35. Bouvier M. Oligomerization of G-protein-coupled transmitter receptors. Nat Rev Neurosci. 2001;2(4):274–286
  36. Harada N, Himeno A, Shigematsu K, et al. Endothelin-1 binding to endothelin receptors in the rat anterior pituitary gland: possible formation of an ETA-ETB receptor heterodimer. Cell Mol Neurobiol. 2002;22(2):207–226
  37. Gregan B, Jurgensen J, Papsdorf G, et al. Ligand-dependent differences in the internalization of endothelin A and endothelin B receptor heterodimers. J Biol Chem. 2004;279(26):27679–27687
  38. Remuzzi G, Perico N, Benigni A. New therapeutics that antagonize endothelin: promises and frustrations. Nat Rev Drug Discov. 2002;1(12):986–1001
  39. Sato K, Oka M, Hasunuma K, et al. Effects of separate and combined ETA and ETB blockade on ET-1-induced constriction in perfused rat lungs. Am J Physiol. 1995;269(5 Pt 1):L668–L672
  40. Jasmin JF, Lucas M, Cernacek P, et al. Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension. Circulation. 2001;103(2):314–318
  41. Sauvageau S, Thorin E, Caron A, et al. Evaluation of endothelin-1-induced pulmonary vasoconstriction following myocardial infarction. Exp Biol Med (Maywood). 2006;231(6):840–846
  42. Cardillo C, Kilcoyne CM, Waclawiw M, et al. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension. 1999;33(2):753–758
  43. Shi-Wen X, Denton CP, Dashwood MR, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol. 2001;116(3):417–425
  44. Dumont AS, Lovren F, McNeill JH, et al. Augmentation of endothelial function by endothelin antagonism in human saphenous vein conduits. J Neurosurg. 2001;94(2):281–286
  45. Rondelet B, Kerbaul F, Motte S, et al. Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension. Circulation. 2003;107(9):1329–1335
  46. Chen SJ, Chen YF, Meng QC, et al. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol. 1995;79(6):2122–2131
  47. Finsnes F, Skjonsberg OH, Tonnessen T, et al. Endothelin production and effects of endothelin antagonism during experimental airway inflammation. Am J Respir Crit Care Med. 1997;155(4):1404–1412
  48. 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):1119–1123
  49. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896–903
  50. 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):3010–3019
  51. Letairis (ambrisentan) tablets [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2008;
  52. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169(4):441–447
  53. Barst RJ, Langleben D, Badesch DB, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006;47:2049–2056
  54. Liu C, Chen J. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev. 2006;3:CD004434
  55. Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J. 2008;31(2):407–415
  56. Segal ES, Valette C, Oster L, et al. Risk management strategies in the postmarketing period: safety experience with the US and European bosentan surveillance programmes. Drug Saf. 2005;28(11):971–980
  57. Humbert M, Segal ES, Kiely DG, et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J. 2007;30(2):338–344
  58. Battistini B, Berthiaume N, Kelland NF, et al. Profile of past and current clinical trials involving endothelin receptor antagonists: the novel “-sentan” class of drug. Exp Biol Med (Maywood). 2006;231(6):653–695
  59. Tracleer (bosentan) tablets [package insert]. San Francisco, CA: Actelion Pharmaceuticals, Inc.; 2007;
  60. Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry. 2001;158(3):360–369
  61. Schirger JA, Chen HH, Jougasaki M, et al. Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin–angiotensin system and sustained sodium retention. Circulation. 2004;109(2):249–254
  62. Wong S, Brennan FE, Young MJ, et al. A direct effect of aldosterone on endothelin-1 gene expression in vivo. Endocrinology. 2007;148(4):1511–1517
  63. Ikebe M, Nonoguchi H, Nakayama Y, et al. Regulation of endothelin-converting enzyme 1 in nephrotic syndrome in rats. Nephron Exp Nephrol. 2003;94(4):e137–e145
  64. Dhaun N, Pollock DM, Goddard J, et al. Selective and mixed endothelin receptor antagonism in cardiovascular disease. Trends Pharmacol Sci. 2007;28(11):573–579
  65. Wu C, Chan MF, Stavros F, et al. Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist. J Med Chem. 1997;40(11):1690–1697

PII: S0954-6111(09)00066-3

doi: 10.1016/j.rmed.2009.02.016

Respiratory Medicine
Volume 103, Issue 7 , Pages 951-962 , July 2009