Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?
Curator: Aviva Lev-Ari, PhD, RN
UPDATED on 8/17/2018
Ambrisentan (U.S. trade name Letairis; E.U. trade name Volibris; India trade name Pulmonext by MSN labs) is a drug indicated for use in the treatment of pulmonary hypertension.
The peptide endothelin constricts muscles in blood vessels, increasing blood pressure. Ambrisentan, which relaxes those muscles, is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA).[1] Ambrisentan significantly improved exercise capacity (6-minute walk distance) compared with placebo in two double-blind, multicenter trials (ARIES-1 and ARIES-2).[2]
Ambrisentan was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency, and designated an orphan drug, for the treatment of pulmonary hypertension.[3][4][5][6][7]
Ambrisentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Ambrisentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.
Ambrisentan was first approved by the U.S. Food and Drug Administration (FDA) on Jun 15, 2007, then approved by the European Medicines Agency (EMA) on Apr 21, 2008 and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jul 23, 2010. In 2000, Abbott, originator of ambrisentan, granted Myogen (acquired by Gilead in 2006) a license to the compound for the treatment of PAH. In 2006, GlaxoSmithKline obtained worldwide rights to market the compound for PAH worldwide, with the exception of the U.S. It is marketed as Letairis® by Gilead in US.
Ambrisentan is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). It is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).
Letairis® is available as film-coated tablet for oral use, containing 5 or 10 mg of free Ambrisentan. The recommended starting dose is 5 mg once daily with or without food, and increase the dose to 10 mg once daily if 5 mg is tolerated.
Introduction to Endothelin
Endothelin (ET) derived from vascular endothelial cells (ECs), which consists of a 21 amino acid peptide, has a strong and persistent vasoconstrictive action (1). ET has three family peptides (ET-1, ET-2, and ET-3). As the distribution and properties of these peptides are different, each peptide is believed to play specific physiological roles. ET has two types of receptor: the ETA receptor with a high affinity for ET-1 and ET-2 is mainly located on muscle cells, whereas the ETB receptor with an affinity for all three peptides lies on endothelial, epithelial, endocrine, and nerve cells. Of the three ET isoforms,
ET-1 plays a much more important role in the regulation of vascular tone than the others and has a powerful effect on the cardiovascular system. Thus, the role of ET-1 and its receptors as the etiology or precipitating factors in various cardiovascular diseases (CVD) has been investigated (2, 3). In addition, numerous studies have reported effective treatment targeted at ET-1 in pulmonary hypertension, salt-sensitive hypertension, diabetes, and acute and chronic kidney diseases using ETconverting enzyme (ECE) inhibitors and ET-receptor antagonists (2, 4). Several animal models genetically lacking ET-1 and ET receptors have also been used as a tool for determining the physiological and pathophysiological roles of ET-1 and ET receptors in CVD (5 – 10).
Fig. 1.
Schematic illustration of ET-1 production and ET receptor–mediated actions on vascular endothelial cells and smooth muscle cells. G: G protein, ROS: reactive oxygen species, CaM: calmodulin, AA: arachidonic acid, PGI2: prostaglandin I2, AC: adenylate cyclase, sGC: soluble guanylate cyclase.
Figure Source: Journal of Pharmacological Sciences, 119, 302 – 313 (2012)
Introduction to the ET system
Endothelial Cells (ECs) are known as the main physiological source of vascular ET-1. Vascular smooth muscle cells (VSMCs), macrophages, leukocytes, cardiomyocytes, and fibroblasts are also capable of ET-1 production (11 – 13).
Several studies have indicated that various physical and chemical factors such as thrombin, angiotensin II, cytokines, hypoxia, and shear stress stimulate ET-1 gene expression in ECs by DNA binding of transcription factors including activator protein-1, GATA-2, Smad, nuclear factor-kappa B (NF-κB), and hypoxia inducible factor-1 (14 – 18). On the other hand, ET-1 is synthesized as an inactive 203-amino-acid precursor, preproET-1, which is proteolytically cleaved to yield a second inactive 39 (or 38)-amino-acid segment called ‘big’ ET-1.
The last part of the proteolytic process is mainly carried out by ECE (ECE-1 and ECE-2) and leads to the production of the bioactive form of 21-amino-acid peptide ET-1. As ET-1 release from ECs is constitutive, ET-1 biosynthesis and release appear to be mainly controlled via regulation of gene transcription and/or ECE activity.
On the other hand, although another ETB-receptor subtype (ETB2) located on VSMCs exerts vasoconstriction, it has become clear that ETB2 receptor–induced vasoconstriction is negligible under normal conditions but becomes more important in some kinds of diseases such as atherosclerosis and essential hypertension (24 – 26).
