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Circulation. 2000;102:2434-2440

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(Circulation. 2000;102:2434.)
© 2000 American Heart Association, Inc.

Current Perspective

Endothelins and Endothelin Receptor Antagonists

Therapeutic Considerations for a Novel Class of Cardiovascular Drugs

Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 9–12, 1998.

Thomas F. Lüscher, MD; Matthias Barton, MD

From the Department of Cardiology, University Hospital Zürich, and the Cardiovascular Research Laboratory, Institute of Physiology, University of Zürich, Switzerland.


*    Abstract
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 *Abstract
down arrowThe Endothelin System
 down arrowEndothelin Blockade: General...
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Abstract—The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of Gi-protein–coupled receptors. ETA receptors mediate vasoconstriction and cell proliferation, whereas ETB receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1.

ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.


Key Words: atherosclerosis • restenosis • heart failure • hypertension • transplantation • nitric oxide


*    The Endothelin System
up arrowTop
 up arrowAbstract
 *The Endothelin System
down arrowEndothelin Blockade: General...
 down arrowTherapeutic Targets
 down arrowReferences
 
Isoforms and Function
After the discovery of the endothelium-derived relaxing factor,1 a contracting factor was isolated from bovine aortic and pulmonary endothelium.2 3 4 Its gene sequence was identified in 1987, and it was named endothelin (ET).5 6 7 ET is a family of four 21-amino acid peptides, ie, ET-1, ET-2, ET-3,8 and ET-4 (vasoactive intestinal constrictor).9 In addition, 31-residue ETs have also been identified.10 ET-1, the predominant isoform, has a striking similarity to the venom of snakes of the Atractaspis family,7 11 and it is a potent vasoconstrictor. In addition to their cardiovascular effects, ETs are involved in embryonic development,12 bronchoconstriction,13 prostate growth,14 carcinogenesis,15 and gastrointestinal16 17 and endocrine function.18 19 20

Biosynthesis and Regulation
In the endothelium, ET-1 is predominantly released abluminally toward the vascular smooth muscle, suggesting a paracrine role.21 ET-1 is also produced by other cells involved in vascular disease, such as leukocytes,22 macrophages,23 smooth muscle cells,24 cardiomyocytes,25 26 and mesangial cells,27 28 and its synthesis is regulated in an autocrine fashion.24 25 26 29 30 31 32 33

Transcriptional Regulation
Transcription of the preproendothelin gene is regulated through the phorbol-ester–sensitive c-fos and c-jun complexes,34 acute phase reactant regulatory elements,35 and binding sites for nuclear factor-1,36 AP-1, and GATA-2.37 38 The translation of preproendothelin mRNA results in the formation of a 203-amino acid preproendothelin peptide, which is cleaved by a furin convertase39 to the 38-amino acid peptide big ET-11–3840 (Figures 1Down and 2Down).



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  		Figure 1. Biosynthesis of ET-11–21 and ET1–31 peptides. Prepro-ET-1 mRNA is translated into prepro-ET-1 protein, a 203-amino acid peptide, which is cleaved by furin convertase to the 38-amino acid precursor big ET-11–38. Big ET-1 is processed into ET-11–21 by ECE(s), mast cell and smooth muscle cell chymases, and non-ECE metalloprotease (left). By a novel pathway involving mast cell chymase 31-amino acid, ET-11–31 is formed (right). Modified from Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–415.



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  		Figure 2. Molecular components of the ET system. Processing of precursor peptides by furin convertases results in formation of big ET-1, big ET-2, and big ET-3. These 38-amino peptides are further processed by ECE, chymases, and non-ECE metalloprotease into vasoactive ETs, which activate tissue ETA and/or ETB receptors. VSMC indicates vascular smooth muscle cell. Modified from Yanagisawa H, Yanagisawa M, Kapur RP, et al. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development. 1998;125:825–836.

