Endothelin (ET) has been identified as playing a fundamental role in many disease processes. Therapeutic efforts at interrupting ET's pathologic effects have focused on endothelin receptor antagonists (ERAs), of which two, bosentan and sitaxsentan, have been evaluated for the treatment of both primary and secondary pulmonary arterial hypertension (PAH). We discuss the multiple actions of ET, its role in various disease states, and the effects of ET receptor stimulation and blockade. Current classification and management of PAH are reviewed, along with the promise of greatly improved treatment generated by recent and ongoing clinical trials using ERAs.
4. Haynes WG, Webb DJ. The endothelin family of peptides: Local hormones with diverse roles in health and disease?Clin Sci84:485-500, 1993
5.
5. Michael JR, Markewitz BA. Endothelins and the lung. Am J Respir Crit Care Med154:555-581, 1996
6.
6. Noveral JP, Rosenberg SM, Anbar RA, Pawlowski NA, Grunstein MM. Role of endothelin-1 in regulating proliferation of cultured rabbit airway smooth muscle cells. Am J Physiol263:L317-324, 1992
7.
7. Stewart AG, Grigoriadis G, Harris T. Mitogenic actions of endothelin-1 and epidermal growth factor in cultured airway smooth muscle. Clin Exp Pharmacol Physiol21:277-285, 1994
8.
8. Hinson JP, Vinson GP, Kapas S, Teja R. The role of endothelin in the control of adrenocortical function: Stimulation of endothelin release by ACTH and the effects of endothelin-I and endothelin-3 on steroidogenesis in rat and human adrenocortical cells. J Endocrinol128: 275-280, 1991
9.
9. Cozza EN, Gomez-Sanchez CE. Mechanisms of ET-1 potentiation of angiotensin II stimulation of aldosterone production. Am J Physiol265:E179-183, 1993
10.
10. Andreis PG, Tortorella C, Malendowicz LK, Nussdorfer GG. Endothelins stimulate aldosterone secretion from dispersed rat adrenal zona glomerulosa cells, acting through ETB receptors coupled with the phospholipase C-dependent signaling pathway. Peptides22(1):117-122, 2001
11.
11. Fernandes LB, Henry PJ, Rigby PJ, Goldie RG. EndothelinB (ETB) receptor-activated potentiation of cholinergic nerve-mediated contraction in human bronchus. Br J Pharmacol118:1873-1874, 1996
12.
12. Yoshida K, Yasujima M, Kohzuki M, Kanazawa M, Yoshinaga K, Abe K. Endothelin-l augments pressor response to angiotensin II infusion in rats. Hypertension20:292-297, 1992
13.
13. Inoue A, Yanagisawa M, Kimura S, et al. The human endothelin family: Three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA86:2863-2867, 1989
15. Haynes WG, Strachan FE, Webb DJ. Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation92:357-363, 1995
16.
16. Neylon CB, Avdonin PV, Dilley RJ, Larsen MA, Tkachuk VA, Bobik A. Different electrical responses to vasoactive agonists in morphologically distinct smooth muscle cell types. Circ Res75:733-741, 1994
17.
17. Masaki T, Miwa S, Sawamura T, Ninomiya H, Okamoto Y. Subcellular mechanisms of endothelin action in vascular system. Eur J Pharmacol375:133-138, 1999
18.
18. Clozel M, Gray GA, Breu V, Loffler BM, Osterwalder R. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun186:867-873, 1992
19.
19. Levin ER. Endothelins. N Engl J Med333:356-363, 1995
20.
20. Benigni A, Ramuzzi G. Endothelin antagonists. Lancet353:133-138, 1999
21.
21. Kobayashi T, Miyauchi T, Sakai S, et al. Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-I in failing rat heart. Am J Physiol276:H1197-1206, 1999
22.
22. Thorin E, Lucas M, Cemacek P, Dupuis J. Role of ET(A) receptors in the regulation of vascular reactivity in rats with congestive heart failure. Am J Physiol Heart Circ Physiol279:H844-851, 2000
23.
