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Endothelin Receptor Antagonists in Cardiovascular Medicine: Challenges and Opportunities

  • Matthias Barton
Chapter

Abstract

The discovery of the release of endothelium-derived vasoconstriction led to studies identifying the endothelium-derived peptide endothelin and its receptors. In the early 1990s, endothelin receptor antagonists (ERAs) were developed and preclinical and clinical studies initiated. Despite strong experimental evidence for a role of endothelin-1, the predominant member of the endothelin peptide family, in cardiovascular physiology and disease, the vast majority of clinical studies in cardiovascular medicine using endothelin receptor antagonists (ERAs) were negative partly because study design and/or patient selection were frequently inadequate. This chapter provides an overview of the endothelin system as well as preclinical data of ERA studies obtained in disease models of arterial hypertension, atherosclerosis, coronary artery disease, pulmonary hypertension, heart failure, renal disease, and allograft rejection following cardiac transplantation. Results and developments in ERA clinical trials in cardiovascular medicine will be discussed also covering reasons for failed ERA trials and discontinuation of clinical drug development of numerous ERAs.

Keywords

Pulmonary Arterial Hypertension Proteinuric Renal Disease Primary Pulmonary Arterial Hypertension Antagonist Darusentan 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by grants from the Swiss National Science Foundation (Nr. 108 258 and 122 504). I thank present and former members of my laboratory as well as my collaborators who have contributed to the original research discussed in this chapter.

References

  1. 1.
    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;299:373–6.CrossRefGoogle Scholar
  2. 2.
    Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA. 1987;84:9265–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Barton M. The discovery of endothelium-dependent contraction: the legacy of Paul M. Vanhoutte. Pharmacol Res. 2011. doi:S1043-6618(11)00064-8 [pii] 10.1016/j.phrs.2011.02.013.Google Scholar
  4. 4.
    De Mey JG, Vanhoutte PM. Contribution of the endothelium to the response to anoxia in the canine femoral artery. Arch Int Pharmacodyn Ther. 1981;253(2):325–6.PubMedGoogle Scholar
  5. 5.
    De Mey JG, Vanhoutte PM. Heterogeneous behavior of the canine arterial and venous wall. Importance of the endothelium. Circ Res. 1982;51(4):439–47.PubMedGoogle Scholar
  6. 6.
    Gillespie MN, Owasoyo JO, McMurtry IF, O’Brien RF. Sustained coronary vasoconstriction provoked by a peptidergic substance released from endothelial cells in culture. J Pharmacol Exp Ther. 1986;236(2):339–43.PubMedGoogle Scholar
  7. 7.
    Hickey KA, Rubanyi GM, Paul RJ, Highsmith RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol. 1985;248:C550–6.PubMedGoogle Scholar
  8. 8.
    O’Brien RF, Robbins RJ, McMurtry IF. Endothelial cells in culture produce a vasoconstrictor substance. J Cell Physiol. 1987;132(2):263–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Rubanyi GM. The discovery of endothelin: the power of bioassay and the role of serendipity in the discovery of endothelium-derived vasoactive substances. Pharmacol Res. 2011. doi:S1043-6618(10)00167-2 [pii] 10.1016/j.phrs.2010.08.004.Google Scholar
  10. 10.
    Masaki T. The discovery of endothelins. Cardiovasc Res. 1998;39(3):530–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Masaki T. Historical review: endothelin. Trends Pharmacol Sci. 2004;25(4):219–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Hillier C, Berry C, Petrie MC, O’Dwyer PJ, Hamilton C, Brown A, et al. Effects of urotensin II in human arteries and veins of varying caliber. Circulation. 2001;103(10):1378–81.PubMedGoogle Scholar
  14. 14.
    Maguire JJ, Davenport AP. Is urotensin-II the new endothelin? Br J Pharmacol. 2002;137(5):579–88.PubMedCrossRefGoogle Scholar
  15. 15.
    Barton M, Carmona R, Krieger JE, Goettsch W, Morawietz H, d’Uscio LV, et al. Endothelin regulates angiotensin-converting enzyme in the mouse kidney. J Cardiovasc Pharmacol. 2000;36(5 Suppl 1):S244–7.PubMedGoogle Scholar
  16. 16.
    Tomobe Y, Miyauchi T, Saito A, Yanagisawa M, Kimura S, Goto K, et al. Effects of endothelin on the renal artery from spontaneously hypertensive and wistar kyoto rats. Eur J Pharmacol. 1988;152(3):373–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Miyauchi T, Yanagisawa M, Tomizawa T, Sugishita Y, Suzuki N, Fujino M, et al. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet. 1989;2(8653):53–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Kisanuki YY, Emoto N, Ohuchi T, Widyantoro B, Yagi K, Nakayama K, et al. Low blood pressure in endothelial cell-specific endothelin 1 knockout mice. Hypertension. 2010;56:121–8. doi:HYPERTENSIONAHA.109.138701 [pii] 10.1161/HYPERTENSIONAHA.109.138701.PubMedCrossRefGoogle Scholar
  19. 19.
    Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851–76.PubMedCrossRefGoogle Scholar
  20. 20.
    Amiri F, Ko EA, Javeshghani D, Reudelhuber TL, Schiffrin EL. Deleterious combined effects of salt-loading and endothelial cell restricted endothelin-1 overexpression on blood pressure and vascular function in mice. J Hypertens. 2010. doi:10.1097/HJH.0b013e328338bb8b.Google Scholar
  21. 21.
    Anggrahini DW, Emoto N, Nakayama K, Widyantoro B, Adiarto S, Iwasa N, et al. Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation. Cardiovasc Res. 2009;82(1):143–51. doi:cvp026 [pii] 10.1093/cvr/cvp026.PubMedCrossRefGoogle Scholar
  22. 22.
    Pollock DM. Dissecting the complex physiology of endothelin. New lessons from genetic models. Hypertension. 2010;56:31–3. doi:HYPERTENSIONAHA.109.139758 [pii] 10.1161/HYPERTENSIONAHA.109.139758.PubMedCrossRefGoogle Scholar
  23. 23.
    Battistini B, Berthiaume N, Kelland NF, Webb DJ, Kohan DE. Profile of past and current clinical trials involving endothelin receptor antagonists: the novel “-sentan” class of drug. Exp Biol Med (Maywood). 2006;231(6):653–95.Google Scholar
  24. 24.
    Bramall AN, Han RN, Deng Y, Yanagisawa M, McInnes RR, Stewart DJ. Endothelin 2 (et-2) plays a critical role in lung alveolarization: novel insight from the et-2-deficient mouse model. Meeting Abstract Book 10th International Conference on Endothelin, Bergamo; September 2007.Google Scholar
  25. 25.
    Chai SP, Chang YN, Fong JC. Endothelin-1 stimulates interleukin-6 secretion from 3t3-l1 adipocytes. Biochim Biophys Acta. 2009;1790(3):213–8. doi:S0304-4165(08)00270-5 [pii] 10.1016/j.bbagen.2008.12.002.PubMedCrossRefGoogle Scholar
  26. 26.
    Hoeper MM, Seyfarth HJ, Hoeffken G, Wirtz H, Spiekerkoetter E, Pletz MW, et al. Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Eur Respir J. 2007;30(6):1096–102.PubMedCrossRefGoogle Scholar
  27. 27.
    Barton M, Yanagisawa M. Endothelin: 20 years from discovery to therapy. Can J Physiol Pharmacol. 2008;86(8):485–98. doi:y08-059 [pii] 10.1139/y08-059.PubMedCrossRefGoogle Scholar
  28. 28.
