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Clin. Cardiol. 23, 803–807 (2000)


Bosentan and the Endothelin System in Congestive Heart Failure

Samer H. Ellahham, M.D., Vincent Charlon, Ph.D.,* Zaid Abassi, Ph.D.,† Karim A. Calis, Pharm.D.,† Wassim K. Choucair, M.D.

Division of Cardiology, Washington Hospital Center, Washington, D.C., USA; *Hoffmann-La Roche, Basel, Switzerland; †Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

Summary: The endothelin system appears to play an important role in the pathophysiology of congestive heart failure (CHF). Endothelin receptor antagonists represent a novel class of agents that are being evaluated for their potential benefits in treating various cardiovascular disorders. Bosentan is an orally active endothelin receptor antagonist that has been studied for the treatment of CHF. Early clinical experience with bosentan has confirmed some benefits on hemodynamic parameters in patients with CHF. Its role in slowing the progression of the disease and improving survival remains to be elucidated.

Key words: endothelin, bosentan, chronic heart failure, receptor antagonist


Congestive heart failure (CHF) is a progressive clinical syndrome resulting from cardiac dysfunction and characterized by signs and symptoms of intravascular and interstitial volume overload, including rales, edema, and shortness of breath, or manifestations of inadequate tissue perfusion, such as poor exercise tolerance or fatigue. The primary cause of CHF is impairment of the ability of the heart to fill or empty the left ventricle properly. In the United States, it is estimated that more than 2 million people have heart failure, and an additional 400,000 cases are diagnosed each year. The prevalence of CHF is increasing as the population continues to age. Mortality during the first 5 years from the time of diagnosis of CHF continues to be high, even among patients on the best available treatments. The last few years have brought significant advances in the understanding of the pathogenesis of CHF. Increasing evidence suggests a potential role of the endothelin system in the pathophysiology of CHF. With the recent discovery and development of endothelin receptor antagonists, the clinical potential of therapeutic agents that target the endothelin system is being actively evaluated. Bosentan, an orally active endothelin receptor antagonist, is to date the most well-studied of these agents for the treatment of CHF.

The Endothelin System

The endothelin family includes a group of three 21-amino acid peptides with very similar structures: endothelin-1 (ET-1), ET-2, and ET-3.1–4 Endothelin-1 is the most important endothelin synthesized in the blood vessels, mainly in endothelial cells.1 Almost 75% of ET-1 secreted by endothelial cells is directed toward the abluminal site (Fig. 1), where it can bind to specific receptors on the smooth muscle cells.5 Therefore, plasma ET-1 concentrations do not necessarily reflect endothelial cell production or the biological effect of ET-1 on smooth muscle cells.

Fig. 1 The endothelin system. NO = nitric oxide, PGI-2 = prostaglandin I-2, ANF = atrial natriuretic factor, ET = endothelin, LDL = low-density lipoprotein, ECE = endothelin-converting enzyme.

The development of specific ET receptor agonists and antagonists has led to the identification of two receptor subtypes in mammalian cells, ETA and ETB.6, 7 ETA receptors are present on smooth muscle cells and are responsible for the contractile response to ET-1. The vasoconstrictor effect persists even after ET-1 is removed from the receptor, probably because intracellular calcium concentrations remain elevated.8 Nitric oxide shortens the duration of this vasoconstriction by accelerating the decrease of intracellular calcium to its basal concentration.9, 10 ETB receptors are also present on vascular smooth muscle cells, where their activation produces vasoconstriction.12–14 Besides short-term regulation of vascular tone, ET-1 exerts a long-term modulation of cell function by affecting nuclear signal transduction mechanisms. Via these mechanisms, ET-1 may participate in the pathogenesis of proliferative disorders, such as atherosclerosis, and also in adaptive changes leading to vascular remodeling and cardiac hypertrophy as observed in CHF.

