(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.
From the Department of Cardiology, University Hospital Zürich, and the Cardiovascular Research Laboratory, Institute of Physiology, University of Zürich, Switzerland.
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Abstract |
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 Top Abstract The Endothelin SystemEndothelin Blockade: General...Therapeutic TargetsReferences |
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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
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The Endothelin System |
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TopAbstractThe Endothelin SystemEndothelin Blockade: General...Therapeutic TargetsReferences |
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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 1
and 2).
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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 1
). 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 1).
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 3). Inhibitors of
ET-1 synthesis include nitric oxide (NO),79
prostacyclin,86 atrial natriuretic
peptides,26 87 and estrogens.38
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(TNF
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 3). 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 2). 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
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Endothelin Blockade: General Considerations |
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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
(Table). 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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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.
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Therapeutic Targets |
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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 4), 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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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 3). 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 5).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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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 6).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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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 7). 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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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.
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Acknowledgments |
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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.
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Footnotes |
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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.
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J. Ortmann, P. C. Nett, J. Celeiro, R. Hofmann-Lehmann, L. Tornillo, L. M. Terracciano, and M. Barton Downregulation of Renal Endothelin-Converting Enzyme 2 Expression in Early Autoimmune Diabetes Exp Biol Med, June 1, 2006; 231(6): 1030 - 1033. [Abstract] [Full Text] [PDF]
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F. He, J. Li, Y. Mu, R. Kuruba, Z. Ma, A. Wilson, S. Alber, Y. Jiang, T. Stevens, S. Watkins, et al. Downregulation of Endothelin-1 by Farnesoid X Receptor in Vascular Endothelial Cells Circ. Res., February 3, 2006; 98(2): 192 - 199. [Abstract] [Full Text] [PDF]
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 E. Thomson, P. Kumarathasan, P. Goegan, R. A. Aubin, and R. Vincent Differential Regulation of the Lung Endothelin System by Urban Particulate Matter and Ozone Toxicol. Sci., November 1, 2005; 88(1): 103 - 113. [Abstract] [Full Text] [PDF]
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J. Rodriguez-Vita, M. Ruiz-Ortega, M. Ruperez, V. Esteban, E. Sanchez-Lopez, J. J. Plaza, and J. Egido Endothelin-1, via ETA Receptor and Independently of Transforming Growth Factor-{beta}, Increases the Connective Tissue Growth Factor in Vascular Smooth Muscle Cells Circ. Res., July 22, 2005; 97(2): 125 - 134. [Abstract] [Full Text] [PDF]
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 M. M. Multani, J. S. Ikonomidis, P. Y. Kim, E. A. Miller, K. J. Payne, R. Mukherjee, B. H. Dorman, and F. G. Spinale Dynamic and differential changes in myocardial and plasma endothelin in patients undergoing cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., March 1, 2005; 129(3): 584 - 590. [Abstract] [Full Text] [PDF]
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 M. Barton Ageing as a determinant of renal and vascular disease: role of endothelial factors Nephrol. Dial. Transplant., March 1, 2005; 20(3): 485 - 490. [Full Text] [PDF]
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A. Lerman and A. M. Zeiher Endothelial Function: Cardiac Events Circulation, January 25, 2005; 111(3): 363 - 368. [Full Text] [PDF]