    Guo C, Ju H, Leung D, Massaeli H, Shi M, Rabinovitch M. A novel vascular smooth muscle chymase is upregulated in hypertensive rats. J Clin Invest. 2001;107(6):703–15. doi:10.1172/JCI9997.PubMedCrossRefGoogle Scholar
  29. 29.
    Guo C, Rabinovitch M. A novel chymase cDNA cloned from rat pulmonary artery smooth muscle cells with increased vascular expression in spontaneously hypertensive rats. Circulation. 1998;98:I–745 (abstract).Google Scholar
  30. 30.
    Ju H, Gros R, You X, Tsang S, Husain M, Rabinovitch M. Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. Proc Natl Acad Sci USA. 2001;98(13):7469–74. doi:10.1073/pnas.131147598 98/13/7469 [pii].PubMedCrossRefGoogle Scholar
  31. 31.
    Ikeda K, Emoto N, Raharjo SB, Nurhantari Y, Saiki K, Yokoyama M, et al. Molecular identification and characterization of novel membrane-bound metalloprotease, the soluble secreted form of which hydrolyzes a variety of vasoactive peptides. J Biol Chem. 1999;274(45):32469–77.PubMedCrossRefGoogle Scholar
  32. 32.
    Gariepy CE, Ohuchi T, Williams SC, Richardson JA, Yanagisawa M. Salt-sensitive hypertension in endothelin-B receptor-deficient rats. J Clin Invest. 2000;105(7):925–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Seyrantepe V, Hinek A, Junzheng P, Fedjaev M, Ernest S, Kadota Y, et al. Enzymatic activity of lysosomal carboxypeptidase (cathepsin) A is required for proper elastic fiber formation and inactivation of endothelin-1. Circulation. 2008;117:1973–81.PubMedCrossRefGoogle Scholar
  34. 34.
    Davenport AP. International union of pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev. 2002;54(2):219–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Evans NJ, Walker JW. Endothelin receptor dimers evaluated by FRET, ligand binding, and calcium mobilization. Biophys J. 2008;95(1):483–92.Google Scholar
  36. 36.
    Watts SW. Endothelin receptors: what’s new and what do we need to know? Am J Physiol Regul Integr Comp Physiol. 2010;298. doi:00584.2009 [pii] 10.1152/ajpregu.00584.2009.Google Scholar
  37. 37.
    Attie T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, et al. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet. 1995;4(12):2407–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, et al. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell. 1994;79(7):1277–85.PubMedCrossRefGoogle Scholar
  39. 39.
    Puffenberger EG, Hosoda K, Washington SS, Nakao K, de Wit D, Yanagisawa M, et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell. 1994;79(7):1257–66.PubMedCrossRefGoogle Scholar
  40. 40.
    Burkhardt M, Barton M, Shaw SG. Receptor- and non-receptor-mediated clearance of big-endothelin and endothelin-1: differential effects of acute and chronic ETA receptor blockade. J Hypertens. 2000;18(3):273–9.PubMedCrossRefGoogle Scholar
  41. 41.
    de Nucci G, Thomas R, D’Orleans-Juste P, Antunes E, Walder C, Warner TD, 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(24):9797–800.PubMedCrossRefGoogle Scholar
  42. 42.
    Luscher T, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation. 2000;102:2434–40.PubMedGoogle Scholar
  43. 43.
    Barton M. Endothelial dysfunction and atherosclerosis: endothelin receptor antagonists as novel therapeutics. Curr Hypertens Rep. 2000;2(1):84–91.PubMedCrossRefGoogle Scholar
  44. 44.
    Barton M, Nett PC, Amann K, Teixeira MM. Anti-inflammatory effects of endothelin receptor antagonists and their importance for treating human disease. In: Chaudhary I, Ur-Rahman A, editors. Frontiers in cardiovascular drug discovery, vol. 1. Oak Parks: Bentham Science; 2010. p. 236–258.CrossRefGoogle Scholar
  45. 45.
    Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994;46(3):325–415.PubMedGoogle Scholar
  46. 46.
    Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet. 1994;344(8926):852–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Schiffrin EL. State-of-the-art lecture. Role of endothelin-1 in hypertension. Hypertension. 1999;34(4 Pt 2):876–81.PubMedGoogle Scholar
  48. 48.
    Proven A, Roderick HL, Conway SJ, Berridge MJ, Horton JK, Capper SJ, et al. Inositol 1,4,5-trisphosphate supports the arrhythmogenic action of endothelin-1 on ventricular cardiac myocytes. J Cell Sci. 2006;119(Pt 16):3363–75.PubMedCrossRefGoogle Scholar
  49. 49.
    Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature. 1996;384(6607):353–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Uchida Y, Ninomiya H, Saotome M, Nomura A, Ohtsuka M, Yanagisawa M, et al. Endothelin, a novel vasoconstrictor peptide, as potent bronchoconstrictor. Eur J Pharmacol. 1988;154(2):227–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Denton CP, Humbert M, Rubin L, Black CM. Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis. 2006;65(10):1336–40.PubMedCrossRefGoogle Scholar
  52. 52.
    Barton M. Reversal of proteinuric renal disease and the emerging role of endothelin. Nat Clin Pract Nephrol. 2008;4(9):490–501. doi:ncpneph0891 [pii] 10.1038/ncpneph0891.PubMedCrossRefGoogle Scholar
  53. 53.
    Chatziantoniou C, Dussaule JC. Insights into the mechanisms of renal fibrosis: is it possible to achieve regression? Am J Physiol. 2005;289(2):F227–34.CrossRefGoogle Scholar
  54. 54.
    Hocher B, Thöne-Reinecke C, Rohmeiss P, Schmager F, Slowinski R, Burst V, et al. Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest. 1997;99:1380–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Remuzzi G, Perico N, Benigni A. New therapeutics that antagonize endothelin: promises and frustrations. Nat Rev Drug Discov. 2002;1(12):986–1001.CrossRefGoogle Scholar
  56. 56.
    Spirig R, Potapova I, Shaw-Boden J, Tsui J, Rieben R, Shaw SG. TLR2 and TLR4 agonists induce production of the vasoactive peptide endothelin-1 by human dendritic cells. Mol immunol 2009;46(15):3178–82.CrossRefGoogle Scholar
  57. 57.
    Nett PC, Teixeira MM, Candinas D, Barton M. Recent developments on endothelin antagonists as immunomodulatory drugs–from infection to transplantation medicine. Recent Pat Cardiovasc Drug Discov. 2006;1(3):265–76.PubMedCrossRefGoogle Scholar
  58. 58.
    Berthiaume N, Carlson CJ, Rondinone CM, Zinker BA. Endothelin antagonism improves hepatic insulin sensitivity associated with insulin signaling in Zucker fatty rats. Metabolism. 2005;54(11):1515–23.PubMedCrossRefGoogle Scholar
  59. 59.
    Lteif A, Vaishnava P, Baron AD, Mather KJ. Endothelin limits insulin action in obese/insulin-resistant humans. Diabetes. 2007;56(3):728–34.PubMedCrossRefGoogle Scholar
  60. 60.
    van Harmelen V, Eriksson A, Astrom G, Wahlen K, Naslund E, Karpe F, et al. Vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis. Diabetes. 2008;57(2):378–86.PubMedCrossRefGoogle Scholar
  61. 61.
    Iwasa S, Fan J, Miyauchi T, Watanabe T. Blockade of endothelin receptors reduces diet-induced hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice. Pathobiology. 2001;69(1):1–10.PubMedCrossRefGoogle Scholar
  62. 62.