- inhibit generation of ET-1 (Jeng et al., 2002) and
- block the action of ET-1 (Battistini et al., 2006)
- selective antagonists in man (Haynes and Webb, 1994) and from
- knockout and transgenic animals
The recent licensing of
- bosentan
- sitaxsentan and
- ambrisentan
for treatment of PAH is the most obvious demonstration of the clinical benefit derived from therapeutic manipulation of the ET-1 system in cardiovascular disease. This development of one of the first effective treatments for a condition with poor prognosis has obvious clinical significance and is likely to be extended to include PAH associated with connective tissue disorders.
Thus, ET antagonists are already realizing their potential in treatment of cardiovascular diseases, while early clinical data suggest these compounds may prove beneficial in other conditions, such as resistant hypertension, chronic kidney disease and SAH. In contrast, a potential role in conditions associated with vascular remodelling (restenosis, chronic obstructive pulmonary disease and transplant graft rejection) remains speculative and requires further investigation. It should also be noted that the clinical experience with ET antagonists in patients with cardiovascular disease remains relatively limited and the design of new trials could be improved using knowledge gained from previous studies, particularly with regard to drug dose and selectivity. These successes must obviously be balanced against the failure of ET antagonists to realize their potential in the treatment of heart failure, and the fact that teratogenic effects have restricted their possible use to treatment of conditions where childbearing potential is unlikely to be an issue.
Several reasons have been proposed to account for the disappointing outcomes in clinical trials as compared to investigations using animal models of disease, including
- inadequate models or a bias in publication towards positive outcomes;
- incorrect dose/timing of administration;
- the need to show additional benefit over existing treatments; and
- ET activation being a consequence rather than a cause of the condition.
Whatever the reason, this experience urges caution in extrapolating data obtained in vitro and in animals to humans. It is hoped that additional information will emerge from unpublished clinical trials that will shed light on previous failures (Kelland and Webb, 2006), and that the combination of powerful pharmacological and molecular approaches will help us to better understand the role of ETA and ETB receptors in health and disease so as to fully realize the clinical potential created by the identification of the powerful vasoconstrictor peptide, ET-1.
Further studies have addressed the role of ET receptor antagonism in erectile dysfunction and aneurysmal SAH, with mixed results. A double-blind pilot study of 53 patients with mild-to-moderate erectile dysfunction demonstrated no benefit of the ETA-selective antagonist BMS-193884 (100mg by mouth) over placebo (Kim et al., 2002).
The ETA-selective antagonist clazosentan was specifically designed for intravenous use in conditions characterized by cerebral vasoconstriction. Its potential in treating severe aneurysmal SAH has recently been addressed in a phase IIa pilot study for the Clazosentan to Overcome Neurological iSChaemia and Infarction OccUrring after Sub-arachnoid haemorrhage (CONSCIOUS-1) trial (Vajkoczy et al., 2005). This ‘pre-CONSCIOUS-1′ study documented a reduction in the frequency and severity of cerebral vasospasm following SAH.
- resistant hypertension,
- chronic kidney disease,
- connective tissue disease and
- sub-arachnoid haemorrhage
Figure 3
Generation and action of endothelin-1 (ET-1) in the vascular wall. The 21-amino-acid peptide, ET-1, is the eventual product of a gene on chromosome 6 that encodes preproET-1 protein. This is converted to proET-1 on secretion into the cytoplasm, which Endothelin-1 is generated from precursor peptides via a two-step proteolytic pathway. Transcription of a gene on chromosome 6 generates mRNA encoding the 212-amino-acid peptide, preproET-1, which, once translated, is stripped of its signal sequence and secreted into the cytoplasm as proET-1 (Inoue et al., 1989). ProET-1 is further cleaved by a furin-like endopeptidase to the 38-amino-acid precursor molecule big ET-1, which circulates in plasma at low concentration but is not thought to possess significant bioactivity (Yanagisawa et al., 1988). Removal of a further 17 COOH-terminal residues, classically but not exclusively by ET-converting enzymes (ECE), results in formation of the mature 21-amino-acid ET-1 (Hirata et al., 1990).
Figure Source: Br J Pharmacol. 2008 March; 153(6): 1105–1119.
The STATE OF SCIENCE for the ET System has been UPDATED by a 2012 study published by the Japanese Pharmacological Society in the Journal of Pharmacological Sciences, 2012.
Since the discovery of ET-1, many researchers have elucidated the physiological and pathophysiological role of ET-1 and ET receptors in the cardiovascular system over the past 20 years. Among many non-peptide and orally available ET-receptor antagonists developed so far, the nonselective ETA/ETB-receptor antagonist bosentan and selective ETA-receptor antagonist ambrisentan are now clinically utilized as agents for pulmonary artery hypertension. There is a possibility that ambrisentan could be widely used in the treatment of pulmonary hypertension because of less interactions with other drugs or side effects such as liver dysfunction. In addition, future clinical applications may provide new findings about which antagonist is more effective, a nonselective ETA/ ETB-receptor or selective ETA-receptor antagonist.