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M.M. Hoeper and A.T. Dinh-Xuan Combination therapy for pulmonary arterial hypertension: still more questions than answers Eur. Respir. J., September 1, 2004; 24(3): 339 - 340. [Full Text] [PDF]
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A. F. Leite-Moreira and C. Bras-Silva Inotropic effects of ETB receptor stimulation and their modulation by endocardial endothelium, NO, and prostaglandins Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1194 - H1199. [Abstract] [Full Text] [PDF]
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K.-H. Ding, Q. Zhong, J. Xu, and C. M. Isales Glucose-dependent insulinotropic peptide: differential effects on hepatic artery vs. portal vein endothelial cells Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E773 - E779. [Abstract] [Full Text] [PDF]
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 L. K. Kelly, S. Wedgwood, R. H. Steinhorn, and S. M. Black Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase Am J Physiol Lung Cell Mol Physiol, May 1, 2004; 286(5): L984 - L991. [Abstract] [Full Text] [PDF]
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N. Galie, A. Manes, and A. Branzi The endothelin system in pulmonary arterial hypertension Cardiovasc Res, February 1, 2004; 61(2): 227 - 237. [Abstract] [Full Text] [PDF]
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A. Carotti, F. Emma, S. Picca, E. Iannace, S. B. Albanese, M. Grigioni, F. Meo, M. Sciarra, and R. M. Di Donato Inflammatory response to cardiac bypass in ewe fetuses: effects of steroid administration or continuous hemodiafiltration J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 1839 - 1848. [Abstract] [Full Text] [PDF]
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 J. M Tovar and J. G Gums Tezosentan in the Treatment of Acute Heart Failure Ann. Pharmacother., December 1, 2003; 37(12): 1877 - 1883. [Abstract] [Full Text] [PDF]
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W. M. Yarbrough, R. Mukherjee, G. P. Escobar, J. T. Mingoia, J. A. Sample, J. W. Hendrick, K. B. Dowdy, J. E. McLean, R. E. Stroud, and F. G. Spinale Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1489 - 1497. [Abstract] [Full Text] [PDF]
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 M. E. DiSanto Corpus Cavernosum Smooth Muscle Physiology: A Role for Sex Hormones? J Androl, November 1, 2003; 24(6_suppl): S6 - S16. [Full Text] [PDF]
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D. Merkus, B. Houweling, A. Mirza, F. Boomsma, A. H van den Meiracker, and D. J Duncker Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation Cardiovasc Res, September 1, 2003; 59(3): 745 - 754. [Abstract] [Full Text] [PDF]
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M.M. Hoeper, N. Taha, A. Bekjarova, R. Gatzke, and E. Spiekerkoetter Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids Eur. Respir. J., August 1, 2003; 22(2): 330 - 334. [Abstract] [Full Text] [PDF]
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 L. E. Spieker and T. F. Luscher Endothelin receptor antagonists in heart failure--a refutation of a bold conjecture? Eur J Heart Fail, August 1, 2003; 5(4): 415 - 417. [Full Text] [PDF]
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K.-H. Ding, Q. Zhong, and C. M. Isales Glucose-dependent insulinotropic peptide stimulates thymidine incorporation in endothelial cells: role of endothelin-1 Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E390 - E396. [Abstract] [Full Text] [PDF]
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 T. Plusczyk, B. Witzel, M. D. Menger, and M. Schilling ETA and ETB receptor function in pancreatitis-associated microcirculatory failure, inflammation, and parenchymal injury Am J Physiol Gastrointest Liver Physiol, June 9, 2003; 285(1): G145 - G153. [Abstract] [Full Text] [PDF]
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H. Wilkens, M. Bauer, N. Forestier, J. Konig, A. Eichler, S. Schneider, H.J. Schafers, and G.W. Sybrecht Influence of Inhaled Iloprost on Transpulmonary Gradient of Big Endothelin in Patients With Pulmonary Hypertension Circulation, March 25, 2003; 107(11): 1509 - 1513. [Abstract] [Full Text] [PDF]
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L. Li, G. D. Fink, S. W. Watts, C. A. Northcott, J. J. Galligan, P. J. Pagano, and A. F. Chen Endothelin-1 Increases Vascular Superoxide via EndothelinA-NADPH Oxidase Pathway in Low-Renin Hypertension Circulation, February 25, 2003; 107(7): 1053 - 1058. [Abstract] [Full Text] [PDF]
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G. P. Rossi, C. Ganzaroli, M. Cesari, A. Maresca, M. Plebani, G. G. Nussdorfer, and A. C. Pessina Endothelin receptor blockade lowers plasma aldosterone levels via different mechanisms in primary aldosteronism and high-to-normal renin hypertension Cardiovasc Res, January 1, 2003; 57(1): 277 - 283. [Abstract] [Full Text] [PDF]
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H. H. Petersen, J. Choy, B. Stauffer, F. Moien-Afshari, C. Aalkjaer, L. Leinwand, B. M. McManus, and I. Laher Coronary artery myogenic response in a genetic model of hypertrophic cardiomyopathy Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2244 - H2249. [Abstract] [Full Text] [PDF]