23. Yokoyama Y, Baveja R, Sonin N, Nakanishi K, Zhang JX, Clemens MG. Altered endothelin receptor subtype expression in hepatic injury after ischemia/reperfusion. Shock13:72-78, 2000
24.
24. Lauth M, Berger MM, Cattaruzza M, Hecker M. Elevated perfusion pressure upregulates endothelin-I and endothelin B receptor expression in the rabbit carotid artery. Hypertension35:648-654, 2000
25.
25. 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 Pathol151:831-841, 1997
26.
26. Cardillo C, Kilcoyne CM, Waclawiw M, Cannon III RO, Panza JA. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension33:753-758, 1999
27.
27. Katwa LC, Guarda E, Weber KT. Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovasc Res27:2125-2129, 1993
28.
28. Gater PR, Wsserman MA, Renzetti LM. Effects of Ro 47-0203 on endothelin-1 and sarafotoxin S6c-induced contractions of human bronchus and guinea-pig trachea. Eur J Pharmacol304:123-128, 1996
29.
29. Carratu P, Scuri M, Styblo JL, Wanner A, Glassberg MK. ET-1 induces mitogenesis in ovine airway smooth muscle cells via ETA and ETB receptors. Am J Physiol272:L1021-L1024, 1997
30.
30. Filep JG, Foumier A, Foldes-Filep E. Acute pro-inflammatory actions of endothelin-1 in the guinea-pig lung: Involvement of ETA and ETB receptors. Br J Pharmacol115:227-236, 1995
31.
31. Rebuffat P, Aragona F, Tortorella C, Malendowicz LK, Nussdorfer GG. Signaling pathways involved in the A and B receptor-mediated cortisol secretagogue effect of endothelins in the human adrenal cortex. Int J Mol Med7(3):301-305, 2001
32.
32. Rossi GP, Andreis PG, Neri G, Tortorella C, Pelizzo MR, Sacchetto A, Nussdorfer GG. Endothelin-1 stimulates aldosterone synthesis in Conn's adenomas via both A and B receptors coupled with the protein kinase Cand cyclooxygenase-dependent signaling pathways. J Investig Med48(5):343-350, 2000
33.
33. Belloni AS, Rossi GP, Andreis PG, et al. Endothelin adrenocortical secretagogue effect is mediated by the B receptor in rats. Hypertension27:1153-1159, 1996
34.
34. Seed A, Love MP, McMurray JJV. Clinical experience with endothelin receptor antagonists in chronic heart failure. Heart Failure Reviews6:317-323, 2001
35.
35. McCulloch KM, Docherty CC, Morecraft I, MacLean MR. EndothelinB receptor-mediated contraction in human pulmonary resistance arteries. Br J Pharmacol119:1125-1130, 1996
36.
36. Hocher B, George I, Rebstock J, et al. Endothelin systemdependent cardiac remodeling in renovascular hypertension. Hypertension33(3):816-822, 1999
37.
37. Piacentini L, Gray M, Honbo NY, Chentoufi J, Bergman M, Karliner JS. Endothelin-l stimulates cardiac fibroblast proliferation through activation of protein kinase C. J Mol Cell Cardiol32:565-576, 2000
38.
38. Burrell KM, Molenaar P, Dawson PJ, Kaumann AJ. Contractile and arrhythmic effects of endothelin receptor agonists in human heart in vitro: Blockade with SB 209670. J Pharmacol Exp Ther292:449-459, 2000
39.
39. Brunner F, Kukovetz WR. Postischemic antiarrhythmic effects of angiotensin-converting enzyme inhibitors. Role of suppression of endogenous endothelin secretion. Circulation94:1752-1761, 1996
40.
40. Ishikawa S, Miyauchi T, Ueno H, et al. Influence of pulmonary blood pressure and flow on endothelin-I production in humans. J Cardiovasc Pharmacol26(Suppl. 3):S429-433, 1995
41.
