Drugs in R & D

, Volume 2, Issue 1, pp 1–12 | Cite as

Endothelin Receptor Antagonists

Promising New Agents in the Management of Cardiovascular Disorders
Leading Article


Since its discovery in 1988, endothelin (ET) has been widely implicated in the pathophysiology of cardiovascular disease. ET antagonists have favourable effects in experimental models of these conditions and have proved useful in elucidating the role of the ET system. Orally acting ET antagonists appear very promising in clinical trials, particularly in patients with chronic heart failure and hypertension, but more information on the roles of the ET receptor subtypes in health and disease is required so that an informed choice can be made between the use of endothelin-A (ET-A) receptor-selective and nonselective receptor antagonists.


Adis International Limited Bosentan Selective Receptor Antagonist Nonselective Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332 (6163): 411–5PubMedCrossRefGoogle Scholar
  2. 2.
    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 U S A 1989; 86 (8): 2863–7PubMedCrossRefGoogle Scholar
  3. 3.
    Arinami T, Ishikawa M, Inoue A, et al. Chromosomal assignments of the human endothelin family genes: The endothelin- 1 gene (EDN1) to 6p23–p24, the endothelin-2 gene (EDN2) to 1p34, and the endothelin-3 gene (EDN3) to 20q13.2–q13.3. Am J Hum Genet 1991; 48 (5): 990–6PubMedGoogle Scholar
  4. 4.
    Eid H, de Bold ML, Chen JH, et al. Epicardial mesothelial cells synthesize and release endothelin. J Cardiovasc Pharmacol 1994; 24 (5): 715–20PubMedCrossRefGoogle Scholar
  5. 5.
    Kohan DE. Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis 1993; 22 (4): 493–510PubMedGoogle Scholar
  6. 6.
    Rossi GP, Colona S, Pavan E, et al. Endothelin-1 and its mRNA in the wall layers of human arteries ex vivo. Circulation 1999; 99 (9): 1147–55PubMedCrossRefGoogle Scholar
  7. 7.
    Brown MA, Smith PL. Endothelin: a potent stimulator of intestinal ion secretion in vitro. Regul Pept 1991; 36 (1): 1–19PubMedCrossRefGoogle Scholar
  8. 8.
    Garvin J, Sanders K. Endothelin inhibits fluid and bicarbonate transport in part by reducing Na+/K+ ATPase activity in the rat proximal straight tubule. J Am Soc Nephrol 1991; 2 (5): 976–82PubMedGoogle Scholar
  9. 9.
    Haynes WG, Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens 1998; 16 (8): 1081–98PubMedCrossRefGoogle Scholar
  10. 10.
    Arai H, Hori S, Aramori I, et al. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348 (6303): 730–2PubMedCrossRefGoogle Scholar
  11. 11.
    Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a non-isopeptide selective subtype of the endothelin receptor. Nature 1990; 348 (6303): 732–5PubMedCrossRefGoogle Scholar
  12. 12.
    Ogawa Y, Nakao K, Arai H, et al. Molecular cloning of a nonisopeptide- selective human endothelin receptor. Biochem Biophys Res Commun 1991; 178 (1): 248–255PubMedCrossRefGoogle Scholar
  13. 13.
    Karet F, Kuc R, Davenport A. Novel ligands BQ 123 and BQ 3020 characterise endothelin receptor subtypes ETA and ETB in human kidney. Kidney Int 1993; 44 (1): 36–42PubMedCrossRefGoogle Scholar
  14. 14.
    Gray GA, Webb DJ. The endothelin system and its potential as a therapeutic target in cardiovascular disease. Pharmacol Ther 1996; 72 (2): 109–48PubMedCrossRefGoogle Scholar
  15. 15.
    Douglas SA. Clinical development of endothelin receptor antagonists. Trends Pharmacol Sci 1997; 18 (11): 408–12PubMedCrossRefGoogle Scholar
  16. 16.
    Fukami T, Niiyami K, Amano Y, et al. Cyclic pentapeptide endothelin A receptor antagonists with attenuated in vivo clearance. Chem Pharm Bull 1996; 44 (3): 609–14PubMedCrossRefGoogle Scholar
  17. 17.
