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Endothelin Receptor Antagonists in Heart Failure

Current Status and Future Directions

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Abstract

Experimental evidence suggests that endothelin substantially contributes to left ventricular remodelling and progression of heart failure. Plasma endothelin (ET)-l levels are increased in patients with heart failure, independent of the aetiology, and correlate with the severity of the disease. Furthermore, tissue endothelin levels and endothelin receptors are upregulated in myocardium from animals and humans with heart failure. In several experimental models of left ventricular remodelling and/or heart failure, treatment with nonselective ET-A and -B as well as selective ET-A antagonists exerted beneficial cardiovascular effects. In patients with heart failure, short-term studies of treatment with endothelin antagonists demonstrated an improvement of haemodynamic parameters; however, long-term treatment with these drugs did not significantly improve combined morbidity/mortality endpoints. Furthermore, in the recently completed Endothelin-A Receptor Antagonist Trial in Heart Failure (EARTH) trial in patients with chronic heart failure, the selective ET-A receptor antagonist darusentan did not significantly affect left ventricular remodelling as assessed by cardiac magnetic resonance imaging.

Potential reasons for the lack of beneficial effects of long-term treatment with ET antagonists in patients with heart failure include the following. Firstly, adverse effects on left ventricular healing have been observed when endothelin antagonist therapy was introduced early after myocardial infarction in rats. Secondly, the role of the ET-B receptor in the pathophysiology of heart failure and remodelling processes has not been clearly defined. Finally, for the detection of improvement in left ventricular remodelling, a study needs to be conducted in patients with recent myocardial infarction and signs of heart failure.

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References

  1. Stewart S, MacIntyre K, MacLeod MMC, et al. Trends in hospitalization for heart failure in Scotland, 1990–1996: an epidemic that has reached its peak? Eur Heart J 2001; 22: 209–17

    Article  PubMed  CAS  Google Scholar 

  2. Jessup MB, Brozena S. Medical progress: heart failure. N Engl J Med 2003; 348: 2007–18

    Article  PubMed  Google Scholar 

  3. Deedwania PC. Endothelin, the bad actor in the play: a marker or mediator of cardiovascular disease. J Am Coll Cardiol 1999 Mar 15; 33(4): 939–42

    Article  PubMed  CAS  Google Scholar 

  4. 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 

  5. 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: 293–300

    Article  PubMed  CAS  Google Scholar 

  6. MacCarthy PA, Grocott-Mason R, Prendergast PD, et al. Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ETA receptor antagonist. Circulation 2000; 101: 142–7

    Article  PubMed  CAS  Google Scholar 

  7. 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 

  8. Moreau P, d’Uscio L, Shaw S, et al. Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ETa receptor antagonist. Circulation 1997; 96: 1593–7

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Dostal DE, Baker KM. Angiotensin and endothelin: messengers that couple ventricular stretch to the Na+/H+ exchanger and cardiac hypertrophy. Circ Res 1998; 83: 870–3

    Article  PubMed  CAS  Google Scholar 

  11. Mortensen LH, Fink GD. Captopril prevents chronic hypertension produced by infusion of endothelin-1 in rats. Hypertension 1992; 19: 676–80

    Article  PubMed  CAS  Google Scholar 

  12. Ming Z, Parent R, Thorin E, et al. Endothelin-dependent tone limits acetylcholine-induced dilation of resistance coronary vessels after blockade of NO formation in conscious dogs. Hypertension 1998; 32: 844–8

    Article  PubMed  CAS  Google Scholar 

  13. 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: 849–53

    Article  PubMed  CAS  Google Scholar 

  14. Lerman A, Sandok EK, Hildebrand Jr FL, et al. Inhibition of endothelium-derived relaxing factor enhances endothelin-mediated vasoconstriction. Circulation 1992; 85: 1894–8

    Article  PubMed  CAS  Google Scholar 

  15. Verma S, Yao L, Stewart DJ, et al. Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo. Hypertension 2001; 37: 328–33

    Article  PubMed  CAS  Google Scholar 

  16. Kiowski W, Siitsch 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 

  17. Kiowski W, Luscher 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: 469–75

    Article  PubMed  CAS  Google Scholar 

  18. Kiowski W, Linder L. Reversal of endothelin-1-induced vasoconstriction by nifedipine in human resistance vessels in vivo in healthy subjects. Am J Cardiol 1992; 69: 1063–6