    Yokokawa K, Tahara H, Kohno M, Murakawa K, Yasunari K, Nakagawa K, et al. Hypertension associated with endothelin-secreting malignant hemangioendothelioma. Ann Intern Med. 1991;114(3):213–5.PubMedGoogle Scholar
  63. 63.
    Barton M, Shaw S, d’Uscio LV, Moreau P, Luscher TF. 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(3):861–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Schiffrin EL. Role of endothelin-1 in hypertension and vascular disease. Am J Hypertens. 2001;14(6 Pt 2):83S–9S.PubMedCrossRefGoogle Scholar
  65. 65.
    Barton M, Kiowski W. The therapeutic potential of endothelin receptor antagonists in cardiovascular disease. Curr Hypertens Rep. 2001;3(4):322–30.PubMedCrossRefGoogle Scholar
  66. 66.
    Barton M, Luscher TF. Endothelin antagonists for hypertension and renal disease. Curr Opin Nephrol Hypertens. 1999;8(5):549–56.PubMedCrossRefGoogle Scholar
  67. 67.
    Schiffrin EL. Vascular endothelin in hypertension. Vascul Pharmacol. 2005;43(1):19–29.PubMedCrossRefGoogle Scholar
  68. 68.
    Schiffrin EL. Endothelin and endothelin antagonists in hypertension. J Hypertens. 1998;16(12 Pt 2):1891–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Kohan DE. Endothelins in the normal and diseased kidney. Am J Kidney Dis. 1997;29(1):2–26.PubMedCrossRefGoogle Scholar
  70. 70.
    Katoh T, Chang H, Uchida S, Okuda T, Kurokawa K. Direct effects of endothelin in the rat kidney. Am J Physiol. 1990;258(2 Pt 2):F397–402.PubMedGoogle Scholar
  71. 71.
    Barton M, Haudenschild CC, d’Uscio LV, Shaw S, Munter K, Luscher TF. Endothelin eta receptor blockade restores no-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA. 1998;95(24):14367–72.PubMedCrossRefGoogle Scholar
  72. 72.
    Schneider MP, Ge Y, Pollock DM, Pollock JS, Kohan DE. Collecting duct-derived endothelin regulates arterial pressure and Na excretion via nitric oxide. Hypertension. 2008;51:1–6.CrossRefGoogle Scholar
  73. 73.
    Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. N Engl J Med. 1998;338:784–90.PubMedCrossRefGoogle Scholar
  74. 74.
    Black HR, Bakris GL, Weber MA, Weiss R, Shahawy ME, Marple R, et al. Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study. J Clin Hypertens. 2007;9(10):760–9.CrossRefGoogle Scholar
  75. 75.
    Nakov R, Pfarr E, Eberle S. Darusentan: an effective endothelinA receptor antagonist for treatment of hypertension. Am J Hypertens. 2002;15(7 Pt 1):583–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Bakris GL, Lindholm LH, Black HR, Krum H, Linas S, Linseman JV, et al. Divergent results using clinic and ambulatory blood pressures: report of a darusentan-resistant hypertension trial. Hypertension. 2010;56(5):824–30. doi:HYPERTENSIONAHA.110.156976 [pii] 10.1161/HYPERTENSIONAHA.110.156976.PubMedCrossRefGoogle Scholar
  77. 77.
    Weber MA, Black H, Bakris G, Krum H, Linas S, Weiss R, et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9699):1423–31. doi:S0140-6736(09)61500-2 [pii] 10.1016/S0140-6736(09)61500-2.PubMedCrossRefGoogle Scholar
  78. 78.
    Pollock DM, Schneider MP. Clarifying endothelin type B receptor function. Hypertension. 2006;48(2):211–2.PubMedCrossRefGoogle Scholar
  79. 79.
    Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, et al. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation. 1998;97(8):752–6.PubMedGoogle Scholar
  80. 80.
    Green S, Bundey RA, Nunley K, Hartman JC, Melvin LS, Gorczynski RJ, Insel PA, Bristow MR, Pitts KR. Determination of endothelin receptor antagonist affinities and selectivities in human cardiac membranes. Meeting Abstract Book 10th International Conference on Endothelin, Bergamo; September 2007.Google Scholar
  81. 81.
    Ergul A. Hypertension in black patients: an emerging role of the endothelin system in salt-sensitive hypertension. Hypertension. 2000;36(1):62–7.PubMedGoogle Scholar
  82. 82.
    Ergul S, Parish DC, Puett D, Ergul A. Racial differences in plasma endothelin-1 concentrations in individuals with essential hypertension. Hypertension. 1996;28(4):652–5.PubMedGoogle Scholar
  83. 83.
    Parrinello G, Scaglione R, Pinto A, Corrao S, Cecala M, Di Silvestre G, et al. Central obesity and hypertension: the role of plasma endothelin. Am J Hypertens. 1996;9(12 Pt 1):1186–91.PubMedCrossRefGoogle Scholar
  84. 84.
    Barton M, Mullins JJ, Bailey MA, Kretzler M. Role of endothelin receptors for renal ­protection and survival in hypertension: waiting for clinical trials. Hypertension. 2006;48(5):834–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Belaidi E, Joyeux-Faure M, Ribuot C, Launois SH, Levy P, Godin-Ribuot D. Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea. J Am Coll Cardiol. 2009;53(15):1309–17. doi:S0735-1097(09)00334-9 [pii] 10.1016/j.jacc.2008.12.050.PubMedCrossRefGoogle Scholar
  86. 86.
    Duru F, Barton M, Luscher TF, Candinas R. Endothelin and cardiac arrhythmias: do endothelin antagonists have a therapeutic potential as antiarrhythmic drugs? Cardiovasc Res. 2001;49(2):272–80.PubMedCrossRefGoogle Scholar
  87. 87.
    Lerman A, Edwards BS, Hallett JW, Heublein DM, Sandberg SM, Burnett Jr JC. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991;325(14):997–1001.PubMedCrossRefGoogle Scholar
  88. 88.
    Winkles JA, Alberts GF, Brogi E, Libby P. Endothelin-1 and endothelin receptor mRNA expression in normal and atherosclerotic human arteries. Biochem Biophys Res Commun. 1993;191(3):1081–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Babaei S, Picard P, Ravandi A, Monge JC, Lee TC, Cernacek P, et al. Blockade of endothelin receptors markedly reduces atherosclerosis in LDL receptor deficient mice: role of endothelin in macrophage foam cell formation. Cardiovasc Res. 2000;48(1):158–67.PubMedCrossRefGoogle Scholar
  90. 90.
    Schiffrin EL. Beyond blood pressure: the endothelium and atherosclerosis progression. Am J Hypertens. 2002;15(10 Pt 2):115S–22S.PubMedCrossRefGoogle Scholar
  91. 91.
    Tepe G, Brehme U, Seeger H, Raschack M, Claussen CD, Duda SH. Endothelin a receptor antagonist LU 135252 inhibits hypercholesterolemia-induced, but not deendothelialization-induced, atherosclerosis in rabbit arteries. Invest Radiol. 2002;37(6):349–55.PubMedCrossRefGoogle Scholar
  92. 92.
    Caligiuri G, Levy B, Pernow J, Thoren P, Hansson GK. Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. Proc Natl Acad Sci USA. 1999;96(12):6920–4.PubMedCrossRefGoogle Scholar
  93. 93.
    Best PJ, Lerman LO, Romero JC, Richardson D, Holmes Jr DR, Lerman A. Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro. Arterioscler Thromb Vasc Biol. 1999;19(11):2769–75.PubMedCrossRefGoogle Scholar
  94. 94.
