American Journal of Cardiovascular Drugs

, Volume 1, Issue 4, pp 293–303 | Cite as

Therapeutic Potential for Endothelin Receptor Antagonists in Cardiovascular Disorders

  • Lukas E. Spieker
  • Georg Noll
  • Thomas F. Lüscher
Review Article


The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from ‘big endothelins’ originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ETA and ETB receptors on vascular smooth muscle cells. In contrast, ETB receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin.

Additionally, ETB receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ETA receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ETA/B as well as selective ETA receptor antagonism ameliorates the clinical status of patients, i. e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ETA/B receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ETA/B receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.


  1. 1.
    Barton M, Haudenschild CC, d’Uscio LV, et al. Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 1998; 95: 14367–72PubMedCrossRefGoogle Scholar
  2. 2.
    Sakai S, Miyauchi T, Kobayashi M, et al. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 1996; 384: 353–5PubMedCrossRefGoogle Scholar
  3. 3.
    MacCarthy PA, Grocott-Mason R, Prendergast BD, et al. Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ET(A) receptor antagonist. Circulation 2000; 101: 142–7PubMedCrossRefGoogle Scholar
  4. 4.
    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 Cardiol 2000; 35: 1745–52PubMedCrossRefGoogle Scholar
  5. 5.
    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; 328:1732–9PubMedCrossRefGoogle Scholar
  6. 6.
    Channick R, Badesch DB, Tapson VF, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a placebocontrolled study. J Heart Lung Transplant 2001; 20: 262–3PubMedCrossRefGoogle Scholar
  7. 7.
    Fleminger G, Bousso-Mittler D, Bdolah A, et al. Immunological and structural characterization of sarafotoxin/endothelin family of peptides. Biochem Biophys Res Commun 1989; 162: 1317–23PubMedCrossRefGoogle Scholar
  8. 8.
    Kloog Y, Bousso-Mittler D, Bdolah A, et al. Three apparent receptor subtypes for the endothelin/sarafotoxin family. FEBS Lett 1989; 253: 199–202PubMedCrossRefGoogle Scholar
  9. 9.
    Kloog Y, Ambar I, Sokolovsky M, et al. Sarafotoxin, a novel vasoconstrictor peptide: phosphoinositide hydrolysis in rat heart and brain. Science 1988; 242: 268–70PubMedCrossRefGoogle Scholar
  10. 10.
    Ikegawa R, Matsumura Y, Tsukahara Y, et al. Phosphoramidon, a metalloproteinase inhibitor, suppresses the secretion of endothelin-1 from cultured endothelial cells by inhibiting a big endothelin-1 converting enzyme. Biochem Biophys Res Commun 1990; 171: 669–75PubMedCrossRefGoogle Scholar
  11. 11.
    Takahashi M, Matsushita Y, Iijima Y, et al. Purification and characterization of endothelin-converting enzyme from rat lung. J Biol Chem 1993; 268: 21394–8PubMedGoogle Scholar
  12. 12.
    Ohnaka K, Takayanagi R, Nishikawa M, et al. Purification and characterization of a phosphoramidon-sensitive endothelin-converting enzyme in porcine aortic endothelium. J Biol Chem 1993; 268: 26759–66PubMedGoogle Scholar
  13. 13.
    Shimada K, Takahashi M, Tanzawa K. Cloning and functional expression of endothelin-converting enzyme from rat endothelial cells. J Biol Chem 1994; 269: 18275–8PubMedGoogle Scholar
  14. 14.
    Inoue A, Yanagisawa M, Takuwa Y, et al. The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression. J Biol Chem 1989; 264: 14954–9PubMedGoogle Scholar
  15. 15.
    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 USA 1989; 86: 2863–7PubMedCrossRefGoogle Scholar
  16. 16.
    Boulanger C, Lüscher TF. Release of endothelin from the porcine aorta. Inhibition of endothelium-derived nitric oxide. J Clin Invest 1990; 85: 587–90PubMedCrossRefGoogle Scholar
  17. 17.
    Boulanger CM, Tanner FC, Bea ML, et al. Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium. Circ Res 1992; 70: 1191–7PubMedCrossRefGoogle Scholar
  18. 18.
    Yoshizumi M, Kurihara H, Sugiyama T, et al. Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. Biochem Biophys Res Commun 1989; 161: 859–64PubMedCrossRefGoogle Scholar
  19. 19.
    Kourembanas S, Marsden PA, McQuillan LP, et al. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest 1991; 88: 1054–7PubMedCrossRefGoogle Scholar
  20. 20.
    Shirakami G, Nakao K, Saito Y, et al. Acute pulmonary alveolar hypoxia increases lung and plasma endothelin-1 levels in conscious rats. Life Sci 1991; 48: 969–76PubMedCrossRefGoogle Scholar
  21. 21.
    Hieda HS, Gomez-Sanchez CE. Hypoxia increases endothelin release in bovine endothelial cells in culture, but epinephrine, norepinephrine, serotonin, histamine and angiotensin II do not. Life Sci 1990; 47: 247–51PubMedCrossRefGoogle Scholar
  22. 22.
    Kohno M, Murakawa K, Yokokawa K, et al. Production of endothelin by cultured porcine endothelial cells: modulation by adrenaline. J Hypertens 1989; 7 Suppl.: S130–1Google Scholar
  23. 23.
    Ohta K, Hirata Y, Imai T, et al. Cytokine-induced release of endothelin-1 from porcine renal epithelial cell line. Biochem Biophys Res Commun 1990; 169: 578–84PubMedCrossRefGoogle Scholar
  24. 24.