Endothelin-1 is the most potent endogenous vasoconstrictor. It is 100 times more potent than norepinephrine and 10 times more potent than angiotensin II on a molar basis. Endothelin-1-induced contraction in isolated blood vessels develops slowly, but is maintained for a longer time and is more resistant to removal than that evoked by any other vasoconstrictor. It also potentiates the vasoconstriction caused by norepinephrine and angiotensin II. The vascular effect of ET-1 in healthy humans has been investigated by local infusion of the peptide into the brachial artery. Endothelin-1 administration causes a dose-dependent vasoconstriction that is slow in onset and may be prevented by verapamil or nifedipine through blockade of voltage-operated calcium channels.8 Because of its high vasoconstrictor potency and long-lasting actions, the continuous release of small amounts of ET could contribute to the maintenance of vascular tone in normal physiology.15, 16 However, ETB receptors are present on endothelial cells,11 where they bind ET-1 and ET-3 with similar affinity, and their stimulation leads to a transient vasodilation, probably caused by increased production of nitric oxide (NO) and prostacyclin.

One postulated mechanism for the maintenance of basal tone is the production of vasoactive substances by endothelial cells. Endothelin-induced vascular contraction is effectively antagonized by endothelium-derived vasorelaxant substances, such as prostacyclin (PGI2) and the potent endogenous vasodilator NO.9, 10, 17 An imbalance between the production of ET and NO could lead to a pathologically elevated vascular tone. Moreover, the vasoconstricting properties of ET-1 are greatly enhanced in atherosclerotic vessels in which the opposing biological effect of nitric oxide is lost. In patients with CHF, higher plasma ET-1 levels were measured.22

A role of the ET system has been postulated in various conditions of disturbed vascular homeostasis, such as hypertension, coronary artery disease, and CHF.18–24 The suspected role of ET-1 in the pathophysiology of CHF relies on several observations: (1) increased local production of the peptide by vascular tissues; (2) increased vasoconstrictor activity because of increased responsiveness of target cells and reduced bioavailability of vasodilator substances; (3) beneficial effects of ET receptor antagonists in animal models and in humans; (4) significant correlation between ET plasma levels and exercise capacity,25 vascular resistance,26 and clinical prognosis in CHF.27

Endothelins are synthesized primarily in the endothelium, but also produced by kidney, brain, and lung. Many factors affect the expression and release of ETs such as shear stress and angiotensin II. Endothelin of either local or circulatory origin significantly contributes to the increased vascular resistance in the renal vasculature.28 The kidney is considered a major site of ET production and an important target organ of this peptide.29 The highest immunoreactive levels of ET in mammalian cells exist in the renal medulla. However, ET has also been localized in the renal cortex.30 The renal vasculature is preferentially sensitive to the vasoconstrictive effects of ET compared with other arteries or veins. In vitro studies utilizing isolated perfused kidney of either rat or rabbit demonstrated that ET is the most potent vasoconstrictor of renal arteries known to date, and its effects exceed those of other well-known vasoconstricting agents such as angiotensin II and norepinephrine. Exogenous endothelin markedly decreases renal blood flow as a result of a severe and sustained increase in renal vascular resistance. In contrast to the consistent effects of ET on the renal hemodynamics, its effects on the excretion of sodium and water are variable. Systemic infusions of high doses of ET results in antinatriuretic and antidiuretic effects, probably as a result of the decrease in the renal blood flow and glomerular filtration rate. In contrast, administration of low doses of the peptide induces natriuresis and diuresis. Also, administration of big ET, the precursor of ET, has been shown to cause effects similar to those of low doses of ET. This finding supports the notion that local ET acts in an autocrine/paracrine manner on the tubular epithelial cells where it inhibits sodium reabsorption, thereby inducing increased salt and water excretion.31–39


Bosentan is the most studied endothelin receptor antagonist to date. Several other compounds with various affinities for endothelin receptors have been described and are currently under evaluation for various clinical indications, including CHF. Bosentan (Ro 47-0203) is a low-molecular weight, orally active, specific antagonist of the endothelin receptors, ETA and ETB.40 Its chemical structure is depicted in Figure 2. The affinity of bosentan for the ETA receptor is about 100 times greater than that for the ETB receptor in cultured cells.40

Fig. 2 Chemical structure of bosentan.

