Mechanisms of ET-1-induced endothelial dysfunction

Journal of Cardiovascular Pharmacology

Volumn 50, Issue 6, 2007, Pages 621-628

  Iglarz, Marc ^a   Clozel, Martine ^a  

^a ACTELION PHARMACEUTICALS LTD   (Switzerland)

Author keywords

Caveolae; Endothelin receptor antagonists; Endothelin 1; Endothelium; Hypertension; Inflammation; Nitric oxide; Oxidative stress

Indexed keywords

2 BUTYL 7 [2 (2 CARBOXYPROPYL) 4 METHOXYPHENYL] 5 (3,4 METHYLENEDIOXYPHENYL)CYCLOPENTENO[1,2 B]PYRIDINE 6 CARBOXYLIC ACID; 2 PYRIDYLCARBAMIC ACID 2 [[5 (2 METHOXYPHENOXY) 6 [[(4 ISOPROPYLPHENYL)SULFONYL]AMINO] 2 MORPHOLINO 4 PYRIMIDINYL]OXY]ETHYL ESTER; 5 DIMETHYLAMINO N (3,4 DIMETHYL 5 ISOXAZOLYL) 1 NAPHTHALENESULFONAMIDE; ANGIOTENSIN II; ATRASENTAN; BOSENTAN; DARUSENTAN; ENDOTHELIN 1; ENDOTHELIN B RECEPTOR; ENDOTHELIN RECEPTOR ANTAGONIST; NITRIC OXIDE;

ALZHEIMER DISEASE; ATHEROSCLEROSIS; AUTOIMMUNE DISEASE; BINDING SITE; CAVEOLA; CONGESTIVE HEART FAILURE; DEGRADATION; DRUG BINDING; DRUG TARGETING; ENDOTHELIAL DYSFUNCTION; ENDOTHELIUM CELL; HUMAN; HYPERTENSION; INFLAMMATORY CELL; INSULIN DEPENDENT DIABETES MELLITUS; ISCHEMIA; NONHUMAN; OBESITY; PATHOLOGY; PHENOTYPE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REPERFUSION INJURY; REVIEW;

ANIMALS; CARDIOVASCULAR DISEASES; ENDOTHELIN-1; ENDOTHELIUM, VASCULAR; HUMANS; MODELS, BIOLOGICAL; RECEPTORS, ENDOTHELIN;

EID: 37349109693     PISSN: 01602446     EISSN: None     Source Type: Journal    
DOI: 10.1097/FJC.0b013e31813c6cc3     Document Type: Review

References (107)

1. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376.
2. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774-1777.
3. Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;2:1057-1058.
4. Corseaux D, Le Tourneau T, Six I, et al. Enhanced monocyte tissue factor response after experimental balloon angioplasty in hypercholesterolemic rabbit: inhibition with dietary L-arginine. Circulation. 1998;98:1776-1782.
5. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415.
6. Clozel M. Effects of bosentan on cellular processes involved in pulmonary arterial hypertension: do they explain the long-term benefit? Ann Med. 2003;35:605-613.
7. Panza JA, Quyyumi AA, Brush JE Jr, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323:22-27.
8. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315:1046-1051.
9. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111-1115.
10. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol. 2004;15:1983-1992.
11. Taddei S, Virdis A, Mattei P, et al. Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients. Circulation. 1996;94:1298-1303.
12. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899-1906.
13. Amiri F, Virdis A, Neves MF, et al. Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation. 2004;110:2233-2240.
14. Minshall RD, Sessa WC, Stan RV, et al. Caveolin regulation of endothelial function. Am J Physiol Lung Cell Mol Physiol. 2003;285:L1179-L1183.
15. Kamoun WS, Karaa A, Kresge N, et al. LPS inhibits endothelin-1-induced endothelial NOS activation in hepatic sinusoidal cells through a negative feedback involving caveolin-1. Hepatology. 2006;43:182-190.
16. Karaa A, Kamoun WS, Clemens MG. Oxidative stress disrupts nitric oxide synthase activation in liver endothelial cells. Free Radic Biol Med. 2005;39:1320-1331.
17. Ramzy D, Rao V, Tumiati LC, et al. Elevated endothelin-1 levels impair nitric oxide homeostasis through a PKC-dependent pathway. Circulation. 2006;114:I319-I326.
18. Yamaguchi T, Murata Y, Fujiyoshi Y, et al. Regulated interaction of endothelin B receptor with caveolin-1. Eur J Biochem. 2003;270:1816-1827.
19. Duerrschmidt N, Wippich N, Goettsch W, et al. Endothelin-1 induces NAD(P)H oxidase in human endothelial cells. Biochem Biophys Res Commun. 2000;269:713-717.
20. Loomis ED, Sullivan JC, Osmond DA, et al. Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther. 2005;315:1058-1064.
21. Vasquez-Vivar J, Whitsett J, Martasek P, et al. Reaction of tetrahydrobiopterin with superoxide: EPR-kinetic analysis and characterization of the pteridine radical. Free Radic Biol Med. 2001;31:975-985.
22. Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113:1708-1714.
23. Verma S, Yao L, Stewart DJ, et al. Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo. Hypertension. 2001;37:328-333.
24. Nandi M, Miller A, Stidwill R, et al. Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse. Circulation. 2005;111:2086-2090.
25. Khoo JP, Zhao L, Alp NJ, et al. Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation. 2005;111:2126-2133.
26. Landmesser U, Dikalov S, Price SR, et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003;111:1201-1209.
27. Zheng JS, Yang XQ, Lookingland KJ, et al. Gene transfer of human guanosine 5′-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in low renin hypertension. Circulation. 2003;108:1238-1245.
28. Iglarz M, Touyz RM, Amiri F, et al. Effect of peroxisome proliferator-activated receptor-alpha and -gamma activators on vascular remodeling in endothelin-dependent hypertension. Arterioscler Thromb Vasc Biol. 2003;23:45-51.
29. Chen S, Mukherjee S, Chakraborty C, et al. High glucose-induced, endothelin-dependent fibronectin synthesis is mediated via NF-kappa B and AP-1. Am J Physiol Cell Physiol. 2003;284:C263-C272.
30. Morawietz H, Duerrschmidt N, Niemann B, et al. Induction of the oxLDL receptor LOX-1 by endothelin-1 in human endothelial cells. Biochem Biophys Res Commun. 2001;284:961-965.
31. Halim A, Kanayama N, el Maradny E, et al. Endothelin-1 increased immunoreactive von Willebrand factor in endothelial cells and induced micro thrombosis in rats. Thromb Res. 1994;76:71-78.