    Kanse SM, Takahashi K, Lam HC, et al. Cytokine stimulated endothelin release from endothelial cells. Life Sci 1991; 48: 1379–84PubMedCrossRefGoogle Scholar
  25. 25.
    Miyamori I, Takeda Y, Yoneda T, et al. Interleukin-2 enhances the release of endothelin-1 from the rat mesenteric artery. Life Sci 1991; 49: 1295–300PubMedCrossRefGoogle Scholar
  26. 26.
    Woods M, Bishop-Bailey D, Pepper JR, et al. Cytokine and lipopolysaccharide stimulation of endothelin-1 release from human internal mammary artery and saphenous vein smooth-muscle cells. J Cardiovasc Pharmacol 1998; 31 Suppl. 1: S348–50PubMedCrossRefGoogle Scholar
  27. 27.
    Dohi Y, Hahn AW, Boulanger CM, et al. Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries. Hypertension 1992; 19: 131–7PubMedCrossRefGoogle Scholar
  28. 28.
    Macarthur H, Warner TD, Wood EG, et al. Endothelin-1 release from endothelial cells in culture is elevated both acutely and chronically by short periods of mechanical stretch. Biochem Biophys Res Commun 1994; 200: 395–400PubMedCrossRefGoogle Scholar
  29. 29.
    Barton M, Shaw S, d’Uscio LV, et al. Angiotensin II increases vascular and renal endothelin-1 and functional endothelin converting enzyme activity in vivo: role of ETA receptors for endothelin regulation. Biochem Biophys Res Commun 1997; 238: 861–5PubMedCrossRefGoogle Scholar
  30. 30.
    Abassi ZA, Tate JE, Golomb E, et al. Role of neutral endopeptidase in the metabolism of endothelin. Hypertension 1992; 20: 89–95PubMedCrossRefGoogle Scholar
  31. 31.
    Abassi ZA, Golomb E, Bridenbaugh R, et al. Metabolism of endothelin-1 and big endothelin-1 by recombinant neutral endopeptidase EC. Br J Pharmacol 1993; 109: 1024–8PubMedCrossRefGoogle Scholar
  32. 32.
    Hirata Y, Takagi Y, Fukuda Y, et al. Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 1989; 78: 225–8PubMedCrossRefGoogle Scholar
  33. 33.
    Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a nonisopeptide-selective subtype of the endothelin receptor. Nature 1990; 348:732–5PubMedCrossRefGoogle Scholar
  34. 34.
    Sumner MJ, Cannon TR, Mundin JW, et al. Endothelin ETA and ETB receptors mediate vascular smooth muscle cell contraction. Br J Pharmacol 1992; 107: 858–60PubMedCrossRefGoogle Scholar
  35. 35.
    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: 1203–8PubMedCrossRefGoogle Scholar
  36. 36.
    Arai H, Hori S, Aramori I, et al. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348: 730–2PubMedCrossRefGoogle Scholar
  37. 37.
    Lin HY, Kaji EH, Winkel GK, et al. Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor. Proc Natl Acad Sci USA 1991; 88: 3185–9PubMedCrossRefGoogle Scholar
  38. 38.
    Davenport AP, O’Reilly G, Molenaar P, et al. Human endothelin receptors characterized using reverse transcriptase-polymerase chain reaction, in situ hybridization, and subtyper-selective ligands BQ123 and BQ3020: evidence for expression of (B) receptors in human vascular smooth muscle. J Cardiovasc Pharmacol 1993; 22 Suppl. 8: S22–5PubMedCrossRefGoogle Scholar
  39. 39.
    Clozel M, Gray GA, Breu V, et al. The endothelin ET(B) receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun 1992; 186: 867–73PubMedCrossRefGoogle Scholar
  40. 40.
    Haynes WG, Strachan FE, Webb DJ. Endothelin ET(A) and ET(B) receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 1995; 92: 357–63PubMedCrossRefGoogle Scholar
  41. 41.
    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: 752–6PubMedCrossRefGoogle Scholar
  42. 42.
    Dupuis J, Goresky CA, Fournier A. Pulmonary clearance of circulating endothelin1 in dogs in vivo: exclusive role of ETB receptors. J Appl Physiol 1996; 81: 1510–5PubMedGoogle Scholar
  43. 43.
    Dupuis J, Stewart DJ, Cernacek P, et al. Human pulmonary circulation is an important site for both clearance and production of endothelin-1. Circulation 1996; 94: 1578–84PubMedCrossRefGoogle Scholar
  44. 44.
    Ozaki S, Ohwaki K, Ihara M, et al. B-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Comm 1995; 209: 483–9PubMedCrossRefGoogle Scholar
  45. 45.
    Fukuroda T, Fujikawa T, Ozaki S, et al. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun 1994; 199: 1461–5PubMedCrossRefGoogle Scholar
  46. 46.
    Hahn AW, Resink TJ, Scott-Burden T, et al. Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell Regul 1990; 1: 649–59PubMedGoogle Scholar
  47. 47.
    Eguchi S, Hirata Y, Imai T, et al. Endothelin-1 as an autocrine growth factor for endothelial cells. J Cardiovasc Pharmacol 1995; 26: S279–83PubMedGoogle Scholar
  48. 48.
    Alberts GF, Peifley KA, Johns A, et al. Constitutive endothelin-1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop. J Biol Chem 1994; 269: 10112–8PubMedGoogle Scholar
  49. 49.
    Iwasaki S, Homma T, Matsuda Y, et al. Endothelin receptor B subtype B mediates autoinduction of endothelin-1 in rat mesangial cells. J Biol Chem 1995; 270: 6997–7003PubMedCrossRefGoogle Scholar
  50. 50.