Endothelin-Forming Enzymes
Once formed, big ET-1 is processed to ET-11–21 through cleavage of the Trp21-Val22 bond by ET-converting enzyme-1 (ECE-1), which exists in 4 isoforms (a, b, c, and d),41 42 43 44 45 46 and by ECE-247 and chymase.48 In addition, chymase cleaves big ET-1 at the Tyr31-Gly32 bond, resulting in the formation of ET-11–3149 (Figure 1Up). ECE-3 selectively converts big ET-1 into ET-3.50 ECEs are localized in endothelial41 45 and smooth muscle cells,51 52 53 cardiomyocytes,54 55 and macrophages.52 55 ECE-like activity has been demonstrated in the human serum lipoprotein fraction.56 ECEs belong to the metalloprotease family,41 44 47 share functional and structural similarity with neutral endopeptidases and Kell blood group proteins,57 58 and are partially inhibited by phosphoramidon.59 These enzymes are not selective for big ET-1; they also hydrolyze peptides such as bradykinin, substance P, and insulin.60 61 ECE-1 expression is regulated through protein kinase C–dependent mechanisms,62 ETB-receptors,63 the transcription factor ets-1,64 and cytokines.65 In ECE-1 knockout mice, tissue levels of ET-1 are reduced by only one-third.66 Thus, ECE-independent pathways also contribute to ET-1 production. Indeed, chymase generates ET-11–21.48 In addition, 2 novel ET-11–21-forming enzymes, a non-ECE metalloprotease and a vascular smooth muscle cell chymase, have been cloned (Figure 1Up).

Factors Regulating Synthesis
Endothelin synthesis is regulated by physicochemical factors such as pulsatile stretch,67 shear stress,68 and pH.69 Exercise upregulates myocardial ET-1 expression, which suggests ET-1 may play a role in maintaining cardiac function.70 Hypoxia is a strong stimulus for ET-1 synthesis71 that may be important in ischemia. ET-1 biosynthesis is stimulated by cardiovascular risk factors such as elevated levels of oxidized LDL cholesterol72 and glucose,73 estrogen deficiency,74 obesity,75 cocaine use,76 aging,77 78 and procoagulant mediators such as thrombin.79 Furthermore, vasoconstrictors,25 31 80 growth factors,24 81 82 cytokines,83 84 and adhesion molecules85 also stimulate ET production (Figure 3Down). Inhibitors of ET-1 synthesis include nitric oxide (NO),79 prostacyclin,86 atrial natriuretic peptides,26 87 and estrogens.38



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  		Figure 3. Vascular effects of ET-1. ET-1 is generated in endothelial and smooth muscle cells in response to oxidized LDL, angiotensin II (Ang II), etc. The stimulation of endothelial ETB receptors increases the release of NO, whereas ETA receptors mediate contraction and cell proliferation and migration. ET-1 stimulates interleukin (IL) and tumor necrosis factor-{alpha} (TNF{alpha}) expression in monocytes, leukocyte adherence, platelet aggregation, and adhesion molecule expression. ET-1 stimulates the production and action of growth factors, DNA and protein synthesis, and cell cycle progression. ONOO- indicates peroxynitrite; NOS, nitric oxide synthase; MCP-1, monocyte chemoattractant protein-1; ICAM-1, intracellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; oxLDL, oxidized low density lipoprotein; O2-, superoxide anion; LOX, lectin-like oxidized LDL receptor; TGF ß-1, transforming growth factor-ß1; NADPHox, nicotinamide adenine dinucleotide phosphate oxidase; PAI-1, plasminogen activator inhibitor-1; VEGF, vascular endothelial growth factor; bFGF-2, basic fibroblast growth factor-2; PDGF, platelet-derived growth factor; +, stimulation; and -, inhibition.

Cardiovascular Actions
In addition to its vasoconstrictive5 and mitogenic effects,30 88 ET stimulates the production of cytokines89 90 and growth factors such as vascular endothelial growth factor,82 basic fibroblast growth factor-2,91 and epiregulin.92 ET-1 also induces the formation of extracellular matrix proteins93 and fibronectin,94 and it potentiates the effects of transforming growth factor-ß95 and platelet-derived growth factor96 (Figure 3Up). Of note, ET-1 interacts with the blood cells stimulating neutrophil adhesion97 and platelet aggregation,98 and it is a chemotactic factor for macrophages.99 Finally, ET-1 promotes cell-cycle progression in an autocrine fashion.100 101 102 ET-1, predominantly via ETA receptors, promotes vasoconstriction, cell growth, cell adhesion, and thrombosis; thus, ET-1 is a promising target for cardiovascular therapy.

Receptor Classification and Function
ET-1 activates Gi-protein–coupled, 7-transmembrane domain receptors. Five ET receptors have been cloned. Mammals possess ETA103 104 and ETB receptors,105 106 and a dual angiotensin II/ET-1 receptor exists in rats.107 A novel ETB receptor occurs in birds,108 and an ETC receptor selective for ET-3 has been found in frogs.109 In the vasculature, ETA receptors are found in smooth muscle cells, whereas ETB receptors are localized on endothelial cells and, to some extent, in smooth muscle cells110 and macrophages.111 The affinity of ETA receptors for ET-1 and ET-2 is >100-fold higher than for ET-3, whereas ETB receptors bind ET isopeptides with a similar affinity112 (Figure 2Up). Cross-talk between ETA and ETB receptors has been reported113 114 ; however, whether it affects receptor function115 is unknown.