    Webb ML, Meek TD. Inhibitors of endothelin. Med Res Rev 1997; 17 (1): 17–67PubMedCrossRefGoogle Scholar
  18. 18.
    Liu G, Henry Jr KJ, Szczepankiewicz BG, et al. Pyrrolidine-3-carboxylic acids as endothelin antagonists: 3. Discovery of a potent, 2-nonaryl, highly selective ETA antagonists (A-216546). J Med Chem 1998; 41 (17): 3261–75PubMedCrossRefGoogle Scholar
  19. 19.
    Wu C, Chan MF, Stavros F, et al. Discovery of TBC-11251, a potent, long-acting, orally active endothelin receptor-Aselective antagonist. J Med Chem 1997; 40 (11): 1690–7PubMedCrossRefGoogle Scholar
  20. 20.
    Hoshino T, Yamauchi R, Kikkawa K, et al. Pharmacological profile of T-0201, a highly potent and orally active endothelin receptor antagonist. J Pharmacol Exp Ther 1998; 286 (2): 643–9PubMedGoogle Scholar
  21. 21.
    Sorensen SS, Madsen JK, Pedersen EB. Systemic and renal effects of intravenous infusion of endothelin-1 in healthy human volunteers. Am J Physiol 1994; 266 (3 Pt 2): F411–8PubMedGoogle Scholar
  22. 22.
    Cirino M, Martin E, Yano M, et al. Cardiovascular and renal actions of the endothelin (B) receptor in pigs. J Cardiovasc Pharmacol 1997; 29 (6): 704–12PubMedCrossRefGoogle Scholar
  23. 23.
    Moravec CS, Reynolds EE, Stewart RW, et al. Endothelin is a positive inotropic agent in human and rat heart in vitro. Biochem Biophys Res Commun 1989; 159 (1): 14–8PubMedCrossRefGoogle Scholar
  24. 24.
    Pieske B, Beyermann B, Breu V, et al. Functional effects of endothelin regulation of endothelin receptors in isolated human nonfailing and failingmyocardium. Circulation 1999; 99 (14): 1082–9CrossRefGoogle Scholar
  25. 25.
    Beyer ME, Slesak G, Hovelborn T, et al. Inotropic effects of endothelin-1. Interaction withmolsidomine and with BQ 610. Hypertension 1999; 33 (1): 145–52PubMedCrossRefGoogle Scholar
  26. 26.
    Rabelink TJ, Kaasjager KA, Boer P, et al. Effects of endothelin- 1 on renal function in humans: Implications for physiology and pathophysiology. Kidney Int 1994; 46 (2): 376–81PubMedCrossRefGoogle Scholar
  27. 27.
    Kruger D, Sheikzadeh A, Giannitsis E, et al. Cardiac release and kinetics of endothelin after severe short-lasting myocardial ischaemia. J Am Coll Cardiol 1997; 30 (4): 942–6PubMedCrossRefGoogle Scholar
  28. 28.
    Yasuda M, Kohno M, Tahara A, et al. Circulating immunoreactive endothelin in ischaemic heart disease. Am Heart J 1990; 119 (4): 801–6PubMedCrossRefGoogle Scholar
  29. 29.
    Toyo-oka T, Aizawa T, Suzuki N, et al. Increased plasma level of endothelin-1 and coronary spasminduction in patientswith vasospastic angina pectoris. Circulation 1991; 83 (2): 476–83PubMedCrossRefGoogle Scholar
  30. 30.
    Ray SG, McMurray JJ, Morton JJ, et al. Circulating endothelin in acute ischaemic syndromes. Br Heart J 1992; 67 (5): 383–6PubMedCrossRefGoogle Scholar
  31. 31.
    Wieczorek I, Haynes WG, Webb DJ, et al. Raised plasma endothelin in unstable angina and non-Q wave myocardial infarction: relation to cardiovascular outcome. Br Heart J 1994; 72 (5): 436–41PubMedCrossRefGoogle Scholar
  32. 32.
    Omland T, Lie RT, Aakvaag A, et al. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 1994; 89 (4): 1573–9PubMedCrossRefGoogle Scholar
  33. 33.
