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(Circulation. 1997;96:1976-1982.)
© 1997 American Heart Association, Inc.
Articles |
Role of Endogenous Endothelin in Chronic Heart Failure
Effect of Long-term Treatment With an Endothelin Antagonist on Survival, Hemodynamics, and Cardiac Remodeling
From VACOMED, Departments of Pharmacology (IFRMP 23) (P.M., V.R., M.H., J.P.H., F.L., P.C., E.C., C.T.), Cardiology (G.D., B.L.), and Histology (B.M.), Rouen University Medical School and Rouen University Hospital, France.
Correspondence to Christian Thuillez, Service de Pharmacologie, Hôpital de Bois Guillaume, CHU de Rouen, 76031 Rouen Cedex, France. E-mail Christian.Thuillez{at}chu-rouen.fr
Background Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.
Methods and Results Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg · kg-1 · d-1). Bosentan 100 mg · kg-1 markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg · kg-1), which had no major hemodynamic or structural effects, also had no effect on survival.
Conclusions Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.
Key Words: echocardiograph • endothelin • heart failure • survival
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H. Kjekshus, O. A. Smiseth, R. Klinge, E. Oie, M. E. Hystad, and H. Attramadal Regulation of ET: pulmonary release of ET contributes to increased plasma ET levels and vasoconstriction in CHF Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1299 - H1310. [Abstract] [Full Text] [PDF]
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P. A. MacCarthy, R. Grocott-Mason, B. D. Prendergast, and A. M. Shah Contrasting Inotropic Effects of Endogenous Endothelin in the Normal and Failing Human Heart : Studies With an Intracoronary ETA Receptor Antagonist Circulation, January 18, 2000; 101(2): 142 - 147. [Abstract] [Full Text] [PDF]
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T. Mishima, M. Tanimura, G. Suzuki, A. Todor, V. G. Sharov, S. Goldstein, and H. N. Sabbah Effects of long-term therapy with bosentan on the progression of left ventricular dysfunction and remodeling in dogs with heart failure J. Am. Coll. Cardiol., January 1, 2000; 35(1): 222 - 229. [Abstract] [Full Text] [PDF]
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Z R Yousef, S R Redwood, and M S Marber Postinfarction left ventricular remodelling: where are the theories and trials leading us? Heart, January 1, 2000; 83(1): 76 - 80. [Full Text] [PDF]
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G. P. Rossi, M. Cesari, A. C. Pessina, B. Hocher, and I. George Endothelins and Cardiac Fibrosis • Response Hypertension, November 1, 1999; e1(5): . [Full Text]
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K. Ono, A. Matsumori, T. Shioi, Y. Furukawa, and S. Sasayama Contribution of Endothelin-1 to Myocardial Injury in a Murine Model of Myocarditis : Acute Effects of Bosentan, an Endothelin Receptor Antagonist Circulation, October 26, 1999; 100(17): 1823 - 1829. [Abstract] [Full Text] [PDF]
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F. Brunner Cardiac endothelin and big endothelin in right-heart hypertrophy due to monocrotaline-induced pulmonary hypertension in rat Cardiovasc Res, October 1, 1999; 44(1): 197 - 206. [Abstract] [Full Text] [PDF]
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G. P. Rossi, A. Sacchetto, M. Cesari, and A. C Pessina Interactions between endothelin-1 and the renin-angiotensin-aldosterone system Cardiovasc Res, August 1, 1999; 43(2): 300 - 307. [Abstract] [Full Text] [PDF]
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R. Varin, P. Mulder, V. Richard, F. Tamion, C. Devaux, J.-P. Henry, F. Lallemand, G. Lerebours, and C. Thuillez Exercise Improves Flow-Mediated Vasodilatation of Skeletal Muscle Arteries in Rats With Chronic Heart Failure : Role of Nitric Oxide, Prostanoids, and Oxidant Stress Circulation, June 8, 1999; 99(22): 2951 - 2957. [Abstract] [Full Text] [PDF]
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R. Yamauchi-Kohno, T. Miyauchi, T. Hoshino, T. Kobayashi, H. Aihara, S. Sakai, H. Yabana, K. Goto, Y. Sugishita, and S. Murata Role of Endothelin in Deterioration of Heart Failure Due to Cardiomyopathy in Hamsters : Increase in Endothelin-1 Production in the Heart and Beneficial Effect of Endothelin-A Receptor Antagonist on Survival and Cardiac Function Circulation, April 27, 1999; 99(16): 2171 - 2176. [Abstract] [Full Text] [PDF]