    Article  PubMed  CAS  Google Scholar 

  19. Neubauer S, Ertl G, Haas U, et al. Effects of endothelin-1 in isolated perfused rat heart. J Cardiovasc Pharmacol 1990; 16: 1–8

    Article  PubMed  CAS  Google Scholar 

  20. Neubauer S, Ertl G, Pulzer F, et al. Effects of endothelin-1 in the isolated heart under ischemic and cardioplegic conditions. J Cardiovasc Pharmacol 1990; 16: 804–11

    Article  PubMed  CAS  Google Scholar 

  21. Neubauer S, Zimmermann S, Hirsch A, et al. Effects of endothelin-1 in the isolated heart in ischemia/reperfusion and hypoxia/reoxygenation injury. J Mol Cell Cardiol 1991; 23: 1397–409

    Article  PubMed  CAS  Google Scholar 

  22. Han H, Neubauer S, Braeker B, et al. Endothelin-1 contributes to ischemia/reperfusion injury in isolated rat heart-attenuation of ischemic injury by the endothelin-1 antagonists BQ123 and BQ610. J Mol Cell Cardiol 1995; 27: 761–6

    Article  PubMed  CAS  Google Scholar 

  23. Masaki T, Kimura S, Yanagisawa M, et al. Molecular and cellular mechanism of endothelin regulation: implications for vascular function. Circulation 1991; 84: 1457–68

    Article  PubMed  CAS  Google Scholar 

  24. Piacentini L, Gray M, Honbo NY, et al. Endothelin-1 stimulates cardiac fibroblast proliferation through activation of protein kinase C. J Mol Cell Cardiol 2000; 32: 565–76

    Article  PubMed  CAS  Google Scholar 

  25. 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 

  26. Suzuki T, Tsuruda A, Katoh S, et al. Purification of endothelin from a conditioned medium of cardiac fibroblastic cells using beating rate assay of myocytes cultured in a serum-free medium. J Mol Cell Cardiol 1997; 29: 2087–93

    Article  PubMed  CAS  Google Scholar 

  27. Yamamoto T, Kimura T, Ota K, et al. Central effects of endothelin-1 on vasopressin release, blood pressure, and renal solute excretion. Am J Physiol 1992; 262: E856–62

    PubMed  CAS  Google Scholar 

  28. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903

    Article  PubMed  CAS  Google Scholar 

  29. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358: 1119–23

    Article  PubMed  CAS  Google Scholar 

  30. HiroeM, Hirata Y, Fujita N, etal. Plasma endothelin-1 levels in idiopathic dilated cardiomyopathy. Am J Cardiol 1991; 68: 1114–5

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. Wei CM, Lerman A, Rodehoeffer RJ, et al. Endothelin in human congestive heart failure. Circulation 1994; 89: 1580–6

    Article  PubMed  CAS  Google Scholar 

  33. 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: 504–9

    Article  PubMed  CAS  Google Scholar 

  34. Cody RJ. Corrected data and analysis of hemodynamic variables influencing plasma endothelin. Circulation 1993; 87: 1053–4

    Article  PubMed  CAS  Google Scholar 

  35. Stewart DJ, Cernacek P, Costello KB, et al. Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 1992; 85: 510–7

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  37. 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 

  38. 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 

  39. Galatius-Jensen S, Wroblewski H, Emmeluth C, et al. Plasma endothelin in congestive heart failure: effect of the ACE inhibitor, fosinopril. Cardiovasc Res 1996; 32: 1148–54

    Article  PubMed  CAS  Google Scholar 

  40. Di Pasquale P, Valdes L, Albano V, et al. Early captopril treatment reduces plasma endothelin concentrations in the acute and subacute phases of myocardial infarction: a pilot study. J Cardiovasc Pharmacol 1997; 29: 202–8

    Article  PubMed  CAS  Google Scholar 

  41. 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: 1578–84

    Article  PubMed  CAS  Google Scholar 

  42. Abassi Z, Winaver J, Rubinstein I, et al. Renal endothelin converting enzyme in rats with congestive heart failure. J Cardiovasc Pharmacol 1998; 31 Suppl. 1: S31–4