41. Cambrey AD, et al. Increased levels of endothelin-I in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Bio11:439-445, 1994
42.
42. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med328: 1732-1739, 1993
43.
43. Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol61:391-415, 1999
44.
44. Chalmers GW, Little SA, Patel KR, Thomson NC. Endothelin-1-induced bronchoconstriction in asthma. Am J Respir Crit Care Med156:382-388, 1997
45.
45. Cardell LO, Uddman R, Edvinsson L. Endothelins: A role in cerebrovascular disease?Cephalgia14:259-265, 1994
46.
46. Goldie RG. Endothelins in health and disease: An overview. Clin Exp Pharmacol Physiol26:145-148, 1999
48. Nelson JB, Carducci MA. The role of endothelin-1 and endothelin receptor antagonists in prostate cancer. BJU Int 85 (Suppl 2):45-48, 2000
49.
49. Sato K, Oka M, Hasunuma K, Ohnishi M, Sato K, Kira S. Effects of separate and combined ETA and ETB blockade on ET-1-induced constriction in perfused rat lungs. Am J Physiol269(5 Pt 1):L668-672, 1995
50.
50. Kiowski W, Sutsch G, Hunziker P, et al. Evidence for endothelin-I mediated vasoconstriction in severe chronic heart failure. Lancet346:732-736, 1995
51.
51. Spieker LE, Mitrovic V, Noll G, et al. Acute hemodynamic and neurohumoral effects of selective ETa receptor blockade in patients with congestive heart failure. J Am Coll Cardiol35:1745-1752, 2000
52.
52. Givertz MM, Colluci WS, Lejemtel TH, et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation101:2922-2927, 2000
53.
53. Sutsch G, Bertel O, Kiowski W. Acute and short-term effects of the non-peptide endothelin-1 receptor antagonists bosentan in humans. Cardiovasc Drugs Ther10:717-725, 1997
54.
54. Ruschitzka FT, Pacher R, Enseleit F, et al. Chronic selective ETa receptor blockade in congestive heart failure: The HEAT trial. Circulation102(suppl):II-593 (Abstract), 2000
55.
55. Abraham WT. Enrasentan cooperative randomized evaluation (ENCOR). Presented at the American College of Cardiology annual meeting, 2001
56.
56. Packer M, Caspi A, Charlon V, et al. Multicenter, doubleblind, placebo controlled study of long-term endothelin blockade with bosentan in chronic heart failure: Results of the REACH-1 trial. Circulation. 98(suppl):I-3 (Abstract), 1998
57.
57. Mylona P, Cleland JGF. Update of REACH-I and MERITHF clinical trials in heart failure. Eur J Heart Failure1:197-200, 1999
58.
58. Krum H, Charlon V, Widmann T, Packer M. Long-term, open-label experience with an endothelin receptor antagonist, bosentan, in patients with severe chronic heart failure [abstract]. Circulation100 (Suppl I):I-646, 1999
59.
59. Williamson DJ, Wallman LL, Jones R, et al. Hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation102:411-418, 2000
60.
60. Channick RN, Rubin LJ, Simmonneau G, et al. Bosentan, a dual endothelin receptor antagonist, improves exercise capacity and hemodynamics in patients with pulmonary arterial hypertension: Results of a double-blind, randomized, placebo-controlled trial [abstract]. Circulation102 (Suppl II):II-100, 2000
61.
61. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: A randomized placebo-controlled study. Lancet358:1119-1123, 2001
62.
62. Park S-H, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Resp Crit Care Med156:600-608, 1997
63.
63. Holm P, Liska J, Clozel M, Franco-Cereceda A. The endothelin antagonist bosentan: Hemodynamic effects during normoxia and hypoxic pulmonary hypertension in pigs. J Thorac Cardiovasc Surg112:890-897, 1996
64.