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B. Pieske, B. Beyermann, V. Breu, B. M. Loffler, K. Schlotthauer, L. S. Maier, S. Schmidt-Schweda, H. Just, and G. Hasenfuss Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium Circulation, April 13, 1999; 99(14): 1802 - 1809. [Abstract] [Full Text] [PDF]
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T. Kobayashi, T. Miyauchi, S. Sakai, M. Kobayashi, I. Yamaguchi, K. Goto, and Y. Sugishita Expression of endothelin-1, ETA and ETB receptors, and ECE and distribution of endothelin-1 in failing rat heart Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1197 - H1206. [Abstract] [Full Text] [PDF]
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B. Hocher, I. George, J. Rebstock, A. Bauch, A. Schwarz, H.-H. Neumayer, and C. Bauer Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension Hypertension, March 1, 1999; 33(3): 816 - 822. [Abstract] [Full Text] [PDF]
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A. Wada, T. Tsutamoto, M. Ohnishi, M. Sawaki, D. Fukai, Y. Maeda, and M. Kinoshita Effects of a Specific Endothelin-Converting Enzyme Inhibitor on Cardiac, Renal, and Neurohumoral Functions in Congestive Heart Failure : Comparison of Effects With Those of Endothelin A Receptor Antagonism Circulation, February 2, 1999; 99(4): 570 - 577. [Abstract] [Full Text] [PDF]
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Y. Matsumura, N. Hashimoto, S. Taira, T. Kuro, R. Kitano, M. Ohkita, T. J. Opgenorth, and M. Takaoka Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats Hypertension, February 1, 1999; 33(2): 759 - 765. [Abstract] [Full Text] [PDF]
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G. Sutsch, W. Kiowski, X.-W. Yan, P. Hunziker, S. Christen, W. Strobel, J.-H. Kim, P. Rickenbacher, and O. Bertel Short-Term Oral Endothelin-Receptor Antagonist Therapy in Conventionally Treated Patients With Symptomatic Severe Chronic Heart Failure Circulation, November 24, 1998; 98(21): 2262 - 2268. [Abstract] [Full Text] [PDF]
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Q. T. Nguyen, P. Cernacek, A. Calderoni, D. J. Stewart, P. Picard, P. Sirois, M. White, and J. L. Rouleau Endothelin A Receptor Blockade Causes Adverse Left Ventricular Remodeling but Improves Pulmonary Artery Pressure After Infarction in the Rat Circulation, November 24, 1998; 98(21): 2323 - 2330. [Abstract] [Full Text] [PDF]
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Y. Iwanaga, Y. Kihara, K. Hasegawa, K. Inagaki, T. Yoneda, S. Kaburagi, M. Araki, and S. Sasayama Cardiac Endothelin-1 Plays a Critical Role in the Functional Deterioration of Left Ventricles During the Transition From Compensatory Hypertrophy to Congestive Heart Failure in Salt-Sensitive Hypertensive Rats Circulation, November 10, 1998; 98(19): 2065 - 2073. [Abstract] [Full Text] [PDF]
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E. Oie, R. Bjonerheim, H. K. Grogaard, H. Kongshaug, O. A. Smiseth, and H. Attramadal ET-receptor antagonism, myocardial gene expression, and ventricular remodeling during CHF in rats Am J Physiol Heart Circ Physiol, September 1, 1998; 275(3): H868 - H877. [Abstract] [Full Text] [PDF]
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B. Geny, F. Piquard, J. Lonsdorfer, and P. Haberey Endothelin and heart transplantation Cardiovasc Res, September 1, 1998; 39(3): 556 - 562. [Full Text] [PDF]
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R. Choussat, L. Hittinger, F. Barbe, G. Maistre, A. Carayon, B. Crozatier, and J. Su Acute effects of an endothelin-1 receptor antagonist bosentan at different stages of heart failure in conscious dogs Cardiovasc Res, September 1, 1998; 39(3): 580 - 588. [Abstract] [Full Text] [PDF]
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P. Mulder, V. Richard, F. Bouchart, G. Derumeaux, K. Munter, and C. Thuillez Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure Cardiovasc Res, September 1, 1998; 39(3): 600 - 608. [Abstract] [Full Text] [PDF]
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M. Ohnishi, A. Wada, T. Tsutamoto, D. Fukai, and M. Kinoshita Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure Cardiovasc Res, September 1, 1998; 39(3): 617 - 624. [Abstract] [Full Text] [PDF]
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T. Hoshino, R. Yamauchi, K. Kikkawa, H. Yabana, and S. Murata Pharmacological Profile of T-0201, a Highly Potent and Orally Active Endothelin Receptor Antagonist J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 643 - 649. [Abstract] [Full Text]
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