    Ohnishi A, Yamaguchi K, Kusuhara M, et al. Mobilization of intracellular calcium by endothelin in Swiss 3T3 cells. Biochem Biophys Res Commun 1989; 161: 489–95PubMedCrossRefGoogle Scholar
  51. 51.
    Nilsson J, Sjolund M, Palmberg L, et al. The calcium antagonist nifedipine inhibits arterial smooth muscle cell proliferation. Atherosclerosis 1985; 58: 109–22PubMedCrossRefGoogle Scholar
  52. 52.
    Yang Z, Bauer E, von Segesser L, et al. Different mobilization of calcium in endothelin-1-induced contractions in human arteries and veins: effects of calcium antagonists. J Cardiovasc Pharmacol 1990; 16: 654–60PubMedCrossRefGoogle Scholar
  53. 53.
    Yang ZH, Richard V, von Segesser L, et al. Threshold concentrations of endothelin1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm?. Circulation 1990; 82: 188–95PubMedCrossRefGoogle Scholar
  54. 54.
    Kiowski W, Lüscher TF, Linder L, et al. Endothelin-1-induced vasoconstriction in humans. Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor. Circulation 1991; 83: 469–75PubMedCrossRefGoogle Scholar
  55. 55.
    Wenzel RR, Duthiers N, Noll G, et al. Endothelin and calcium antagonists in the skin microcirculation of patients with coronary artery disease. Circulation 1996; 94: 316–22PubMedCrossRefGoogle Scholar
  56. 56.
    Wagner OF, Christ G, Wojta J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992; 267: 16066–8PubMedGoogle Scholar
  57. 57.
    Sorensen SS. Radio-immunoassay of endothelin in human plasma. Scand J Clin Lab Invest 1991; 51: 615–23PubMedCrossRefGoogle Scholar
  58. 58.
    Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994; 344: 852–4PubMedCrossRefGoogle Scholar
  59. 59.
    Lysko PG, Feuerstein G, Pullen M, et al. Identification of endothelin receptors in cultured cerebellar neurons. Neuropeptides 1991; 18: 83–6PubMedCrossRefGoogle Scholar
  60. 60.
    Nambi P, Pullen M, Feuerstein G. Identification of endothelin receptors in various regions of rat brain. Neuropeptides 1990; 16: 195–9PubMedCrossRefGoogle Scholar
  61. 61.
    Knuepfer MM, Han SP, Trapani AJ, et al. Regional hemodynamic and baroreflex effects of endothelin in rats. Am J Physiol 1989; 257: H918–26PubMedGoogle Scholar
  62. 62.
    Gardiner SM, Compton AM, Kemp PA, et al. Regional and cardiac haemodynamic responses to glyceryl trinitrate, acetylcholine, bradykinin and endothelin-1 in conscious rats: effects of NG-nitro-L-arginine methyl ester. Br J Pharmacol 1990; 101: 632–9PubMedCrossRefGoogle Scholar
  63. 63.
    Nakamoto H, Suzuki H, Murakami M, et al. Different effects of low and high doses of endothelin on haemodynamics and hormones in the normotensive conscious dog. J Hypertens 1991; 9: 337–44PubMedCrossRefGoogle Scholar
  64. 64.
    Donckier JE, Hanet C, Berbinschi A, et al. Cardiovascular and endocrine effects of endothelin-1 at pathophysiological and pharmacological plasma concentrations in conscious dogs. Circulation 1991; 84: 2476–84PubMedCrossRefGoogle Scholar
  65. 65.
    van den Buuse M, Itoh S. Central effects of endothelin on baroreflex of spontaneously hypertensive rats. J Hypertens 1993; 11: 379–87PubMedCrossRefGoogle Scholar
  66. 66.
    Kannan H, Tanaka H, Ueta Y, et al. Effects of centrally administered endothelin-3 on renal sympathetic nerve activity and renal blood flow in conscious rats. J Auton Nerv Syst 1994; 49: 105–13PubMedCrossRefGoogle Scholar
  67. 67.
    Chapleau MW, Hajduczok G, Abboud FM. Suppression of baroreceptor discharge by endothelin at high carotid sinus pressure. Am J Physiol 1992; 263: R103–8PubMedGoogle Scholar
  68. 68.
    Mosqueda-Garcia R, Appalsamy M, Fernandez-Violante R, et al. Modulatory effects of endothelin on baroreflex activation in the nucleus of the solitary tract. Eur J Pharmacol 1998; 351: 203–7PubMedCrossRefGoogle Scholar
  69. 69.
    Sorensen SS, Madsen JK, Pedersen EB. Systemic and renal effect of intravenous infusion of endothelin-1 in healthy human volunteers. Am J Physiol 1994; 266: F411–8PubMedGoogle Scholar
  70. 70.
    Kurihara Y, Kurihara H, Oda H, et al. Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1. J Clin Invest 1995; 96: 293–300PubMedCrossRefGoogle Scholar
  71. 71.
    Gariepy CE, Williams SC, Richardson JA, et al. Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease. J Clin Invest 1998; 102: 1092–101PubMedCrossRefGoogle Scholar
  72. 72.
    Hosoda K, Hammer RE, Richardson JA, et al. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 1994; 79: 1267–76PubMedCrossRefGoogle Scholar
  73. 73.
    Baynash AG, Hosoda K, Giaid A, et al. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 1994; 79: 1277–85PubMedCrossRefGoogle Scholar
  74. 74.
    Hofstra RM, Osinga J, Tan-Sindhunata G, et al. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah- Waardenburg syndrome). Nat Genet 1996; 12: 445–7PubMedCrossRefGoogle Scholar
  75. 75.
