Skip to main content
SpringerLink
Log in

Endothelin Receptor Antagonists and Cardiovascular Diseases of Aging

  • Review Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Our understanding of the role of the endothelin system in human cardiovascular physiology and pathophysiology has evolved very rapidly since the initial description of its constituent parts in 1988. Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system and has potent vasoconstrictor, mitogenic and antinatriuretic properties which have implicated it in the pathophysiology of a number of cardiovascular diseases. The effects of ET-1 have been shown to be mediated by 2 principal endothelin receptor subtypes: ETA and ETB.

The development of a range of peptidic and nonpeptidic endothelin receptor antagonists represents an exciting breakthrough in human cardiovascular therapeutics. Two main classes of endothelin receptor antagonist have been developed for possible human therapeutic use: ETA-selective and nonselective antagonists. Extensive laboratory and clinical research with these agents has highlighted their promise in various cardiovascular diseases. Randomised, placebo-controlled clinical trials have yielded very encouraging results in patients with hypertension and chronic heart failure with more preliminary data suggesting a possible role in the treatment and prevention of atherosclerosis and stroke. Much more research is needed, however, before endothelin receptor antagonists can be considered for clinical use.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Table I
Fig. 3
Table II
Table III
Table IV
Table V

Similar content being viewed by others

References

  1. Braunwald E. Cardiovascular medicine at the turn of the millenium: triumphs, concerns and opportunities. N Engl J Med 1997; 337: 1360–9

    Article  PubMed  CAS  Google Scholar 

  2. Thorn TJ, Epstein FH. Heart disease, cancer, and stroke mortality trends and their interrelations: an international perspective. Circulation 1994; 90: 574–82

    Article  Google Scholar 

  3. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–5

    Article  PubMed  CAS  Google Scholar 

  4. Ferro CJ, Webb DJ. The clinical potential of endothelin receptor antagonists in cardiovascular medicine. Drugs 1996; 51: 12–27

    Article  PubMed  CAS  Google Scholar 

  5. Benigni A, Remuzzi G. Endothelin antagonists. Lancet 1999; 353: 133–8

    Article  PubMed  CAS  Google Scholar 

  6. 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: 784–90

    Article  PubMed  CAS  Google Scholar 

  7. Sütsch W, Kiowski W, Xiao-Wei Y, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic chronic heart failure. Circulation 1998; 98: 2262–8

    Article  PubMed  Google Scholar 

  8. 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: 2863–7

    Article  PubMed  CAS  Google Scholar 

  9. Haynes WG, Webb DJ. The endothelin family of peptides: local hormones with diverse roles in health and disease? Clin Sci 1993; 84: 485–500

    PubMed  CAS  Google Scholar 

  10. Love MP, McMurray MV. Endothelin in chronic heart failure; current position and future prospects. Cardiovasc Res 1996; 31: 665–74

    PubMed  CAS  Google Scholar 

  11. Xu D, Emoto N, Giaid A, et al. ECE-1: a membrane bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 1994; 78: 473–85

    Article  PubMed  CAS  Google Scholar 

  12. Schweizer A, Valdenaire O, Nelböck P, et al. Human endothelin converting enzyme (ECE-I): three isoforms with distinct subcellular localizations. Biochem J 1997; 328: 871–7

    PubMed  CAS  Google Scholar 

  13. Arai H, Hori S, Aramori I, et al. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348: 730–3

    Article  PubMed  CAS  Google Scholar 

  14. Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a nonisopeptide selective subtype of the endothelin receptor. Nature 1990; 348: 732–5

    Article  PubMed  CAS  Google Scholar 

  15. Clarke JG, Benjamin N, Larkin SW, et al. Endothelin is a potent long-lasting vasoconstrictor in men. Am J Physiol 1989; 257: H–2033–2035

    Google Scholar 

  16. Haynes WG, Clarke JG, Cockcroft JR, et al. Pharmacology of endothelin-1 in vivo in humans. J Cardiovasc Pharmacol 1991; 17Suppl. 7: 284–6

    Article  Google Scholar 

  17. 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: F411–8

    PubMed  CAS  Google Scholar 

  18. Riezebos J, Watts IS, Vallance PM. Endothelin receptors mediating functional responses in human small arteries and veins. Br J Phamacol 1994; 111: 609–15