The binding of ET-1 to ETA receptors activates phospholipase C, which leads to an accumulation of inositol triphosphate and intracellular calcium116 117 and, in turn, to long-lasting vasoconstriction.2 5 118 The activation of ETA receptors also induces cell proliferation in different tissues.30 119 In contrast, the activation of endothelial ETB receptors stimulates the release of NO and prostacyclin,120 121 prevents apoptosis,122 and inhibits ECE-1 expression in endothelial cells.63 ETB receptors also mediate the pulmonary clearance of circulating ET-1123 and the reuptake of ET-1 by endothelial cells.124


*    Endothelin Blockade: General Considerations
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 up arrowAbstract
 up arrowThe Endothelin System
 *Endothelin Blockade: General...
down arrowTherapeutic Targets
 down arrowReferences
 
Value of Plasma Levels
In the clinical setting, only plasma concentrations of ET-1 can be measured; these concentrations are affected by the production, clearance, and breakdown of ET-1.125 126 ET-1 plasma levels are high in children127 but rather low (1 to 2 pg/mL) in adults, and the levels are different between races.128 In atherosclerosis,52 129 130 myocardial infarction,131 pulmonary hypertension,132 heart failure,133 and renal failure,134 ET-1 levels are elevated in both tissue and plasma. The expression of ET-1 protein is enhanced by ischemia135 136 and/or mechanical injury (ie, balloon angioplasty).137 138 Therefore, in many cardiovascular diseases, increased plasma ET-1 levels are a marker of ET activation. Depending on the condition, such changes may reflect increased production, reduced clearance, and/or the metabolism of ET-1. In patients treated with nonselective ET antagonists, ET-1 plasma levels increase139 140 because of reduced ETB-mediated pulmonary clearance.123

Which Receptor Should Be Blocked?
Given the opposing actions of the ETA and ETB receptors, therapeutic applications must be carefully assessed. ET antagonists can block either ETA or ETB receptors or both.141 The blockade of ETB receptors impairs the pulmonary clearance of ET-1123 and reduces NO-mediated vasodilatation.142 Interestingly, an infusion of ETB antagonists increases systemic vascular resistance in humans,143 and ETB receptor deficiency is associated with hypertension in mice.144 Thus, during chronic hypoxia, the increase in ETB receptor expression and ETB-mediated, NO-mediated vasodilation145 may provide additional vasodilatory capacity. However, in most experimental146 147 148 and clinical studies,139 140 149 combined antagonists improved cardiovascular function and structure, suggesting that therapeutic effects can be expected provided that ETA receptors are blocked, regardless of concomitant ETB receptor blockade.

Current Compounds
Several peptides and nonpeptide compounds that block ET receptors are now available, and some are in clinical development (TableDown). The inhibition of ECE inhibits the production of ET-1. However, the recent identification of ECE-independent pathways contributing to ET-1 formation, such as chymase and non-ECE metalloprotease, limits the effectiveness of these drugs. In addition to the blockade of ET receptors, ET-1 production can be inhibited indirectly through renin-angiotensin system inhibitors150 151 or statins, which reduce ET-1 expression independently of their lipid-lowering effects.152 In the future, antisense gene therapy153 154 may be useful, as has been for other Gi-protein–coupled receptors.155


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  		Table 1. Endothelin Antagonists

Safety
Because of their teratogenic effects, which lead to craniofacial and organic malformations, 12ET antagonists are contraindicated during pregnancy and in women with child-bearing potential. In clinical trials, the administration of ET antagonists was occasionally associated with an increase in heart rate, facial flush, and/or facial edema,156 probably because of cerebral vasodilatation. A nitrate-like headache occurred in healthy volunteers but was less strong in patients.157 Potential gastrointestinal side effects include nausea, vomiting, and constipation. Also, certain ET antagonists may interfere with anticoagulants (ie, warfarin).158 Additional hypotensive effects may occur if ET antagonists are combined with angiotensin-converting enzyme (ACE) inhibitors.159 160 161 Long-term studies using high doses of bosentan in patients with chronic heart failure were associated with the marked elevation of liver enzymes.