    Best PJ, McKenna CJ, Hasdai D, Holmes Jr DR, Lerman A. Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. Circulation. 1999;99(13):1747–52.PubMedGoogle Scholar
  95. 95.
    Barton M, Glodny B. Endothelin receptor blockade and nitric oxide bioactivity. Cardiovasc Res. 2001;52(1):161–3.PubMedCrossRefGoogle Scholar
  96. 96.
    Verma S, Lovren F, Dumont AS, Mather KJ, Maitland A, Kieser TM, et al. Endothelin receptor blockade improves endothelial function in human internal mammary arteries. Cardiovasc Res. 2001;49(1):146–51. doi:S0008-6363(00)00244-3 [pii].PubMedCrossRefGoogle Scholar
  97. 97.
    Bohm F, Beltran E, Pernow J. Endothelin receptor blockade improves endothelial function in atherosclerotic patients on angiotensin converting enzyme inhibition. J Intern Med. 2005;257(3):263–71. doi:JIM1448 [pii] 10.1111/j.1365-2796.2005.01448.x.PubMedCrossRefGoogle Scholar
  98. 98.
    Bohm F, Jensen J, Svane B, Settergren M, Pernow J. Intracoronary endothelin receptor blockade improves endothelial function in patients with coronary artery disease. Can J Physiol Pharmacol. 2008;86(11):745–51. doi:y08-081 [pii] 10.1139/y08-081.PubMedCrossRefGoogle Scholar
  99. 99.
    Bohm F, Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res. 2007;76(1):8–18. doi:S0008-6363(07)00281-7 [pii] 10.1016/j.cardiores.2007.06.004.PubMedCrossRefGoogle Scholar
  100. 100.
    Kalani M, Pernow J, Bragd J, Jorneskog G. Improved peripheral perfusion during endothelin–A receptor blockade in patients with type 2 diabetes and critical limb ischemia. Diabetes Care. 2008;31(7):e56. doi:31/7/e56 [pii] 10.2337/dc08-0409.PubMedCrossRefGoogle Scholar
  101. 101.
    Settergren M, Pernow J, Brismar K, Jorneskog G, Kalani M. Endothelin-A receptor blockade increases nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy. J Vasc Res. 2008;45(4):295–302. doi:000113601 [pii] 10.1159/000113601.PubMedCrossRefGoogle Scholar
  102. 102.
    Raichlin E, Prasad A, Mathew V, Kent B, Holmes Jr DR, Pumper GM, et al. Efficacy and safety of atrasentan in patients with cardiovascular risk and early atherosclerosis. Hypertension. 2008;52(3):522–8. doi:HYPERTENSIONAHA.108.113068 [pii] 10.1161/HYPERTENSIONAHA. 108.113068.PubMedCrossRefGoogle Scholar
  103. 103.
    Reriani M, Raichlin E, Prasad A, Mathew V, Pumper GM, Nelson RE, et al. Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis. Circulation. 2010;122(10):958–66. doi:CIRCULATIONAHA. 110.967406 [pii] 10.1161/CIRCULATIONAHA.110.967406.PubMedCrossRefGoogle Scholar
  104. 104.
    Clavell AL, Mattingly MT, Stevens TL, Nir A, Wright S, Aarhus LL, et al. Angiotensin ­converting enzyme inhibition modulates endogenous endothelin in chronic canine thoracic inferior vena caval constriction. J Clin Invest. 1996;97(5):1286–92. doi:10.1172/JCI118544.PubMedCrossRefGoogle Scholar
  105. 105.
    Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998;101(12):2711–9. doi:10.1172/JCI1500.PubMedCrossRefGoogle Scholar
  106. 106.
    Sutherland AJ, Nataatmadja MI, Walker PJ, Cuttle L, Garlick RB, West MJ. Vascular remodeling in the internal mammary artery graft and association with in situ endothelin-1 and receptor expression. Circulation. 2006;113(9):1180–8. doi:CIRCULATIONAHA.105.582890 [pii] 10.1161/CIRCULATIONAHA.105.582890.PubMedCrossRefGoogle Scholar
  107. 107.
    Cesaroni G, Forastiere F, Agabiti N, Valente P, Zuccaro P, Perucci CA. Effect of the Italian smoking ban on population rates of acute coronary events. Circulation. 2008;117(9):1183–8. doi:CIRCULATIONAHA.107.729889 [pii] 10.1161/CIRCULATIONAHA.107.729889.PubMedCrossRefGoogle Scholar
  108. 108.
    Bhavsar TM, Liu X, Cerreta JM, Liu M, Cantor JO. Endothelin-1 potentiates smoke-induced acute lung inflammation. Exp Lung Res. 2008;34(10):707–16. doi:906804275 [pii] 10.1080/01902140802389701.PubMedCrossRefGoogle Scholar
  109. 109.
    Muller-Schweinitzer E, Muller SE, Reineke DC, Kern T, Carrel TP, Eckstein FS, et al. Reactive oxygen species mediate functional differences in human radial and internal thoracic arteries from smokers. J Vasc Surg. 2010;51(2):438–44. doi:S0741-5214(09)01928-4 [pii] 10.1016/j.jvs.2009.09.040.PubMedCrossRefGoogle Scholar
  110. 110.
    Cox RA, Soejima K, Burke AS, Traber LD, Herndon DN, Schmalstieg FC, et al. Enhanced pulmonary expression of endothelin-1 in an ovine model of smoke inhalation injury. J Burn Care Rehabil. 2001;22(6):375–83.PubMedCrossRefGoogle Scholar
  111. 111.
    Chen Y, Hanaoka M, Droma Y, Chen P, Voelkel NF, Kubo K. Endothelin-1 receptor antagonists prevent the development of pulmonary emphysema in rats. Eur Respir J. 2009. doi:09031936.00003909 [pii] 10.1183/09031936.00003909.Google Scholar
  112. 112.
    Brook RD, Rajagopalan S, Pope 3rd CA, Brook JR, Bhatnagar A, Diez-Roux AV, et al. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American heart association. Circulation. 2010;121(21):2331–78. doi:CIR.0b013e3181dbece1 [pii] 10.1161/CIR.0b013e3181dbece1.PubMedCrossRefGoogle Scholar
  113. 113.
    Cherng TW, Campen MJ, Knuckles TL, Gonzalez Bosc L, Kanagy NL. Impairment of coronary endothelial cell ET(B) receptor function after short-term inhalation exposure to whole diesel emissions. Am J Physiol Regul Integr Comp Physiol. 2009;297(3):R640–7. doi:90899.2008 [pii]10.1152/ajpregu.90899.2008.PubMedCrossRefGoogle Scholar
  114. 114.
    Campen MJ, Lund AK, Knuckles TL, Conklin DJ, Bishop B, Young D, et al. Inhaled diesel emissions alter atherosclerotic plaque composition in ApoE(−/−) mice. Toxicol Appl Pharmacol. 2009. doi:S0041-008X(09)00466-9 [pii] 10.1016/j.taap. 2009.10.021.Google Scholar
  115. 115.
    Lund AK, Knuckles TL, Obot Akata C, Shohet R, McDonald JD, Gigliotti A, et al. Gasoline exhaust emissions induce vascular remodeling pathways involved in atherosclerosis. Toxicol Sci. 2007;95(2):485–94. doi:kfl145 [pii] 10.1093/toxsci/kfl145.PubMedCrossRefGoogle Scholar
  116. 116.
    Langrish JP, Lundback M, Mills NL, Johnston NR, Webb DJ, Sandstrom T, et al. Contribution of endothelin 1 to the vascular effects of diesel exhaust inhalation in humans. Hypertension. 2009;54(4):910–5. doi:HYPERTENSIONAHA.109.135947 [pii] 10.1161/HYPERTENSIONAHA.109.135947.PubMedCrossRefGoogle Scholar
  117. 117.