    Clouthier DE, Hosoda K, Richardson JA, et al. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 1998; 125: 813–24PubMedGoogle Scholar
  76. 76.
    Shin MK, Levorse JM, Ingram RS, et al. The temporal requirement for endothelin receptor-B signalling during neural crest development. Nature 1999; 402: 496–501PubMedCrossRefGoogle Scholar
  77. 77.
    Fant ME, Nanu L, Word RA. A potential role for endothelin-1 in human placental growth: interactions with the insulin-like growth factor family of peptides. J Clin Endocrinol Metab 1992; 74: 1158–63PubMedCrossRefGoogle Scholar
  78. 78.
    Linder L, Kiowski W, Bühler FR, et al. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation 1990; 81: 1762–7PubMedCrossRefGoogle Scholar
  79. 79.
    Panza JA, Quyyumi AA, Brush JJ, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323: 22–7PubMedCrossRefGoogle Scholar
  80. 80.
    Spieker LE, Noll G, Ruschitzka FT, et al. Working under pressure: the vascular endothelium in arterial hypertension. J Hum Hypertens 2000; 14: 617–30PubMedCrossRefGoogle Scholar
  81. 81.
    Lüscher TF, Vanhoutte PM. The Endothelium: modulator of cardiovascular function. Boca Raton (FL): CRC Press, 1990Google Scholar
  82. 82.
    Lüscher TF. Imbalance of endothelium-derived relaxing and contracting Factors. A new concept in hypertension?. Am J Hypertens 1990; 317: 317–30Google Scholar
  83. 83.
    Vierhapper H, Wagner O, Nowotny P, et al. Effect of endothelin-1 in man. Circulation 1990; 81: 1415–8PubMedCrossRefGoogle Scholar
  84. 84.
    Kiely DG, Cargill RI, Struthers AD, et al. Cardiopulmonary effects of endothelin-1 in man. Cardiovasc Res 1997; 33: 378–86PubMedCrossRefGoogle Scholar
  85. 85.
    Ito H, Hirata Y, Hiroe M, et al. ET-1 induces hypertrophy with enhanced expression of muscle specific genes in cultured neonatal rat cardiomyocytes. Circ Res 1991; 69: 209–15PubMedCrossRefGoogle Scholar
  86. 86.
    Barton M, d’Uscio LV, Shaw S, et al. ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in saltsensitive hypertension. Hypertension 1998; 31: 499–504PubMedCrossRefGoogle Scholar
  87. 87.
    Yang Z, Krasnici N, Lüscher TF. Endothelin-1 potentiates smooth muscle cell growth to PDGF: role of ETA and ETB receptor blockade. Circulation 1999; 100: 5–8PubMedCrossRefGoogle Scholar
  88. 88.
    Taddei S, Virdis A, Ghiadoni L, et al. Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation of patients with essential hypertension. Circulation 1999; 100: 1680–3PubMedCrossRefGoogle Scholar
  89. 89.
    Saito Y, Nakao K, Mukoyama M, et al. Increased plasma endothelin level in patients with essential hypertension [letter]. N Engl J Med 1990; 322: 205PubMedGoogle Scholar
  90. 90.
    Miyauchi T, Yanagisawa M, Iida K, et al. Age- and sex-related variation of plasma endothelin-1 concentration in normal and hypertensive subjects. Am Heart J 1992; 123: 1092–3PubMedCrossRefGoogle Scholar
  91. 91.
    Haynes WG, Ferro CJ, Webb DJ. Bosentan in essential hypertension [letter; comment]. N Engl J Med 1998; 339: 346; discussion 7PubMedCrossRefGoogle Scholar
  92. 92.
    Stevens PA, Brown MJ. Genetic variability of the ET-1 and the ETA receptor genes in essential hypertension. J Cardiovasc Pharmacol 1995; 26 Suppl. 3: S9–12PubMedGoogle Scholar
  93. 93.
    Tiret L, Poirier O, Hallet V, et al. The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 1999; 33: 1169–74PubMedCrossRefGoogle Scholar
  94. 94.
    Nicaud V, Poirier O, Behague I, et al. Polymorphisms of the endothelin-A and -B receptor genes in relation to blood pressure and myocardial infarction: the Etude Cas-Temoins sur l’Infarctus du Myocarde (ECTIM) Study. Am J Hypertens 1999; 12: 304–10PubMedCrossRefGoogle Scholar
  95. 95.
    Sharma P, Hingorani A, Jia H, et al. Quantitative association between a newly identified molecular variant in the endothelin-2 gene and human essential hypertension. J Hypertens 1999; 17: 1281–7PubMedCrossRefGoogle Scholar
  96. 96.
    d’Uscio LV, Moreau P, Shaw S, et al. Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension. Hypertension 1997; 29: 435–41PubMedCrossRefGoogle Scholar
  97. 97.
    Moreau P, Takase H, Kung CF, et al. Blood pressure and vascular effects of endothelin blockade in chronic nitric oxide-deficient hypertension. Hypertension 1997; 29: 763–9PubMedCrossRefGoogle Scholar
  98. 98.
    Li JS, Lariviere R, Schiffrin EL. Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats. Evidence for a role of endothelin in vascular hypertrophy. Hypertension 1994; 24: 183–8PubMedCrossRefGoogle Scholar
  99. 99.
    Li JS, Schurch W, Schiffrin EL. Renal and vascular effects of chronic endothelin receptor antagonism in malignant hypertensive rats [published erratum appears in Am J Hypertens 1996;9:1144-5]. Am J Hypertens 1996; 9: 803–11PubMedCrossRefGoogle Scholar
  100. 100.