    Richards AM, Webb DJ, Yandle TG, et al. Comparison of amino terminal pro-brain natriuretic peptide and big endothelin-1 as prognostic indicators after myocardial infarction [abstract]. J Am Coll Cardiol 1999; 33 (2 Suppl. A): 194AGoogle Scholar
  34. 34.
    Seo B, Oemar BS, Siebenmann R, et al. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994; 89 (3): 1203–8PubMedCrossRefGoogle Scholar
  35. 35.
    Awane-Igata Y, Ikeda S, Watanabe T. Inhibitory effects of TAK- 044 on endothelin induced vasoconstriction in various canine arteries and porcine coronary arteries: a comparison with selective ETA and ETB receptor antagonists. Br J Pharmacol 1997; 120 (3): 516–22PubMedCrossRefGoogle Scholar
  36. 36.
    Wenzel RR, Fleisch M, Shaw S, et al. Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease. Circulation 1998; 98 (21): 2235–40PubMedCrossRefGoogle Scholar
  37. 37.
    Grover GJ, Dzonczyk S, Parham CS. The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion. Cardiovasc Res 1993; 27 (9): 1613–8PubMedCrossRefGoogle Scholar
  38. 38.
    Watanabe T, Awane Y, Ikeda S, et al. Pharmacology of a nonselective ETA and ETB receptor antagonist, TAK 044 and the inhibition of myocardial infarct size in rats. Br J Pharmacol 1995; 114 (5): 949–54PubMedCrossRefGoogle Scholar
  39. 39.
    Lerman A, Edwards BS, Hallett JW, et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991; 325 (14): 997–1001PubMedCrossRefGoogle Scholar
  40. 40.
    Zeiher AM, Gobel H, Schachinger V, et al. Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque. A clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina. Circulation 1995; 91 (4): 941–7PubMedCrossRefGoogle Scholar
  41. 41.
    Kowala MC, Rose PM, Stein PD, et al. Selective blockade of the endothelin subtype Areceptor decreases early atherosclerosis in hamsters fed cholesterol. Am J Pathol 1995; 146 (4): 819–26PubMedGoogle Scholar
  42. 42.
    Barton M, Haudenschild CC, D’Uscio LV, et al. Endothelin ET(A) receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 1998; 95(24): 14367–72PubMedCrossRefGoogle Scholar
  43. 43.
    Best PJM, McKenna CJ, Hasdai D, et al. Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolaemia. Circulation 1999; 99 (13): 1747–52PubMedCrossRefGoogle Scholar
  44. 44.
    Hirata Y, Takagi Y, Fukuda Y, et al. Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 1989; 78 (2–3): 225–8PubMedCrossRefGoogle Scholar
  45. 45.
    Weissberg PL, Witchell C, Davenport AP, et al. The endothelin peptides ET-1, ET-2, ET-3 and sarafotoxin S6b are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells. Atherosclerosis 1990; 85 (2–3): 257–62PubMedCrossRefGoogle Scholar
  46. 46.
    Wang X, Douglas SA, Louden C, et al. Expression of endothelin-1, endothelin-3, endothelin-converting enzyme-1, and endothelin- A and endothelin-B receptor mRNAs after angioplasty induced neointimal formation in the rat. Circ Res 1996; 78 (2): 322–8PubMedCrossRefGoogle Scholar
  47. 47.
    Douglas SA, Louden C, Vickery-Clark LM, et al. A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Protective effects of the novel non-peptide endothelin receptor antagonist SB 209670. Circ Res 1994; 75 (1): 190–7PubMedCrossRefGoogle Scholar
  48. 48.
    Tahara A, Kohno M, Yanagai S, et al. Circulating immunoreactive endothelin in patients undergoing percutaneous transluminal coronary angioplasty. Metabolism 1991; 40 (12): 1235–7PubMedCrossRefGoogle Scholar
  49. 49.
    Hasdai D, Holmes DRJ, Garratt KN, et al.Mechanical pressure and stretch release endothelin-1 from human atherosclerotic coronary arteries in vivo. Circulation 1997; 95 (2): 357–62PubMedCrossRefGoogle Scholar
  50. 50.