On the other hand, although the selective ETA-receptor antagonist sitaxsentan, which was released in Europe and the United States, was recently forced to be withdrawn because of a high risk of liver failure, it is hoped in the future that other ET-receptor antagonists, including macitentan and zibotentan, currently being developed can be utilized in clinical treatment targeted at the cardiovascular ET-1 system.
In Pathophysiological Roles of Endothelin Receptors in Cardiovascular Diseases
J Pharmacol Sci 119, 302 – 313 (2012) the Japanese Team reported the following important developments:
POINT # 1:
Endothelin (ET)-1 derived from endothelial cells has a much more important role in cardiovascular system regulation than the ET-2 and ET-3 isoforms. Numerous lines of evidence indicate that ET-1 possesses a number of biological activities leading to cardiovascular diseases (CVD) including hypertension and atherosclerosis. Physiological and pathophysiological responses to ET-1 in various tissues are mediated by interactions with ETA- and ETB-receptor subtypes. Both subtypes on vascular smooth muscle cells mediate vasoconstriction, whereas the ETB-receptor subtype on endothelial cells contributes to vasodilatation and ET-1 clearance. Although selective ETA- or nonselective ETA/ETB-receptor antagonisms have been assumed as potential strategies for the treatment of several CVD based on clinical and animal experiments, it remains unclear which antagonisms are suitable for individuals with CVD because upregulation of the nitric oxide system via the ETB receptor is responsible for vasoprotective effects such as vasodilatation and anti-cell proliferation. In this review, we have summarized the current understanding regarding the role of ET receptors, especially the ETB receptor, in CVD.
POINT # 2:
The downstream effects of ET-1 are mediated by two G-protein-coupled receptors ETA and ETB. In the vasculature, the
- ETA receptor on VSMCs mediates vasoconstriction and cell proliferation, whereas the
- Endothelial ETB receptor (generally called ETB1) exerts opposite effects.
Stimulation of the ETB1 receptor leads to the release of vasodilators such as
- nitric oxide (NO) and
- prostaglandin I2 and
- clearance of ET-1 from the circulation within the lungs, kidneys, and liver (19 – 23).
Many vascular relaxing or contraction factors produced in the blood vessel wall maintain normal endothelial function by mutually antagonistic actions. In particular, there are various reports regarding the interaction of ET-1 and NO (27). For instance, ET-1 binding to the ETB1 receptor leads to phosphoinositide 3-kinase (PI3K) activation and subsequent production of phosphatidylinositol- 3,4,5-trisphosphate, which results in recruitment and activation of protein kinase B / Akt (28). This PI3K/Akt pathway is responsible for the phosphorylation and activation of endothelial NO synthase (eNOS). On the other hand, ET-1 also reduces eNOS expression and its activity through increases in hydrogen peroxide by the ETA receptor (29). Therefore, reduced ETB-receptor function and/or overactivation of the ETA receptor eliminate the protective function by NO in vessels and promote the pathological formation of various circulatory diseases
POINT # 3:
3.1 Activation of PKC
Locally generated ET-1 contributes to tissue repair or remodeling of the infarcted heart in an autocrine/paracrine manner, thereby exerting an immediate beneficial effect on damaged tissue (33, 34). Other studies reported that ET-1 administered prior to the onset of ischemia exhibited cardioprotective effects (35, 36). Exogenous ET-1 mimics the cardioprotective effect of pre-conditioning against infarction, apparently via ETA receptor– mediated activation of PKC and a mitochondrial type of ATP-sensitive K+ channel (37, 38). On the other hand, a substantial and long lasting rise in ET-1 induces myocardial hypertrophy, which is associated with a maladaptive effect on myocardial structure and function, thereby leading to fatal events (39 – 42).
The ET-1 / ETA receptor pathway also promotes myocardial fibrosis by enhancing
- cardiac fibroblast proliferation,
- adhesion molecule expression,
- and extracellular matrix deposition (43, 44).
Therefore, the use of ET-receptor antagonists, mostly targeting the ETA receptor, provides beneficial effects in chronic heart failure as evidenced by a reduced infarct size, improved reperfusion coronary flow, or protection during ischemia/reperfusion (39 – 42).
3.2 Sympathetic overactivity and norepinephrine (NE) release
Activation of the ETB receptor may likely prevent post-ischemic cardiac dysfunction through the attenuation of NE release.