32. Callera GE, Montezano AC, Touyz RM, et al. ETA receptor mediates altered leukocyte-endothelial cell interaction and adhesion molecules expression in DOCA-salt rats. Hypertension. 2004;43:872-879.
33. Rossi GP, Colonna S, Pavan E, et al. Endothelin-1 and its mRNA in the wall layers of human arteries ex vivo. Circulation. 1999;99:1147-1155.
34. Zouki C, Baron C, Fournier A, et al. Endothelin-1 enhances neutrophil adhesion to human coronary artery endothelial cells: role of ET(A) receptors and platelet-activating factor. Br J Pharmacol. 1999;127:969-979.
35. Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation. 2002;105:1890-1896.
36. Goldfine AB, Beckman JA, Betensky RA, et al. Family history of diabetes is a major determinant of endothelial function. J Am Coll Cardiol. 2006;47:2456-2461.
37. Juan CC, Fang VS, Huang YJ, et al. Endothelin-1 induces insulin resistance in conscious rats. Biochem Biophys Res Commun. 1996;227:694-699.
38. Jiang ZY, Zhou QL, Chatterjee A, et al. Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells. Diabetes. 1999;48:1120-1130.
39. Berthiaume N, Carlson CJ, Rondinone CM, et al. Endothelin antagonism improves hepatic insulin sensitivity associated with insulin signaling in Zucker fatty rats. Metabolism. 2005;54:1515-1523.
40. Sutherland AJ, Nataatmadja MI, Walker PJ, et al. Vascular remodeling in the internal mammary artery graft and association with in situ endothelin-1 and receptor expression. Circulation. 2006;113:1180-1188.
41. Chen S, Apostolova MD, Cherian MG, et al. Interaction of endothelin-1 with vasoactive factors in mediating glucose-induced increased permeability in endothelial cells. Lab Invest. 2000;80:1311-1321.
42. Pollock DM. Endothelin, angiotensin, and oxidative stress in hypertension. Hypertension. 2005;45:477-480.
43. d'Uscio LV, Shaw S, Barton M, et al. Losartan but not verapamil inhibits angiotensin II-induced tissue endothelin-1 increase: role of blood pressure and endothelial function. Hypertension. 1998;31:1305-1310.
44. Rajagopalan S, Laursen JB, Borthayre A, et al. Role for endothelin-1 in angiotensin II-mediated hypertension. Hypertension. 1997;30:29-34.
45. Ortiz MC, Sanabria E, Manriquez MC, et al. Role of endothelin and isoprostanes in slow pressor responses to angiotensin II. Hypertension. 2001;37:505-510.
46. Ortiz MC, Manriquez MC, Romero JC, et al. Antioxidants block angiotensin II-induced increases in blood pressure and endothelin. Hypertension. 2001;38:655-659.
47. Tedgui A, Mallat Z. Anti-inflammatory mechanisms in the vascular wall. Circ Res. 2001;88:877-887.
48. Cheng C, Tempel D, van Haperen R, et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation. 2006;113:2744-2753.
49. Malek AM, Zhang J, Jiang J, et al. Endothelin-1 gene suppression by shear stress: pharmacological evaluation of the role of tyrosine kinase, intracellular calcium, cytoskeleton, and mechanosensitive channels. J Mol Cell Cardiol. 1999;31:387-399.
50. Ziegler T, Bouzourene K, Harrison VJ, et al. Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1998;18:686-692.
51. Ihling C, Gobel HR, Lippoldt A, et al. Endothelin-1-like immunoreactivity in human atherosclerotic coronary tissue: a detailed analysis of the cellular distribution of endothelin-1. J Pathol. 1996;179:303-308.
52. Lerman A, Edwards BS, Hallett JW, et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991;325:997-1001.
53. Ishizuka T, Takamizawa-Matsumoto M, Suzuki K, et al. Endothelin-1 enhances vascular cell adhesion molecule-1 expression in tumor necrosis factor alpha-stimulated vascular endothelial cells. Eur J Pharmacol. 1999;369:237-245.
54. Wilson SH, Simari RD, Lerman A. The effect of endothelin-1 on nuclear factor kappa B in macrophages. Biochem Biophys Res Commun. 2001;286:968-972.
55. Kowala MC, Rose PM, Stein PD, et al. Selective blockade of the endothelin subtype A receptor decreases early atherosclerosis in hamsters fed cholesterol. Am J Pathol. 1995;146:819-826.
56. Barton M, Haudenschild CC, d'Uscio LV, et al. Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A. 1998;95:14367-14372.
57. Best PJ, McKenna CJ, Hasdai D, et al. Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. Circulation. 1999;99:1747-1752.
