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Endothelin, vascular hypertrophy, and hypertension

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Summary

The endothelins (ET-1,2, and 3) constitute a family of 21 amino-acid peptides with potent biological activities. They are synthesized in several tissues, including the vascular endothelium (ET-1 exclusively) and smooth muscle cells. The production and release of endothelin is stimulated by many factors, hormonal and metabolic, and by growth factors, hypoxia, and shear stress. Released endothelin binds to the endothelin receptors ETA and ETB, the ETA receptors on vascular smooth muscle cells mediating vasoconstriction, and the ETB receptors on the endothelium linked to nitric oxide (NO) and prostacyclin release. The ETA receptors activate the PLC-IP3-DAG transduction pathway, which through an increase in cytosolic Ca2+ and protein kinase C (PKC) causes vasoconstriction and stimulation of vascular smooth muscle cell growth and proliferation. In the pathogenesis of vascular hypertrophy in hypertension, there is a complex interaction between endothelin, angiotensin II, 795-1 agonists, Ca2+, and other growth factors. In animal models of hypertension, endothelin causes vascular hypertrophy, more pronounced in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat than in the spontaneously hypertensive rat. In humans there is an increase in the plasma concentration of endothelin in severe atherosclerotic disease, but not consistently in hypertension. Evidence for the role of endothelin in the vascular hypertrophy of human hypertension is scanty, but the development of nonpeptide and receptor subtype-selective antagonists will permit meaningful studies, including clinical trials of a new class of antihypertensive agents.

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References

  1. Hickey, KA, Rubanyi, GM, Paul, RJ, Highsmith, RF. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol 1985;248:550–556.

    Google Scholar 

  2. Yanagisawa, M, Kurihara, H, Kimura, S et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–415.

    Google Scholar 

  3. Inoue, A, Yanagisawa, M, Kimura, S, Kasuya, Y, Miyauchi, T. The human endothelin family-3 structurally and pharmacologically distinct isopeptides predicted by 3 separate genes. Proc Natl Acad Sci USA 1989;86:2863–2867.

    Google Scholar 

  4. Block, DK, Hong, CC, Eddy, RL, Shows, TB, Quertermous, T. cDNA cloning and chromosomal assignment of the endothelin-2 gene: Vasoactive intestinal contractor peptide in rat endothelin-2. Genomics 1991;10:236–242.

    Google Scholar 

  5. Shimada, K, Matsushita, Y, Wakabayashi, K, et al. Cloning and functional expression of human endothelin converting enzyme cDNA. Biochem Biophys Res Commun 1995;207:807–812.

    Google Scholar 

  6. Tamarisa, P, Frishman, WH, Kumar, A. Endothelin and endothelin antagonism: Roles in cardiovascular health and disease. Am Heart J 1995;130:601–610.

    Google Scholar 

  7. Sakurai, T, Goto, K. Endothelins. Vascular actions and clinical implications. Drugs 1993;46:795–804.

    Google Scholar 

  8. Marsault, R, Vigne, P, Frelin, C. The irreversibility of endothelin action is a property of a late intracellular signalling event. Biochem Biophys Res Commun 1991;179:1408–1413.

    Google Scholar 

  9. Warner, TD, Allock, GH, Corder, R, Vane, JR. Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF. Br J Pharmacol 1993; 110:777–782.

    Google Scholar 

  10. Seo, B, Oemar, BS, Siebenmann, R, von, Segesser, L, Lüscher, TF. Both ET-A and ET-B receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994;89: 1203–1208.

    Google Scholar 

  11. Teerlink, JR, Breu, V, Sprecher, U, Clozel, M, Clozel, J-P. Potent vasoconstriction mediated by endothelin ET-B receptors in canine coronary arteries. Circ Res 1994;74: 105–114.

    Google Scholar 

  12. Sargent, CA, Liu, EC, Chao, CC, Monshizadegan, H, Webb, ML, Grover, GJ. Role of endothelin receptor subtype B (ET-B) in myocardial ischemia. Life Sci 1994;55:1833–1844.