In myocardial ischemia, sympathetic overactivity accompanied by excessive norepinephrine (NE) release is associated with cardiac dysfunction and arrhythmia, thereby exaggerating primary ischemia and initiating a malignant cycle that can cause further myocardial damage and high-risk cardiac dysfunction (45, 46). Both ETA and ETB receptors exist in the sympathetic nerve varicosities of guinea pig hearts and exhibit opposite effects on NE release in association with reperfusion arrhythmias: ETA receptors evoke NE release, whereas ETB receptors prevent it (47).
Previous studies showed that a selective ETA-receptor antagonist or the combination of ETA- and ETB-receptor antagonists suppressed excessive NE release from sympathetic nerve endings in postischemic rat hearts and improved cardiac dysfunction after ischemia/reperfusion (9, 47). In addition, exogenous ET-1 induced excessive NE release and subsequent cardiac dysfunction, counteracted with the Na+/H+ exchanger (NHE) inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA). Thus, the excessive NE overflow triggered by the ET-1 / ETA / NHE pathway seems to be contributive to post-ischemic cardiac dysfunction in rats.
On the other hand, both pharmacological blockade and genetic deficiency of ETB receptors exaggerated the post-ischemic excessive NE release and cardiac dysfunction. Oikonomidis et al. demonstrated that NE levels during the early phase of myocardial infarction are much higher in ETB-deficient rats than wild-type rats and this contributes to the incidence of ventricular arrhythmogenesis, thereby suggesting that the ETB receptor exerts a suppressive effect in sympathetic hyperactivity during the early phase of myocardial infarction (48). Furthermore, activation of the ETB receptor with sarafotoxin-6c substantially
- reduced NE release,
- myocardial infarct size, and
- ischemic arrhythmias (47, 49).
3.3 Big ET-1 must be converted to ET-1 and exerts similar physiological functions
Big ET-1 exerts several physiological actions similar to ET-1, but it must be converted to ET-1 via enzymatic degradation by ECE (50). ECE expression and its enzyme activities are increased in myocardial infarction (51), thereby suggesting that a selective ECE inhibitor may be useful in ischemic cardiac diseases at the clinical level, which warrants further attention. In fact, SM-19712 and FR901533, both of which are highly selective ECE inhibitors, exert a desirable influence on myocardial infarction by decreasing plasma concentrations of ET-1 (52, 53).
On the other hand, exogenously applied big ET-1 has qualitatively similar effects to ET-1 in the cardiovascular system in vivo and in vitro (54 – 57). Against this background, Sharif et al. demonstrated that exogenously applied ET-1 exhibited opposite effects to endogenously released ET-1 on ischemic ventricular arrhythmias (58).
The Japanese Team also reported that exogenous big ET-1 suppressed ischemia/reperfusion-induced NE overflow and improved cardiac dysfunction observed after reperfusion, in spite of the fact that ET-1 content in coronary effluent from the heart exposed to ischemia/reperfusion was increased by exogenous big ET-1 application (59). In addition, treatment with big ET-1 in the presence of A-192621, a selective ETB-receptor antagonist, failed to exert beneficial effects against ischemia/reperfusion-induced NE overflow and subsequent cardiac dysfunction. Thus, ET-1 generated from exogenously applied big ET-1 preferentially may act on ETB receptors rather than ETA receptors, leading to an increase in NO production and subsequent suppression of NE overflow.
POINT # 4:
Neointimal Formaion and Baloon Angioplasty Intervention
Cardiovascular hypertrophy and remodeling are not simply a response to elevated blood pressure. Various vasoactive substances, such as angiotensin II, are implicated in the development of these structural changes (72). ET-1 has potent mitogenic and hypertrophic properties, mainly via stimulation of ETA receptors (73). ETB receptor– mediated actions also protect against cardiovascular hypertrophy via endothelial NO generation, which inhibits mitogenesis and the proliferation of VSMCs (74).
Balloon angioplasty and stent insertion are now widely used for the treatment of coronary arterial disease. Although these procedures improve regional myocardial blood flow by dilating stenotic coronary vessels, one major drawback of this therapeutic approach is restenosis after the procedure because of the proliferation of VSMCs and neointimal formation triggered by mechanical damage to ECs. Several growth factors or vasoactive peptides are related to the process of neointimal formation. In a clinical study, expressions of ECE, ET-1, and ET receptors were enhanced in neointimal VSMCs after percutaneous coronary intervention in human coronary arteries (75). In addition, increases in ET-1 levels were observed in the coronary circulation after percutaneous transluminal coronary angioplasty (76). Anggrahini et al. recently demonstrated that ET-1 derived from ECs mainly contributes to the process of vascular remodeling in the model of flow cessation (10). Thus, ET-1 is closely related to the pathogenesis of restenosis after angioplasty. Similar results have been reported in animal models with restenosis such as balloon injury (77, 78).