Clinical Pharmacology

Following oral administration of an aqueous solution of bosentan, peak plasma concentrations were reached within 2–3 h.41 Bosentan exhibits a strong binding to plasma proteins, especially albumin.42 This drug has a low systemic plasma clearance and a terminal half-life of approximately 4 h. The clearance and volume of distribution of bosentan were 10 l/h and 0.2-0.3 l/kg, respectively, after an intravenous dose of 250 mg (systemic exposure comparable with 500 mg of the oral solution). Bosentan is metabolized by the liver and undergoes some biliary excretion.

Animal Studies

Bosentan improves hemodynamics, left ventricular function, and cardiac remodeling in animal models of chronic heart failure. Several factors may account for the cardioprotective effects of bosentan, including reduced cardiac preload and afterload, improved coronary blood flow, inhibition of neurohormonal activation, and chronic structural effects (inhibition of cardiac remodeling, cardiac hypertrophy and cardiac fibrosis) by direct inhibition of the actions of ET-1 on myocardial cells.43–51 In animal experiments, treatment with bosentan has been associated with beneficial pharmacologic effects, including vasodilation, prevention of cardiac remodeling, and improvement of ventricular performance. In several models of hypertension in rats, bosentan reduced blood pressure, and in the DOCA-salt model, decreased cardiac hypertrophy and fibrosis.43–45 These effects may result from the blockade of the cardiac actions of endothelins (i.e., myocardial hypertrophy,46 smooth muscle cell,47 and fibroblast48 proliferation, and protein [glycoproteins, thrombospondin, fibronectin] synthesis and secretion).49 In a rat model of heart failure, following acute coronary ligation, bosentan increased survival.50 Bosentan treatment resulted in decreased preload and afterload; increased cardiac output; and decreased left ventricular hypertrophy, left ventricular dilatation, and cardiac fibrosis. Heart rate was slightly decreased, and neurohormonal activation was reduced.50 In another model, in which heart failure results from aortocaval fistula, renal blood flow increased following treatment with bosentan, suggesting that the vasodilatory properties of bosentan could be beneficial in the treatment of altered renal hemodynamics associated with heart failure. In dogs with heart failure due to repeated coronary embolization, acute injection of bosentan had no significant effect on mean aortic blood pressure but reduced left ventricular end-diastolic pressure and systemic and pulmonary vascular resistance. Furthermore, bosentan increased cardiac output.51 Given these pharmacologic effects, bosentan could potentially reduce the pulmonary hypertension which occurs in CHF.

By blocking both ETA and ETB receptors, bosentan may be of particular benefit in heart failure. Indeed, stimulation of ETA receptors contributes to renal and systemic vasoconstriction as well as cardiac hypertrophy. On the other hand, ETB receptors are upregulated in the media of coronary arteries from patients with ischemic heart failure.52 The ETB receptors contribute to vasoconstriction in dogs and in humans with heart failure.52, 53 In addition, ETB receptors are important mediators of cardiac fibrosis54 and of aldosterone secretion.55 Oral administration of bosentan is associated with an increase in the levels of circulating ET-1 in various animal species.40 The mechanism leading to this reactive increase in ET-1 remains unknown, although it has been suggested that it may result from blockade of ETB receptors involved in the clearance of ETs from the circulation. The apparent absence of functional consequences of increased ET-1 concentrations may be due to complete inhibition of the ET system as result of bosentan's blockade of both ETA and ETB.

Human Studies

Three clinical studies have been reported to date including patients with moderate to severe chronic heart failure. In addition, one large dose-ranging study has been completed in patients with mild to moderate essential hypertension. All three studies were placebo-controlled, double-blind trials that provide the first evidence of the potential clinical benefits of bosentan.