    Brook RD, Urch B, Dvonch JT, Bard RL, Speck M, Keeler G, et al. Insights into the mechanisms and mediators of the effects of air pollution exposure on blood pressure and vascular function in healthy humans. Hypertension. 2009;54(3):659–67. doi:HYPERTENSIONAHA. 109.130237 [pii] 10.1161/HYPERTENSIONAHA.109.130237.PubMedCrossRefGoogle Scholar
  118. 118.
    Liu L, Ruddy T, Dalipaj M, Poon R, Szyszkowicz M, You H, et al. Effects of indoor, outdoor, and personal exposure to particulate air pollution on cardiovascular physiology and systemic mediators in seniors. J Occup Environ Med. 2009;51(9):1088–98. doi:10.1097/JOM. 0b013e3181b35144.PubMedCrossRefGoogle Scholar
  119. 119.
    Xie YH, Wang SW, Zhang Y, Edvinsson L, Xu CB. Up-regulation of G-protein-coupled receptors for endothelin and thromboxane by lipid-soluble smoke particles in renal artery of rat. Basic Clin Pharmacol Toxicol. 2010; Epub April 22. doi:PTO585 [pii] 10.1111/j.1742-7843.2010.00585.x.Google Scholar
  120. 120.
    Upadhyay S, Stoeger T, Harder V, Thomas RF, Schladweiler MC, Semmler-Behnke M, et al. Exposure to ultrafine carbon particles at levels below detectable pulmonary inflammation affects cardiovascular performance in spontaneously hypertensive rats. Part Fibre Toxicol. 2008;5:19. doi:1743-8977-5-19 [pii] 10.1186/1743-8977-5-19.PubMedCrossRefGoogle Scholar
  121. 121.
    Barton M, Carmona R, Ortmann J, Krieger JE, Traupe T. Obesity-associated activation of angiotensin and endothelin in the cardiovascular system. Int J Biochem Cell Biol. 2003;35(6):826–37.PubMedCrossRefGoogle Scholar
  122. 122.
    Meyer MR, Clegg DJ, Prossnitz ER, Barton M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol (Oxf). 2011;203(1):259–69. doi:10.1111/ j.1748-1716.2010.02237.x.Google Scholar
  123. 123.
    Malik SM, Popkin BM, Bray GA, Despres JP, Hu FB. Sugar-sweetened beverages, obesity, type 2 diabetes mellitus, and cardiovascular disease risk. Circulation. 2010;121:1256–364.CrossRefGoogle Scholar
  124. 124.
    Balsiger B, Rickenbacher A, Boden PJ, Biecker E, Tsui J, Dashwood M, et al. Endothelin a-receptor blockade in experimental diabetes improves glucose balance and gastrointestinal function. Clin Sci (Lond). 2002;103 Suppl 48:430S–3.Google Scholar
  125. 125.
    Harris AK, Elgebaly MM, Li W, Sachidanandam K, Ergul A. Effect of chronic endothelin receptor antagonism on cerebrovascular function in type 2 diabetes. Am J Physiol Regul Integr Comp Physiol. 2008;294(4):R1213–9. doi:00885.2007 [pii] 10.1152/ajpregu. 00885.2007.PubMedCrossRefGoogle Scholar
  126. 126.
    Ortmann J, Nett PC, Celeiro J, Traupe T, Tornillo L, Hofmann-Lehmann R, et al. Endothelin inhibition delays onset of hyperglycemia and associated vascular injury in type I diabetes: evidence for endothelin release by pancreatic islet beta-cells. Biochem Biophys Res Commun. 2005;334(2):689–95.PubMedCrossRefGoogle Scholar
  127. 127.
    Sachidanandam K, Elgebaly MM, Harris AK, Hutchinson JR, Mezzetti EM, Portik-Dobos V, et al. Effect of chronic and selective endothelin receptor antagonism on microvascular function in type 2 diabetes. Am J Physiol Heart Circ Physiol. 2008;294(6):H2743–9. doi:91487.2007 [pii] 10.1152/ajpheart.91487.2007.PubMedCrossRefGoogle Scholar
  128. 128.
    Kohan DE, Pritchett Y, Molitch M, Wen S, Garimella T, Audhya P, et al. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol. 2011;22(4):763–72. doi:ASN.2010080869 [pii] 10.1681/ASN.2010080869.PubMedCrossRefGoogle Scholar
  129. 129.
    Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21(3):527–35. doi:ASN.2009060593 [pii] 10.1681/ASN.2009060593.PubMedCrossRefGoogle Scholar
  130. 130.
    Wenzel RR, Littke T, Kuranoff S, Jurgens C, Bruck H, Ritz E, et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol. 2009;20(3):655–64. doi:ASN.2008050482 [pii] 10.1681/ASN.2008050482.PubMedCrossRefGoogle Scholar
  131. 131.
    Zanatta CM, Gerchman F, Burttet L, Nabinger G, Jacques-Silva MC, Canani LH, et al. Endothelin-1 levels and albuminuria in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008;80:299–304.PubMedCrossRefGoogle Scholar
  132. 132.
    Nett PC, Ortmann J, Celeiro J, Haas E, Hofmann-Lehmann R, Tornillo L, et al. Transcriptional regulation of vascular bone morphogenetic protein by endothelin receptors in early autoimmune diabetes mellitus. Life Sci. 2006;78(19):2213–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Emmanuele L, Ortmann J, Doerflinger T, Traupe T, Barton M. Lovastatin stimulates human vascular smooth muscle cell expression of bone morphogenetic protein-2, a potent inhibitor of low-density lipoprotein-stimulated cell growth. Biochem Biophys Res Commun. 2003;302(1):67–72. doi:S0006291X03001098 [pii].PubMedCrossRefGoogle Scholar
  134. 134.
    Mundy AL, Haas E, Bhattacharya I, Widmer CC, Kretz M, Hofmann-Lehmann R, et al. Fat intake modifies vascular responsiveness and receptor expression of vasoconstrictors: implications for diet-induced obesity. Cardiovasc Res. 2007;73(2):368–75.PubMedCrossRefGoogle Scholar
  135. 135.
    Traupe T, Lang M, Goettsch W, Munter K, Morawietz H, Vetter W, et al. Obesity increases prostanoid-mediated vasoconstriction and vascular thromboxane receptor gene expression. J Hypertens. 2002;20(11):2239–45.PubMedCrossRefGoogle Scholar
  136. 136.
    Cardillo C, Campia U, Bryant MB, Panza JA. Increased activity of endogenous endothelin in patients with type II diabetes mellitus. Circulation. 2002;106(14):1783–7.PubMedCrossRefGoogle Scholar
  137. 137.
    Cardillo C, Campia U, Iantorno M, Panza JA. Enhanced vascular activity of endogenous endothelin-1 in obese hypertensive patients. Hypertension. 2004;43(1):36–40.PubMedCrossRefGoogle Scholar
  138. 138.
    Eriksson AK, van Harmelen V, Stenson BM, Astrom G, Wahlen K, Laurencikiene J, et al. Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor. Int J Obes. 2009;33(1):67–74. doi:ijo2008212 [pii] 10.1038/ijo.2008.212.CrossRefGoogle Scholar
  139. 139.
    Juan CC, Chang LW, Huang SW, Chang CL, Lee CY, Chien Y, et al. Effect of endothelin-1 on lipolysis in rat adipocytes. Obesity (Silver Spring). 2006;14(3):398–404.CrossRefGoogle Scholar
  140. 140.