64. Chen S-J, Chen Y-F, Meng QC, Durand J, DiCarlo VS, Oparil S. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol79(6):2122-2131, 1995
65.
65. Eddahibi S, Raffestin B, Clozel M, Levame M, Adnot S. Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats. Am J Physiol268:H828-835, 1995
66.
66. Chen S-J, Chen Y-F, Opgenorth TJ, et al. The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Spraguedawley rats. J Cardiovasc Pharmacol29:713-725, 1997
67.
67. Prie S, Leung TK, Cemacek P, Ryan JW, Dupuis J. The orally active ETA receptor antagonist (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (LU 135252) prevents the development of pulmonary hypertension and endothelial metabolic dysfunction in monocrotaline-treated rats. J Pharmacol Exp Ther282:1312-1318, 1997
68.
68. Rich S. Executive summary of the World Symposium on PPH. 1999. Available at: http://www.who.int/ncd/cvd/pph.html. Accessed July 5, 2001
69.
69. Gaine S. Pulmonary hypertension. JAMA284:3160-3168, 2000
70.
70. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-I1, a receptor member of the TGF-beta family. J Med Genet37:741-745, 2000
71.
71. Newman JH, Wheeler L, Lane KB, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med345:319-324, 2001
72.
72. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med335:609-616, 1996
74. Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: Evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation76:135-141, 1987a
75.
75. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med107:216-223, 1987b
76.
76. Rubin LJ. Primary pulmonary hypertension. N Eng J Med336:111-117, 1997
77.
77. Krowka MJ. Pulmonary hypertension: Diagnostics and therapeutics. Mayo Clin Proc75:625-630, 2000
78.
78. Brenot F. Primary pulmonary hypertension. Case series from France. Chest105 (Suppl 2):33S-36S, 1994
79.
79. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med115:343-349, 1991
80.
80. Oakley CW. Primary pulmonary hypertension. Case series from the United Kingdom. Chest105(Suppl 2):29S-32S, 1994
81.
81. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med327:76-81, 1992
82.
82. Woodmansey PA, O'Toole L, Channer KS, Morice AH. Acute pulmonary vasodilatory properties of amlodipine in humans with pulmonary hypertension. Heart75:171-173, 1996
83.
83. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: Natural history and the importance of thrombosis. Circulation70:580-587, 1984
84.
84. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med112:485-491, 1990
85.
85. Conte JV, Gaine SP, Orens JB, Harris T, Rubin LJ. The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation. J Heart Lung Transplant17:679-685, 1998
86.
86. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Eng J Med334:296-302, 1996
87.
87. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med121:463-464, 1994
88.
88. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 132:425-434, 2000
89.
89. Olschewski H, Walmrath D, Schermuly R, Ghofrani A, Grimminger F, Seeger W. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med124:820-824, 1996
90.
90. Saji T, Ozawa Y, Ishikita T, Matsuura H, Matsuo N. Shortterm hemodynamic effect of a new oral PGI2 analogue, beraprost, in primary and secondary pulmonary hypertension. Am J Cardiol78:244-247, 1996
91.
91. Gaine SP, Barst RJ, Rich S, et al. Acute hemodynamic effects of subcutaneous UT-15 in primary pulmonary hypertension [abstract]. Am J Respir Crit Care Med159:A161-A161, 1999
92.
92. Gaine SP, Rubin LJ. Medical and surgical treatment options for pulmonary hypertension. Am J Med Sci315:179-184, 1998
93.
93. Hosenpud JD, Bennett LE, Keck BM, Fiol B, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: Fourteenth official report-1997. J Heart Lung Transplant16:691-712, 1997
94.
94. Barst RJ, Rich S, Horn EM, et al. Efficacy and safety of chronic treatment with the oral selective endothelin-A receptor blocker sitaxsentan in pulmonary arterial hypertension (PAH) [abstract]. Circulation102(Suppl ll):ll-426, 2000