    Google Scholar 

  13. Ivy, DD, Kinsella, JP, Abman, SH. Physiologic characterization of endothelin A and B receptor activity in the ovine fetal pulmonary circulation. J Clin Invest 1994;93:2141–2148.

    Google Scholar 

  14. Kitazono, T, Heistad, DD, Faraci, FM. Enhanced responses of the basilar artery to activation of endothelin-B receptors in stroke-prone spontaneously hypertensive rats. Hypertension 1995;25:490–494.

    Google Scholar 

  15. Masaki, T, Kimura, S, Yanagisawa, M, Goto, K. Molecular and cellular mechanism of endothelin regulation. Implications for vascular function. Circulation 1991;84:1457–1468.

    Google Scholar 

  16. Denning, GM, Clark, RA, Welsh, MJ. cAMP and inositol 1,4,5-trisphosphate increase Ca2+ in HT-29 cells by activating different Ca2+ influx pathways. Am J Physiol 1994;267:C776-C783.

    Google Scholar 

  17. Lüscher, TF, Yang, Z, Kiowski, W, et al. Endothelin-induced vasoconstriction and calcium antagonists. J Hum Hypertens 1992;6(Suppl 2):S3-S8.

    Google Scholar 

  18. Rosendorff, C. The renin-angiotensin system and vascular hypertrophy. J Am Coll Cardiol 1996;28:803–812.

    Google Scholar 

  19. Rosendorff, C, Kalliatakis, B, Radford, HM, Patton, J. Age dependence of the pressor sensitivity to noradrenaline and angiotensin II during calcium channel blockade in hypertensive patients. J Cardiovasc Pharmacol 1988;12:S69-S71.

    Google Scholar 

  20. Taubman, MB, Berk, BC, Izumo, S, Tsuda, T, Alexander, RW, Nadal Ginard, B. Angiotensin II induces c-fos mRNA in aortic smooth muscle: Role of Ca2+ mobilization and protein kinase C activation. J Biol Chem 1989;264:526–530.

    Google Scholar 

  21. Davis, RJ. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem 1993;268:14,553–14,556.

    Google Scholar 

  22. Bobik, A, Grooms, A, Millar, JA, Mitchell, A, Grinpukel, S. Growth factor activity of endothelin on vascular smooth muscle. Am J Physiol 1990;258(Pt 1):C408-C415.

    Google Scholar 

  23. Tsuda, T, Griendling, KK, Ollerenshaw, JD, Lassegue, B, Alexander, RW. Angiotensin-II and endothelin-induced protein phosphorylation in cultured vascular smooth muscle cells. J Vasc Res 1993;30:241–249.

    Google Scholar 

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

    Google Scholar 

  25. Yorikane, R, Sakai, S, Miyauchi, T, Sakurai, T, Goto, K. Possible involvement of endothelin-1 in cardiac hypertrophy. Arzneimittelforschung 1994;44:412–415.

    Google Scholar 

  26. Brown, LA, Nunez, DJ, Brookes, CI, Wilkins, MR. Selective increase in endothelin-1 and endothelin A receptor subtype in the hypertrophied myocardium of the aorto-venacaval fistula rat. Cardiovasc Res 1995;29:768–774.

    Google Scholar 

  27. Ito, H, Hiroe, M, Hirata, Y, et al. Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload. Circulation 1994;89:2198–2203.

    Google Scholar 

  28. Li, JS, Schiffrin, EL. Effect of chronic treatment of adult spontaneously hypertensive rats with an endothelin receptor antagonist. Hypertension 1995;25:495–500.

    Google Scholar 

  29. Li, JS, Schiffrin, EL. Chronic endothelin receptor antagonist treatment of young spontaneously hypertensive rats. J Hypertens 1995;13:647–652.

    Google Scholar 

  30. Li, JS, Lariviere, R, Schiffrin, EL. Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats. Evidence for a role of endothelin in vascular hypertrophy. Hypertension 1994;24:183–188.

