European Journal of Internal Medicine
Volume 18, Issue 4 , Pages 272-282, July 2007

Endothelins in health and disease

  • Rahman Shah

      Affiliations

    • Corresponding Author InformationTel.: +1 617 525 6733; fax: +1 617 582 6027.

Section of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA

Received 26 August 2006; received in revised form 3 January 2007

Article Outline

Abstract 

Endothelins are powerful vasoconstrictor peptides that also play numerous other roles. The endothelin (ET) family consists of three peptides produced by a variety of tissues. Endothelin-1 (ET-1) is the principal isoform produced by the endothelium in the human cardiovascular system, and it exerts its actions through binding to specific receptors, the so-called type A (ETA) and type B (ETB) receptors. ET-1 is primarily a locally acting paracrine substance that appears to contribute to the maintenance of basal vascular tone. It is also activated in several diseases, including congestive heart failure, arterial hypertension, atherosclerosis, endothelial dysfunction, coronary artery diseases, renal failure, cerebrovascular disease, pulmonary arterial hypertension, and sepsis. Thus, ET-1 antagonists are promising new agents. They have been shown to be effective in the management of primary pulmonary hypertension, but disappointing in heart failure. Clinical trials are needed to determine whether manipulation of the ET system will be beneficial in other diseases.

Keywords: Endothelins, Vasoconstriction, Vasoactive agents

 

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1. Introduction 

The endothelium has been recognized as an extremely active source of vasoactive substances and a major regulator of vascular tone [1]. The endothelin family is one such group, and a rich body of evidence suggests that endothelins play significant roles in both health and disease, as described in detail below.

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2. History 

In 1985, Hickey showed that the vascular endothelium generates a vasoconstrictor substance that produces prolonged vasoconstriction [2]. This long-acting agent appeared to be a peptide. It was finally isolated and sequenced from endothelial cell cultures by Yanagisawa in 1988 [3] and was named endothelin. Since then, additional endothelins have been isolated.

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3. Types of endothelin 

The endothelin (ET) family consists of three closely related peptides—ET-1, ET-2, and ET-3—which are produced in a wide variety of cells [4] (Table 1). Endothelins are peptides comprising 21 amino acids and are derived from separate genes [5], [6], [7]. Each isoform contains two intra-chain disulphide bridges linking paired cysteine amino acid residues, thus producing an unusual semi-conical structure [6] (Fig. 1). ET-1 is the principal isoform in the human cardiovascular system [4], [7] and is produced by endothelial cells. It is a very potent vasoconstrictor, has inotropic, pro-inflammatory, and mitogenic properties, influences the homeostasis of salt and water, and stimulates the renin–angiotensin–aldosterone and sympathetic nervous systems [8], [9]. On the other hand, the roles of ET-2 and ET-3, except in embryonic development, remain unclear.

Table 1. Sites of production of ET-1, ET-2, and ET-3
ET-1ET-2ET-3
• Endothelial cells• Kidney epithelial cells• Neurons
• Heart• Gastrointestinal stromal cells• Glia
• Aortic vascular smooth muscle cells• Heart• Adrenal cells
• Kidney epithelial cells• Placenta• Lung epithelial cells
• Hepatocytes• Uterus• Gastrointestinal
• Neurons stromal cells • Kidney epithelial cells
• Astrocyte cells
• Posterior pituitary
• Kidney mesangial cells
• Sertoli cells
• Endometrial cells
• Breast epithelial cells
• Leukocytes
• Macrophages

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4. Endothelin-1 synthesis 

ET-1 is not stored and released, but instead is generated in response to a range of stimuli, as shown in Fig. 2 [7]. Because ET-1 secretion occurs mostly via a constitutive pathway, regulation of ET-1 secretion primarily entails changes in gene expression. With a half-life of approximately 15–20 min, the mRNA is generated mainly in the endothelial cells of blood vessels and requires several processing steps before the mature peptide is formed (Fig. 2). The final step in the ET-1 pathway involves cleavage of the 38-amino-acid ‘big’ ET-1 by the highly selective membrane-bound metalloproteinase, endothelin-converting enzyme (ECE-1) [10]. ECE-1-independent pathways of ET-1 formation have also been described: they involve tissue chymases and non-ECE metalloproteinases [11].