Murakoshi et al. showed that vascular remodeling caused by the cessation of blood flow was markedly accelerated in the carotid artery of ETB receptor–knockout mice, and long-term treatment with an ETB-receptor antagonist worsened vascular remodeling in wild-type mice (6).
In contrast, selective ETA-receptor blockade could attenuate this vascular remodeling in the same animals. There has also been a report showing that ET-1 contributes to the remodeling of mesenteric resistance arteries in diabetes via activation of ETA receptors, and ETB receptor–mediated actions provide vasoprotective effects (79). Our previous report has demonstrated that vascular remodeling is markedly attenuated by treatment with a selective ETA receptor antagonist, whereas pharmacological blockade of ETB receptors aggravates neointimal hyperplasia after balloon injury (80). Treatment with an ETA/ETB dual receptor antagonist also suppresses neointimal hyperplasia and the efficacy of treatment is comparable with that of a selective ETA-receptor antagonist (80), thereby suggesting that the antagonism of ETB receptors does not seem to impair the positive effects of concomitant ETA receptor antagonism. Furthermore, we also confirmed similar results in ETB-deficient rats. Therefore, antagonism of the ET-1 / ETA receptor pathway appears to be essential for preventing neointimal hyperplasia after balloon injury, irrespective of the presence of ETB receptor–mediated actions.
POINT # 5:
Pulmonary Hypertention
The lungs are known to synthesize ET-1 and possess ETA and ETB receptors, both of which are involved in physiological and pathophysiological actions of ET-1 in the lung. In particular, endothelial ETB receptors in lungs are responsible for circulating ET-1 clearance, with close to 50% removal during pulmonary transit in humans (81).
These findings suggest that an ETA/ETB-receptor antagonist brings reasonable validity by suppressing overactivation of the ET-1 / ETA receptor system and vasoconstriction via the ETB2 receptor. Moreover, it is less likely that the ETB1 receptor actively functions as a protective factor through increases in NO production.
POINT # 6:
Hypertension: Salt-sensitive type
ETB receptor–mediated actions are protective in the pathogenesis of salt-sensitive hypertension. These results also suggest that the antagonism of the ETA receptor is essential for protection from cardiovascular disease including salt-sensitive hypertension, irrespective of the presence of the ETB receptor. This view may explain the findings that selective ETA-receptor antagonists and nonselective ETA/ETB-receptor antagonists similarly improve salt-sensitive hypertension and related tissue injuries.
POINT # 7:
Gender Differences in CVD
ETB receptor–mediated actions seem to occur downstream of the vasoprotective effects of estrogen, although the relationship between ETB receptor– and estrogen receptor– signaling systems remains unclear. On the other hand, neointimal hyperplasia observed in female ETB deficient rats is almost completely suppressed by ETA or ETA/ETB-receptor antagonists. Thus, augmentation of ETA receptor–mediated actions under ETB-receptor dysfunction seems to be responsible for the abolition of sex differences in vascular remodeling.
Sex differences are considered to be caused by the vasoprotective effect of estrogen (108 – 110). In fact, several clinical studies showed that postmenopausal women who receive estrogen replacement therapy (ERT) have a substantially lower risk of incidence of cardiovascular disease (111, 112). The protective effect of estrogen on the cardiovascular system is closely related to the up-regulation of endothelial NO production and downregulation of adhesion molecule activity, smooth muscle proliferation/migration, and superoxide production (113 – 115).
It is reasonable to assume that 17β-estradiol is mainly involved in sex differences in the ET system. Sex differences in ET-receptor density, as well as in the ratio of ET-receptor subtypes, have been also investigated. Ergul et al. reported that men’s saphenous veins have a larger number of ET receptors and an increased ratio of ETA to ETB receptors compared to women’s saphenous veins and that these differences were reflected by the sex differences in ET-1-induced vascular contractile responses (127). On the other hand, although several animal studies also indicated that ET receptors are involved
in the sex differences in the incidence of CVD, the effect of estrogen on these receptors is quite contradictory.
For example, Nuedling et al. demonstrated upregulation of the ETB receptor in the heart of ovariectomized female spontaneously hypertensive rats, which could be reversed by exogenous estrogen replacement (128). They also confirmed downregulation of the ETB receptor by 17β-estradiol in cultured cardiomyocytes. Others reported similar results showing that vascular mRNA expression of ETB, but not ETA receptors in DOCA-salt–induced hypertensive rats was higher in males than that observed in females (129, 130).