    Google Scholar 

  31. Schiffrin, EL, Lariviere, R, Li, JS, Sventek, P, Touyz, RM. Enhanced expression of endothelin-1 gene may cause blood pressure-independent vascular hypertrophy. J Cardiovasc Pharmacol 1995;26(Suppl 3):S5-S8.

    Google Scholar 

  32. Hirita, Y, Eguchi, S, Tsujino, M. Effects of manidipine on DNA and protein synthesis in cultured vascular smooth muscle and endothelial cells and on proto-oncogene expression. Blood Pressure 1992;1(Suppl 3):30–35.

    Google Scholar 

  33. Grohe, C, Nouskas, J, Vetter, H, Neyses, L. Effects of nisoldipine on endothelin-1 and angiotensin II-induced immediate/early gene expression and protein synthesis in adult rat ventricular cardiomyocytes. J Cardiovasc Pharmacol 1994; 24:13–16.

    Google Scholar 

  34. Sung, CP, Arleth, AJ, Storer, BL, Ohlstein, EH. Angiotensin type 1 receptors mediate smooth muscle proliferation and endothelin biosynthesis in rat vascular smooth muscle. J Pharmacol Exp Ther 1994;271:429–437.

    Google Scholar 

  35. Hatakeyama, H, Miyamori, I, Yamagishi, S, Takeda, Y, Takeda, R, Yamamoto, H. Angiotensin II up-regulates the expression of type A endothelin receptor in human vascular smooth muscle cells. Biochem Mol Biol Int 1994;34:127–134.

    Google Scholar 

  36. Weber, H, Webb, ML, Serafino, R, et al., Endothelin-I and angiotensin-II stimulate delayed mitogenesis in cultured rat aortic smooth muscle cells: Evidence for common signaling mechanisms. Mol Endocrinol 1994;8:148–158.

    Google Scholar 

  37. Neyses, L, Nouskas, J, Luyken, J et al.. Induction of immediate-early genes by angiotensin-II and endothelin-1 in adult rat cardiomyocytes. J Hypertens 1993;11:927–934.

    Google Scholar 

  38. Chua, BH, Chua, CC, Diglio, CA, Siu, BB. Regulation of endothelin-1 mRNA by angiotensin II in rat heart endothelial cells. Biochim Biophys Acta 1993;1178:201–206.

    Google Scholar 

  39. Ishiye, M, Umemura, K, Uematsu, T, Nakashima, M. Angiotensin AT-1 receptor-mediated attenuation of cardiac hypertrophy due to volume overload: Involvement of endothelin. Eur J Pharmacol 1995;280:11–17.

    Google Scholar 

  40. Kohno, M, Horio, T, Ikeda, M, et al. Angiotensin II stimulates endothelin-1 secretion in cultured rat mesangial cells. Kidney Int 1992;42:860–866.

    Google Scholar 

  41. Bakris, GL, Re, RN. Endothelin modulates angiotensin II-induced mitogenesis of human mesangial cells. Am J Physiol 1993;264(6):F937-F942.

    Google Scholar 

  42. Battistini, B, Chailler, P, D'Orleans-Juste, P, Briere, N, Sirois, P. Growth regulatory properties of endothelins. Peptides 1993;14:385–399.

    Google Scholar 

  43. Boulanger, C, Lüscher, TF. Release of endothelin from the porcine aorta. J Clin Invest 1990;85:587–590.

    Google Scholar 

  44. Brunner, F, Stessel, H, Kukevetz, WR. Novel guanylyl cyclase inhibitor, ODQ reveals role of nitric oxide, but not of cyclic GMP in endothelin-1 secretion. FEBS Lett 1995;376:262–266.

    Google Scholar 

  45. Deng LY, Li JS, Sventek P, Schiffrin EL. Correlation of vascular hypertrophy with topography of endothelin-1 gene expression in L-NAME-treated SHR in comparison to DOCA-salt hypertensive rats. Am J Hypertens 1996;9(4): 83A.

  46. Sventek P, Turgeon A, Schiffrin EL. Effect of L-NAME on vascular endothelin-1 gene expression in normal rats. Am J Hypertens 1996;9(4):82A.