    Article  CAS  Google Scholar 

  19. Davenport AP, Maguire JJ. Is endothelin-induced vasoconstriction mediated only by ETA receptors in humans? Trends Pharmacol Sci 1994; 15: 9–11

    Article  PubMed  CAS  Google Scholar 

  20. Haynes WG, Strachan FE, Webb DJ. Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 1995; 92: 357–63

    Article  PubMed  CAS  Google Scholar 

  21. McCulloch KM, Docherty CC, Morecroft I, et al. Endothelin B receptor mediated contraction in human pulmonary resistance arteries. Br J Pharmacol 1996; 119: 1125–30

    Article  PubMed  CAS  Google Scholar 

  22. 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: 1203–8

    Article  PubMed  CAS  Google Scholar 

  23. de Nucci G, Thomas R, D’Orléans-Juste P, et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 1988; 85: 9797–800

    Article  PubMed  Google Scholar 

  24. Dupuis J, Stewart DJ, Cemacek P, et al. Human pulmonary circulation is an important site for both clearance and production of endothelin-1. Circulation 1996; 94: 1578–84

    Article  PubMed  CAS  Google Scholar 

  25. Fukuroda T, Fujikawa T, Ozaki S, et al. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun 1994; 199: 1461–5

    Article  PubMed  CAS  Google Scholar 

  26. Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994; 344: 852–4

    Article  PubMed  CAS  Google Scholar 

  27. 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: 1860–70

    Article  PubMed  CAS  Google Scholar 

  28. Kornuro I, Kudhara H, Sugiyama T, et al. Endothelin stimulatesc-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett 1988; 238: 249–52

    Article  Google Scholar 

  29. Hirata Y, Takagi Y, Fukuda Y, et al. Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 1989; 78: 225–8

    Article  PubMed  CAS  Google Scholar 

  30. Ichikawa KI, Hidai C, Okuda C, et al. Endogenous endothelin-1 mediates cardiac hypertrophy and switching of myosin heavy chain gene expression in rat ventricular myocardium. J Am Coll Cardiol 1996; 27: 1286–91

    Article  PubMed  CAS  Google Scholar 

  31. Fujisaki H, Ito H, Hirata Y, et al. Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. J Clin Invest 1995; 96: 1059–65

    Article  PubMed  CAS  Google Scholar 

  32. Yang Z, Krasnici N, Lüscher T. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETb receptor blockade. Circulation 1999; 100: 5–8

    Article  PubMed  CAS  Google Scholar 

  33. Ito H, Hirata Y, Adachi S, et al. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 1993; 92: 398–403

    Article  PubMed  CAS  Google Scholar 

  34. Kaddoura S, Firth JD, Boheler KR, et al. Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in vivo: acute effects of bosentan, an orally-active, mixed endothelin ETa and ETb receptor antagonist. Circulation 1996; 93: 2068–79

    Article  PubMed  CAS  Google Scholar 

  35. Pieske B, Beyermann B, Breu V, et al. Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium. Circulation 1999; 99: 1802–9

    Article  PubMed  CAS  Google Scholar 

  36. Beyer ME, Slesak G, Hdvelborn T, et al. Inotropic effects of endothelin-1: interaction with molsidomine and with BQ 610. Hypertension 1999; 33: 145–52

    Article  PubMed  CAS  Google Scholar 

  37. Ishikawa T, Yanagisawa M, Kimura S, et al. Positive chronotropic effects of endothelin, a novel endothelium-derived vasoconstrictor peptide. Eur J Physiol 1988; 413: 108–10

    Article  CAS  Google Scholar 

  38. Wagner OF, Vierhapper H, Gasic S, et al. Regional effects and clearance of endothelin-1 across pulmonary and splanchnic circulation. Eur J Clin Invest 1992; 22: 277–82

    Article  PubMed  CAS  Google Scholar 

  39. Kiely DG, Cargill RI, Struthers AD, et al. Cardiopulmonary effects of endothelin-1 in man. Cardiovasc Res 1997; 33: 378–86

    Article  PubMed  CAS  Google Scholar 

  40. MacCarthy PA, Grocott-Mason R, Prendergast BD, et al. Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart. Circulation 2000; 101: 142–7

