Endothelin-1(ET-1) is not only a potent vasoconstrictor, but causes proliferation of many of the vascular cells involved in vascular remodelling. ETA receptors mediate vasoconstriction and cell proliferation, whereas ETB receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of endothelin-converting enzyme (ECE)-1. ET is activated in pulmonary arterial hypertension (PAH), heart failure (HF) and many other cardiovascular diseases. The most efficient way to antagonize the ET-1 system is the use of ET-1 receptor antagonists that can block either ETA- or ETA- and ETB-receptors, or ECE inhibition which blocks the conversion of big ET-1 to ET-1. In this brief review, we will try to summarize the progress of anti-endothelin therapy in the treatment of PAH and HF treatment therapies.

[1] MATSUMOTO T,OZAWA Y,TAGUCHI K,et al.Diabetes-associated changes and role of N epsilon-(carboxymethyl)lysine in big ET-1-induced coronary vasoconstriction[J].Peptides,2010,31(2):346-353.
[2] TERELAK-BORYS B,CZECHOWICZ-JANICKA K.Investigation into the vasospastic mechanisms in the pathogenesis of glaucomatous neuropathy[J].Klin Oczna,2011,113(7-9):201-208.
[3] WENNER M M,TAYLOR H S,STACHENFELD N S.Endothelin B receptor contribution to peripheral microvascular function in women with polycystic ovary syndrome[J].J Physiol,2011,589(Pt 19):4671-4679.
[4] DAVENPORT A P,MAGUIRE J J.Pharmacology of renal endothelin receptors[J].Contrib Nephrol,2011,172:1-17.
[5] SCHEIDER M P,BOESEN E O,POLLOCK D M.Contrasting actions of endothelin ETA and ETB receptors in cardiovascular disease[J].Ann Rev Pharmacol Toxicol,2007,47:731-759.
[6] BARTON M,KOHAN D E.Endothelin in renal physiology and disease[J].Basel Karger,2011,172:1-17.
[7] SIMARD E,JIN D,TAKAI S,et al.Chymase-dependent conversion of big endothe-lin-1 in the mouse in vivo[J].J Pharmacol Exp Ther,2009,328(2):540-548.
[8] PLUMPTON C,FERRO C J,HAYNES W G,et al.The increase in human plasma immunoreactive endothelin but not big endothelin-1 or its C-terminal fragment induced by systemic administration of the endothelin antagonist TAK-044[J].Br J Pharmacol,1996,119:311-314.
[9] BARTON M,YANAGISA W A.20 years from discovery to therapy.Endothelin M[J].Can J Physiol Pharmacol,2008,86:485-499.[ZK)]
[10] [ZK(#]PALMER J C,TAYLER H M,LOVE S.Endothelin-converting enzyme-activity,endothelin-1 production,and free radical-dependent vasoconstriction in Alzheimer's disease[J].J lzheimers Dis,2013,36(3):577-587.
[11] SHARKOVSKA Y,KALK P,von WEBSKY K,et al.Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage[J].Clin Lab,2011,57(7-8):507-515.
[12] LAMBERT L A,WHYTESIDE A R,TURNER A J,et al.Isoforms of endothelin-converting enzyme-1(ECE-1) have opposing effects on prostate cancer cell invasion[J].Br J Cancer,2008,99(7):1114-1120.
[13] SCHNEIDER M P,BOESEN E I,POLLOCK D M.Contrasting actions of endothelin ETA and ETB receptors in cardiovascular disease[J].Annu Rev Pharmacol Toxicol,2007,47:731-759.
[14] PATOCKA J,MERKA V,HRDINA V,et al.Pharmacological potential of endothelin receptors agonists & antagonists[J].Acta Medica,2005,48(2):67-73.
[15] RITZ E,WENZEL R.Endothelin receptor antagonists in proteinuric renal disease:every rose has its thorn[J].J Am Soc Nephrol,2010,21:392-394.
[16] SARAFIDIS P A,LASARIDIS A N.Diabetic nephropathy:endothelin antagonism for diabetic nephropathy[J].Nat Rev Nephrol,2010,6:447-449.
[17] SIMONNEAU G,GATZOULIS M A,ADATIA I,et al.Updated clinical classification of pulmonary hypertension[J].J Am Coll Cardiol,2009,54(1 Suppl):S43-54.
[18] O'CALLAGHAN D S,SAVALE L,MONTANI D,et al.Treatment of pulmonary arterial hypertension with targeted therapies[J].Nat Rev Cardiol,2011,8(9):526-538.
[19] RAJA S G,RAJA S M,Treating pulmonary arterial hypertension current treatments and future prospects[J].Ther Adv Chronic Dis,2011,2(6):359-370.
[20] GALIE N,RUBIN L J,HOEPER M,et al.Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan(EARLY study):a double-blind,randomised controlled trial[J].Lancet,2008,371(9630):2093-2100.
[21] DUPUIS J,HOEPER M M.Endothelin receptor antagonists in pulmonary arterial hypertension[J].Eur Respir J,2008,31:407-415.
[22] JAIS X,D'ARMINI A M,JANSA P,et al.Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension:BENEFiT(Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension),a randomized,placebo-controlled trial[J].J Am Coll Cardiol,2008,52:2127-2134.