In the study by Krum et al.,56 293 patients with mild to moderate hypertension were randomized to receive treatment with placebo, enalapril 20 mg once daily, or bosentan (100, 500, or 1,000 mg once daily, or 1,000 mg twice daily). Patients receiving bosentan exhibited blood pressure reductions similar to those receiving the angiotensin-converting enzyme (ACE) inhibitor enalapril. Heart rate, angiotensin II, renin, norepinephrine, and epinephrine plasma concentrations remained unchanged during therapy with bosentan, whereas ET-1 plasma levels increased by approximately 50% from baseline. Bosentan was well tolerated overall, with only a few reports of adverse effects. These adverse effects were ones commonly seen with other vasodilators and included headache, leg edema, and dizziness. Fewer than 5% of the patients receiving bosentan developed increases in hepatic transaminases that were asymptomatic and reversible. Concomitant changes in bilirubin serum concentrations were not reported.

In the study by Kiowski et al.,57 24 patients with CHF (New York Heart Association [NYHA] functional class III) in whom therapy for heart failure had been discontinued were studied. Patients received placebo or bosentan intravenously (100 mg followed by 200 mg 1 h later). Cardiac, pulmonary, and systemic hemodynamic parameters were assessed repeatedly for 2 h. Infusion of bosentan resulted in pronounced systemic, pulmonary, and venous vasodilation accompanied by an improvement in cardiac performance without reflex tachycardia. These effects were submaximal at the first 100-mg dose. Plasma concentrations of norepinephrine, angiotensin II, and renin remained unchanged, suggesting an absence of neurohormonal stimulation

The second study in patients with CHF was conducted in two phases. In Phase I, seven patients with CHF NYHA functional class III received bosentan 500 mg twice daily for 14 days in an open-label fashion.58 Hemodynamic and neurohormonal parameters were measured repeatedly after the first dose and after 14 days of therapy. All patients continued to receive their prestudy CHF medications. These included digoxin, diuretics, and ACE inhibitors in all patients. Bosentan therapy was well tolerated and was associated with a marked improvement in cardiac performance and decreased pulmonary resistance and systemic vascular resistance. Heart rate increased slightly at the initiation of therapy but was difficult to evaluate because of the absence of a control group. In Phase II,59 the same protocol was followed as in Phase I, but 24 patients received bosentan 1,000 mg twice daily, and 12 patients received placebo twice daily for 14 days in a double-blind fashion. The administration of the ACE inhibitor was delayed by 3 h on the days of repeated hemodynamic assessments. Statistically significant hemodynamic improvements were observed with the 1,000 mg dose of bosentan compared with placebo. As with the 500 mg dose used in Phase I, a slight increase in heart rate was observed during the first hours following administration of bosentan. However, a similar increase in heart rate was observed in patients receiving placebo, suggesting that this effect was related to the study protocol rather than to a true effect of bosentan. Norepinephrine, epinephrine, renin, and angiotensin II remained unchanged, and ET-1 increased in patients treated with bosentan. The most recent trial using bosentan in patients with CHF was the Research on Endothelin Antagonism in Chronic Heart Failure (REACH-1) trial.60 It demonstrated some worsening of heart failure upon initiation of therapy, as with the initiation of beta blockers in CHF. However, long-term therapy may have resulted in improved symptoms and reduced progression of heart failure. This study which included 370 patients with severe CHF (NYHA class IIIB and IV) was stopped following the decision to conduct future trials at a lower dose (due to elevations in hepatic transaminases); only 50% had reached the intended endpoint of 6 months. In the proportion of patients who received bosentan for 6 months, there was a significant clinical improvement and a reduction in risk of clinical events. Longer-term studies with a lower dose of bosentan in CHF have been launched.