    Article  PubMed  CAS  Google Scholar 

  41. Kohan DE. Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis 1993; 22: 493–510

    PubMed  CAS  Google Scholar 

  42. Rabelink TJ, Kaasjager KAH, Boer P, et al. Effects of endothelin-1 on renal function in humans: implications for physiology and pathophysiology. Kidney Int 1994; 46: 376–381

    Article  PubMed  CAS  Google Scholar 

  43. Tabuchi Y, Nakamura M, Rakugi H, et al. Endothelin enhances adrenergic vasoconstriction in perfused rat mesenteric arteries. Biochem Biophys Res Commun 1989; 159: 1304–8

    Article  PubMed  CAS  Google Scholar 

  44. Wong-Dusting HK, La M, Rand MJ. Mechanisms of the effects of endothelin on responses to noradrenaline and sympathetic nerve stimulation. Clin Exp Pharmacol Physiol 1990; 17: 269–73

    Article  PubMed  CAS  Google Scholar 

  45. Haynes WG, Hand M, Johnstone H, et al. Direct and sympathetically mediated venoconstriction in essential hypertension: enhanced responses to endothelin-1. J Clin Invest 1994; 94: 1359–64

    Article  PubMed  CAS  Google Scholar 

  46. Kawaguchi H, Sawa H, Yasuda H. Endothelin stimulates angiotensin I to angiotensin II conversion in cultured pulmonary artery endothelial cells. J Mol Cell Cardiol 1990; 22: 839–42

    Article  PubMed  CAS  Google Scholar 

  47. Boarder MR, Marriot DB. Characterization of endothelin-1 stimulation of catecholamine release from adrenal chromaffin cells. J Cardiovasc Pharmacol 1989; 13Suppl. 5: 223–4

    Article  Google Scholar 

  48. Cao L, Banks RO. Cardiorenal actions of endothelin, part 1:effects of converting enzyme inhibition. Life Sci 1990; 46: 577–83

    Article  PubMed  CAS  Google Scholar 

  49. Yoshida K, YastiJima M, Kolizuki M, et al. Endothelinl augments pressor response to angiotensin II infusion in rats. Hypertension 1992; 20: 292–7

    Article  PubMed  CAS  Google Scholar 

  50. Yang Z, Richard V, von Segesser L, et al. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. Circulation 1990; 82: 188–95

    Article  PubMed  CAS  Google Scholar 

  51. Vanhoutte PM. Is endothelin involved in the pathogenesis of hypertension? Hypertension 1993; 21: 747–51

    Article  PubMed  CAS  Google Scholar 

  52. Yoshida M, Nonoguchi H, Owada A, et al. Three cases of malignant hypertension: the roles of endothelin-1 and the renin-angiotensin-aldosterone systems. Clin Nephrol 1994; 42: 295–9

    PubMed  CAS  Google Scholar 

  53. Wagner OF, Christ G, Wojta J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992; 267: 16066–8

    PubMed  CAS  Google Scholar 

  54. Miyauchi T, Ishikawa T, Tomobe Y, et al. Characteristics of pressure response to endothelin in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 1989; 14: 427–34

    Article  PubMed  CAS  Google Scholar 

  55. Roberts-Thomson P, McRitchie RJ, Chalmers RP. Experimental hypertension produces diverse changes in the regional vascular responses to endothelin-1 in the rabbit and the rat. J Hypertens 1994; 12: 1225–34

    Article  PubMed  CAS  Google Scholar 

  56. Cardillo Q, Kilcoyne CM, Waclawiw M, et al. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension 1999; 33: 753–8

    Article  PubMed  CAS  Google Scholar 

  57. Clozel M. Endothelin sensitivity and receptor binding in the aorta of spontaneously hypertensive rats. J Hypertens 1989; 7: 913–7

    Article  PubMed  CAS  Google Scholar 

  58. Dohi Y, Lüscher TF. Endothelin-1 in hypertensive resistance arteries: intraluminal and extraluminal dysfunction. Hypertension 1991; 18: 543–9

    Article  PubMed  CAS  Google Scholar 

  59. Schiffrin EL, Thibault G. Blunted effects of endothelin upon small subcutaneous resistance arteries of mild essential hypertensive patients. J Hypertens 1992; 10: 437–44