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M. R. Dashwood and J. C. S. Tsui Endothelins and the 'French Paradox': Are Detrimental Effects of Red Wine Also Associated with an Action on Endothelin Synthesis? Angiology, November 1, 2002; 53(6): 749 - 751. [PDF]
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N. Galie, A. Manes, and A. Branzi The new clinical trials on pharmacological treatment in pulmonary arterial hypertension Eur. Respir. J., October 1, 2002; 20(4): 1037 - 1049. [Abstract] [Full Text] [PDF]
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 J J V McMurray Heart failure in 10 years time: focus on pharmacological treatment Heart, October 1, 2002; 88(90002): ii40 - 46. [Full Text] [PDF]
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H. Ooi, W. S. Colucci, and M. M. Givertz Endothelin Mediates Increased Pulmonary Vascular Tone in Patients With Heart Failure: Demonstration by Direct Intrapulmonary Infusion of Sitaxsentan Circulation, September 24, 2002; 106(13): 1618 - 1621. [Abstract] [Full Text] [PDF]
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R. A. Mangiafico, L. S. Malatino, T. Attina, R. Messina, and C. E. Fiore Exaggerated Endothelin Release in Response to Acute Mental Stress in Patients with Intermittent Claudication Angiology, July 1, 2002; 53(4): 383 - 390. [Abstract] [PDF]
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E. V. Balyakina, D. Chen, M. L. Lawrence, S. Manning, R. E. Parker, S. B. Shappell, and B. Meyrick ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L42 - L51. [Abstract] [Full Text] [PDF]
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F. G. Spinale The bioactive peptide endothelin causes multiple biologic responses relevant to myocardial and vascular performance after cardiac surgery J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1031 - 1034. [Full Text] [PDF]
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M. M. Hoeper, N. Galie, G. Simonneau, and L. J. Rubin New Treatments for Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1209 - 1216. [Full Text] [PDF]
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 L. Ko, A. Maitland, P. W.M. Fedak, A. S. Dumont, M. Badiwala, F. Lovren, C. R. Triggle, T. J. Anderson, V. Rao, and S. Verma Endothelin blockade potentiates endothelial protective effects of ace inhibitors in saphenous veins Ann. Thorac. Surg., April 1, 2002; 73(4): 1185 - 1188. [Abstract] [Full Text] [PDF]
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 R Sharma and S.D Anker From tissue wasting to cachexia: changes in peripheral blood flow and skeletal musculature Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D12 - D17. [Abstract] [PDF]
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M. Bauer, H. Wilkens, F. Langer, S. O. Schneider, H. Lausberg, and H.-J. Schafers Selective Upregulation of Endothelin B Receptor Gene Expression in Severe Pulmonary Hypertension Circulation, March 5, 2002; 105(9): 1034 - 1036. [Abstract] [Full Text] [PDF]
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P. Martin, D. Ninio, and H. Krum Effect of Endothelin Blockade on Basal and Stimulated Forearm Blood Flow in Patients With Essential Hypertension Hypertension, March 1, 2002; 39(3): 821 - 824. [Abstract] [Full Text] [PDF]
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W. Kiowski The endothelin-type-A receptor in dilated cardiomyopathy: another key player? Eur. Heart J., October 2, 2001; 22(20): 1849 - 1851. [PDF]
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M. Barton and B. Glodny Endothelin receptor blockade and nitric oxide bioactivity: [Cardiovascular Research 2001;49:146-151] Cardiovasc Res, October 1, 2001; 52(1): 161 - 163. [Full Text] [PDF]
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A. Gaspardone Endothelin: a new marker of risk of rapid coronary stenosis progression in patients with stable angina? Eur. Heart J., September 1, 2001; 22(17): 1519 - 1520. [PDF]
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 S. J. Wort, M. Woods, T. D. Warner, T. W. Evans, and J. A. Mitchell Endogenously Released Endothelin-1 from Human Pulmonary Artery Smooth Muscle Promotes Cellular Proliferation . Relevance to Pathogenesis of Pulmonary Hypertension and Vascular Remodeling Am. J. Respir. Cell Mol. Biol., July 1, 2001; 25(1): 104 - 110. [Abstract] [Full Text] [PDF]
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E. Braunwald Congestive heart failure: a half century perspective Eur. Heart J., May 2, 2001; 22(10): 825 - 836. [PDF]
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F. Duru, M. Barton, T. F. Luscher, and R. Candinas Endothelin and cardiac arrhythmias: do endothelin antagonists have a therapeutic potential as antiarrhythmic drugs? Cardiovasc Res, February 1, 2001; 49(2): 272 - 280. [Abstract] [Full Text] [PDF]
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S. D.R. Thackray, K. K.A. Witte, A. Khand, A. Dunn, A. L. Clark, and J. G.F. Cleland Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure Eur J Heart Fail, January 1, 2001; 3(1): 117 - 124. [Abstract] [Full Text] [PDF]
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