    Douglas SA, Vickery-Clarke LM, Louden C, et al. Endothelin receptor subtypes in the pathogenesis of angioplasty-induced neointima formation in the rat: a comparison of selective ETA receptor antagonism and dual ETA/ETB receptor antagonism using BQ-123 and SB 209670. J Cardiovasc Pharmacol 1995; 26 (3 Suppl.): S186–9Google Scholar
  51. 51.
    Chandra S, Sarkar S, Elliott JD, et al. Application of magnetic resonance imaging for evaluation of the efficacy of SB 217242 in neointimal formation. J Cardiovasc Pharmacol 1998; 31 (1 Suppl.): S317–9CrossRefGoogle Scholar
  52. 52.
    McKenna CJ, Burke SE, Opgenorth TJ, et al. Selective ET(A) receptor antagonism reduces neointimal hyperplasia in a porcine coronary stent model. Circulation 1998; 97 (25): 2551–6PubMedCrossRefGoogle Scholar
  53. 53.
    Douglas SA, Nichols AJ, Feuerstein GZ, et al. SB 209670 inhibits the arrhythmogenic actions of endothelin-1 in the anesthetized dog. J Cardiovasc Pharmacol 1998; 31 (1 Suppl.): S99–102CrossRefGoogle Scholar
  54. 54.
    Raschack M, Juchelka F, Rozek-Schaefer G. The endothelin-A antagonist LU 135 252 suppresses ischaemic extrasystoles and fibrillation in pigs and prevents hypoxic cellular decoupling. J Cardiovasc Pharmacol 1998; 31 (1 Suppl.): S145–8CrossRefGoogle Scholar
  55. 55.
    Garjani A, Wainwright CL, Zeitlin I, et al. Effects of endothelin- 1 and the ET(A) receptor antagonist BQ-123, on ischaemic arrhythmias in anesthetized rats. J Cardiovasc Pharmacol 1995; 25 (4): 634–42PubMedCrossRefGoogle Scholar
  56. 56.
    Kramer BK, Ittner ME, Beyer ME, et al. Circulatory and myocardial effects of endothelin. J Mol Med 1997; 75 (11–12): 886–90PubMedGoogle Scholar
  57. 57.
    Prasad MR. Endothelin stimulates degradation of phospholipids in isolated rat hearts. Biochem Biophys Res Commun 1991; 174 (2): 952–7PubMedCrossRefGoogle Scholar
  58. 58.
    Sakai S, Miyauchi T, Kobayashi M, et al. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 1996; 384 (6607): 353–5PubMedCrossRefGoogle Scholar
  59. 59.
    Sakai S, Miyauchi T, Sakurai T, et al. Endogenous endothelin-1 participates in themaintenance of cardiac function in ratswith congestive heart failure. Marked increase in endothelin-1 production in the failing heart. Circulation 1996; 93 (6): 1214–22PubMedCrossRefGoogle Scholar
  60. 60.
    Wei CM, Clavell AL, Burnett JCJ. Atrial and pulmonary endothelin mRNA is increased in a canine model of chronic low cardiac output. Am J Physiol 1997; 273 (2–2): R838–44PubMedGoogle Scholar
  61. 61.
    Tonnessen T, Lunde PK, Giaid A, et al. Pulmonary and cardiac expression of preproendothelin-1 mRNA are increased in heart failure after myocardial infarction in rats. Localization of preproendothelin- 1 mRNA and endothelin peptide. Cardiovasc Res 1998; 39 (3): 633–43PubMedCrossRefGoogle Scholar
  62. 62.
    Iwanaga Y, Kihara Y, Hasegawa K, et al. Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats. Circulation 1998; 98 (19): 2065–73PubMedCrossRefGoogle Scholar
  63. 63.
    Teerlink JR, Breu V, Sprecher U, et al. Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries. Circ Res 1994; 74 (1): 105–14PubMedCrossRefGoogle Scholar
  64. 64.
    Cannan CR, Burnett Jr JC, Lerman A. Enhanced coronary vasoconstriction to endothelin-B-receptor activation in experimental congestive heart failure. Circulation 1996; 93 (4): 646–51PubMedCrossRefGoogle Scholar
  65. 65.