    Article  PubMed  CAS  Google Scholar 

  60. Schiffrin EL, Ytian Deng L, Sventek P, et al. Enhanced expression of endothelin-1 gene in resistance arteries in severe human essential hypertension. J Hypertens 1997; 15: 57–63

    Article  PubMed  CAS  Google Scholar 

  61. Nishikibe M, Tsuchida S, Okada M, et al. Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertension model. Life Sci 1993; 52: 717–24

    Article  PubMed  CAS  Google Scholar 

  62. Douglas SA, Gellai M, Ezekiel M, et al. BQ-123, a selective endothelin subtype-A receptor antagonist, lowers blood pressure in different rat models of hypertension. J Hypertens 1994; 12: 561–7

    Article  PubMed  CAS  Google Scholar 

  63. Clozel M, Breu V, Burri K, et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 1993; 365: 759–61

    Article  PubMed  CAS  Google Scholar 

  64. Moreau P, d’Uscio LV, Takase H, et al. Angiotensin H increases tissue endothelin and induced vascular hypertrophy in vivo: reversal by ETA-receptor antagonist. Circulation 1997; 96: 1593–7

    Article  PubMed  CAS  Google Scholar 

  65. d’Uscio LV, Moreau P, Shaw S, et al. Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension. Hypertension 1997; 29: 435–41

    Article  PubMed  Google Scholar 

  66. Herizi A, Jover B, Bouriquet N, et al. Prevention of the cardiovascular and renal effects of angiotensin II by endothelin blockade. Hypertension 1998; 31: 10–4

    Article  PubMed  CAS  Google Scholar 

  67. d’Uscio L, Barton M, Shaw S, et al. Structure and function of small arteries in salt-induced hypertension: effects of chronic ETA-receptor blockade. Hypertension 1997; 30: 905–11

    Article  PubMed  Google Scholar 

  68. Li JS, Larivière R, Schiffrin EL. Effect of a non selective endothelin antagonist on vascular remodelling in deoxycorticosterone acetate-salt hypertensive rats: evidence for a role of endothelin in vascular hypertrophy. Hypertension 1994; 24: 183–8

    Article  PubMed  CAS  Google Scholar 

  69. Karam H, Heudes D, Hess P, et al. Respective role of humoral factors and blood pressure in cardiac remodelling of DOCA hypertensive rats. Cardiovasc Res 1996; 31: 287–95

    PubMed  CAS  Google Scholar 

  70. Schiffrin EL, Turgeon A, Deng LY. Effects of chronic ETA-selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in rats. Br J Pharmacol 1997; 121: 935–40

    Article  PubMed  CAS  Google Scholar 

  71. Stasch J-P, Hirth-Dietrich Q, Froberl K, et al. Prolonged endothelin blockade prevents hypertension and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats. Am J Hypertens 1995; 8: 1128–34

    Article  PubMed  CAS  Google Scholar 

  72. Chillon J-M, Heistad DD, Baumbach GL. Effects of endothelin receptor inhibition on cerebral arterioles in hypertensive rats. Hypertension 1996; 27: 794–8

    Article  PubMed  CAS  Google Scholar 

  73. Heagerty AM, Aalkjaer C. Bund SJ, et al. Small artery structure in hypertension: dual process of remodelling and growth. Hypertension 1993; 21: 391–7

    Article  PubMed  CAS  Google Scholar 

  74. Fujita K, Matsumara Y, Miyazaki Y, et al. Effects of the endothelin ETA-receptor antagonist FR139317 on development of hypertension and cardiovascularhypertrophy in deoxycorticosterone acetate-salt hypertensive rats. Jpn J Pharmacol 1996,70: 313–9

    Article  PubMed  CAS  Google Scholar 

  75. Matsumara Y, Hashimoto N, Taira S, et al. Different contributions of endothelin-A and endothelin-B receptors in the pathogenesis of deoxycorticosterone acetate-salt-induced hypertension in rats. Hypertension 1999; 33: 759–65

    Article  Google Scholar 

  76. Barton M, d’Uscio LV, Shaw S, et al. ETA-receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Hypertension 1998; 31: 499–504

    Article  PubMed  CAS  Google Scholar 

  77. Moreau P, Takase H, Küng CF, et al. Blood pressure and vascular effects of endothelin blockade in chronic nitric oxide-deficient hypertension. Hypertension 1997; 29: 763–9