Table 1
Comparison of ECE inhibitors in clinical development and experimental use
| Drug | Development phase | Selectivity | IC50 (nM) | Reference | ||
|---|---|---|---|---|---|---|
| ECE/NEP | ECEa | NEP | ACE | |||
| TMC 66 | Preclinical | 2900 | Asai et al. (1999) | |||
| Daglutril (SLV 306, KC 12615) | II | Tabrizchi (2003) | ||||
| CGS 26303, CGS 26393 | Preclinical | 0.0033 | 410 | 0.9 | DeLombaert et al. (1994) | |
| Phosphoramidon | Preclinical | 0.0097 | 3500 | 34 | 78 000 |
Kukkola et al. (1995) |
| CGS 35601, CGS 37808 | Preclinical | 0.036 | 55 | 2 | 22 | Battistini et al. (2005) |
| CGS 31447 | Preclinical | 0.23 | 21 | 4.8 | Shetty et al. (1998) | |
| SCH 54470 | Preclinical | 1.3 | 70 | 90 | 2.5 | McKittrick et al. (1996) |
| CGS 34043 | Preclinical | 19 | 5.8 | 110 | DeLombaert et al. (2000) | |
| WS 75624 B | Preclinical | 42 | 79 | 3300 | Tsurumi et al. (1995b) | |
| B 90063 | Preclinical | 70 | 1000 | 70000 |
Takaishi et al. (1998) | |
| CGS 35066 | Preclinical | 100 | 22 | 2300 | Trapani et al. (2000) | |
| PD 069185, PD 159790 | Preclinical | >200 | 900 | >180000 |
Ahn et al. (1998) | |
| SM 19712 | Preclinical | >240 | 42 | >10000 |
>10000 |
Umekawa et al. (2000) |
| FR 901533, WS 79089 B | Preclinical | >700 | 140 | >100000 |
Tsurumi et al. (1995a) | |
| Ro 68-7629 | Preclinical | >90000 |
1.1 | >100000 |
>100000 |
Muller et al. (2002) |
Table 2
Comparison of ET receptor antagonists in clinical use, clinical development and experimental use
| Drug | Trade name | Development phase | Selectivity | Ki (nM) | Bioavailability | Eliminationt1/2 (hours) | Reference | |
|---|---|---|---|---|---|---|---|---|
| ETA/ETB | ETA | ETB | ||||||
| (a) Mixed ETA/ETB receptor antagonists | ||||||||
| Tezosentan (Ro 61-0612) | Veletri | III | 1.2 | 18 | 21 | i.v. | 2.1 (rat) | Clozel et al. (1999) |
| PD 145065 | Preclinical | 3.8 | 4a | 15a | Doherty et al. (1993) | |||
| PD 142893 | Preclinical | 10 | 15a | 150a | Cody et al. (1992) | |||
| Bosentan (Ro 47-0203) | Tracleer | IV | 20 | 4.7 | 95 | Oral | 3.7–7.5 (human) | Clozel et al. (1994); Weber et al. (1996) |
| TAK 044 | II | 34 | 3.8a | 130a | i.v. | 0.5–1.0 (human) | Watanabe et al. (1995);Haynes et al. (1996) | |
| Avosentan (SPP 301) | III | 50 | Oral | 7.5–15.2 (human) | Dieterle et al. (2004)b | |||
| (b) Selective ETA receptor antagonists | ||||||||
| Enrasentan (SB 217242) | III | 100 | 1.1 | 111 | Oral | 3.3 (rat) | Ohlstein et al. (1996) | |
| Darusentan (LU 135252) | III | 170 | 6 | 1000 | Oral | 12.0 (rat) | Riechers et al. (1996);Cernacek et al. (1998) | |
| Ambrisentan (LU 208075) | Letairis | IV | 200 | 1 | 195 | Oral | 9.0–15.0 (PAH patients) | Riechers et al. (1996); Galiéet al. (2005) |
| YM 598 | II | 390 | 3.1a | 1200a | Oral | 2.5 (rat) | Harada et al. (2001) | |
| S 0139 | II | 1000 | 1 | 1000 | Oral | Mihara et al. (1994) | ||
| Clazosentan (Ro 61-1790) | IIb | 1300 | 9.5c | 6.4c | i.v. | 0.8 (monkey) | Roux et al. (1997) | |
| Atrasentan (A 147627) | Xinlay | III | 2000 | 0.069 | 139 | Oral | 2.5 (monkey) | Opgenorth et al. (1996) |
| BQ 123 | Preclinical | 2500 | 7.3a | 18000a |
i.v. | Ihara et al. (1992) | ||
| ZD 4054 | IIa | >4800 | 21a | >100000a |
Oral | 9.1–9.7 (human) | Morris et al. (2005) | |
| Sitaxsentan (TBC 11251) | Thelin | IV | 7000 | 1.4a | 9800a | Oral | 5.9–7.5 (rat) | Wu et al. (1997) |
| BMS 193884 | II | 13000 |
1.4 | 18700 |
Oral | 9.0 (monkey) | Murugesan et al. (2000) | |
| FR 139317 | Preclinical | 7300 | 1 | 7300 | i.v. | Aramori et al. (1993) | ||
| Edonentan (BMS 207940) | IIa | 81000 |
0.01 | 810 | Oral | 17.0 (monkey) | Murugesan et al. (2003) | |
| TBC 3711 | I | 440000 |
0.08a | Oral | 5.3 (rat) | Wu et al. (2004) | ||
| (c) Selective ETB receptor antagonists | ||||||||