In recent years, significant progress has been made in our understanding of the ET receptors and the role of the ET system in the pathophysiology of CHF. This research has led to the development of several selective and highly specific ET receptor antagonists. Bosentan is the most studied orally active endothelin receptor antagonist currently in clinical trials for the treatment of CHF. Early clinical experience with this compound has confirmed some short-term benefits, especially in terms of hemodynamic improvement. Endothelin receptor antagonism may also prove to be useful in essential hypertension, pulmonary hypertension, atherosclerosis, and nephropathy. However, long-term trials to investigate the effects of chronic inhibition of the ET system are needed. It is hoped that ET receptor antagonists such as bosentan will slow the progression of CHF and improve survival in patients who remain symptomatic despite optimal therapy with currently available pharmacologic treatments.


  1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–415
  2. Advenier C, Sarria B, Naline E, Puybasset L, Lagente V: Contractile activity of three endothelins (ET-1, ET-2, ET-3) on the human isolated bronchus. Br J Pharmacol 1990;100:168–172
  3. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T: The human endothelin family: Three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 1989;86:2863–2867
  4. McMillen MA, Sumpio BE: Endothelins: Polyfunctional cytokines. J Am Coll Surg 1995;180:621–637
  5. Rubanyi GM, Polokoff MA: Endothelins: Molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmacol Rev 1994;46:328–415
  6. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T: Cloning of a cDNA encoding a non-isopeptide selective subtype of the endothelin receptor. Nature 1990;348:732–735
  7. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S: Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990;348:730–732
  8. Kiowski W, Luscher TF, Linder L, Buhler 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
  9. Goligorsky MS, Tsukahara H, Magazine H, Andersen TT, Malik AB, Bahou WF: Termination of endothelin signaling: Role of nitric oxide. J Cell Physiol 1994;158:485–494
  10. Boulanger C, Luscher TF: Release of endothelin from the porcine aorta: Inhibition by endothelium-derived nitric oxide. J Clin Invest 1990;85:587–590
  11. Tsukahara H, Ende H, Magazine HI, Bahou WF, Goligorsky MS: Molecular and functional characterization of the non-isopeptide-selective ETB receptor in endothelial cells. Receptor coupling to nitric oxide synthase. J Biol Chem 1994;269:21778–21785
  12. Sumner MJ, Cannon TR, Mundin JM, White DG, Watts IS: Endothelin ETA and ETB receptors mediate vascular smooth muscle contraction. Br J Pharmacol 1992;107:858–860
  13. La Douceur DM, Flynn MA, Keiser JA, Reynolds E, Haleen SJ: ETA and ETB receptors coexist on rabbit pulmonary artery vascular smooth muscle mediating contraction. Biochem Biophys Res Commun 1993;196:209–215
  14. Seo B, Oemar BS, Siebenmann R, von Segesser L, Lüscher TF: Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994;89:1203–1208
  15. Clarke JG, Benjamin N, Larkin SW, Webb DJ, Davies GJ, Maseri A: Endothelin is a potent long-lasting vasoconstrictor in men. Am J Physiol 1989;257:H 2033–2035
  16. Haynes WG, Webb DJ: Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994;344:852–854
  17. de Nucci G, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD: Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 1988;85:9797–9800
  18. Lüscher TF, Seo B-G, Bühler FR: Controversy on endothelin in hypertension: The potential role of endothelin in hypertension. Hypertension 1993;21:752–757