    Article  PubMed  CAS  Google Scholar 

  78. Kassab S, Novak J, Miller T, et al. Role of endothelin in mediating the attenuated renal hemodynamics in Dahl salt-sensitive hypertension. Hypertension 1997; 30: 682–6

    Article  PubMed  CAS  Google Scholar 

  79. Karam H, Heudes D, Bruvenal P, et al. Endothelin antagonism in end-organ damage of spontaneously hypertensive rats: comparison with angiotensin-converting enzyme inhibition and calcium antagonism. Hypertension 1996; 28: 379–85

    Article  PubMed  CAS  Google Scholar 

  80. Bouriquet N, Dupont M, Herizi A, et al. Preglomerular sudan-ophilia in L-NAME hypertensive rats: involvement of endothelin. Hypertension 1996; 27: 382–91

    Article  PubMed  CAS  Google Scholar 

  81. Okada M, Kobayashi M, Maruyama H, et al. Effects of selective endothelin A-receptor antagonist, BQ-123, in salt-loaded stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 1995; 22: 763–8

    Article  PubMed  CAS  Google Scholar 

  82. 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: 1680–3

    Article  PubMed  CAS  Google Scholar 

  83. 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: 1191–7

    Article  PubMed  CAS  Google Scholar 

  84. Haller H, Schaberg T, Lindschau C, et al. Endothelin increases [Ca2+]i, protein phosphorylation, and O2 production in human alveolar macrophages. Am J Physiol 1991; 261: L478–84

    PubMed  CAS  Google Scholar 

  85. Alberts GF, Peifley KA, Johns A, et al. Constitutive endothelin1 overexpression promotes smooth muscle cell proliferation via an external autocrine loop. J Biol Chem 1994; 269: 10112–8

    PubMed  CAS  Google Scholar 

  86. Lerman A, Edwards BS, Hallett JW, et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991; 325: 997–1001

    Article  PubMed  CAS  Google Scholar 

  87. Horio T, Kohno M, Murakawa K, et al. Increased plasma immunoreactive endothelin-1 concentration in hypercholester-olemic rats. Atherosclerosis 1991; 89: 2923–8

    Article  Google Scholar 

  88. Mangiafico RA, Malatino LS, et al. Raised plasma endothelin-1 concentrations in patients with primary hypercholesterolaemia without evidence of atherosclerosis. Int Angiol 1996; 15: 240–4

    PubMed  CAS  Google Scholar 

  89. Ray SG, McMurray JJV, Morton JJ, et al. Circulating endothelin in acute ischaemic syndromes. Br Heart J 1992; 67: 383–6

    Article  PubMed  CAS  Google Scholar 

  90. Zeilier 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: 941–7

    Article  Google Scholar 

  91. 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: 1573–9

    Article  PubMed  CAS  Google Scholar 

  92. Wieczorek I, Haynes WG, Webb DJ, et al. Raised plasma endothelin in unstablo angina and non-Q wave myocardial infarction: relation to cardiovascular outcome. Br Heart J 1994; 72: 436–41

    Article  PubMed  CAS  Google Scholar 

  93. Kowala MC, Rose PM, Stein PD, et al. Selective blockade of the endothelin subtype A receptor decreases early atherosclerosis in hamsters fed cholesterol. Am J Pathol 1995; 146: 819–26

    PubMed  CAS  Google Scholar 

  94. 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: 14367–72

    Article  PubMed  CAS  Google Scholar 

  95. Best PJM, McKenna CJ, Hasdai D, et al. Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolaemia. Circulation 1999; 99: 1747–52

    Article  PubMed  CAS  Google Scholar 

  96. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242–50

    Article  PubMed  CAS  Google Scholar 

  97. Best WM, Lerman LO, Romero JC, et al. Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolaemia in vitro [abstract]. Circulation 1999; 19: 2769

    CAS  Google Scholar 

  98. Leskinen H, Cataliotti A, Jougasaki M, et al. Chronic endothelin A receptor antagonism improves vasorelaxations to natriuretic peptides in atherosclerosis [abstract]. J Am Coll Cardiol 2000; 35Suppl. A: 316

