Summary
In recent years, evidence from various animal experiments has accumulated that emphasizes the role of endothelin-1 in the pathophysiology of several cardiovascular diseases, including congestive heart failure. The recent advent of potent antagonists of this system now allows the assessment of the involvement of endothelin-1 in the maintenance of vascular tone in animals and humans. We report hemodynamic data from two trails in patients with chronic severe congestive heart failure (i.e., reduced left ventricular ejection fraction of <30%, elevated resting pulmonary capillary wedged pressure >15 mmHg, and/or reduced cardiac index of 2.5 L/min/m2 or less) who were treated with the mixed endothelin-type A and type B-receptor antagonist bosentan. In the first study, the acute effect of bosentan (300 mg, intravenous) on hemodynamics and neurohormones was investigated. Bosentan was well tolerated and significantly improved impaired hemodynamics due to systemic and venous vasodilation. In the second trial, bosentan was given orally (0.5 g bid) for 14 days, in addition to conventional triple treatment for congestive heart failure, including digitalis, angiotensin-converting enzyme inhibitors, and diuretics. Cardiac hemodynamics were monitored during the first 24 hours of treatment, and measurements were repeated during the last day of bosentan therapy. Bosentan was well tolerated in these patients as well, and hemodynamic measures were compatible with an additional effect of bosentan after 2 weeks. However, there was a slight increase in heart rate as well. Our result underline the importance of endogenously generated endothelin-1 in congestive heart failure and suggest a potential benefit of endothelin antagonism in such patients. However, long-term studies are needed to establish whether chronic endothelin antagonism has beneficial clinical effects and is capable of improving survival and/or symptoms in severe heart failure patients who remain symptomatic despite standard triple therapy.
Similar content being viewed by others
References
Furchgott, RF, Zawadzki, JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373–376.
Yanagisawa, M, Kurihara, H, Kimura, S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1989;332:411–415.
Vane, JR, Änggard, EE, Botting, RM. Regulatory functions of the endothelium. N Engl J Med 1990;323:27–36.
Palmer, RMJ, Ferrige, AG, Moncada, S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–526.
Vallance, P, Collier, J, Moncada, S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989;2:997–1000.
Kiowski, W, Linder, L, Stoschitzky, K, et al. Diminished vascular response to inhibition of endothelium-derived nitric oxide and enhanced vasoconstriction to exogeneously administered endothelin-1 in clinically healthy smokers. Circulation 1994;90:27–34.
Drexler, H, Hayoz, D, Münzel, T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992;69: 1596–1601.
Linder, L, Kiowski, W, Bühler, FR, Lüscher, TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation 1990;81:1762–1767.
Creager, MA, Cooke, JP, Mendelsohn, ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990;86:228–234.
Kiowski, W, Lüscher, TF, Linder, L, Bühler, FR. Endothelin-1-induced vasoconstriction in humans. Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor. Circulation 1991;83:469–475.
Komuro, I, Kurihara, H, Sugiyama, T, Yoshizumi, M, Takaku, F, Yazaki, Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett 1988;238:249–252.
Ito, H, Hirata, Y, Hiroe, M, et al. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res 1991;69:209–215.
Kaddoura, S, Firth, JD, Boheler, KR, Sugden, PH, Poole-Wilson, PA. Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in vivo. Circulation 1996; 93:2068–2079.
Koyama, H, Tabata, T, Nishzawa, Y, Inoue, T, Morii, H, Yamaji, T. Plasma endothelin levels in patients with uraemia. Lancet 1989;1:991–992.
Kohno, M, Yasunari, K, Murakawa, K, et al. Plasma immuno-reactive endothelin in essential hypertension. Am J Med 1990;88:614–618.
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.
Lerman, A, Holmes, DR, Bell, MR, Garratt, KN, Nishimura, RA, Burnett, JC. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation 1995;92:2426–2431.
Matsuyama, K, Yasue, H, Okumura, K, et al. Increased plasma level of endothelin-1-like immunoreactivity during coronary spasm in patients with coronary spastic angina. Am J Cardiol 1991;68:991–995.
Stewart, DJ, Cernacek, P, Costello, KB, Rouleau, RL. Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 1992;85:510–517.
Wei, CM, Lerman, A, Rodeheffer, RJ, et al. Endothelin in human congestive heart failure. Circulation 1994;89: 1580–1586.