[23] PADELETTI M,CAPUTO M,ZACA V,et al.Effect of bosentan on pulmonary hypertension secondary to systolic heart failure[J].Pharmacology,2013,92(5-6):281-285.
[24] KLINGER J R,OUDIZ R J,SPENCE R,et al.Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension[J].Am J Cardiol,2011,108(2):302-307.
[25] FARUQI S,FATHI H,MORICE A H.Combination of sitaxentan and tadalafil for idiopathic pulmonary arterial hypertension following relapse on bosentan[J].Int J Cardiol,2010,144(3):e43-45.
[26] RUBIN L T,PULIDO T,ADZERIKIHO I,et al.Effect of macitentan on morbidity and mortality in pulmonary arterial hypertension(PAH):results from the SERAPHIN trial[J].Chest,2012,142:1026A.
[27] IGLARZ M,BINKEERT C,MORRISON K.Pharmacology of macitentan,an orally active tissue targeting dual endothelin receptor antagonist[J].J Pharmacol Exp Ther,2008,327(3):736-745.
[28] VOELKEL N F,GOMEZ-ARROYO J,ABBATE A,et al.Pathobiology of pulmonary arterial hypertension and right ventricular failure[J].Eur Respir J,2012,40:1555-1565.
[29] RAJA S G.Macitentan,a tissue-targeting endothelia receptor antagonist for the potential oral treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis[J].Curr Opin Investig Drugs,2010,11:1066-1073.
[30] PULIDO T,ADZERIKHO I,CHANNICK R N,et al.Macitentan and morbidity and mortality in pulmonary arterial hypertension[J].N Engl J Med,2013,369:809-818.
[31] SIDHARTA P N,van GIERSBERGEN P L,HALABI A,et al.Macitentan:entry-into-humans study with a new endothelin receptor antagonist[J].Eur J Clin Pharmacol,2011,67(10):977-984.
[32] GATFIELD J,GRANDJEAN C M,SASSE T,et al.Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells[J].PLoS One,2012,7:e47662.
[33] BOLLI M H,BOSS C,BINKERT C,et al.The discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide(macitentan),an orally active,potent dual endothelin receptor antagonist[J].J Med Chem,2012,55:7849-7861.
[34] TAPSON V F,TORRES F,KERMEEN F,et al.Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy(the FREEDOM-C study):a randomized controlled trial[J].Chest,2012,142:1383-1390.
[35] MacCARTHY P A,GROCOTT-MASON R,et al.Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart:studies with an intracoronary ET(A) receptor antagonist[J].Circulation,2000,101:142-147.
[36] KOMUKAI K,UCHI J,MORIMOTO S,et al.Role of Ca(2+)/calmodulin-dependent protein kinase Ⅱ in the regulation of the cardiac L-type Ca(2+) current during endothelin-1 stimulation[J].Am J Physiol Heart Circ Physiol,2010,298:H1902-H1907.
[37] VIGNON-ZELLWEGER N,RELLE K,KIENLEN E,et al.Endothelin-1 overexpression restores diastolic function in eNOS knockout mice[J].J Hypertens,2011,29:961-970.
[38] NAMEKATA I,FUJIKI S,KAWAKAMI Y,et al.Intracellular mechanisms and receptor types for endothelin-1-induced positive and negative inotropy in mouse ventricular myocardium[J].Naunyn Schmiedebergs Arch Pharmacol,2008,376:385-395.
[39] NISHIMARU K,MIURA Y,ENDOH M.Mechanisms of endothelin-1-induced decrease in contractility in adult mouse ventricular myocytes[J].Br J Pharmacol,2007,152(4):456-463.
[40] TEERLINK J R,McMURRAY J J,BOURGE R C,et al.Tezosentan in patients with acute heart failure:design of the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Study(VERITAS)[J].Am Heart J,2005,150:46-53.
[41] KALUSKI E,COTTER G,LEITMAN M,et al.Clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction,associated with secondary pulmonary hypertension - a multi-center randomized study[J].Cardiology,2008,109:273-280.
[42] JIANG B H,TARDIF J C,SHI Y,et al.Bosentan does not improve pulmonary hypertension and lung remodelling in heart failure[J].Eur Respir J,2011,37:578-586.
[43] PARKER J D,THIESSEN J J.Increased endothelin-1 production in patients with chronic heart failure[J].Am J Physiol Heart Circ Physiol,2004,286:H1141-H1145.
[44] LESLIE S J,SPRATT J C,McKEE S P,et al.Direct comparison of selective endothelin A and non-selective endothelin A/B receptor blockade in chronic heart failure[J].Heart,2005,91:914-919.
[45] PRASAD S K,DARGIE H J,SMITH G C,et al.Comparison of the dual receptor endothelin antagonist enrasentan with enalapril in asymptomatic left ventricular systolic dysfunction:a cardiovascular magnetic resonance study[J].Heart,2006,92(6):798-803.
[46] ANAND I,McMURRAY J,COHN J N,et al.Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure(EARTH):Randomised,double-blind,placebo-controlled trial[J].Lancet,2004,364:347-354.
[47] SCHIRGER J A,CHEN H H,JOUGASAKI M,et al.Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention[J].Circulation,2004,109:249-254.
[48] YANG L L,GROS R,KABIR M G,et al.Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice[J].Circulation,2004,109:255-261.