    Google Scholar 

  99. MacCarthy PA, Pegge NC, Prendergast BD, et al. The physiological role of endogenous endothelin in the regulation of human coronary vasomotor tone [abstract]. Circulation 1999; 100: I–346

    Google Scholar 

  100. 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: 2235–40

    Article  PubMed  CAS  Google Scholar 

  101. 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: 370–7

    Article  PubMed  CAS  Google Scholar 

  102. 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: 1613–8

    Article  PubMed  CAS  Google Scholar 

  103. 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: 949–54

    Article  PubMed  CAS  Google Scholar 

  104. Nguyen QT, Cemacek P, Calderoni A, et al. Endothelin A receptor blockade causes adverse left ventricular remodeling but improves pulmonary artery pressure after infarction in the rat. Circulation 1998; 98: 2323–30

    Article  PubMed  CAS  Google Scholar 

  105. Caligiuri G, Levy B, Pernow J, et al. Myocardial infarction mediated by endothelin receptor signaling in hypercholester-olemic mice. Proc Natl Acad Sci USA 1999; 96: 6920–4

    Article  PubMed  CAS  Google Scholar 

  106. Kirchengast M, Munter K. Endothelin and restenosis. Cardiovasc Res 1998; 39: 550–5

    Article  PubMed  CAS  Google Scholar 

  107. Hasdai D, Holmes Jr DR, Garratt KN, et al. Mechanical pressure and stretch release endothelin-1 from human atherosclerotic coronary arteries in vivo. Circulation 1997; 95: 357–62

    Article  PubMed  CAS  Google Scholar 

  108. Ferrer P, Valentine M, Jenkins-West T, et al. Orally active endothelin receptor antagonist BMS-182874 suppresses neointimal development in balloon-injured rat carotid arteries. J Cardiovasc Pharmacol 1995; 26: 908–15

    Article  PubMed  CAS  Google Scholar 

  109. Tsujino M, Hirata Y, Eguchi S, et al. Nonselective ETA/ETB receptor antagonist blocks proliferation of rat vascular smooth muscle cells after balloon angioplasty. Life Sci 1995; 56: 449–54

    Article  Google Scholar 

  110. Ziv I, Fleminger G, Djaidetti R, et al. Increased plasma endothelin-1 levels in acute ischaemic stroke. Stroke 1992; 23: 1014–6

    Article  PubMed  CAS  Google Scholar 

  111. Lampl Y, Fleminger G, Gilad R, et al. Endothelin in cerebrospinal fluid and plasma of patients in the early stage of ischemic stroke. Stroke 1997; 10: 1951–5

    Article  Google Scholar 

  112. Tatlisumak T, Carano RA, Takano K, et al. A novel endothelin antagonist, A-127722, attenuates ischemic lesion size in rats with temporary middle cerebral artery occlusion: a diffusion and perfusion MRI study. Stroke 1998; 4: 850–7

    Article  Google Scholar 

  113. Barone FC, White RF, Elliott JD, et al. The endothelin receptor antagonist SB217242 reduces cerebral focal ischemic brain injury. J Cardiovasc Pharmacol 1995; 26Suppl. 3: 404–7

    Google Scholar 

  114. Webb DJ, Monge JC, Rabelink TJ, et al. Endothelin: new discoveries and rapid progress in the clinic. Trends Pharmacol Sci 1998; 19: 5–8

    Article  PubMed  Google Scholar 

  115. McMurray JJ, Ray SG, Abdullah I, et al. Plasma endothelin in chronic heart failure. Circulation 1992; 85: 1374–9

    Article  PubMed  CAS  Google Scholar 

  116. Rodeheffer RJ, Lerman A, Heublein DM, et al. Increased plasma concentrations of endothelin in chronic heart failure in humans. Mayo Clin Proc 1992; 67: 719–24

    Article  PubMed  CAS  Google Scholar 

  117. Cacoub P, Dorent R, Nataf P, et al. Plasma endothelin and pulmonary pressures in patients with congestive heart failure. Am Heart J 1993; 126: 1484–8

    Article  PubMed  CAS  Google Scholar 

  118. 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: 803–8

    Article  PubMed  CAS  Google Scholar 

  119. Galatius-Jensen S, Wroblewski H, Emmeluth C, et al. Plasma endothelin in congestive heart failure: a predictor of cardiac death? J Cardiac Failure 1996; 2: 71–6