    Chillon M, Heistad DD, Baumbach GL. Effects of endothelin receptor inhibition on cerebral arterioles in hypertensive rats. Hypertension 1996; 27: 794–8PubMedCrossRefGoogle Scholar
  101. 101.
    Moreau P, d’Uscio LV, Shaw S, et al. Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ET(A)-receptor antagonist. Circulation 1997; 96: 1593–7PubMedCrossRefGoogle Scholar
  102. 102.
    d’Uscio LV, Barton M, Shaw S, et al. Structure and function of small arteries in salt-induced hypertension: effects of chronic endothelin-subtype-A-receptor blockade. Hypertension 1997; 30: 905–11PubMedCrossRefGoogle Scholar
  103. 103.
    Ehmke H, Faulhaber J, Munter K, et al. Chronic ETA receptor blockade attenuates cardiac hypertrophy independently of blood pressure effects in renovascular hypertensive rats. Hypertension 1999; 33: 954–60PubMedCrossRefGoogle Scholar
  104. 104.
    Krum H, Viskoper RJ, Lacourciere Y, et al. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators. N Engl J Med 1998; 338: 784–90PubMedCrossRefGoogle Scholar
  105. 105.
    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–5PubMedCrossRefGoogle Scholar
  106. 106.
    Noll G, Wenzel RR, Schneider M, et al. Increased activation of sympathetic nervous system and endothelin by mental stress in normotensive offspring of hypertensive parents. Circulation 1996; 93: 866–72PubMedCrossRefGoogle Scholar
  107. 107.
    Ikeda U, Yamamoto K, Maeda Y, et al. Endothelin-1 inhibits nitric oxide synthesis in vascular smooth muscle cells. Hypertension 1997; 29: 65–9PubMedCrossRefGoogle Scholar
  108. 108.
    Kohno M, Yokokawa K, Yasunari K, et al. Effect of the endothelin family of peptides on human coronary artery smooth-muscle cell migration. J Cardiovasc Pharmacol 1998; 31: S84–9PubMedCrossRefGoogle Scholar
  109. 109.
    Lopez Farre A, Riesco A, Espinosa G, et al. Effect of endothelin-1 on neutrophil adhesion to endothelial cells and perfused heart. Circulation 1993; 88: 1166–71PubMedCrossRefGoogle Scholar
  110. 110.
    Knofler R, Urano T, Malyszko J, et al. In vitro effect of endothelin-1 on collagen, and ADP-induced aggregation in human whole blood and platelet rich plasma. Thromb Res 1995; 77: 69–78PubMedCrossRefGoogle Scholar
  111. 111.
    Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endotheliumderived relaxing factor. Am J Physiol 1986; 250: H1145–9PubMedGoogle Scholar
  112. 112.
    Lüscher TF, Yang Z, Tschudi M, et al. Interaction between endothelin-1 and endothelium-derived relaxing factor in human arteries and veins. Circ Res 1990; 66: 1088–94PubMedCrossRefGoogle Scholar
  113. 113.
    Joannides R, Haefeli WE, Linder L, et al. Nitric oxide is responsible for flowdependent dilatation of human peripheral conduit arteries in vivo. Circulation 1995; 91: 1314–9PubMedCrossRefGoogle Scholar
  114. 114.
    Yamauchi T, Ohnaka K, Takayanagi R, et al. Enhanced secretion of endothelin-1 by elevated glucose levels from cultured bovine endothelial cells. FEBS Lett 1990; 267: 16–8PubMedCrossRefGoogle Scholar
  115. 115.
    Yildiz L, Akcay F, Kaynar H, et al. Increased plasma endothelin-1 in heavy and light smokers [letter]. Clin Chem 1996; 42: 483–4PubMedGoogle Scholar
  116. 116.
    Lerman A, Edwards BS, Hallett JW, et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991; 325: 997–1001PubMedCrossRefGoogle Scholar
  117. 117.
    Rossi GP, Colonna S, Pavan E, et al. Endothelin-1 and its mRNA in the wall layers of human arteries ex vivo. Circulation 1999; 99: 1147–55PubMedCrossRefGoogle Scholar
  118. 118.
    Minamino T, Kurihara H, Takahashi M, et al. Endothelin-converting enzyme expression in the rat vascular injury model and human coronary atherosclerosis. Circulation 1997; 95: 221–30PubMedCrossRefGoogle Scholar
  119. 119.
    Ruschitzka F, Moehrlen U, Quaschning T, et al. Tissue endothelin-converting enzyme activity correlates with cardiovascular risk factors in coronary artery disease. Circulation 2000; 102: 1086–92PubMedCrossRefGoogle Scholar
  120. 120.
    Zeiher AM, Ihling C, Pistorius K, et al. Increased tissue endothelin immunoreactivity in atherosclerotic lesions associated with acute coronary syndromes. Lancet 1994; 344: 1405–6PubMedCrossRefGoogle Scholar
  121. 121.
    Zeiher AM, Goebel 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: 941–7PubMedCrossRefGoogle Scholar
  122. 122.
    Watanabe M, Yanagisawa M, Hamaguchi H, et al. TaqI polymorphism at the human preproendothelin-1 gene (EDN1). Nucleic Acids Res 1991; 19: 5099PubMedCrossRefGoogle Scholar
  123. 123.
    Hoehe MR, Ehrenreich H, Caenazzo L, et al. TaqI identifies a four allele DNA polymorphism of the human endothelin- 1 gene (EDN1). Nucleic Acids Res 1991; 19: 3161PubMedCrossRefGoogle Scholar
  124. 124.
    Berge KE, Berg K. A TaqI RFLP at the EDN1 gene locus. Nucleic Acids Res 1990; 18: 6176PubMedCrossRefGoogle Scholar
  125. 125.