    Article  PubMed  CAS  Google Scholar 

  43. Abassi Z, Gurbanov K, Mulroney SE, et al. Impaired nitric oxide-mediated renal vasodilation in rats with experimental heart failure: role of angiotensin II. Circulation 1997; 96: 3655–64

    Article  PubMed  CAS  Google Scholar 

  44. Bauersachs J, Braun C, Fraccarollo D, et al. Improvement of renal dysfunction in rats with chronic heart failure after myocardial infarction by treatment with the endothelin A receptor antagonist, LU 135252. J Hypertens 2000; 18(10): 1507–14

    Article  PubMed  CAS  Google Scholar 

  45. Fraccarollo D, Hu K, Galuppo P, et al. Chronic endothelin receptor blockade attenuates progressive ventricular dilatation 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 

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

    Article  PubMed  CAS  Google Scholar 

  47. 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 

  48. Iwanaga Y, Kihara Y, Inagaki K, et al. Differential effects of angiotensin II versus endothelin-1 inhibitions in hypertrophic left ventricular myocardium during transition to heart failure. Circulation 2001; 104: 606–12

    Article  PubMed  CAS  Google Scholar 

  49. 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 

  50. Ooi H, Colucci WS, Givertz MM. Endothelin mediates increased pulmonary vascular tone in patients with heart failure: demonstration by direct intrapulmonary infusion of sitaxsentan. Circulation 2002; 106: 1618–21

    Article  PubMed  CAS  Google Scholar 

  51. Qi XL, Sia YT, Stewart DJ, et al. Myocardial contractile responsiveness to endothelin-1 in the post-infarction rat model of heart failure: effects of chronic quinapril. J Mol Cell Cardiol 2001; 33: 2023–35

    Article  PubMed  CAS  Google Scholar 

  52. Kakinuma Y, Miyauchi T, Yuki K, et al. Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxiainducible factor-1alpha induced for impaired myocardial energy metabolism. Circulation 2001; 103: 2387–94

    Article  PubMed  CAS  Google Scholar 

  53. Wei CM, Clavell AL, Burnett JC. Atrial and pulmonary endothelin mRNA is increased in a canine model of chronic low cardiac output. Am J Physiol 1997; 273: R838–44

    PubMed  CAS  Google Scholar 

  54. 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 

  55. Ponicke K, Vogelsang M, Heinroth M, et al. Endothelin receptors in the failing and nonfailing human heart. Circulation 1998; 97: 744–51

    Article  PubMed  CAS  Google Scholar 

  56. Herrmann S, Schmidt-Petersen K, Pfeifer J, et al. A polymorphism in the endothelin-A receptor gene predicts survival in patients with idiopathic dilated cardiomyopathy. Eur Heart J 2001; 22: 1948–53

    Article  PubMed  CAS  Google Scholar 

  57. 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 

  58. 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 

  59. 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 

  60. Liu JL, Pliquett RU, Brewer E, et al. Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure.Am J Physiol Regul Integr Comp Physiol 2001; 280: R1906–13

    PubMed  CAS  Google Scholar 

  61. Rothermund L, Vetter R, Dieterich M, et al. Endothelin-A receptor blockade prevents left ventricular hypertrophy and dysfunction in salt-sensitive experimental hypertension. Circulation 2002; 106: 2305–8

    Article  PubMed  CAS  Google Scholar 

  62. Sakai S, Miyauchi T, Yamaguchi I. Long-term endothelin receptor antagonist administration improves alterations in expression of various cardiac genes in failing myocardium of rats with heart failure. Circulation 2000; 101: 2849–53

    Article  PubMed  CAS  Google Scholar 

  63. Miyauchi T, Sato R, Sakai S, et al. Endothelin-1 and right-sided heart failure in rats: effects of an endothelin receptor antagonist on the failing right ventricle. J Cardiovasc Pharmacol 2000; 36: S327–30

    PubMed  CAS  Google Scholar 

  64. Mulder P, Boujedaini H, Richard V, et al. Long-term survival and hemodynamics after endothelin-a receptor antagonism and angiotensin-converting enzyme inhibition in rats with chronic heart failure: monotherapy versus combination therapy. Circulation 2002; 106: 1159–64

    Article  PubMed  CAS  Google Scholar 

  65. Fraccarollo D, Bauersachs J, Kellner M, et al. Cardioprotection by long-term ET(A) receptor blockade and ACE inhibition in rats with congestive heart failure: monoversus combination therapy. Cardiovasc Res 2002; 54: 85–94