    Article  CAS  Google Scholar 

  120. 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: 254–8

    Article  PubMed  CAS  Google Scholar 

  121. 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: 2118–23

    Article  PubMed  CAS  Google Scholar 

  122. Teerlink JR, Uffler B-M, Hess P, et al. Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Circulation 1994; 90: 2510–8

    Article  PubMed  CAS  Google Scholar 

  123. Clavell AL, Mattingly MT, Stevens TL, et al. Angiotensin converting enzyme inhibition modulates endogenous endothelin in chronic canine thoracic inferior vena caval constriction. J Clin Invest 1996; 97: 1286–92

    Article  PubMed  CAS  Google Scholar 

  124. Sakai S, Miyauchi T, Sakurai T, et al. Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Circulation 1996; 93: 1214–22

    Article  PubMed  CAS  Google Scholar 

  125. Shimoyama H, Sabbah HN, Borzak S, et al. Short-term hemodynamic effects of endothelin receptor blockade in dogs with chronic heart failure. Circulation 1996; 94: 779–84

    Article  PubMed  CAS  Google Scholar 

  126. 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: 1385–92

    Article  PubMed  CAS  Google Scholar 

  127. Ohnishi M, Wada A, Tsutamoto T, et al. Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure. Cardiovasc Res 1998; 39: 617–24

    Article  PubMed  CAS  Google Scholar 

  128. Choussat R, Hittinger L, Barbe F, et al. Acute effects of an endothelin-1 receptor antagonist bosentan at different stages of heart failure in conscious dogs. Cardiovasc Res 1998; 39: 580–8

    Article  PubMed  CAS  Google Scholar 

  129. Wada A, Tsutamoto T, Ohnishi M, et al. Effects of a specific endothelin-converting enzyme inhibitor on cardiac, renal, and neurohumoral functions in congestive heart failure: comparison of effects with those of endothelin A receptor antagonism. Circulation 1999; 99: 576–7

    Article  Google Scholar 

  130. Sakai S, Miyauchi T, Kobayashi M, et al. Inhibition of myocardial endothelin pathway improves long term survival in heart failure. Nature 1996; 384: 353–5

    Article  PubMed  CAS  Google Scholar 

  131. Spinale FG, Walker JD, Mukherjee R, et al. Concomitant endothelin receptor subtype-A blockade during the progression of pacing-induced congestive heart failure in rabbits. Circulation 1997; 95: 1918–29

    Article  PubMed  CAS  Google Scholar 

  132. 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 remodeling. Circulation 1997; 96: 1976–82

    Article  PubMed  CAS  Google Scholar 

  133. Fraccarollo D, Hu K, Galuppo P, et al. Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction: possible involvement of myocardial endothelin system in ventricular remodeling. Circulation 1997; 96: 3963–73

    Article  PubMed  CAS  Google Scholar 

  134. Mulder P, Richard V, Bouchart F, et al. Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure. Cardiovasc Res 1998; 39: 600–8

    Article  PubMed  CAS  Google Scholar 

  135. 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: 571–9

    Article  PubMed  CAS  Google Scholar 

  136. 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: 2065–73

    Article  PubMed  CAS  Google Scholar 

  137. Pandey AS, Stewart DJ, Cernacek P, et al. Chronic endothelin-1 blockade preserves myocardial contractility in dilated cardiomyopathy. J Cardiovasc Pharmacol 1998; 31: S306–308

    Article  PubMed  CAS  Google Scholar 

  138. Ohnishi M, Wada A, Tsutamoto T, et al. Chronic effects of a novel, orally active endothelin receptor antagonist, T-0201, in dogs with congestive heart failure. J Cardiovasc Pharmacol 1998;31: S236–238

    Article  PubMed  CAS  Google Scholar 

  139. 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: S424–426

    Article  PubMed  CAS  Google Scholar 

  140. Saad D, Mukherjee R, Thomas PB, et al. The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure. J Am Coll Cardiol 1998; 32: 1779–86

    Article  PubMed  CAS  Google Scholar 

  141. Borgeson DD, Grantham JA, Williamson EE, et al. Chronic oral endothelin type A receptor antagonism in experimental heart failure. Hypertension 1998; 31: 766–70