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5. Plasma concentrations of ET-1 

Circulating concentrations of ET-like immunoreactivity in venous plasma lie in the range 1–10 pmol/L in healthy subjects [6], [12]. This immunoreactivity comprises big ET-1 (∼60%), ET-2 (∼30%), and ET-3 (∼10%) [6], [12]. The measurement of ET-1 immunoreactivity is strongly influenced by the experimental conditions of sample preparation, as well as by the nature of the radioimmunoassay employed [13]. It has also been shown that recovery of ET-1 depends on the extraction procedure, the type and size of the extraction columns, and the biological matrix itself [13].

Under normal circumstances, ET-1 produced by endothelial cells is released abluminally and, therefore, the circulating level of ET-1 is thought to be the result of spillover [14]. ET-1 appears to be foremost a locally acting paracrine substance, rather than a circulating endocrine hormone. Thus, the circulating level of ET-1 might not directly reflect the full physiological impact of ET-1 and interpretation of ET-1 and big ET-1 plasma concentrations require some caution. In addition, it is important to bear in mind that ET-1 plasma concentration is dependent not only on generation, but also on renal and receptor-mediated clearance and enzyme-mediated metabolism of the peptide [6], [12]. Nevertheless, ET-1 plasma concentration could be useful as an index of ET-1 synthetic activity, and venous plasma ET-1 concentrations have been used as a marker for endothelial synthesis of the peptide [7].

African ethnicity [15], [16], male gender [17], and older age [18] are associated with an elevated plasma ET-1 level. On the other hand, angiotensin-converting enzyme inhibitors [18], [19], [20], statins [21], [22], [23], beta-blockers [24], [25], [26], and vasodilators [27] decrease plasma ET-1 level.

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6. Clearance of ET-1 

The plasma half-life of ET-1 is less than 2 min, owing to its efficient extraction in the pulmonary and renal vascular beds [6]. This extraction involves binding to cell surface clearance ETB receptors, followed by internalization and degradation, probably within lysosomes. Endothelins are also degraded by neutral endopeptidases (NEP), which are mainly found in the brush border vesicles of kidney proximal tubules. Thus, plasma concentrations of immunoreactive endothelin vary inversely with renal function. Selective assays also reveal that patients with chronic renal failure have marked elevations in plasma concentration of ET-1 with little or no change in concentrations of big ET-1.

On the other hand, its biological effects last considerably longer (about 60 min) because of the almost irreversible binding of ET-1 to its receptor, as shown by the fact that ET-1 remains associated with the ET receptor up to 2 h after endocytosis [4].

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7. Endothelin receptors 

ET-1 exerts its actions through binding to specific receptors, the so-called type A (ETA) and type B (ETB) receptors [4], [5], [28], [29] (Table 2). Both of them are G-protein-coupled transmembrane proteins with different molecular and pharmacological characteristics and functions based on their location [4].

Table 2. Classification of ET receptors
ETAETB
• Order of potencyET-1>ET-2>ET-3ET-1=ET-2=ET-3
• Predominant tissueVascular smooth muscleEndothelium, vascular smooth muscle
• Cardiac tissueMyocytes>FibroblastsFibroblasts>Myocytes
• Vessel typeConduit and resistanceAll vessels
• Main actionsVasoconstrictionVasodilatation
MitogenesisNatriuresis
AngiogenesisET clearance
Matrix formationVasoconstriction
Pro-inflammatoryPrevents apoptosis
Apoptosis

The production of ET receptors is affected by several factors [4]. Hypoxia, cyclosporine, epidermal growth factor, basic fibroblast growth factor, cyclic AMP, and estrogen up-regulate ETA receptors in some tissues, and C-type natriuretic hormone, angiotensin II, and perhaps basic fibroblast growth factor up-regulate ETB receptors. In contrast, the endothelins, angiotensin II, platelet-derived growth factor, and transforming growth factor down-regulate ETA receptors, whereas cyclic AMP and catecholamines down-regulate ETB receptors.

The ETA receptor contains 427 amino acids and binds with the following affinity: ET-1>ET-2>ET-3 [4]. It is predominantly expressed in vascular smooth muscle cells and cardiac myocytes. Its interaction with ET-1 results in vasoconstriction and cell proliferation.

In contrast, the ETB receptor contains 442 amino acids and binds all endothelins with equal affinity [4]. It is predominantly expressed on vascular endothelial cells and is linked to an inhibitory G protein. Activation of ETB receptors stimulates the release of NO and prostacyclin, prevents apoptosis, and inhibits ECE-1 expression in endothelial cells. ETB receptors also mediate the pulmonary clearance of circulating ET-1 and the re-uptake of ET-1 by endothelial cells.