    Article  PubMed  CAS  Google Scholar 

  66. Bauersachs J, Fraccarollo D, Schafer A, et al. Angiotensin-converting enzyme inhibition and endothelin antagonism for endothelial dysfunction in heart failure: mono-or combination therapy. J Cardiovasc Pharmacol 2002; 40: 594–600

    Article  PubMed  CAS  Google Scholar 

  67. Fraccarollo D, Galuppo P, Bauersachs J, et al. Collagen accumulation after myocardial infarction: effects of ETA receptor blockade and implications for early remodeling. Cardiovasc Res 2002; 54: 559–67

    Article  PubMed  CAS  Google Scholar 

  68. Hu K, Gaudron P, Schmidt TJ, et al. Aggravation of left ventricular remodeling by a novel specific endothelin ETa antagonist EMD94246 in rats with myocardial infarction. J Cardiovasc Pharmacol 1998; 32: 505–8

    Article  PubMed  CAS  Google Scholar 

  69. Nguyen QT, Cernacek 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 

  70. Nguyen QT, Cernacek P, Sirois MG, et al. Long-term effects of nonselective endothelin A and B receptor antagonism in postinfarction rat: importance of timing. Circulation 2001; 104: 2075–81

    Article  PubMed  CAS  Google Scholar 

  71. Clozel M, Qiu C, Qiu CS, et al. Short-term endothelin receptor blockade with tezosentan has both immediate and long-term beneficial effects in rats with myocardial infarction. J Am Coll Cardiol 2002; 39: 142–7

    Article  PubMed  CAS  Google Scholar 

  72. Teerlink JR, Löffler 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; 90: 2510–8

    Article  PubMed  CAS  Google Scholar 

  73. 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 

  74. Bauersachs J, Fraccarollo D, Galuppo P, et al. Endothelin receptor blockade improves endothelial vasomotor dysfunction in heart failure. Cardiovasc Res 2000; 47: 142–9

    Article  PubMed  CAS  Google Scholar 

  75. 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: beneficial effects on left ventricular and myocyte function. Circulation 1997; 95: 1918–29

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  77. Givertz MM, Colucci WS, LeJemtel TH, et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation 2000; 101: 2922–7

    Article  PubMed  CAS  Google Scholar 

  78. 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 

  79. 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 

  80. Torre-Amione G, Young JB, Durand J, 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 

  81. Cotter G, Kiowski W, Kaluski E, et al. Tezosentan (an intravenous endothelin receptor A/B antagonist) reduces peripheral resistance and increases cardiac power therefore preventing a steep decrease in blood pressure in patients with congestive heart failure. Eur J Heart Fail 2001; 3: 457–61

    Article  PubMed  CAS  Google Scholar 

  82. Cardillo C, Campia U, Kilcoyne CM, et al. Improved endothelium-dependant vasodilation after blockade of endothelin receptors in patients with essential hypertension. Circulation 2002; 105(4): 452–6

    Article  PubMed  CAS  Google Scholar 

  83. Berger R, Stanek B, Hülsmann M, et al. Effects of endothelin A receptor blockade on endothelial function in patients with chronic heart failure. Circulation 2001; 103: 981–6

    Article  PubMed  CAS  Google Scholar 

  84. Cardillo C, Kilcoyne CM, Cannon RO, et al. Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo. Hypertension 2000; 35(6): 1237–41

    Article  PubMed  CAS  Google Scholar 

  85. Mylona P, Cleland JG. Update of REACH-1 and MERIT-HF clinical trials in heart failure: Cardio.net Editorial Team. Eur J Heart Fail 1999; 1: 197–200

    Article  PubMed  CAS  Google Scholar 

  86. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol 2002; 85: 195–7

    Article  PubMed  Google Scholar 

  87. Luscher TF, Enseleit F, Pacher R, et al. Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT). Circulation 2002; 106: 2666–72

    Article  PubMed  CAS  Google Scholar 

  88. O’Connor CM, Gattis WA, Adams KF, et al. Tezosentan in patients with acute heart failure and acute coronary syndromes: results of the Randomized Intravenous Tezosentan Study (RITZ-4). J Am Coll Cardiol 2003; 41: 1452–7