    Article  PubMed  CAS  Google Scholar 

  142. Øie E, Bjonerheim R, Grogaard HK, et al. ET receptor antagonism, myocardial gene expression, and ventricular remodeling during CHF in rats. Am J Physiol 1998; 275: H868–877

    PubMed  Google Scholar 

  143. Yamauchi-Kohno R, Miyauchi T, Hoshino T, et al. Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters: increase in endothelin-1 production in the heart and beneficial effect of endothelin-A receptor antagonist on survival and cardiac function. Circulation 1999; 99: 2171–6

    Article  PubMed  CAS  Google Scholar 

  144. McConnell PI, Olson CE, Patel KP, et al. Chronic endothelin blockade in dogs with pacing-induced heart failure: possible modulation of sympathoexcitation. J Card Fail 2000; 6: 56–65

    Article  PubMed  CAS  Google Scholar 

  145. 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: 2131–7

    Article  PubMed  CAS  Google Scholar 

  146. Cowburn PJ, Cleland JGF, McArthur JD, et al. Short-term hemodynamic effects of BQ-123, a selective endothelin ETa-receptor antagonist, in chronic heart failure [letter]. Lancet 1998; 352: 201–2

    Article  PubMed  CAS  Google Scholar 

  147. 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:I–578

    Google Scholar 

  148. Spieker LE, Mitrovic V, Noll G, et al. Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. J Am Coll Cardiol 2000; 35: 1745–52

    Article  PubMed  CAS  Google Scholar 

  149. Smith W, Iteld B, LeJemtel T, et al. Improved hemodynamics with the ETA selective receptor antagonist BMS-193884 in patients with heart failure [abstract]. J Am Coll Cardiol 2000; 35Suppl. A: 241

    Google Scholar 

  150. Kiowski W, Sütsch G, Hunziker P, et al. Evidence for endothelin-1 mediated vasoconstriction in severe chronic heart failure. Lancet 1995; 346: 732–6

    Article  PubMed  CAS  Google Scholar 

  151. Torre-Amione G, Young JB, Durand J-B, et al. Hemodynamic effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with class III to IV congestive heart failure. Circulation 2001; 103: 973–80

    Article  PubMed  CAS  Google Scholar 

  152. Sütsch W, Bertel O, Kiowski W. Acute and short-term effects of the nonpeptide endothelin-1 receptor antagonist bosentan in humans. Cardiovasc Drugs Ther 1996; 10: 717–25

    Article  Google Scholar 

  153. Packer M, Swedberg K, McMurray JW, et al. Multi-centre, double-blind, placebo-controlled study of long-term endothelin blockade with bosentan in chronic heart failure: results of the Reach trial [abstract]. Eur Heart J 1999; 20: 95

    Google Scholar 

  154. Love MP, Ferro CJ, Haynes WG, et al. Endothelin receptor antagonism in patients with chronic heart failure. Cardiovasc Res 2000; 47: 166–72

    Article  PubMed  CAS  Google Scholar 

  155. Gray GA, Battistini B, Webb D. Endothelins are potent vasoconstrictors, and much more besides. Trends Pharmacol Sci 2000; 21: 38–40

    Article  PubMed  CAS  Google Scholar 

  156. Trapani AJ, De Lombaert S, Kuzmich S, et al. Inhibition of big ET-1 induced pressor response by an orally active dual inhibitor of endothelin-converting enzyme and neutral endo-peptidase 24.11. J Cardiovasc Pharmacol 1995; 26Suppl. 3: 69–71

    Google Scholar 

  157. Channick R, Badesch DB., Tapson V, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a placebo-controlled study. J Heart Lung Transplant 2001; 20: 262–3

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Cardiology, Glasgow Royal Infirmary, Queen Elizabeth Building, Alexandra Parade, Glasgow, G31 2ER, Scotland

    Michael P. Love

  2. Clinical Research Initiative in Heart Failure, Glasgow, Scotland

    John J. V. McMurray

Authors
  1. Michael P. Love
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John J. V. McMurray
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael P. Love.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Love, M.P., McMurray, J.J.V. Endothelin Receptor Antagonists and Cardiovascular Diseases of Aging. Drugs & Aging 18, 425–440 (2001). https://doi.org/10.2165/00002512-200118060-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002512-200118060-00005

Keywords

Search

Navigation