  19. Weitzberg E, Lundberg JM, Rudehill A: Elevated plasma levels of endothelin in patients with sepsis syndrome. Circ Shock 1991;33:222–227
  20. Lerman A, Edwards BS, Hallett JW, Heublin DM, Sandberg SM, Burnett JCJ: Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991;325:997–1001
  21. Stewart DJ, Kubag G, Costello KB, Cernacek P: Increased plasma endothelin-1 in early hours of acute myocardial infarction. J Am Coll Cardiol 1991;18:38–43
  22. McMurray JJ, Ray SG, Abdullah I, Dargie HJ, Morton JJ: Plasma endothelin in chronic heart failure. Circulation 1992;85:1374–1379
  23. Koyama H, Tabata T, Nishzawa Y, Inoue T, Morii H, Yamaji T: Plasma endothelin levels in patients with uremia. Lancet 1989;1:991–992
  24. Springall DR, Howarth PH, Counihan H, Djukanovic R, Holgate S, Polak JM: Endothelin immunoreactivity of airway epithelium in asthmatic patients. Lancet 1991;337:697–701
  25. Krum H, Goldsmith R, Wilshire-Clement M, Miller M, Packer M: Role of endothelin in the exercise intolerance of chronic heart failure. Am J Cardiol 1995;75:1282–1283
  26. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R: Plasma endothelin correlates with the extent of the pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992;85:504–509
  27. Pacher R, Stanek B, Hulsmann M, Bojic A, Berger R, Frey B, Siegel A, Kos T, Ogris E, Grimm M, Laufer G: 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
  28. Kaasjager KA, Shaw S, Koomans HA, Rabelink TJ: Role of endothelin receptor subtypes in the systemic and renal responses to endothelin-1 in humans. J Am Soc Nephrol 1997;8:32–39
  29. Kohan DE: Endothelin in the normal and diseased kidney. Am J Kidney Dis 1997;29:2–26
  30. Ujiie K, Terada Y, Nonoguchi H, Shinohara M, Tomita-K, Marumo F: Messenger RNA expression and synthesis of endothelin-1 along rat nephron segments. J Clin Invest 1992;90:1043–1048
  31. Marsen TA, Schramek H, Dunn MJ: Renal actions of endothelin: Linking cellular signaling pathways to kidney diseases. Kidney Int 1994;45:336–344
  32. Katoh T, Chang H, Uchida S, Okuda T, Kurokawa K: Direct effects of endothelin in the rat kidney. Am J Physiol 1990;258:F397–F402
  33. Badr KF, Murray JJ, Breyer MD, Takahashi K, Inagami T, Harris RC: Mesangial cell, glomerular and renal vascular response to endothelin in the rat kidney. Elucidation of signal transduction pathways. J Clin Invest 1989;83:336–342
  34. Tsuchiaya K, Naruse M, Sanak T, Naruse K, Kato Y, Seng ZP: Effects of endothelin on renal hemodynamics and excretory functions in anesthetized dogs. Life Sci 1990;46:59–65
  35. Stacy DL, Scott JW, Granger JP: Control of renal function during intrarenal infusion of endothelin. Am J Physiol 1990;258:F1232–F1236
  36. Gurbanov K, Rubinstein I, Hoffman A, Abassi Z, Better OS, Winaver J: Differential regulation of renal regional blood flow by endothelin-1. Am J Physiol 1996;271:F1166–F1172
  37. Clavell AL, Stingo AJ, Margulies KB, Brandt RR, Burnett JC: Role of endothelin receptor subtypes in the in vivo regulation of renal function. Am J Physiol 1995;268:F455–F460
  38. Kone V, Yoshioke T, Fogo A, Ichikawa I: Glomerular actions of endothelin in vivo. J Clin Invest 1989;83:1762–1767
  39. Zeidel ML, Brady MR, Kone BC, Gullans SR, Brenner BM: Endothelin, a peptide inhibitor of Na+, K+-ATPase in intact renal tubular epithelial cells. Am J Physiol 1989;257:1101–1107
  40. Breu V, Ertel SI, Roux S, Clozel M: The pharmacology of bosentan. Exp Opin Invest Drugs 1998;7(7):1173–1192
  41. Weber C, Schmitt R, Birnboeck H, Hopfgartner G, van Marle SP, Peeters PA, Jonkman JH, Jones CR: Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther 1996;60:124–137
  42. Wu-Wong JR, Chiou WJ, Hoffman DJ, Winn M, von Geldern TW, Opgenorth TJ: Endothelins and endothelin receptor antagonists: Binding to plasma proteins. Life Sci 1996;58:1839–1847