Initially, it was thought that ETB receptors were present only on endothelial cells, where they cause vasodilatation. However, it is now recognized that ETB receptors are also present on the smooth muscle of human arteries and can mediate vasoconstriction [30]. However, the vasoconstriction in response to ETB receptor agonists is variable and appears to depend markedly on species, vessel type, and vessel size [6], [31].

In the absence of disease, ET-1 actions result in a complex modulation of vasomotor tone, tissue differentiation, and cell proliferation, driven by the interplay between effects on ETA and ETB receptors. However, in pathological states, ET receptors are differently regulated, thus contributing to unbalanced effects tending towards vasoconstriction and cell proliferation.

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8. Vascular actions of ET-1 

ET-1 is a very potent vasoconstrictor, about ten times more than other vasoconstrictors [3]. Activation of ETA by ET-1 leads to potent vasoconstriction due to an increase in cytosolic calcium levels via influx of extracellular calcium [32] and release from intracellular stores [32].

All three endothelins also cause transient endothelium-dependent vasodilatation before the development of constriction, though this is most apparent for ET-1 [6], [33]. Endothelins induce vasodilatation via the endothelial cell ETB receptors through generation of endothelium-derived dilator substances (Fig. 3), including nitric oxide (NO) [34], which perhaps acts by physiologically antagonizing ETA receptor-mediated vasoconstriction. The transient early vasodilator actions of the endothelins are attenuated by NO synthase inhibitors [35]. Additionally, ET-1 increases generation of prostacyclin by cultured endothelial cells [34], whereas cyclo-oxygenase inhibitors potentiate ET-1-induced constriction [35], suggesting that vasodilator prostaglandins play a similar modulatory role.

It has also been proposed that ET-1 can affect vascular tone indirectly through its effect on the sympathetic nervous system [8], [9]. Additionally, in vitro studies have demonstrated that ET-1 may increase peripheral sympathetic activity through postsynaptic potentiation of the effects of norepinephrine [36]. While in vitro low concentrations of ET-1 potentiate the effects of other vasoconstrictor hormones, including norepinephrine and serotonin [36], these findings have not been confirmed in vivo in the forearm resistance bed of healthy subjects [37], though another study suggested that ET-1 might potentiate sympathetically induced vasoconstriction in hypertensive subjects [8].

In addition to its action on vascular vasomotion, ET-1 is thought to be a mediator in the vascular remodelling process by promoting smooth muscle proliferation [38], protein synthesis [39], and the production of a variety of cytokines [40] and growth factors [41]. It seems that ET-1 interactions with the renin–angiotensin–aldosterone system play a significant role in this remodelling process [42].

In summary, activation of vascular smooth muscle ETA receptors causes vasoconstriction and tends to elevate blood pressure. Activation of endothelial and renal ETB receptors promotes vasodilatation and natriuresis and is apt to decrease blood pressure. Thus, the overall cardiovascular effect of endogenous ET-1 depends on the balance between ETA-mediated and ETB-mediated effects. The hypotensive effects of combined ETA/B receptor antagonists on healthy subjects indicate that the overall physiological effect of ET-1 is to increase blood pressure [43] and maintain vascular tone [44]. However, the cardiovascular effects of endogenous generation of ET-1 could change in cardiovascular disease if there are changes in the population or functions of ETA and ETB receptors. Fig. 3 summarizes vascular actions [45] of ET-1.

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9. Association with cardiovascular and non-cardiovascular diseases 

9.1. Heart failure 

Accumulating evidence indicates that the ET system makes an important contribution to the pathophysiology of congestive heart failure (CHF). As with other neurohumoral systems, the ET system is activated in patients with CHF. ET-1 appears to exert differential effects on normal and failing myocardium, exerting a positive inotropic effect in the normal heart and a negative inotropic effect in the failing heart. ETA receptors are unregulated in heart failure, whereas the ETB receptor appears to be down-regulated, but functional effects of ET-1 are attenuated [46].

Plasma ET-1 concentrations are generally increased in patients with CHF [47], and animal studies suggest that at least part of this increase is mediated by angiotensin II [48]. Thus, the beneficial action of ACE inhibitors in CHF might be mediated by a diminished release of ET. In symptomatic patients, resting plasma ET-1 is often two to three times higher than in control subjects, with the elevation in plasma big ET-1 and ET-1 in CHF primarily due to increased production rather than decreased clearance [49]. The increase in production includes enhanced release from the lungs and myocardial cells [50].