    Love MP, Haynes WG, Gray GA, et al. Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation 1996; 94 (9): 2131–7PubMedCrossRefGoogle Scholar
  66. 66.
    Kelso EJ, Geraghty RF, McDermott BJ, et al. Mechanical effects of ET-1 in cardiomyocytes isolated from normal and heartfailed rabbits. Mol Cell Biochem 1996; 157 (1–2): 149–55PubMedGoogle Scholar
  67. 67.
    Thomas PB, Liu EC, Webb ML, et al. Exogenous effects and endogenous production of endothelin in cardiac myocytes: potential significance in heart failure. AmJ Physiol 1996; 271 (6 Pt 2): H2629–37Google Scholar
  68. 68.
    Mulder P, Richard V, Derumeaux G, et al. Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodelling. Circulation 1997; 96 (6): 1976–82PubMedCrossRefGoogle Scholar
  69. 69.
    Shen Y-T, Buie P, Moussa T, et al. Chronic therapy with L-753,037, an ETA/B receptor antagonist, in conscious dogs during development of heart failure [abstract]. Circulation 1998; 98 (17 Suppl. I): I–578Google Scholar
  70. 70.
    Pacher R, Bergler-Klein J, Globits S, et al. Plasma big endothelin- 1 concentrations in congestive heart failure patients with or without systemic hypertension. Am J Cardiol 1993; 71(15): 1293–9PubMedCrossRefGoogle Scholar
  71. 71.
    Wei CM, Lerman A, Rodeheffer RJ, et al. Endothelin in human congestive heart failure. Circulation 1994; 89 (4): 1580–6PubMedCrossRefGoogle Scholar
  72. 72.
    Kiowski W, Sütsch G, Hunziker P, et al. Evidence for endothelin- 1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995; 346 (8977): 732–6PubMedCrossRefGoogle Scholar
  73. 73.
    Sütsch G, Kiowski W, Yan X-W, et al. Short-term oral endothelinreceptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998; 98 (1): 2262–8PubMedCrossRefGoogle Scholar
  74. 74.
    Packer M, Caso A, Charlton V, et al. Multicenter, double-blind, placebo-controlled study of long-term endothelin blockade with Bosentan in chronic heart failure — results of theREACH-1 trial [abstract]. Circulation 1998; 98 (17 Suppl. I): I–3Google Scholar
  75. 75.
    Cowburn PJ, Cleland JGF, McArthur JD, et al. Short-term haemodynamic effects of BQ-123, a selective endothelin ETA-receptor antagonist, in chronic heart failure. Lancet 1998; 352 (9123): 201–2PubMedCrossRefGoogle Scholar
  76. 76.
    Cowburn PJ, Cleland JGF, McDonagh TA, et al. Adverse hemodynamic effects of a selective endothelin ETB receptor antagonist in patients with chronic heart failure: reversal with a selective endothelin ETA receptor antagonist. Circulation 1998; 98 (17 Suppl. I): I–718Google Scholar
  77. 77.
    Givertz MM, Colucci WS, Gottlieb SS, et al. Acute ETA receptor blockade reduces pulmonary vascular resistance in patients with chronic heart failure [abstract]. Circulation 1998; 98 (17 Suppl. I): I–578Google Scholar
  78. 78.
    Webb DJ, Monge JC, Rabelink TJ, et al. Endothelin: new discoveries and rapid progress in the clinic. Trends Pharmacol Sci 1998; 19 (1): 5–8PubMedCrossRefGoogle Scholar
  79. 79.
    Rakugi H, Tabuchi Y, Nakamaru M, et al. Endothelin activates the vascular renin-angiotensin system in rat mesenteric arteries. Biochem Int 1990; 21 (5): 867–72PubMedGoogle Scholar
  80. 80.
    Ferro CJ, Webb DJ. The clinical potential of endothelin receptor antagonists in cardiovascular medicine. Drugs 1996; 51 (1): 12–27PubMedCrossRefGoogle Scholar
  81. 81.
    Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994; 344 (8926): 852–4PubMedCrossRefGoogle Scholar
  82. 82.