    Teuscher AU, Lerch M, Shaw S, Pacini G, Ferrari P, Weidmann P. Endothelin-1 infusion inhibits plasma insulin responsiveness in normal men. J Hypertens. 1998;16(9):1279–84.PubMedCrossRefGoogle Scholar
  141. 141.
    Ahlborg G, Shemyakin A, Bohm F, Gonon A, Pernow J. Dual endothelin receptor blockade acutely improves insulin sensitivity in obese patients with insulin resistance and coronary artery disease. Diabetes Care. 2007;30(3):591–6.PubMedCrossRefGoogle Scholar
  142. 142.
    Anfossi G, Cavalot F, Massucco P, Mattiello L, Mularoni E, Hahn A, et al. Insulin influences immunoreactive endothelin release by human vascular smooth muscle cells. Metabolism. 1993;42(9):1081–3.PubMedCrossRefGoogle Scholar
  143. 143.
    Gregersen S, Thomsen JL, Hermansen K. Endothelin-1 (et-1)-potentiated insulin secretion: involvement of protein kinase C and the ET(A) receptor subtype. Metabolism. 2000;49(2): 264–9.PubMedCrossRefGoogle Scholar
  144. 144.
    Rachdaoui N, Nagy LE. Endothelin-1-stimulated glucose uptake is desensitized by tumor necrosis factor-alpha in 3t3-l1 adipocytes. Am J Physiol Endocrinol Metab. 2003;285(3):E545–51.PubMedGoogle Scholar
  145. 145.
    Said SA, Ammar el SM, Suddek GM. Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes. Pharmacol Res. 2005;51(2):107–15.PubMedCrossRefGoogle Scholar
  146. 146.
    Wu-Wong JR, Berg CE, Wang J, Chiou WJ, Fissel B. Endothelin stimulates glucose uptake and glut4 translocation via activation of endothelin ETA receptor in 3t3-l1 adipocytes. J Biol Chem. 1999;274(12):8103–10.PubMedCrossRefGoogle Scholar
  147. 147.
    Kirchengast M, Luz M. Endothelin receptor antagonists: clinical realities and future directions. J Cardiovasc Pharmacol. 2005;45(2):182–91.PubMedCrossRefGoogle Scholar
  148. 148.
    McMurray JJ. Heart failure in 10 years time: focus on pharmacological treatment. Heart. 2002;88 Suppl 2:ii40–6.PubMedGoogle Scholar
  149. 149.
    Sutsch G, Barton M. Endothelin in heart failure. Curr Hypertens Rep. 1999;1(1):62–8.PubMedCrossRefGoogle Scholar
  150. 150.
    Omland T, Lie RT, Aakvaag A, Aarsland T, Dickstein K. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation. 1994;89(4):1573–9.PubMedGoogle Scholar
  151. 151.
    Pacher R, Stanek B, Hulsmann M, Koller-Strametz J, Berger R, Schuller 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(3):633–41.PubMedCrossRefGoogle Scholar
  152. 152.
    Staniloae C, Dupuis J, White M, Gosselin G, Dyrda I, Bois M, et al. Reduced pulmonary clearance of endothelin in congestive heart failure: a marker of secondary pulmonary hypertension. J Card Fail. 2004;10(5):427–32.PubMedCrossRefGoogle Scholar
  153. 153.
    Cernacek P, Stewart DJ, Monge JC, Rouleau JL. The endothelin system and its role in acute myocardial infarction. Can J Physiol Pharmacol. 2003;81(6):598–606.PubMedCrossRefGoogle Scholar
  154. 154.
    Fukunaga K, Takada Y, Taniguchi H, Mei G, Seino KI, Yuzawa K, et al. Endothelin antagonist treatment for successful liver transplantation from non-heart-beating donors. Transplantation. 1999;67(2):328–32.PubMedCrossRefGoogle Scholar
  155. 155.
    Miyauchi T, Goto K. Heart failure and endothelin receptor antagonists. Trends Pharmacol Sci. 1999;20(5):210–7.PubMedCrossRefGoogle Scholar
  156. 156.
    Kaye DM, Krum H. Drug discovery for heart failure: a new era or the end of the pipeline? Nat Rev. 2007;6(2):127–39.CrossRefGoogle Scholar
  157. 157.
    Vetter D, Shaw SG, Brandes RP, Munter K, Vetter W, Barton M. Beneficial cardiovascular effects of endothelin ET(A) receptor blockade in established long-term heart failure after myocardial infarction. Exp Biol Med (Maywood). 2006;231(6):857–60.Google Scholar
  158. 158.
    Kiowski W, Sutsch G, Hunziker P, Muller P, Kim J, Oechslin E, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet. 1995;346(8977): 732–6.PubMedCrossRefGoogle Scholar
  159. 159.
    Cowburn PJ, Cleland JG, McArthur JD, MacLean MR, McMurray JJ, Dargie HJ. Short-term haemodynamic effects of BQ-123, a selective endothelin ET(A)-receptor antagonist, in chronic heart failure. Lancet. 1998;352(9123):201–2.PubMedCrossRefGoogle Scholar
  160. 160.
    Cowburn PJ, Cleland JG. Endothelin antagonists for chronic heart failure: do they have a role? Eur Heart J. 2001;22(19):1772–84.PubMedCrossRefGoogle Scholar
  161. 161.
    Kelland NF, Webb DJ. Clinical trials of endothelin antagonists in heart failure: publication is good for the public health. Heart. 2007;93(1):2–4.PubMedCrossRefGoogle Scholar
  162. 162.
    Dupuis J. Endothelin-receptor antagonists in pulmonary hypertension. Lancet. 2001;358(9288):1113–4.PubMedCrossRefGoogle Scholar
  163. 163.
    Dupuis J. Endothelin receptor antagonists and their developing role in cardiovascular therapeutics. Can J Cardiol. 2000;16(7):903–10.PubMedGoogle Scholar
  164. 164.
    Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358(9288):1119–23.PubMedCrossRefGoogle Scholar
  165. 165.
    Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896–903.PubMedCrossRefGoogle Scholar
  166. 166.
    Davenport AP, Maguire JJ. Of mice and men: advances in endothelin research and first antagonist gains FDA approval. Trends Pharmacol Sci. 2002;23(4):155–7.PubMedCrossRefGoogle Scholar
  167. 167.
    Puri A, McGoon MD, Kushwaha SS. Pulmonary arterial hypertension: current therapeutic strategies. Nat Clin Pract. 2007;4(6):319–29.CrossRefGoogle Scholar
  168. 168.
    Shapiro S. Management of pulmonary hypertension resulting from interstitial lung disease. Curr Opin Pulm Med. 2003;9(5):426–30.PubMedCrossRefGoogle Scholar
  169. 169.
    Kaisers U, Bodil P, Deja M, Bartholdy R, Donaubauer B, Laudi S, et al. Inhalation of the ETA receptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction. Am J Physiol. 2008;294:R601–5.Google Scholar
  170. 170.
    Kaisers U, Busch T, Wolf S, Lohbrunner H, Wilkens K, Hocher B, et al. Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury. Intensive Care Med. 2000;26(9):1334–42.PubMedCrossRefGoogle Scholar
  171. 171.
    Kalk P, Senf P, Deja M, Petersen B, Busch T, Bauer C, Boemke W, Kaisers U, Hocher B. Inhalation of an endothelin receptor A antagonist attenuates pulmonary inflammation in experimental acute lung injury. Can J Physiol Pharmacol 2008;86(8):511–5.Google Scholar
  172. 172.