Circulating ET-1 levels have been correlated with the severity of hemodynamics and with symptoms in patients with CHF [51]. Moreover, studies have shown that big ET and ET-1 are independent predictors of survival [52], [53], so these observations provide the rationale for administration of ET antagonists to patients with CHF.

Unfortunately, results of several recent trials, including ENCOR (enrasentan clinical outcomes randomized), ENABLE (I/II) (endothelin antagonist bosentan for lowering cardiac events), EARTH (endothelin antagonist receptor trial in heart failure), and the RITZ project (randomized intravenous tezosentan) have been disappointing [54], [55]. Thus, overall, interest in the possible use of ET antagonists in CHF has now declined considerably.

9.2. Arterial hypertension 

ET-1 is the most potent vasoconstrictor substance produced by the cardiovascular system. Therefore, a pathophysiological role for this peptide has been proposed in arterial hypertension. However, the involvement of ET in the development or maintenance of human hypertension remains unclear. The ET system has been implicated in the pathogenesis of hypertension on the basis of studies that demonstrated that infusion of ET-1 increased blood pressure in animals and humans [56] and that blocking of the ET system decreased blood pressure [57]. Yet, plasma ET-1 concentrations are normal in most patients with essential hypertension [7], despite a common exaggerated vasodilator response to ET receptor blockade [58], [59]. Similarly, in 293 patients with mild-to-moderate essential hypertension, a 4-week treatment trial with bosentan at a fairly high dose of 1000 mg twice per day produced a fall in ambulatory diastolic blood pressure of approximately 10 mm Hg, an effect similar to treatment with 20 mg enalapril [57]. To date, no large clinical trials of ET receptor antagonists have been conducted for hypertension.

Current evidence does suggest that overall activity of the ET system is increased under certain circumstances, notably salt-sensitive hypertension, accelerated-phase hypertension, pre-eclampsia, hemangioendothelioma-associated hypertension, renal hypertension, and hypertension in patients of African origin [16], [42], [59], [60], [61], [62]. In addition, ET-1 could contribute to the vascular, cardiac, and renal complications of hypertension, including atherosclerosis, left ventricular hypertrophy, and progressive renal disease [63], [64]. Trials that address these issues are needed to determine whether manipulation of the ET system is of benefit in treating certain forms of hypertension, thus avoiding the aggressive progression of end-organ damage that frequently accompanies hypertension.

9.3. Atherosclerosis 

Hypercholesterolemia is associated with increased ET-1 levels in plasma [65], [66] and tissue [67] in humans. ET-1 is markedly increased in the aortas of rabbits fed high-cholesterol diets [68]. Similarly, in experimental hypercholesterolemia, ET receptor blockade decreased early atherosclerosis [69]. Oxidized low-density lipoprotein cholesterol has been demonstrated to induce the production of ET-1 in human macrophages and increases ET-1 release from endothelial cells by inducing ET-1 gene expression [70]. In addition, the increased release of ET-1 stimulates the synthesis of transforming growth factor-β1, basic fibroblast growth factor, epiregulin, platelet-derived growth factor, and various adhesion molecules implicated in atherogenesis [71].

It has been proposed that ET-1 might contribute to the pathogenesis of atherosclerosis at all stages, even when the plaque is clinically imperceptible [72], [73], [74]. ET-1 immunoreactivity is ubiquitous within the intracellular and extracellular compartments of human coronary atherosclerotic tissue and is released from these sites in response to mechanical stress [75], [76]. In addition, ET-converting enzyme-1, the final enzyme for ET-1 production, is expressed in smooth muscle cells and macrophages of human coronary atherosclerotic lesions at all stages of development [72], [77]. Thus, clinical trials are needed to determine whether ET antagonists can prevent atherosclerosis in patients with multiple risk factors.

9.4. Endothelial dysfunction 

It has been shown that intra-arterial infusion of ET-1 significantly blunts endothelial-dependent vasodilation in young healthy males [78] and that ET receptor blockade significant increases endothelial-dependent vasodilation in patients with atherosclerosis [78], [79].