    Google Scholar 

  47. Sventek, P, Li, JS, Grove, K, Deschepper, CF, Schiffrin, EL. Vascular structure and expression of endothelin-1 gene in L-NAME-treated spontaneously hypertensive rats. Hypertension 1996;27:49–55.

    Google Scholar 

  48. Kung, CF, Moreau, P, Takase, H, Lüscher, TF. L-NAME hypertension alters endothelial and smooth muscle function in rat aorta. Prevention by trandolapril and verapamil. Hypertension 1995;26:744–751.

    Google Scholar 

  49. Vanhoutte, PM. Is endothelin involved in the pathogenesis of hypertension? Hypertension 1993;21:747–751.

    Google Scholar 

  50. Suzuki, N, Miyauchi, T, Tomobe, Y, et al. Plasma concentrations of endothelin-1 in spontaneously hypertensive rats and DOCA-salt hypertensive rats. Biochem Biophys Res Commun 1990;167:941–947.

    Google Scholar 

  51. Schiffrin, EL. Endothelin: Potential role in hypertension and vascular hypertrophy. Hypertension 1995;25:1135–1143.

    Google Scholar 

  52. Miyauchi, T, Yanagisawa, M, Iida, K, et al. Age and sexrelated variation of plasma endothelin-1 concentration in normal and hypertensive subjects. Am Heart J 1992;123:1092–1093.

    Google Scholar 

  53. Masaki, T. The discovery, the present state, and the future prospects of endothelin. J Cardiovasc Pharmacol 1989; 13(Suppl 5):S1-S4.

    Google Scholar 

  54. Wagner, OF, Christ, G, Wojta, J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992;267:16066–16088.

    Google Scholar 

  55. Brunner, F. Tissue endothelin-1 levels in perfused rat heart following stimulation with agonists in ischaemia and reperfusion. J Mol Cell Cardiol 1995;27:1953–1963.

    Google Scholar 

  56. Brunner, F. Cardiac tissue endothelin-1 levels under basal, stimulated and ischemic conditions. J Cardiovasc Pharmacol 1995;26(Suppl 3):S44-S46.

    Google Scholar 

  57. Lariviere, R, Day, R, Schiffrin, EL. Increased expression of endothelin-1 gene in blood vessels of deoxycorticosterone acetate-salt hypertensive rats. Hypertension 1993;21: 916–920.

    Google Scholar 

  58. Lariviere, R, Thibault, G, Schiffrin, EL. Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats. Hypertension 1993;21:294–300.

    Google Scholar 

  59. Kohno, M, Murakawa, KI, Horio, T, et al. Plasma immunoreactive endothelin-1 in experimental malignant hypertension. Hypertension 1991;18:93–100.

    Google Scholar 

  60. Ferri C, Bellini C, Desideri G, et al. Increased endothelin-1 levels in human salt-sensitive hypertension. Am J Hypertens 1996;9(4):79A.

    Google Scholar 

  61. Januszewicz A, Lapinski M, Kuch-Wocial A, et al. Endothelin-1 plasma concentration in patients with essential hypertension, pheochromocytoma and renovascular hypertension. Am J Hypertens 1996;9(4):91A.

    Google Scholar 

  62. Noll, G, Wenzel, RR, Schneider, M, et al.. Increased activation of sympathetic nervous system and endothelin by mental stress in normotensive offspring of hypertensive parents. Circulation 1996;93:866–869.

    Google Scholar 

  63. Tarquini R, de Leonardis V, Perfetto F, Piluso A, Naldi E, Tarquini B. Endothelin-1 plasma levels in dipper and non dipper hypertensive patients. Am J Hypertens. 1996;9(4): 81A.

  64. Yokokawa, K, Tahara, H, Kohno, M, et al. Endothelin-secreting tumor. J Cardiovasc Pharmacol 1991:17(Suppl 7): S398-S401.