*    Therapeutic Targets
up arrowTop
 up arrowAbstract
 up arrowThe Endothelin System
 up arrowEndothelin Blockade: General...
 *Therapeutic Targets
down arrowReferences
 
Hypertension and Renal Disease
Patients with ET-1–producing hemangioendotheliomas are hypertensive, and their blood pressure normalizes after surgery.162 ET-1 levels, however, are low in most hypertensives, except those who are black.163 In patients with essential hypertension, bosentan showed an antihypertensive efficacy similar to the ACE inhibitor enalapril.157

In angiotensin II–induced, salt-sensitive hypertension in deoxycorticosterone acetate–salt rats and Dahl rats, chronic ET receptor blockade lowers blood pressure, whereas in spontaneously hypertensive rats, this blockade is ineffective. Similarly, the pharmacological or molecular inhibition of ET-1 demonstrated that ET contributes to vascular hypertrophy and that local expression of ET-1 increases in vascular and renal tissue in most,31 164 165 166 but not all, forms of experimental hypertension.167 168 Thus, an increase in blood pressure per se is not sufficient to activate the ET system,169 a concept supported by the finding that rats transgenic for the human ET-1 gene exhibit profound vascular hypertrophy and glomerulosclerosis but lack hypertension.170

Studies in L-NG-nitroarginine methyl ester hypertension suggest that ET-1 is linked to the dysfunction of the L-arginine/NO pathway171 because ETA-selective172 but not combined ET blockade173 improves endothelial function, independent of blood pressure. Thus, selective inhibition of ETA receptors improves the endothelial L-arginine/NO pathway, which agrees with observations in humans.142 This is supported by the fact that the concomitant blockade of ETB receptors abolishes the beneficial effects of an ETA-selective antagonist on vascular structure.174

ET-1 promotes vasoconstriction and cell growth in the vasculature and in the kidney. Accordingly, in experimental models, chronic ET receptor blockade inhibits vascular injury (Figure 4Down), reduces hypertension-associated31 165 166 175 176 177 178 179 and other forms of renal and vascular injury,134 180 181 182 and also prolongs survival.183 184



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  		Figure 4. Inhibition of hypertensive vascular hypertrophy by ETA receptor blockade. Histological sections from the thoracic aorta from normotensive Dahl salt-sensitive rats on a high-sodium diet (A, baseline; B, after 2 months), leading to hypertension and increased media thickness and intralamellar widening. ETA receptor antagonist LU135252 normalized vascular hypertrophy, despite a moderate pressure-lowering effect (C). Magnification x63. Reproduced with permission from Barton M, d’Uscio L, Shaw S, et al. ETA receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy and endothelial dysfunction in salt-sensitive hypertension. Hypertension. 1998;31:499–504.

Occlusive Vascular Disease
Atherosclerosis
Hypercholesterolemia leads to endothelial dysfunction185 and is associated with increased ET levels in plasma186 and tissue.187 Oxidized LDL induces ET-1 gene expression in endothelial cells72 and the proliferation of vascular smooth muscle cells via ETA receptors.188 In addition, the increased release of ET-1 stimulates the synthesis of transforming growth factor-ß1, basic fibroblast growth factor, epiregulin, platelet-derived growth factor, and various adhesion molecules implicated in atherogenesis (Figure 3Up). ET-1 also increases neutrophil97 and platelet adhesion, thereby promoting lesion growth and coronary thrombosis. In experimental hypercholesterolemia, ETA receptor blockade reduced macrophage infiltration in fatty streaks.189 In hypercholesterolemic pigs, impaired endothelium-dependent vasodilatation is improved after ET receptor blockade.190

In apolipoprotein E–deficient mice, ET-1 is involved in atherogenesis.191 Long-term ETA blockade reduces the extent of atherosclerosis, without affecting blood pressure or plasma cholesterol; it also restores NO-mediated endothelium-dependent relaxation and prevents increased vascular ET-1 (Figure 5Down).191 ET-1 also contributes to myocardial infarction in mice with atherosclerosis.192 ET receptor blockade is also effective in reducing ischemic brain injury and vasospasm,184 193 2 major factors determining the severity of stroke and its sequelae.