| BQ 788 | Preclinical | 1100 | 1300a | 1.2a | i.v. | Ishikawa et al. (1994) | ||
| A 192621 | Preclinical | 1300 | 8200a | 6.4a | Oral | 5.0 (rat) | von Geldern et al. (1999) | |
Table 3
Summary and completed clinical trials of ET receptor antagonists in indicated cardiovascular diseases
| Condition | Antagonist | Study | Outcome |
|---|---|---|---|
| Pulmonary arterial hypertension | Bosentan | BREATHE-1 | Improvement in primary and secondary end points, well tolerated |
| BREATHE-4 | Improvement in end points, well tolerated | ||
| Sitaxsentan | Open label | ||
| STRIDE 1–6 | Sustained improvement, well tolerated | ||
| Ambrisentan | AMB-220 | Improvement in end points, sustained for >2 years, well tolerated | |
| ARIES-2 | Improvement in end points, well tolerated | ||
| Heart failure | |||
| Chronic | Bosentan | Pilot | Short-term haemodynamic improvements |
| ENABLE-1; -2 | No benefit, early worsening of symptoms | ||
| REACH-1 | No benefit, toxic effects, trial stopped, trend to reduced mortality | ||
| Enrasentan | ENCOR | No benefit, increased adverse events, trend to increased mortality | |
| Darusentan | EARTH | No benefit, increased adverse events | |
| HEAT-CHF | Some haemodynamic benefit, adverse events (including death) at higher dose | ||
| BMS 193884 | No data, trial probably discontinued | ||
| Edonentan | No data, trial probably discontinued | ||
| Acute | Tezosentan | RITZ-1 | Safety trial, well tolerated, some haemodynamic improvement |
| RITZ-2 | Acute improvement in haemodynamics, dose dependence | ||
| RITZ-3 | Follow-up to RITZ-2, never conducted | ||
| RITZ-4 | No benefit and adverse events | ||
| 204 | Dose-dependent improvements in haemodynamics, decreased urine production | ||
| VERITAS-1, -2 | Limited benefit, trials discontinued | ||
| Hypertension | Bosentan | Reduction of SBP and DBP in essential HT | |
| Darusentan | HEAT-HTN | Dose-dependent reduction of SBP and DBP in essential HT | |
| DAR-201 | Reduction of SBP and DBP in refractory HT | ||
| Aneurysmal SAH | Clazosentan | Pre-CONSCIOUS-1 | Reduced frequency and severity of cerebral vasospasm |
| Erectile dysfunction | BMS 193884 | No improvement over placebo | |
| Scleroderma (ulcers) | Bosentan | RAPIDS-1, -2 | Significant reduction in ulcers, well-tolerated |
Table 4
[Source: J Pharmacol Sci 119, 302 – 313 (2012)]
Randomized clinical trials evaluating endothelin receptor antagonists in
Chronic Heart Failure
| ETR antagonist(selectivity) | Study | Patients | Outcome |
| Bosentan(ETA/ETB) | REACH-1 | N=370 NYHA IIIb-IV, LVEF<35% | No improvements in end point |
| ENABLE I | N=1613 NYHA , LVEF<35% | No improvements in end point | |
| ENABLE II | Same NYHA, LVEF<35% | No improvements in end point | |
| Tozosertan(ETA/ETB) | RITZ 1 | N=675 ADHF | No difference in all end points |
| RITZ-2 | N=292 ADHF | Increase in Cardiac Index decrease in PCWP | |
| RITZ-4 | N=193 ADHF w/ACS | No difference in all end points | |
| RITZ-5 | N=84 ACHF | No improvements in end point | |
| Darusentan(ETA) | HEAT | N=157 NYHA II, LVEF<35% | Improvement in Cardiac Index |
| EARTH | N=642 NYHA II-IV, LVEF<35% | No difference in end points | |
| Enrasentan(ETA/ETB) | ENCOR | N=419 NYHA II-III, LVEF<35% | Better outcome in placebo group |
REACH-1: Research on Endothelin Antagonism in Chronic Heart Failure,
ENABLE: Endothelin Antagonist Bosentan for Lowering Cardiac Events
RITZ: Randomized Intravenous TeZosentan,
HEAT: Heart Failure ET[A] Receptor Blockade Trial,
EARTH: EndothelinA Receptor Antagonist Trial in Heart Failure,
ENCOR: ENrasentan COoperative Randomized, ETR: endothelin receptor, NYHA: New York Heart Association,
Abbreviations: ADHF: acute decompensated heart failure, ACS: acute coronary syndrome, ACHF: acute congestive heart failure, LVEF: left ventricular ejection fraction.