Increased circulating ET-1 levels have been found in subjects with hyperlipoproteinemia [65], [66], [67], insulin resistance [80], [81], diabetes [18], [82], [83], [84], and microvascular angina [85], as well as in smokers [59] and in obese subjects with metabolic syndrome [83], [86], suggesting that elevated ET-1 levels could be a marker for endothelial dysfunction. Circulating ET-1 levels have also been associated with the degree of atherosclerosis present, and high concentrations have been found in human atherosclerotic lesions [75], [76]. Thus, increased circulating ET-1 could reflect an overproduction of ET-1 by endothelial cells and, consequently, endothelial dysfunction [67], [82], [83], [84]. Similarly, oxidative stress increases ET-1 generation and autocrine ET-1 activity in vascular smooth muscle, a mechanism that might contribute to endothelial dysfunction in atherosclerosis [87], [88].

ET-1 also seems to play a significant role in cyclosporine-induced endothelial dysfunction and allograft vasculopathy [89], [90]. Likewise, it seems that statins improve endothelial function by modulating the expression of endothelial vasoactive factors, including ET [21]. In addition, chronic ET receptor antagonism has been shown to improve coronary endothelial function in experimental hypercholesterolemia [91] and in patients with atherosclerotic diseases [92]. Thus, ET receptor antagonists could have a therapeutic role to play by maintaining coronary endothelial function in pathophysiological states.

9.5. Coronary artery diseases 

In experimental models, ET-1 has been shown to cause segmental coronary vasospasm [93]. Moreover, experiments have demonstrated that endogenous ET-1 exerts a vasoconstrictor effect on the epicardial arteries, as evidenced by increased coronary flow through the ET-1 receptor antagonist both in patients with coronary artery disease [94] and in subjects with normal coronary angiograms [95]. This indicates that ET-1 might have an important role in governing the coronary resistance and regulating the capillary flow in the myocardium [93], [95]. Indeed, a recent study suggested that ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses [96].

In patients with angina pectoris and acute myocardial infarction (AMI), ET-1 levels have been shown to be elevated [85], [97], [98]. ET-1 plasma levels also correlate with 1-year prognosis [99] in patients with AMI. Similarly, increased tissue ET immunoreactivity in atherosclerotic lesions has been associated with acute coronary syndromes [76], and the extent of immunoreactive staining for ET-1 in atheromatous lesions appears to be related to angina class [100]. Consistent with these findings, ETA/ETB receptor blockade was shown to cause vasodilation in patients with coronary atherosclerosis [94]. Likewise, tezosentan (a dual ETA/ETB receptor antagonist) administered during the first day after MI in rats was shown to increase long-term survival [101]. Thus, therapies that reduce ET-1 concentration and inhibit its action should be of interest for reducing myocardial ischemia.

It is also thought that ET-1 is involved in the occurrence of coronary vasoconstriction after successful percutaneous transluminal coronary angioplasty (PTCA), and this might have important implications with respect to coronary re-stenosis after PTCA [102], [103]. ETA receptor blockade has been shown to prevent distal coronary artery vasoconstriction occurring after angioplasty [102].

9.6. Renal failure 

A large body of experimental evidence suggests involvement of ET-1 in the pathophysiology of chronic renal failure (CRF) [104], [105]. In humans, infusion of ET-1 exerts potent biologic actions on the kidney through activation of ETA receptors, as it decreases renal blood flow, GFR, urine volume, and natriuresis [106]. In experimental models, ET receptor antagonists improved glomerular filtration, renal blood flow, and sodium excretion after renal artery occlusion [104], [107] and protected the kidney against ischemia-reperfusion damage, cyclosporine, glycerol, rhabdomyolysis, endotoxin, immune nephritis, lupus nephritis, and diabetic nephritis [104].

In an interesting clinical study, Goddard et al. directly compared ETA, ETB, and combined ETA/ETB receptor antagonists at systemic doses in humans [105]. They showed that in CRF patients, selective ETA receptor antagonism produces substantial reductions in blood pressure associated with renal vasodilation. Additionally, the reduction in filtration fraction and proteinuria in CRF patients indicates a potentially renoprotective action. These findings are encouraging, indicating a need for longer-term studies in patients with CRF, with particular attention to effects on proteinuria as a surrogate marker for the progression of renal disease.

9.7. Cerebrovascular disease 

Plasma and brain tissue levels of ET-1 are increased in patients with ischemic stroke, as well as in animal models with stroke [104], [108], [109], [110]. In addition to its effects on vascular tonus, ET-1 increases blood-brain barrier permeability [110], induces neuronal damage [110], and contributes to the vasospasm associated with subarachnoid hemorrhage [109]. Likewise, ET receptor antagonists are protective in animal models of stroke [104], [111], [112]. These findings suggest that ET-1 might be involved in the pathogenesis of cerebrovascular (CVS) diseases. Thus, clinical trials needed to evaluate the protective effect of ET receptor blockade in CVS diseases.