    Leuchte HH, Meis T, El-Nounou M, Michalek J, Behr J. Inhalation of endothelin receptor blockers in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2008;294:L772–7.PubMedCrossRefGoogle Scholar
  173. 173.
    Ravalli S, Szabolcs M, Albala A, Michler RE, Cannon PJ. Increased immunoreactive endothelin-1 in human transplant coronary artery disease. Circulation. 1996;94(9):2096–102.PubMedGoogle Scholar
  174. 174.
    Lattmann T, Ortmann J, Horber S, Shaw SG, Hein M, Barton M. Upregulation of endothelin converting enzyme-1 in host liver during chronic cardiac allograft rejection. Exp Biol Med (Maywood). 2006;231(6):899–901.Google Scholar
  175. 175.
    Lattmann T, Hein M, Horber S, Ortmann J, Teixeira MM, Souza DG, et al. Activation of pro-inflammatory and anti-inflammatory cytokines in host organs during chronic allograft rejection: role of endothelin receptor signaling. Am J Transplant. 2005;5(5):1042–9.PubMedCrossRefGoogle Scholar
  176. 176.
    Braun C, Conzelmann T, Vetter S, Schaub M, Back WE, Yard B, et al. Prevention of chronic renal allograft rejection in rats with an oral endothelin A receptor antagonist. Transplantation. 1999;68(6):739–46.PubMedCrossRefGoogle Scholar
  177. 177.
    Orth SR, Odoni G, Amann K, Strzelczyk P, Raschack M, Ritz M. The ETA receptor blocker LU 135252 prevents chronic transplant nephropathy in the “Fisher to lewis” model. J Am Soc Nephrol. 1999;10:387–91.PubMedGoogle Scholar
  178. 178.
    Orth SR, Odoni G, Karkoszka H, Ogata H, Viedt C, Amann K, et al. Combination treatment with an ET(A)-receptor blocker and an ace inhibitor is not superior to the respective monotherapies in attenuating chronic transplant vasculopathy in different aorta allotransplantation rat models. Nephrol Dial Transplant. 2003;18(1):62–9.PubMedCrossRefGoogle Scholar
  179. 179.
    Shennib H, Lee AG, Kuang JQ, Yanagisawa M, Ohlstein EH, Giaid A. Efficacy of administering an endothelin-receptor antagonist (SB209670) in ameliorating ischemia-reperfusion injury in lung allografts. Am J Respir Crit Care Med. 1998;157(6 Pt 1):1975–81.PubMedGoogle Scholar
  180. 180.
    Tang JL, Aitouche A, Subbotin V, Salam A, Sun H, Gandhi C, et al. Endothelin-1 receptor blockade and its effect on chronic rejection. Transplant Proc. 1999;31(1–2):1249.PubMedCrossRefGoogle Scholar
  181. 181.
    Fukunaga K, Takada Y, Taniguchi H, Otsuka M, Goto K, Fukao K. Successful liver transplantation from non-heart-beating donors by blockade of endothelin and PAE. Transplant Proc. 1998;30(7):3797.PubMedCrossRefGoogle Scholar
  182. 182.
    Burke GW, Ciancio G, Cirocco R, Markou M, Roth D, Esquenazi V, et al. Tacrolimus-related microangiopathy in kidney and simultaneous pancreas-kidney recipients: evidence of endothelin and cytokine involvement. Transplant Proc. 1998;30(2):661–2.PubMedCrossRefGoogle Scholar
  183. 183.
    Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol. 1999;246(5):339–46.PubMedCrossRefGoogle Scholar
  184. 184.
    Carrier M, Tronc F, Stewart D, Pelletier LC. Dose-dependent effect of cyclosporin on renal arterial resistance in dogs. Am J Physiol. 1991;261(6 Pt 2):H1791–6.PubMedGoogle Scholar
  185. 185.
    Cauduro RL, Costa C, Lhulier F, Garcia RG, Cabral RD, Goncalves LF, et al. Endothelin-1 plasma levels and hypertension in cyclosporine-treated renal transplant patients. Clin Transplant. 2005;19(4):470–4.PubMedCrossRefGoogle Scholar
  186. 186.
    Benigni A. Endothelin antagonists in renal disease. Kidney Int. 2000;57(4):1778–94.PubMedCrossRefGoogle Scholar
  187. 187.
    Benigni A, Zoja C, Corna D, Orisio S, Longaretti L, Bertani T, et al. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int. 1993;44(2):440–4.PubMedCrossRefGoogle Scholar
  188. 188.
    Bruzzi I, Remuzzi G, Benigni A. Endothelin: a mediator of renal disease progression. J Nephrol. 1997;10(4):179–83.PubMedGoogle Scholar
  189. 189.
    Bruno S, Cattaneo D, Perico N, Remuzzi G. Emerging drugs for diabetic nephropathy. Expert Opin Emerg Drugs. 2005;10(4):747–71.PubMedCrossRefGoogle Scholar
  190. 190.
    Benigni A, Perico N, Remuzzi G. Research on renal endothelin in proteinuric nephropathies dictates novel strategies to prevent progression. Curr Opin Nephrol Hypertens. 2001;10(1):1–6.PubMedCrossRefGoogle Scholar
  191. 191.
    Benigni A, Remuzzi G. Endothelin antagonists. Lancet. 1999;353(9147):133–8.PubMedCrossRefGoogle Scholar
  192. 192.
    Gagliardini E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, Longaretti L, Remuzzi A, Remuzzi G, Benigni A. Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes. Am J Physiol Renal Physiol. 2009;297(5):1448–56.Google Scholar
  193. 193.
    Opocensky M, Kramer HJ, Backer A, Vernerova Z, Eis V, Cervenka L, et al. Late-onset endothelin-a receptor blockade reduces podocyte injury in homozygous Ren-2 rats despite severe hypertension. Hypertension. 2006;48(5):965–71.PubMedCrossRefGoogle Scholar
  194. 194.
    Ortmann J, Amann K, Brandes RP, Kretzler M, Munter K, Parekh N, et al. Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. Hypertension. 2004;44(6):974–81.PubMedCrossRefGoogle Scholar
  195. 195.
    Morigi M, Buelli S, Angioletti S, Zanchi C, Longaretti L, Zoja C, et al. In response to ­protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication for permselective dysfunction of chronic nephropathies. Am J Pathol. 2005;166(5):1309–20.PubMedCrossRefGoogle Scholar
  196. 196.
    Morigi M, Buelli S, Zanchi C, Longaretti L, Macconi D, Benigni A, et al. Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol. 2006;169(6):1965–75.PubMedCrossRefGoogle Scholar
  197. 197.
    Wesson DE. Regulation of kidney acid excretion by endothelins. Kidney Int. 2006;70(12):2066–73.PubMedGoogle Scholar
  198. 198.
    Collino F, Bussolati B, Gerbaudo E, Marozio L, Pelissetto S, Benedetto C, et al. Pre-eclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells. Am J Physiol. 2008;294:F1185.CrossRefGoogle Scholar
  199. 199.
    Pisoni R, Ruggenenti P, Remuzzi G. Renoprotective therapy in patients with nondiabetic nephropathies. Drugs. 2001;61(6):733–45.PubMedCrossRefGoogle Scholar
  200. 200.
    Opocensky M, Dvorak P, Maly J, Kramer HJ, Backer A, Kopkan L, et al. Chronic endothelin receptor blockade reduces end-organ damage independently of blood pressure effects in salt-loaded heterozygous Ren-2 transgenic rats. Physiol Res. 2004;53(6):581–93.PubMedGoogle Scholar
  201. 201.