    Haynes WG, Strachan FE, Webb DJ. Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 1995; 92 (3): 357–63PubMedCrossRefGoogle Scholar
  83. 83.
    Haynes WG, Strachan FE, Gray GA, et al. Forearm vasoconstriction to endothelin-1 is mediated by ETA and ETB receptors in vivo in humans. J Cardiovasc Pharmacol 1995; 26 (3 Suppl.): S40–3Google Scholar
  84. 84.
    Verhaar MC, Strachan FE, Newby DE, et al. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 1998; 97 (8): 752–6PubMedCrossRefGoogle Scholar
  85. 85.
    Haynes WG, Ferro CJ, O’Kane KPJ, et al. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 1996; 93 (10): 1860–70PubMedCrossRefGoogle Scholar
  86. 86.
    Strachan FE, Spratt JC, Wilkinson IB, et al. Systemic blockade of the endothelin-B receptor increases peripheral resistance in healthy men. Hypertension 1999; 33 (1 Pt 2): 581–5PubMedCrossRefGoogle Scholar
  87. 87.
    Spratt JC, Goddard J, Labinjoh C, et al. Systemic blockade of the ETA receptor decreases peripheral vascular resistance in healthy men [abstract]. Br J Clin Pharmacol 1999; 47: 575PGoogle Scholar
  88. 88.
    Schiffrin EL. Endothelin and endothelin antagonists in hypertension. J Hypertens 1998; 16 (12II): 1891–5PubMedCrossRefGoogle Scholar
  89. 89.
    Goddard J, Webb DJ. Plasma endothelin concentrations in hypertension. J Cardiovasc Pharmacol 1999. In pressGoogle Scholar
  90. 90.
    Cardillo C, Kilcoyne CM, Quyyumi AA, et al. Selective defect in nitric oxide synthesis may explain the impaired endothelium- dependent vasodilation in patients with essential hypertension. Circulation 1998; 97 (9): 851–6PubMedCrossRefGoogle Scholar
  91. 91.
    Cardillo C, Kilcoyne CM, Cannon RO, et al. Attenuation of cyclic nucleotide-mediated smooth muscle relaxation in blacks as a cause of racial differences in vasodilator function. Circulation 1999; 99 (1): 90–5PubMedCrossRefGoogle Scholar
  92. 92.
    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): 753–8PubMedCrossRefGoogle Scholar
  93. 93.
    Krum H, Viskoper RJ, Lacourciere Y, et al. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. N Engl J Med 1998; 338 (12): 784–90PubMedCrossRefGoogle Scholar
  94. 94.
    Barone FC, White RF, Elliot JD, et al. The endothelin receptor antagonist SB 217242 reduces cerebral focal ischaemic brain injury. J Cardiovasc Pharmacol 1995; 26 (3 Suppl.): S404–7Google Scholar
  95. 95.
    Roux S, Breu V, Giller T, et al. Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther 1997; 283 (3): 1110–8PubMedGoogle Scholar
  96. 96.
    Dawson DA, Hallenbeck JM, Spatz M. The endothelin antagonist Ro 61-1790 attenuates focal cerebral ischaemic injury. Stroke 1998; 29: 323CrossRefGoogle Scholar
  97. 97.
    Frasch HF, Marshall C, Marshall BE. Endothelin-1 is elevated in monocrotaline pulmonary hypertension. Am J Physiol 1999; 276 (2 Pt 1): L304–10PubMedGoogle Scholar
  98. 98.
    Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin- 1 in pulmonary hypertension: marker or mediator of disease? Ann Int Med 1991; 114: 464–9PubMedGoogle Scholar
  99. 99.
    Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin- 1 in lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328 (24): 1732–9PubMedCrossRefGoogle Scholar
  100. 100.
    Franco-Cereceda A, Holm P. Selective or nonselective endothelin antagonists in porcine hypoxic pulmonary hypertension. J Cardiovasc Pharmacol 1998; 31 Suppl. 1: S447–52CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Clinical Pharmacology Unit & Research Centre, Department of Medical SciencesUniversity of Edinburgh, Western General HospitalEdinburghScotland

Personalised recommendations