58. Oliver FJ, de la Rubia G, Feener EP, et al. Stimulation of endothelin-1 gene expression by insulin in endothelial cells. J Biol Chem. 1991;266:23251-23256.
59. Quehenberger P, Bierhaus A, Fasching P, et al. Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells. Diabetes. 2000;49:1561-1570.
60. Andronico G, Mangano M, Ferrara L, et al, Cerasola G. In vivo relationship between insulin and endothelin role of insulin-resistance. J Hum Hypertens. 1997;11:63-66.
61. Schneider JG, Tilly N, Hierl T, et al. Elevated plasma endothelin-1 levels in diabetes mellitus. Am J Hypertens. 2002;15:967-972.
62. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991;87:432-438.
63. Dumont AS, Dumont RJ, McNeill JH, et al. Chronic endothelin antagonism restores cerebrovascular function in diabetes. Neurosurgery. 2003;52:653-660; discussion, 659-660.
64. Wolkart G, Stessel H, Saad Z, et al. Cardioprotective effects of atrasentan, an endothelin-A receptor antagonist, but not of nitric oxide in diabetic mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Br J Pharmacol. 2006;148:671-681.
65. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.
66. Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med. 1991;114:464-469.
67. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732-1739.
68. Adnot S, Raffestin B, Eddahibi S, et al. Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J Clin Invest. 1991;87:155-162.
69. Ross GA, Oishi P, Azakie A, et al. Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension. Am J Physiol Lung Cell Mol Physiol. 2005;288:L27-L35.
70. Girgis RE, Champion HC, Diette GB, et al. Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy. Am J Respir Crit Care Med. 2005;172:352-357.
71. Filep JG, Bodolay E, Sipka S, et al. Plasma endothelin correlates with antiendothelial antibodies in patients with mixed connective tissue disease. Circulation. 1995;92:2969-2974.
72. Kanmogne GD, Primeaux C, Grammas P. Induction of apoptosis and endothelin-1 secretion in primary human lung endothelial cells by HIV-1 gp120 proteins. Biochem Biophys Res Commun. 2005;333:1107-1115.
73. Hu J, Discher DJ, Bishopric NH, et al. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun. 1998;245:894-899.
74. Tang BT, Fonte TA, Feinstein JA, et al. Shear stress quantification and regulation of endothelial cell dysfunction in models of pulmonary arterial hypertension. Circulation. 2006;114(Suppl):11-52.
75. Clozel M, Hess P, Rey M, et al. Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats. Exp Biol Med (Maywood). 2006;231:967-973.
76. Lima J, Fonollosa V, Fernandez-Cortijo J, et al. Platelet activation, endothelial cell dysfunction in the absence of anticardiolipin antibodies in systemic sclerosis. J Rheumatol. 1991;18:1833-1836.
77. Hashimoto Y, Ziff M, Hurd ER. Increased endothelial cell adherence, aggregation, and superoxide generation by neutrophils incubated in systemic lupus erythematosus and Felty's syndrome sera. Arthritis Rheum. 1982;25:1409-1418.
78. Yoshio T, Masuyama J, Mimori A, et al. Endothelin-1 release from cultured endothelial cells induced by sera from patients with systemic lupus erythematosus. Ann Rheum Dis. 1995;54:361-365.
79. Papa ND, Raschi E, Moroni G, et al. Anti-endothelial cell IgG fractions from systemic lupus erythematosus patients bind to human endothelial cells and induce a pro-adhesive and a pro-inflammatory phenotype in vitro. Lupus. 1999;8:423-429.
80. Verma S, Lovren F, Dumont AS, et al. Endothelin receptor blockade improves endothelial function in human internal mammary arteries. Cardiovasc Res. 2001;49:146-151.
81. Dumont AS, Lovren F, McNeill JH, et al. Augmentation of endothelial function by endothelin antagonism in human saphenous vein conduits. J Neurosurg. 2001;94:281-286.
82. Ko L, Maitland A, Fedak PW, et al. Endothelin blockade potentiates endothelial protective effects of ACE inhibitors in saphenous veins. Ann Thorac Surg. 2002;73:1185-1188.
83. Bohm F, Beltran E, Pernow J. Endothelin receptor blockade improves endothelial function in atherosclerotic patients on angiotensin converting enzyme inhibition. J Intern Med. 2005;257:263-271.