    Placier S, Boffa JJ, Dussaule JC, Chatziantoniou C. Reversal of renal lesions following interruption of nitric oxide synthesis inhibition in transgenic mice. Nephrol Dial Transplant. 2006;21(4):881–8.PubMedCrossRefGoogle Scholar
  202. 202.
    Boffa JJ, Tharaux PL, Dussaule JC, Chatziantoniou C. Regression of renal vascular fibrosis by endothelin receptor antagonism. Hypertension. 2001;37(2 Part 2):490–6.PubMedGoogle Scholar
  203. 203.
    Essalihi R, Dao HH, Gilbert LA, Bouvet C, Semerjian Y, McKee MD, et al. Regression of medial elastocalcinosis in rat aorta: a new vascular function for carbonic anhydrase. Circulation. 2005;112(11):1628–35.PubMedCrossRefGoogle Scholar
  204. 204.
    Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990;348(6303):730–2.PubMedCrossRefGoogle Scholar
  205. 205.
    Eguchi S, Hirata Y, Ihara M, Yano M, Marumo F. A novel eta antagonist (BQ-123) inhibits endothelin-1-induced phosphoinositide breakdown and DNA synthesis in rat vascular smooth muscle cells. FEBS Lett. 1992;302(3):243–6.PubMedCrossRefGoogle Scholar
  206. 206.
    Davenport AP, Maguire JJ. Pharmacology of renal endothelin receptors. Contrib Nephrol. 2011;172:1–17.Google Scholar
  207. 207.
    Kirkby NS, Hadoke PW, Bagnall AJ, Webb DJ. The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol. 2007.Google Scholar
  208. 208.
    Barton M. Endothelin antagonism and reversal of proteinuric renal disease in humans. Contrib Nephrol. 2011a;172:210–222.Google Scholar
  209. 209.
    Bagnato A, Loizidou M, Pflug B, Curwen J, Growcott J. Role of the endothelin axis and its antagonists in the treatment of cancer. Br J Pharmacol. 2011. doi:10.1111/j.1476-5381. 2011.01217.x.Google Scholar
  210. 210.
    Bagnato A, Rosano L. The endothelin axis in cancer. Int J Biochem Cell Biol. 2008;40(8):144351. doi:S1357-2725(08)00044-7 [pii] 10.1016/j.biocel.2008.01.022.PubMedCrossRefGoogle Scholar
  211. 211.
    Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008;113(9):2478–87. doi:10.1002/cncr.23864.PubMedCrossRefGoogle Scholar
  212. 212.
    Abraham DJ, Vancheeswaran R, Dashwood MR, Rajkumar VS, Pantelides P, Xu SW, et al. Increased levels of endothelin-1 and differential endothelin type A and B receptor expression in scleroderma-associated fibrotic lung disease. Am J Pathol. 1997;151(3):831–41.PubMedGoogle Scholar
  213. 213.
    Denton CP. Therapeutic targets in systemic sclerosis. Arthritis Res Ther. 2007;9 Suppl 2:S6.PubMedCrossRefGoogle Scholar
  214. 214.
    Denton CP, Black CM. Pulmonary hypertension in systemic sclerosis. Rheum Dis Clin North Am. 2003;29(2):335–49. vii.PubMedCrossRefGoogle Scholar
  215. 215.
    Denton CP, Black CM, Abraham DJ. Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol. 2006;2(3):134–44. doi:ncprheum0115 [pii] 10.1038/ncprheum0115.PubMedCrossRefGoogle Scholar
  216. 216.
    Dhaun N, MacIntyre IM, Bellamy CO, Kluth DC. Endothelin receptor antagonism and renin inhibition as treatment options for scleroderma kidney. Am J Kidney Dis. 2009;54(4):726–31. doi:S0272-6386(09)00515-0 [pii] 10.1053/j.ajkd.2009.02.015.PubMedCrossRefGoogle Scholar
  217. 217.
    Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the rapids-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2010;70(1):32–8. doi:ard.2010.130658 [pii] 10.1136/ard.2010.130658.PubMedCrossRefGoogle Scholar
  218. 218.
    Sfikakis PP, Papamichael C, Stamatelopoulos KS, Tousoulis D, Fragiadaki KG, Katsichti P, et al. Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis. Arthritis Rheum. 2007;56(6):1985–93.PubMedCrossRefGoogle Scholar
  219. 219.
    Honing MLH, Bouter PK, Ballard DE, Padley R, Morrison P, Rabelink T. ABT-627, a selective ETA-receptor anatagonist, reduces proteinuria in patients with diabetes mellitus. In: Regulation of vascular tone in humans by endothelium-derived mediators [thesis]. Utrecht, The Netherlands: Elinkwijk BV; 2000. p. 89–102.Google Scholar
  220. 220.
    Dhaun N, Macintyre IM, Kerr D, Melville V, Johnston NR, Haughie S, et al. Selective endothelin-a receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease. Hypertension. 2011;57(4):772–9. doi:HYPERTENSIONAHA. 110.167486 [pii] 10.1161/HYPERTENSIONAHA.110.167486.PubMedCrossRefGoogle Scholar
  221. 221.
    Dhaun N, Macintyre IM, Melville V, Lilitkarntakul P, Johnston NR, Goddard J, et al. Blood pressure-independent reduction in proteinuria and arterial stiffness after acute endothelin-A receptor antagonism in chronic kidney disease. Hypertension. 2009;54(1):113–9. doi:HYPERTENSIONAHA.109.132670 [pii] 10.1161/HYPERTENSIONAHA.109.132670.PubMedCrossRefGoogle Scholar
  222. 222.
    Dhaun N, Macintyre IM, Melville V, Lilitkarntakul P, Johnston NR, Goddard J, et al. Effects of endothelin receptor antagonism relate to the degree of renin-angiotensin system blockade in chronic proteinuric kidney disease. Hypertension. 2009;54(3):e19–20. doi:HYPERTENSIONAHA. 109.138263 [pii] 10.1161/HYPERTENSIONAHA.109.138263.PubMedCrossRefGoogle Scholar
  223. 223.
    MacIntyre IM, Dhaun N, Lilitkarntakul P, Melville V, Goddard J, Webb DJ. Greater functional ETB receptor antagonism with bosentan than sitaxsentan in healthy men. Hypertension. 2010;55(6):1406–11. doi:HYPERTENSIONAHA.109.148569 [pii] 10.1161/HYPERTEN­SIONAHA. 109.148569.PubMedCrossRefGoogle Scholar
  224. 224.
    Hall JE. Louis K. Dahl memorial lecture. Renal and cardiovascular mechanisms of hypertension in obesity. Hypertension. 1994;23(3):381–94.PubMedGoogle Scholar
  225. 225.
    Said N, Smith S, Sanchez-Carbayo M, Theodorescu D. Tumor endothelin-1 enhances metastatic colonization of the lung in mouse xenograft models of bladder cancer. J Clin Invest. 2010;121(1):132–47. doi:42912 [pii] 10.1172/JCI42912.PubMedCrossRefGoogle Scholar
  226. 226.
    Bagnato A, Spinella F, Rosano L. The endothelin axis in cancer: the promise and the challenges of molecularly targeted therapy. Can J Physiol Pharmacol. 2008;86(8):473–84. doi:y08-058 [pii] 10.1139/y08-058.PubMedCrossRefGoogle Scholar
  227. 227.

Copyright information

© Springer-Verlag London Limited 2012

Authors and Affiliations

  1. 1.Molecular Internal Medicine, LTK Y44 G22University of ZurichZürichSwitzerland

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