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  		Figure 5. Effects of chronic ETA receptor blockade in experimental atherosclerosis. Compared with untreated apolipoprotein E–deficient mice (a), ETA receptor blockade using LU135252 reduced atherosclerosis (b) and aortic ET-1 content (c; ET-1 tissue levels were comparable with C57BL/6J control mice) and normalized impaired NO-mediated endothelium-dependent relaxation to acetylcholine (d). In c, open column indicates untreated mice; filled column, mice treated with LU135252. Reproduced with permission from Barton M, Haudenschild CC, d’Uscio LV, et al. Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apoE-deficient mice. Proc Natl Acad Sci U S A. 1998;95:14367–14372.

Coronary Artery Disease
In atherosclerotic human arteries, ETA receptor mRNA is downregulated,194 while the binding capacity of ETA receptors is increased in atherosclerotic mice.191 In patients with angina pectoris but normal angiograms195 and in those with coronary artery disease129 and acute myocardial infarction,131 ET-1 plasma levels are increased. In human atherosclerotic lesions, the expression of ET-1 and ECE is enhanced.52 53 129 196 A functional role for tissue ET-1 in coronary artery disease is suggested by the observation that the extent of immunoreactive staining for ET-1 in atheromatous lesions is related to angina class.130 In line with this observation, ETA/ETB receptor blockade causes vasodilation, at least in certain patients with coronary atherosclerosis.149

Restenosis
Restenosis is a major limitation of balloon angioplasty. Experimentally, the ET system is activated after vascular injury for several weeks.137 The extent of restenosis can be augmented by concomitant infusion of ET-1.197 Consequently, ET receptor blockade is effective in reducing neointima formation after balloon angioplasty in both rodents and pigs.198 199 200 201

Transplant-Associated Arteriosclerosis
Organ transplantation is associated with an increase in circulating ET-1 levels, probably because of the activation of the ET system in the transplanted kidney,202 heart,203 coronary circulation,204 and the lung.205 206 In rats, transplant-associated obliterative bronchiolitis207 can be mimicked by pulmonary preproendothelin-1 gene transfer in vivo.208 ET receptor blockade reduces reperfusion injury and improves graft survival after lung transplantation.209 It also inhibits transplant arteriosclerosis after heterotopic heart transplantation in rats concomitantly treated with cyclosporin A. In line with findings in the heart, ETA receptor blockade inhibits transplant-associated glomerulosclerosis and arteriosclerosis in the kidney, despite the discontinuation of immunosuppression after 10 days.210 Interestingly, gene therapy using antisense-oligonucleotides for cdk-2 kinase reduces ET-1 expression in allograft arteries.211

Pulmonary Hypertension
ET-1 expression in pulmonary tissue is increased in patients with primary and secondary pulmonary hypertension.132 Circulating ET-1 increases at high altitudes in mountaineers and correlates with pulmonary pressures and oxygen tension.212 ET increases even more in mountaineers prone to high-altitude pulmonary edema.213 Similar observations were made in patients with congestive heart failure.214 In heart failure, elevated ET-1 plasma levels215 are, at least in part, related to impaired ETB receptor–mediated clearance.216 Acute and short-term treatment of heart failure patients with the nonselective ET antagonist bosentan markedly lowers pulmonary artery pressure.139 140 However, the increase in circulating ET-1 during therapy suggests that ETB-mediated clearance123 is reduced by bosentan. In experimental studies of hypoxia-induced217 218 and monocrotaline-induced pulmonary hypertension,219 chronic ET receptor blockade lowered pulmonary artery pressures and the incidence of vascular and pulmonary injury and improved NO-mediated pulmonary vasodilatation. Similar observations were made in rats with high altitude–sensitive pulmonary hypertension.220

Congestive Heart Failure and Left Ventricular Dysfunction
Heart failure due to coronary artery disease or hypertension is a major cause of morbidity and mortality.221 Although ACE-inhibitors, ß-blockers, and spironolactone reduce cardiovascular events, prognosis remains poor. In experimental animals and in patients with heart failure, the plasma levels of ET-1 are increased,222 223 224 225 226 and they predict survival.226

The growth-promoting effects of ET-1 on cardiomyocytes25 26 227 228 have been implicated in the development of left ventricular hypertrophy. Cardiac growth can be augmented by hypoxia,229 which may be important in chronic ischemia. In addition, ET-1–mediated cardiac hypertrophy is enhanced by the renin-angiotensin system.26 230 However, the mechanism by which ET-1 affects the progression of left ventricular hypertrophy into heart failure seems to be biphasic. Prolonged exercise in rats leads to the upregulation of myocardial ET expression.70 Similarly, in early stages of heart failure, ET-1 maintains cardiac function as ETA receptor inhibition worsens contractility.231 ETA receptors, ECE, and the preproendothelin gene are upregulated in heart failure in rats and humans55 231 232 233 234 and in hamsters with dilated cardiomyopathy,228 and they contribute to impaired ventricular function.235