84. Gonon AT, Erbas D, Broijersen A, et al. Nitric oxide mediates protective effect of endothelin receptor antagonism during myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2004;286:H1767-H1774.
85. Taner CB, Severson SR, Best PJ, et al. Treatment with endothelinreceptor antagonists increases NOS activity in hypercholesterolemia. J Appl Physiol. 2001;90:816-820.
86. Taddei S, Virdis A, Ghiadoni L, et al. Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation of patients with essential hypertension. Circulation. 1999;100:1680-1683.
87. Verhaar MC, Strachan FE, Newby DE, et al. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation. 1998;97:752-756.
88. Cardillo C, Kilcoyne CM, Cannon RO 3rd, et al. Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo. Hypertension. 2000;35:1237-1241.
89. Bohm F, Ahlborg G, Johansson BL, et al. Combined endothelin receptor blockade evokes enhanced vasodilatation in patients with atherosclerosis. Arterioscler Thromb Vasc Biol. 2002;22:674-679.
90. Cardillo C, Campia U, Bryant MB, et al. Increased activity of endogenous endothelin in patients with type II diabetes mellitus. Circulation. 2002;106:1783-1787.
91. Cardillo C, Kilcoyne CM, Cannon RO 3rd. Increased activity of endogenous endothelin in patients with hypercholesterolemia. J Am Coll Cardiol. 2000;36:1483-1488.
92. Shemyakin A, Bohm F, Wagner H, et al. Enhanced endothelium-dependent vasodilatation by dual endothelin receptor blockade in individuals with insulin resistance. J Cardiovasc Pharmacol. 2006;47:385-390.
93. Cardillo C, Kilcoyne CM, Waclawiw M, et al. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension. 1999;33:753-758.
94. Kakoki M, Hirata Y, Hayakawa H, et al. Effects of hypertension, diabetes mellitus, and hypercholesterolemia on endothelin type B receptor-mediated nitric oxide release from rat kidney. Circulation. 1999;99:1242-1248.
95. Wang QD, Li XS, Pernow J. The nonpeptide endothelin receptor antagonist bosentan enhances myocardial recovery and endothelial function during reperfusion of the ischemic rat heart. J Cardiovasc Pharmacol. 1995;26(Suppl 3):S445-S447.
96. Besse S, Tanguy S, Riou B, et al. Coronary and aortic vasoreactivity protection with endothelin receptor antagonist, bosentan, after ischemia and hypoxia in aged rats. Eur J Pharmacol. 2001;432:167-175.
97. Kanie N, Kamata K. Effects of chronic administration of the novel endothelin antagonist J-104132 on endothelial dysfunction in streptozotocin-induced diabetic rat. Br J Pharmacol. 2002;135:1935-1942.
98. Shen YT, Buie PS, Lynch JJ, et al. Chronic therapy with an ET(A/B) receptor antagonist in conscious dogs during progression of congestive heart failure. Intracellular Ca(2+) regulation and nitric oxide mediated coronary relaxation. Cardiovasc Res. 2000;48:332-345.
99. Bauersachs J, Fraccarollo D, Galuppo P, et al. Endothelin-receptor blockade improves endothelial vasomotor dysfunction in heart failure. Cardiovasc Res. 2000;47:142-149.
100. Elesber AA, Bonetti PO, Woodrum JE, et al. Bosentan preserves endothelial function in mice overexpressing APP. Neurobiol Aging. 2006;27:446-450.
101. Barton M, d'Uscio LV, Shaw S, et al. ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Hypertension. 1998;31:499-504.
102. d'Uscio LV, Moreau P, Shaw S, et al. Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension. Hypertension. 1997;29:435-441.
103. Ruschitzka F, Quaschning T, Noll G, et al. Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide. Circulation. 2001;103:3129-3135.
104. Iglarz M, Matrougui K, Levy BI, et al. Chronic blockade of endothelin ETA receptors improves flow dependent dilation in resistance arteries of hypertensive rats. Cardiovasc Res. 1998;39:657-664.
105. Fedak PW, Rao V, Verma S, et al. Combined endothelial and myocardial protection by endothelin antagonism enhances transplant allograft preservation. J Thorac Cardiovasc Surg. 2005;129:407-415.
106. Traupe T, D'Uscio LV, Muenter K, et al. Effects of obesity on endothelium-dependent reactivity during acute nitric oxide synthase inhibition: modulatory role of endothelin. Clin Sci (Lond). 2002;103(Suppl 48):13S-15S.
107. Prie S, Stewart DJ, Dupuis J. EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension. Circulation. 1998;97:2169-2174.