    Pages JC, Drieu C, Blanche H, et al. A short tandem repeat polymorphism at the endothelin 1 (EDN1) locus. Hum Mol Genet 1993; 2: 90PubMedCrossRefGoogle Scholar
  126. 126.
    Charron P, Tesson F, Poirier O, et al. Identification of a genetic risk factor for idiopathic dilated cardiomyopathy. Involvement of a polymorphism in the endothelin receptor type A gene. CARDIGENE group. Eur Heart J 1999; 20: 1587–91PubMedCrossRefGoogle Scholar
  127. 127.
    Best PJ, McKenna CJ, Hasdai D, et al. Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. Circulation 1999; 99: 1747–52PubMedCrossRefGoogle Scholar
  128. 128.
    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: 2235–40PubMedCrossRefGoogle Scholar
  129. 129.
    Miyauchi T, Yanagisawa M, Tomizawa T, et al. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction [letter]. Lancet 1989; II: 53–4CrossRefGoogle Scholar
  130. 130.
    Omland T, Terje Lie R, Aakvaag A, et al. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 1994; 89: 1573–9PubMedCrossRefGoogle Scholar
  131. 131.
    Ray SG, McMurray JJ, Morton JJ, et al. Circulating endothelin in acute ischaemic syndromes. Br Heart J 1992; 67: 383–6PubMedCrossRefGoogle Scholar
  132. 132.
    Tomoda H. Plasma endothelin-1 in acute myocardial infarction with heart failure. Am Heart J 1993; 125: 667–72PubMedCrossRefGoogle Scholar
  133. 133.
    Watanabe T, Awane Y, Ikeda S, et al. Pharmacology of a non-selective ETA and ETB receptor antagonist, TAK- 044 and the inhibition of myocardial infarct size in rats. Br J Pharmacol 1995; 114: 949–54PubMedCrossRefGoogle Scholar
  134. 134.
    Kojima M, Kusumoto K, Fujiwara S, et al. Role of endogenous endothelin in the extension of myocardial infarct size studied with the endothelin receptor antagonist, TAK-044. J Cardiovasc Pharmacol 1995; 26 Suppl. 3: S365–8PubMedGoogle Scholar
  135. 135.
    Kusumoto K, Awane Y, Fujiwara S, et al. Role of endogenous endothelin in extension of rabbit myocardial infarction. J Cardiovasc Pharmacol 1993; 22 Suppl. 8: S339–42PubMedCrossRefGoogle Scholar
  136. 136.
    Watanabe T, Suzuki N, Shimamoto N, et al. Contribution of endogenous endothelin to the extension of myocardial infarct size in rats. Circ Res 1991; 69: 370–7PubMedCrossRefGoogle Scholar
  137. 137.
    Grover GJ, Dzwonczyk 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: 1613–8PubMedCrossRefGoogle Scholar
  138. 138.
    Leimbach WJ, Wallin BG, Victor RG, et al. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986; 73: 913–9PubMedCrossRefGoogle Scholar
  139. 139.
    Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311: 819–23PubMedCrossRefGoogle Scholar
  140. 140.
    Levine TB, Francis GS, Goldsmith SR, et al. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982; 49: 1659–66PubMedCrossRefGoogle Scholar
  141. 141.
    Sakai S, Yorikane R, Miyauchi T, et al. Altered production of endothelin-1 in the hypertrophied rat heart. J Cardiovasc Pharmacol 1995; 26: S452–5PubMedGoogle Scholar
  142. 142.
    Tonnessen T, Christensen G, Oie E, et al. Increased cardiac expression of endothelin-1 mRNA in ischemic heart failure in rats. Cardiovasc Res 1997; 33: 601–10PubMedCrossRefGoogle Scholar
  143. 143.
    Sakai S, Miyauchi T, Sakurai T, et al. Pulmonary hypertension caused by congestive heart failure is ameliorated by long-term application of an endothelin receptor antagonist. Increased expression of endothelin-1 messenger ribonucleic acid and endothelin-1-like immunoreactivity in the lung in congestive heart failure in rats. J Am Coll Cardiol 1996; 28: 1580–8PubMedCrossRefGoogle Scholar
  144. 144.
    Huntington K, Picard P, Moe G, et al. Increased cardiac and pulmonary endothelin-1 mRNA expression in canine pacing-induced heart failure. J Cardiovasc Pharmacol 1998; 31: S424–6PubMedCrossRefGoogle Scholar
  145. 145.
    Picard P, Smith PJ, Monge JC, et al. Coordinated upregulation of the cardiac endothelin system in a rat model of heart failure. J Cardiovasc Pharmacol 1998; 31: S294–7PubMedCrossRefGoogle Scholar
  146. 146.
    Margulies KB, Hildebrand FJ, Lerman A, et al. Increased endothelin in experimental heart failure. Circulation 1990; 82: 2226–30PubMedCrossRefGoogle Scholar
  147. 147.
    McMurray JJ, Ray SG, Abdullah I, et al. Plasma endothelin in chronic heart failure. Circulation 1992; 85: 1374–9PubMedCrossRefGoogle Scholar
  148. 148.
    Rodeheffer RJ, Lerman A, Heublein DM, et al. Increased plasma concentrations of endothelin in congestive heart failure in humans. Mayo Clin Proc 1992; 67: 719–24PubMedGoogle Scholar
  149. 149.
    Wei CM, Lerman A, Rodeheffer RJ, et al. Endothelin in human congestive heart failure. Circulation 1994; 89: 1580–6PubMedCrossRefGoogle Scholar
  150. 150.