In animal models of chronic heart failure, prolonged ET blockade improves cardiac hemodynamics, reduces ventricular dilatation, and prolongs survival (Figure 6Down).233 236 237 238 239 The time point for the initiation of treatment, however, may be important because ET blockade can interfere with scar formation in injured myocardium.240 Whether selective ETA or nonselective ET blockade should be favored in heart failure is unclear. Beneficial hemodynamic and clinical effects occur with ETA receptor blockade, both with selective and nonselective ET antagonists. However, concomitant ETB blockade markedly increases circulating ET-1 levels. Whether this is of clinical relevance is unknown. Endothelin antagonists increase blood flow in the forearm conduit arteries241 and skin microcirculation,242 an effect that seems to involve the release of NO mediated by the blockade of ETA receptors.142 Although increased ETB-mediated systemic vasoconstriction has been reported in patients with heart failure,243 ETB receptor blockade may abrogate the beneficial effects of ETA receptor blockade on cardiac hemodynamics and renal function in humans and animals with heart failure.244 245



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  		Figure 6. Effect of ETA receptor blockade on survival in rats after myocardial infarction. Treatment with BQ-123 was initiated 10 days after ligation of left coronary artery. ETA blockade improved ventricular remodeling and survival. Reproduced with permission from Sakai S, Miyauchi T, Kobayashi M, et al. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature. 1996;384:353–355. Copyright 1996; MacMillan Magazines.

The first hemodynamic studies of ETA blockade in humans have been promising. In patients with severe congestive heart failure, acute infusion of the nonselective antagonist bosentan increased cardiac output and reduced systemic and pulmonary resistance.139 140 Similar data have been obtained with the selective ETA receptor antagonists BQ-123 and LU135252 (Lüscher and Barton, unpublished data, 1999). The beneficial clinical and hemodynamic effects of the blockade persist, and the increase in cardiac index is even more pronounced after 2 weeks of chronic treatment with bosentan140 (Figure 7Down). The Research on Endothelin Antagonism in Chronic Heart failure (REACH-1) trial with bosentan was terminated early because of hepatic side effects. The results showed an early worsening (at 3 months) and a potential benefit at 6 months, with decreased symptoms and reduced progression of heart failure. Possibly, the high dosages used without up-titration in the first weeks of therapy worsened heart failure in some patients. Lower dosages of bosentan are now being evaluated in the Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure (ENABLE) trial. Whether selective ETA blockade will improve clinical symptoms and outcome in heart failure is currently being investigated in several small trials.



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  		Figure 7. Effects of ETA/ETB antagonist bosentan on hemodynamics in patients with congestive heart failure. On day 1, bosentan decreased mean arterial pressure, mean pulmonary artery and capillary wedge pressures, and right atrial pressure. Cardiac output increased, with no change in heart rate. Both systemic and pulmonary vascular resistance were reduced. After 2 weeks, cardiac output further increased, and systemic and pulmonary vascular resistances decreased compared with day 1. BP indicates blood pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; CI, cardiac index; SVI, stroke volume index; SVR, systemic vascular resistance; and PVR, pulmonary vascular resistance. Reproduced with permission from Sütsch G, Kiowski W, Yan XW, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation. 1998;98:2262–2268.

Conclusions
The ET system is involved in cardiovascular control and disease progression. ET receptor blockade has been shown to have therapeutic potential in experimental and early clinical studies of hypertension, atherosclerosis, heart failure, pulmonary disease, and renal end-organ damage. Controlled clinical studies will determine whether these new drugs, which promise to be powerful tools in cardiovascular medicine, have the potential to reduce morbidity and mortality.


*    Acknowledgments
 
The original research of the authors was supported by the Swiss National Foundation (grants No. 32-51069.97 and SCORE 32.58421.99), the Deutsche Forschungsgemeinschaft (Ba 1543/1-1), the ADUMED Foundation, and the Swiss Heart Foundation.


*    Footnotes
 
Guest editor for this article was Dr Wilson S. Colucci.

The Reference section of this article can be found at http://www.circulationaha.org

Correspondence to Thomas F. Lüscher, MD, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland.


*    References
up arrowTop
 up arrowAbstract
 up arrowThe Endothelin System
 up arrowEndothelin Blockade: General...
 up arrowTherapeutic Targets
 *References
 

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