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;89:1573–1579.
Pacher, R, Stanek, B, Hülsmann, 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;27:633–641.
Lerman, A, Hildebrand, FLJ, Aarhus, LL, Burnett, JCJ. Endothelin has biological actions at pathophysiological concentrations. Circulation 1991;83:1808–1814.
Ahlborg, G, Ottoson-Seeberger, A, Hemsen, A, Lundberg, JM. Big ET-1 infusion in man causes renal ET-1 release, renal and splanchnic vasoconstriction, and increased mean arterial blood pressure. Cardiovasc Res 1994;28:1559–1563.
Clozel, M, Breu, V, Burri, K, et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 1993;365:759–761.
Haynes, WG, Webb, DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994;344: 852–854.
Teerlink, JR, Carteaux, JP, Sprecher, U, Löffler, BM, Clozel, M, Clozel, JP. Role of endogenous endothelin in normal hemodynamic status of anesthetized dogs. Am J Physiol 1995; 268:H432-H440.
Clozel, M, Gray, GA, Breu, V, Löffler, BM, Osterwalder, R. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun 1992;186:867–873.
Takayanagi, R, Kitazumi, K, Takasaki, C, et al. Presence of non-selective type of endothelin receptor on vascular endothelium and its linkage to vasodilation. FEBS Lett 1991;282: 103–106.
Kiowski, W, Sütsch, G, Hunziker, P, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346:732–736.
Cody, R, Haas, GJ, Binkley, PF, Capers, Q, Kelley, R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992;85:504–509.
Wagner, OF, Christ, G, Wojta, J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992;267:16066–16068.
Li, JS, Lariviere, R, Schiffrin, EL. Effect of a nonselective endothelin antagonist on vascular remodeling in DOCA-salt hypertensive rats. Evidence for a role of endothelin in vascular hypertrophy. Hypertension 1994;24:183–188.
Fukuroda, T, Fujikawa, T, Ozaki, S, Ishikawa, K, Yano, M, Nishikibe, M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun 1994;199: 1461–1465.
Teerlink, JR, Löffler, BM, Hess, P, Maire, JP, Clozel, M, Clozel, JP. Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47–0203 (bosentan). Circulation 1994;90:2510–2518.
Ichikawa, KI, Hidai, C, Okuda, C, et al. Endogenous endothelin-1 mediates cardiac hypertrophy and switching of myosin heavy chain gene expression in rat ventricular myocardium. J Am Coll Cardiol 1996;27:1286–1291.
Bakris, GL, Re, RN. Endothelin modulates angiotensin II-induced mitogenesis of human mesangial cells. Am J Physiol 1993;246:F937-F942.
Fujisaki, H, Ito, H, Hirata, Y, et al. Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. J Clin Invest 1995;96:1059–1065.
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.
Hirata, Y, Kanno, K, Eguchi, S, Kano, H. Effect of an AT1 receptor antagonist (CV-11974) on angiotensin II-induced cardiomyocyte hypertrophy in vitro. Blood Press 1994; 5(Suppl):84–88.
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.
Chen, L, McNeill, JR, Wilson, TW, Gopalakrishnan, V. Heterogeneity in vascular smooth muscle responsiveness to angiotensin II. Role of endothelin. Hypertension 1995;26: 83–88.
Kawaguchi, H, Sawa, H, Yasuda, H. Endothelin stimulates angiotensin I to angiotensin II conversion in cultured pulmonary artery endothelial cells. J Mol Cell Cardiol 1990; 22:839–842.
Yang, ZH, Richard, V, von, Segesser, L, et al. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm? Circulation 1990;82:188–195.
Yoshida, H, Nakamura, M. Inhibition by angiotensin converting enzyme inhibitors of endothelin secretion from cultured human endothelial cells. Life Sci 1992;50:PL195-PL200.
Cannan, CR, Burnett, JC, Lerman, A. Enhanced coronary vasoconstriction to endothelin-B-receptor activation in experimental congestive heart failure. Circulation 1996;93: 646–651.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sütsch, G., Bertel, O. & Kiowski, W. Acute and short-term effects of the nonpeptide endothelin-1 receptor antagonist bosentan in humans. Cardiovasc Drug Ther 10, 717–725 (1997). https://doi.org/10.1007/BF00053029
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00053029