    Tuinenburg AE, Van Veldhuisen DJ, Boomsma F, et al. Comparison of plasma neurohormones in congestive heart failure patients with atrial fibrillation versus patients with sinus rhythm. Am J Cardiol 1998; 81: 1207–10PubMedCrossRefGoogle Scholar
  151. 151.
    Cody RJ, Haas GJ, Binkley PF, et al. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992; 85: 504–9PubMedCrossRefGoogle Scholar
  152. 152.
    Lerman A, Kubo SH, Tschumperlin LK, et al. Plasma endothelin concentrations in humans with end-stage heart failure and after heart transplantation. J Am Coll Cardiol 1992; 20: 849–53PubMedCrossRefGoogle Scholar
  153. 153.
    Tsutamoto T, Hisanaga T, Fukai D, et al. Prognostic value of plasma soluble intercellular adhesion molecule-1 and endothelin-1 concentration in patients with chronic congestive heart failure. Am J Cardiol 1995; 76: 803–8PubMedCrossRefGoogle Scholar
  154. 154.
    Fukuchi M, Giaid A. Expression of endothelin-1 and endothelin-converting enzyme-1 mRNAs and proteins in failing human hearts. J Cardiovasc Pharmacol 1998; 31: S421–3PubMedCrossRefGoogle Scholar
  155. 155.
    Zolk O, Quattek J, Sitzler G, et al. Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure. Circulation 1999; 99: 2118–23PubMedCrossRefGoogle Scholar
  156. 156.
    Krum H, Goldsmith R, Wilshire-Clement M, et al. Role of endothelin in the exercise intolerance of chronic heart failure. Am J Cardiol 1995; 75: 1282–3PubMedCrossRefGoogle Scholar
  157. 157.
    Pacher R, Stanek B, Hülsmann M, et al. Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure. J Am Coll Cardiol 1996; 27: 633–41PubMedCrossRefGoogle Scholar
  158. 158.
    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: 1293–9PubMedCrossRefGoogle Scholar
  159. 159.
    Pousset F, Isnard R, Lechat P, et al. Prognostic value of plasma endothelin-1 in patients with chronic heart failure. Eur Heart J 1997; 18: 254–8PubMedCrossRefGoogle Scholar
  160. 160.
    Hulsmann M, Stanek B, Frey B, et al. Value of cardiopulmonary exercise testing and big endothelin plasma levels to predict short-term prognosis of patients with chronic heart failure. J Am Coll Cardiol 1998; 32: 1695–700PubMedCrossRefGoogle Scholar
  161. 161.
    Thomas PB, Liu EC, Webb ML, et al. Exogenous effects and endogenous production of endothelin in cardiac myocytes: potential significance in heart failure. Am J Physiol 1996; 271: H2629–37PubMedGoogle Scholar
  162. 162.
    Teerlink JR, Loffler BM, Hess P, et al. Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan). Circulation 1994; 89: 2510–8CrossRefGoogle Scholar
  163. 163.
    Kiowski W, Sütsch G, Hunziker P, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995; 346: 732–6PubMedCrossRefGoogle Scholar
  164. 164.
    Sütsch G, Kiowski W, Yan X-W, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998; 98: 2262–8PubMedCrossRefGoogle Scholar
  165. 165.
    Packer M, Caspi A, Charlon V, et al. Multicenter, double-blind, placebo-controlled study of long-term endothelin blockade with bosentan in chronic heart failure -Results of the REACH-1 trial. Circulation 1998; 98 Suppl. S: 12Google Scholar
  166. 166.
    Strachan FE, Spratt JC, Wilkinson IB, et al. Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. Hypertension 1999; 33: 581–5PubMedCrossRefGoogle Scholar
  167. 167.
    Wada A, Tsutamoto T, Fukai D, et al. Comparison of the effects of selective endothelin ETA and ETB receptor antagonists in congestive heart failure. J Am Coll Cardiol 1997; 30: 1385–92PubMedCrossRefGoogle Scholar
  168. 168.
    Cowburn PJ, Cleland JG, McArthur JD, et al. Endothelin B receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction. J Am Coll Cardiol 1999; 33: 932–8PubMedCrossRefGoogle Scholar
  169. 169.
    Cowburn PJ, Cleland JG, McArthur JD, et al. Short-term haemodynamic effects of BQ-123, a selective endothelin ET(A)-receptor antagonist, in chronic heart failure [letter]. Lancet 1998; 352: 201–2PubMedCrossRefGoogle Scholar
  170. 170.
    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: 2131–7PubMedCrossRefGoogle Scholar
  171. 171.
    Smith W, Iteld B, LeJemtel T, et al. Improved hemodynamics with the ET(A) selective receptor antagonist BMS-193884 in patients with heart failure [abstract]. J Am Coll Cardiol 2000; 34: 241AGoogle Scholar
  172. 172.
    Inada T, Fujiwara H, Hasegawa K, et al. Upregulated expression of cardiac endothelin-1 participates in myocardial cell growth in Bio 14.6 Syrian cardiomyopathic hamsters. J Am Coll Cardiol 1999; 33: 565–71PubMedCrossRefGoogle Scholar
  173. 173.
    Ito H, Adachi S, Tamamori M, et al. Mild hypoxia induces hypertrophy of cultured neonatal rat cardiomyocytes: a possible role for endogenous endothelin-1-mediated mechanism. J Moll Cell Cardiol 1996; 28: 1271–7CrossRefGoogle Scholar
  174. 174.
    Gray MO, Long CS, Kalinyak JE, et al. Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts. Cardiovasc Res 1998; 40: 352–63PubMedCrossRefGoogle Scholar
  175. 175.