    Article  PubMed  CAS  Google Scholar 

  89. Louis A, Cleland JG, Crabbe S, et al. Clinical trials update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure: highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail 2001; 3: 381–7

    Article  PubMed  CAS  Google Scholar 

  90. Coletta AP, Cleland JG. Clinical trials update. Highlights of the scientific sessions of the XXIII Congress of the European Society of Cardiology: WARIS II, ESCAMI, PAFAC, RITZ-1 and TIME. Eur J Heart Fail 2001; 3: 747–50

    Article  PubMed  CAS  Google Scholar 

  91. Kaluski E, Kobrin I, Zimlichman R, et al. RITZ-5: Randomized Intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study. J Am Coll Cardiol 2003; 41: 204–10

    Article  PubMed  CAS  Google Scholar 

  92. Anand IS, Luscher TF. The EARTH trial [presented in a hot-line session]. 24th Congress of the European Society of Cardiology; 2002 Aug 31–Sep 4; Berlin

  93. Araki M, Hasegawa K, Iwai-Kanai E, et al. Endothelin-1 as a protective factor against beta-adrenergic agonist-induced apoptosis in cardiac myocytes. J Am Coll Cardiol 2000; 36: 1411–8

    Article  PubMed  CAS  Google Scholar 

  94. Thiemermann C, Lidbury PS, Thomas GR, et al. Endothelin-1 releases prostacyclin and inhibits ex vivo platelet aggregation in the anesthetized rabbit. J Cardiovasc Pharmacol 1989; 13 Suppl. 5: S138–41

    Article  PubMed  CAS  Google Scholar 

  95. Berthold H, Munter K, Just A, et al. Stimulation of the reninangiotensin system by endothelin subtype a receptor blockade in conscious dogs. Hypertension 1999; 33(6): 1420–4

    Article  PubMed  CAS  Google Scholar 

  96. Mulder P, Boujedaini H, Richard V, et al. Selective endothelin-A versus combined endothelin-A/endothelin-B receptor blockade in rat chronic heart failure. Circulation 2000; 102: 491–3

    Article  PubMed  CAS  Google Scholar 

  97. 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 

  98. 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: 932–8

    Article  PubMed  CAS  Google Scholar 

  99. 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 

  100. Sawaki M, Wada A, Tsutamoto T, et al. Chronic effects of an orally active selective endothelin-B-receptor antagonist in experimental congestive heart failure. J Cardiovasc Pharmacol 2000; 36: S323–6

    PubMed  CAS  Google Scholar 

  101. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial: the SAVE Investigators. N Engl J Med 1992; 327: 669–77

    Article  PubMed  CAS  Google Scholar 

  102. Pfeffer MA, Pfeffer JM, Steinberg C, et al. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circ Res 1985; 72: 406–12

    CAS  Google Scholar 

  103. Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985; 57: 84–95

    Article  PubMed  CAS  Google Scholar 

  104. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation 1990; 81: 1161–72

    Article  PubMed  CAS  Google Scholar 

  105. Pfeffer MA, Lamas GA, Vaughan DE, et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 319: 80–6

    Article  PubMed  CAS  Google Scholar 

  106. Sharpe N, Murphy J, Smith H, et al. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988; I: 255–9

    Article  Google Scholar 

  107. White HD, Norris RM, Brown MA, et al. Left ventricular endsystolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987; 76: 44–51

    Article  PubMed  CAS  Google Scholar 

  108. Bart BA, Ertl G, Held P, et al. Contemporary management of patients with left ventricular systolic dysfunction: results from the Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE) Registry. Eur Heart J 1999; 20: 1182–90

    Article  PubMed  CAS  Google Scholar 

  109. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348: 1309–21

    Article  PubMed  CAS  Google Scholar 

  110. Murugesan N, Gu Z, Spergel S, et al. Discovery of N-isoxazolyl biphenylsulphonamides as potent dual angiotensin II and endothelin A receptor antagonists. J Med Chem 2002; 45: 3829–35

    Article  PubMed  CAS  Google Scholar 

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Supported by grant SFB 355 of the Deutsche Forschungsgemeinschaft. The authors have provided no information on conflicts of interest directly relevant to the content of this review.

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Ertl, G., Bauersachs, J. Endothelin Receptor Antagonists in Heart Failure. Drugs 64, 1029–1040 (2004). https://doi.org/10.2165/00003495-200464100-00001

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