Source:
Pathophysiological Roles of Endothelin Receptors in Cardiovascular Disease
Big Endothelin in chronic heart failure: marker of disease severity or genetic determination?
Source
1st Internal Cardio-angiological Department, St. Anne’s Hospital, Brno, Czech Republic.
Abstract
The first objective of the study was to compare the levels of big endothelin and endothelin-1 and other noninvasive parameters used for evaluation of disease severity in patients with stable chronic heart failure (CHF). Endothelin-1 and big endothelin plasma concentrations were measured in 124 chronic heart failure patients. The second objective of the study was to prove an association between endothelin-1 and big endothelin plasma levels and two frequent polymorphisms in the endothelin-1 coding gene (6p21-23) -3A/-4A and G (8002) A in patients with chronic heart failure. Thirdly, we tried to associate other noninvasive parameters of CHF, especially cardiothoracic index (CTI), NYHA classification, signs of pulmonary congestion (PC) and ejection fraction (EF) with determined genotypes of the two ET-1 polymorphic variants. There were significant differences between big endothelin levels in NYHA II versus IV (P<0.001) and NYHA III versus IV (P<0.001) and endothelin-1 in NYHA II versus IV (P<0.001) and NYHA III versus IV (P<0.001). No associations between plasma levels of endothelin-1 and big endothelin and polymorphisms G (8002) A and -3A/-4A in gene coding endothelin-1 were found. In patients with CHF with CTI above 60% the number of carriers of genotypes with ET-1 8002A (AA and AG genotypes) increases. Concerning on the -3A/-4A ET-1 polymorphism, we observed a significant difference in genotype distribution as well as in allelic frequency in the group of patients with CTI above 60% between patients without and with pulmonary congestion. The allelic frequency of 3A allele is twice elevated in the patients with pulmonary congestion (37.8 vs. 78.1%, respectively).
- ALL THE TABLES ABOVE AND NARRATIVE based chiefly on the following two seminal papers:
J Pharmacol Sci 119, 302 – 313 (2012)
https://www.jstage.jst.go.jp/article/jphs/119/4/119_12R01CR/_pdf
Pathophysiological Roles of Endothelin Receptors in Cardiovascular Diseases
Mamoru Ohkita1, Masashi Tawa1,2, Kento Kitada1,3, and Yasuo Matsumura1,*
1Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences,
4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
2Department of Pharmacology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
3Department of Pharmacology, Kagawa University Medical School,
1750–1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?
N S Kirkby,1 P W F Hadoke,1 A J Bagnall,1 and D J Webb1,*
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275436/#bib140
http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0707516/full
http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0707516/references
References from
Journal of Pharmacological Sciences
© The Japanese Pharmacological Society
J Pharmacol Sci 119, 302 – 313 (2012)
https://www.jstage.jst.go.jp/article/jphs/119/4/119_12R01CR/_pdf
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Abbreviations
- BP- blood pressure
- EC – endothelial cell
- ECE – endothelin-converting enzyme
- ET – endothelin
- ET-1 – endothelin-1
- ETA/B – ETA/B receptor
- IMCD – inner-medullary collecting duct
- NEP – neutral endopeptidase
- NO – nitric oxide
- NYHA – New York Heart Association
- PAH- pulmonary arterial hypertension
- SAH- subarachnoid haemorrhage
- SSc – systemic sclerosis
- VSMC – vascular smooth muscle cell
Other Research on ET and Cardiovascular Disease on this Scientific Web Site include:
Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production
Curator and Research Study Originator: Aviva Lev-Ari, PhD, RN, 7/19/2012
Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk
An Investigation of the Potential of circulating Endothelial Progenitor Cells (cEPCs) as a Therapeutic Target for Pharmacological Therapy Design for Cardiovascular Risk Reduction: A New Multimarker Biomarker Discovery
Curator: Aviva Lev-Ari, PhD, RN 7/2/2012
Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation
Author: Aviva Lev-Ari, PhD, 10/4/2012
Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography
Curator: Aviva Lev-Ari, 10/4/2012.
Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents
Author: Aviva Lev-Ari, PhD, RN, 8/13/2012
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This is a remarkable work. It is more comprehensive than any I can find, and it will require several rereads.
Dr. Larry,
Thank you for your comment. It is based on two SEMINAL papers in the UK, 2008 and in Japan 2012. I am the curator who wrote about ET in 2006, as per the references on ET on this Scientific Web Site.
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
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Many thanks,Annette