  43. 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
  44. Schiffrin EL, Larivière R, Li JS, Sventek P, Touyz RM: Deoxycorticosterone acetate plus salt induce overexpression of vascular endothelin-1 and severe vascular hypertrophy in spontaneously hypertensive rats. Hypertension 1995;25(part 2):769–773
  45. Karam H, Heudes D, Hess P, Gonzales MF, Löffler BM, Clozel M, Clozel JP: Respective role of humoral factors and blood pressure in cardiac remodeling of DOCA hypertensive rats. Cardiovasc Res 1996;21:287–295
  46. Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, Marumo F: Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res 1991;69:209–215
  47. Janakidevi K, Fisher MA, Del Vecchio PJ, Tiruppathi C, Figge J, Malik AB: Endothelin 1 stimulates DNA synthesis and proliferation of pulmonary artery smooth muscle. Am J Physiol 1992;263:C1295–C1301
  48. Takuwa N, Takuwa Y, Yanagisawa M, Yamashita K, Masaki T: A novel vasoactive peptide, endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts. J Biol Chem 1989;264:7856–7861
  49. Hahn AW, Resink TJ, Kern F, Buhler FR: Peptide vasoconstrictors, vessel structure, and vascular smooth muscle cell proliferation. J Cardiovasc Pharmacol 1993;22:S37–S43
  50. Mulder P, Richard V, Derumeaux G, Hogie M, Henry JP, Lallemand F: Role of endogenous endothelin in chronic heart failure: Effect of long- term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling. Circulation 1997;96:1976–1982
  51. Shimoyama H, Sabbah HN, Borzak S, Tanimura M, Shevlyagin S, Scicli G, Goldstein S: Short-term hemodynamic effects of endothelin receptor blockade in dogs with chronic heart failure. Circulation 1996;94:779–784
  52. Dagassan PH, Breu V, Clozel M, Kunzli A, Vogt P, Turina M: Up-regulation of endothelin-B receptors in atherosclerotic human coronary arteries. J Cardiovasc Pharmacol 1996;27:147–153
  53. Cannan CR, Burnett JC, Lerman A: Enhanced coronary vasoconstriction to endothelin-B-receptor activation in experimental congestive heart failure. Circulation 1996;93:646–651
  54. Katwa LC, Guarda E, Weber KT: Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovasc Res 1993;27:2125–2129
  55. Mazzocchi G, Rebuffat P, Gottardo G, Meneghelli V, Nussdorfer GG: Evidence that both ETA and ETB receptor subtypes are involved in the in vivo aldosterone secretagogue effect of endothelin-1 in rats. Res Exp Med (Berl) 1996;196:145–152
  56. Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V: The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. N Engl J Med 1998;338:784–790
  57. Kiowski W, Sütsch G, Hunziker P, Muller P, Kim J, Oechslin E, Schmitt R, Jones R, Bertel O: Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346:732–736
  58. Sütsch G, Bertel O, Kiowski W: Acute and short-term effects of the nonpeptide endothelin-1 receptor antagonist bosentan in humans. Cardiovasc Drugs Ther 1997;10:717–725
  59. Sütsch G, Stefan C, Yan XW, Strobel W, Rickenbacher P, Hunziker P, Bertel O: Clinical and hemodynamic effects of an orally active endothelin-1-receptor antagonist in patients with refractory chronic heart failure. Circulation 1997;96(suppl I):I93–I94
  60. Packer M: Multicenter, double-blind, placebo-controlled study of long term endothelin blockade with bosentan in chronic heart failure--results of the REACH-1 trial (abstr). Circulation (suppl) 1998;98(17):I-3

This work was partially supported by the Medlantic Research Institute.

Address for reprints:
Samer H. Ellahham, M.D.
Division of Cardiology
Washington Hospital Center, Room 1103
110 Irving Street, N.W.
Washington, D.C. 20010, USA

Received: August 4, 1999
Accepted with revision: December 1, 1999

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