    Sakai S, Miyauchi T, Kobayashi T, et al. Altered expression of isoforms of myosin heavy chain mRNA in the failing rat heart is ameliorated by chronic treatment with an endothelin receptor antagonist. J Cardiovasc Pharmacol 1998; 31: S302–5PubMedCrossRefGoogle Scholar
  176. 176.
    Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993; 87: 464–9PubMedCrossRefGoogle Scholar
  177. 177.
    Ohnishi M, Wada A, Tsutamoto T, et al. Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/B receptor antagonist in heart failure. Cardiovasc Res 1998; 39: 617–24PubMedCrossRefGoogle Scholar
  178. 178.
    Moe GW, Albernaz A, Naik GO, et al. Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure. Cardiovasc Res 1998; 39: 571–9PubMedCrossRefGoogle Scholar
  179. 179.
    Spinale FG, Walker JD, Mukherjee R, et al. Concomitant endothelin receptor sub-type-A blockade during the progression of pacing-induced congestive heart failure in rabbits. Beneficial effects on left ventricular and myocyte function. Circulation 1997; 95: 1918–29PubMedCrossRefGoogle Scholar
  180. 180.
    Borgeson DD, Grantham JA, Williamson EE, et al. Chronic oral endothelin type A receptor antagonism in experimental heart failure. Hypertension 1998; 31: 766–70PubMedCrossRefGoogle Scholar
  181. 181.
    CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Group (CONSENSUS). N Engl J Med 1987; 316: 1429–35CrossRefGoogle Scholar
  182. 182.
    SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293–302CrossRefGoogle Scholar
  183. 183.
    CIBIS investigators and committees. A randomized trial of ß-blockade in heart failure: the cardiac insufficiency bisoprolol study (CIBIS). Circulation 1994; 90: 1765–73CrossRefGoogle Scholar
  184. 184.
    MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001–7CrossRefGoogle Scholar
  185. 185.
    Miller WL, Redfield MM, Burnett Jr JC. Integrated cardiac, renal, and endocrine actions of endothelin. J Clin Invest 1989; 83: 317–20PubMedCrossRefGoogle Scholar
  186. 186.
    Morishita R, Higaki J, Ogihara T. Endothelin stimulates aldosterone biosynthesis by dispersed rabbit adreno-capsular cells. BiochemBiophys Res Commun 1989; 160: 628–32CrossRefGoogle Scholar
  187. 187.
    Cozza EN, Gomez-Sanchez CE, Foecking MF, et al. Endothelin binding to cultured calf adrenal zona glomerulosa cells and stimulation of aldosterone secretion. J Clin Invest 1989; 84: 1032–5PubMedCrossRefGoogle Scholar
  188. 188.
    Otsuka A, Mikami H, Katahira K, et al. Changes in plasma renin activity and aldosterone concentration in response to endothelin injection in dogs. Acta Endocrinol (Copenh) 1989; 121: 361–4Google Scholar
  189. 189.
    Nakamoto H, Suzuki H, Murakami M, et al. Effects of endothelin on systemic and renal haemodynamics and neuroendocrine hormones in conscious dogs. Clin Sci 1989; 77: 567–72PubMedGoogle Scholar
  190. 190.
    Tsuchiya K, Naruse M, Sanaka T, et al. Effects of endothelin on renal hemodynamics and excretory functions in anesthetized dogs. Life Sci 1990; 46: 59–65PubMedCrossRefGoogle Scholar
  191. 191.
    Woodcock EA, Tanner JK, Caroccia LM, et al. Mechanisms involved in the stimulation of aldosterone production by angiotensin II, vasopressin and endothelin. Clin Exp Pharmacol Physiol 1990; 17: 263–7PubMedCrossRefGoogle Scholar
  192. 192.
    Gomez-Sanchez CE, Cozza EN, Foecking MF, et al. Endothelin receptor subtypes and stimulation of aldosterone secretion. Hypertension 1990; 15: 744–7PubMedCrossRefGoogle Scholar
  193. 193.
    Fleisch M, Sutsch G, Yan XW, et al. Systemic, pulmonary, and renal hemodynamic effects of endothelin ET(A/B)-receptor blockade in patients with maintained left ventricular function. J Cardiovasc Pharmacol 2000; 36: 302–9PubMedCrossRefGoogle Scholar
  194. 194.
    Clozel M, Breu V, Burri K, et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 1993; 365: 759–61PubMedCrossRefGoogle Scholar
  195. 195.
    Gellai M, Jugus M, Fletcher T, et al. Reversal of postischemic acute renal failure with a selective endothelinA receptor antagonist in the rat. J Clin Invest 1994; 93: 900–6PubMedCrossRefGoogle Scholar
  196. 196.
    Gurbanov K, Rubinstein I, Hoffman A, et al. Bosentan improves renal regional blood flow in rats with experimental congestive heart failure. Eur J Pharmacol 1996; 310: 193–6PubMedCrossRefGoogle Scholar
  197. 197.
    Cacoub P, Dorent R, Maistre G, et al. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 1993; 71: 448–50PubMedCrossRefGoogle Scholar
  198. 198.
    Cacoub P, Dorent R, Nataf P, et al. Endothelin-1 in the lungs of patients with pulmonary hypertension. Cardiovasc Res 1997; 33: 196–200PubMedCrossRefGoogle Scholar
  199. 199.
    Williamson DJ, Wallman LL, Jones R, et al. Hemodynamic effects of Bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation 2000; 102: 411–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  • Lukas E. Spieker
    • 1
  • Georg Noll
    • 1
  • Thomas F. Lüscher
    • 1
  1. 1.Cardiovascular Centre, Division of CardiologyUniversity Hospital and Cardiovascular Research, Institute of PhysiologyZürichSwitzerland

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