9.8. Pulmonary arterial hypertension 

Several lines of evidence have demonstrated a strong relationship between ET system dysfunction and pulmonary arterial hypertension (PAH). For example, patients with idiopathic PAH (IPAH) have high plasma levels of ET-1 [113]. In addition, PAH has been associated with increased expression of ET-1 in pulmonary vascular endothelial cells, implying that local production of ET-1 might contribute to the vascular abnormalities associated with this disorder [114]. Finally, there is a strong correlation between the intensity of ET-1-like immunoreactivity in the pulmonary vasculature and pulmonary vascular resistance in patients with IPAH [114].

These results have led to a rational therapeutic approach provided by ET receptor antagonists. In the BREATHE-1 (bosentan randomized trial of endothelin receptor antagonist therapy for pulmonary hypertension) trial, bosentan improved exercise capacity, WHO functional class, and the time to clinical deterioration [115]. On the basis of this data, bosentan has been approved for the treatment of PAH in patients with grade III WHO functional status.

Selective blockers of the ET receptor ETA, such as sitaxsentan and ambrisentan, are being investigated for the treatment of PAH [116]. In theory, such drugs could block the vasoconstrictor effects of ETA receptors while maintaining the vasodilator and clearance effects of ETB receptors. Early reports from the STRIDE-1 trial (sitaxsentan to relieve impaired exercise in pulmonary arterial hypertension) with 300 mg sitaxsentan are encouraging [117]. Several studies including STRIDE-2, STRIDE-6, and BREATHE-5 are exploring different types of ET antagonists in subtypes of PAH [116].

9.9. Sepsis 

Plasma levels of ET-1 and big ET have been shown to be elevated in severe sepsis and to be positively correlated with the severity of illness [118], [119], [120]. It has also been suggested that some of the complications of sepsis are mediated by endothelins [118], [119], [120]. Thus, trials are needed to examine the potential beneficial effect of ET antagonists in sepsis.

9.10. Other diseases 

Several studies also highlight the possibility of a role for ET in Crohn's disease, ulcerative colitis, glaucoma, pulmonary fibrosis, asthma, hepatopulmonary syndrome, systemic sclerosis, peripheral vascular disease, severe maldevelopment of craniofacial tissues, acute pancreatitis, tumors, and psychosocial stress-induced cardiovascular diseases [7], [121], [122], [123], [124], [125].

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10. Conclusions 

ET-1 appears to have a diverse role as a modulator of vascular tone and growth and as a mediator in many cardiovascular and non-cardiovascular diseases. To date, no disease entity, however, has been attributed solely to an abnormality in ET-1. Yet, ET-1 receptor antagonists have been studied in clinical trials involving a wide spectrum of cardiovascular diseases, though the only proven efficacy has been in patients with PAH. Results with ET-1 receptor antagonists in CHF have thus far been disappointing. Nevertheless, the use of ET-1 receptor antagonists for other conditions has not been fully explored, which invites the employment of future clinical trials to investigate their potential role in other diseases.

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11. Learning points 


•Endothelins are powerful vasoconstrictors and major regulators of vascular tone.

•The endothelin (ET) family consists of three peptides (ET-1 ∼60%, ET-2 ∼30%, and ET-3 ∼10%) produced by a variety of tissues.

•ET-1 is the principal isoform produced by the endothelium in the human cardiovascular system and appears to be foremost a locally acting paracrine substance rather than a circulating endocrine hormone.

•Several human studies suggest that circulating ET-1 levels, which are elevated in heart failure and pulmonary hypertension, correlate with the prognosis of the disease.

•ET-1 antagonists have been shown to be effective in the management of primary pulmonary hypertension, but disappointing in heart failure.

•Clinical trials are needed to investigate the role of ET-1 receptor antagonists for other conditions, as ET-1 levels have been shown to be elevated in arterial hypertension, atherosclerosis, endothelial dysfunction, coronary artery disease, renal failure, cerebrovascular disease, and sepsis.

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PII: S0953-6205(07)00087-8

doi:10.1016/j.ejim.2007.04.002

European Journal of Internal Medicine
Volume 18, Issue 4 , Pages 272-282, July 2007

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