    Google Scholar 

  65. Tomobe, Y, Miyauchi, T, Saito, A, et al. Effects of endothelin on the renal artery of spontaneously hypertensive and Wistar-Kyoto rats. Eur J Pharmacol 1988;152:373–374.

    Google Scholar 

  66. Miyauchi, T, Ishikawa, T, Tomobe, Y, et al. Characteristics of the pressor response to endothelin in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 1989;14: 427–434.

    Google Scholar 

  67. Bolger, GT, Liard, F, Jodoin, A, Jaramillo, J. Vascular reactivity, tissue levels and binding sites for endothelin: A comparison in the spontaneously hypertensive and Wistar-Kyoto rats. Can J Physiol Pharmacol 1991;69:406–413.

    Google Scholar 

  68. Clozel, M. Endothelin sensitivity and receptor binding in the aorta of spontaneously hypertensive rats. J Hypertens 1989; 17:913–917.

    Google Scholar 

  69. Flückiger, JP, Nguyen, PV, Li, G, Yang, XP, Schiffrin, EL. Phosphoinositide, calcium and 1,2 diacylgycerol response of blood vessels of DOCA-salt hypertensive rats to endothelin-1. Hypertension 1992;19:743–749.

    Google Scholar 

  70. Nguyen, PV, Parent, A, Deng, LY, Flückiger, JP, Thibault, G, Schiffrin, EL. Endothelin vascular receptors and responses in DOCA-salt hypertensive rats. Hypertension 1992;19(Suppl II):II98-II104.

    Google Scholar 

  71. Schiffrin, EL, Deng, LY, Larochelle, P. Blunted effects of endothelin on small subcutaneous resistance arteries of mild essential hypertensive patients. J Hypertens 1992;10: 437–444.

    Google Scholar 

  72. Yasujima, M, Abe, K, Kanazawa, M, et al. Chronic effects of synthetic endothelin on blood pressure and sodium excretion in rats. Am J Hypertens 1990;3:635–637.

    Google Scholar 

  73. Mortensen, LH, Pawloski, CM, Kanagy, NL, Fink, GD. Chronic hypertension produced by infusion of endothelin in rats. Hypertension 1990;15:729–733.

    Google Scholar 

  74. Liefeldt, L, Bocker, W, Schonfelder, G, Zintz, M, Paul, M. Regulation of the endothelin system in transgenic rats expressing the human endothelin-2 gene. J Cardiovasc Pharmacol 1995;26(Suppl 3):S32-S33.

    Google Scholar 

  75. Kurihara, Y, Kurihara, H, Suzuki, H, et al.. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 1994;368:703–710.

    Google Scholar 

  76. Okada, M, Kobayashi, M, Maruyama, H, et al. Effects of a selective endothelin A-receptor antagonist, BQ-123, in salt-loaded stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 1995;22:763–768.

    Google Scholar 

  77. Bird, JE, Moreland, S, Waldron, TL, Powell, JR. Antihypertensive effects of a novel endothelin-A receptor antagonist in rats. Hypertension 1995;25:1191–1195.

    Google Scholar 

  78. Stasch, JP, Hirth-Dietrich, C, Frobel, K, Wegner, M. Prolonged endothelin blockade prevents hypertension and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats. Am J Hypertens 1995;8:1128–1134.

    Google Scholar 

  79. Schiffrin, EL, Sventek, P, Li, JS, Turgeon, A, Reudelhuber, T. Antihypertensive effect of an endothelin receptor antagonist in DOCA-salt spontaneously hypertensive rats. Br J Pharmacol 1995;115:1377–1381.

    Google Scholar 

  80. Lüscher, TF, Seo, B-G, Bühler, FR. Potential role of endothelin in hypertension. Hypertension 1993;21:752–757.

    Google Scholar 

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  1. Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA

    Clive Rosendorff

  2. Veterans Affairs Medical Center, Bronx, New York, USA

    Clive Rosendorff

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Rosendorff, C. Endothelin, vascular hypertrophy, and hypertension. Cardiovasc Drug Ther 10, 795–802 (1997). https://doi.org/10.1007/BF00053038

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