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The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis

Agata Kowalczyk, Paulina Kleniewska, Michal Kolodziejczyk and 2 more

Archivum Immunologiae et Therapiae Experimentalis · 2014 · Review

doi:10.1007/s00005-014-0310-1

Abstract

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

Pathogenesis of Sepsis

Sepsis is defined as a systemic inflammatory response syndrome, most commonly provoked by severe bacterial infection (Naito et al.; Sagy et al.; Zhang et al. ) This critical condition, with a mortality rate of about 50–80 %, is characterised by hyperthermia or hypothermia, tachypnea, tachycardia, leucocytosis or leucopenia, with immature neutrophils, and organ dysfunction due to impaired tissue perfusion (Sagy et al. ). Endotoxic shock is also associated with pulmonary hypertension, systemic hypotension and cardiac dysfunction (Forni et al. ). The mechanisms underlying the pathogenic effects of sepsis are still not completely understood.

The primary cause of escalated inflammatory response in septic shock is the presence of bacterial toxins. These include the lipopolysaccharide (LPS) endotoxin, which is a compound of a Gram-negative bacterial cell wall and an exotoxin (superantigen) from Gram-positive bacteria. When released into the blood, these bacterial products induce macrophages to secrete large amounts of inflammatory cytokines like tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-8, by the activation of signalling cascades such as nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPKs) pathways. Exotoxins also activate T-lymphocytes to produce proinflammatory mediators, IL-2 and interferon γ, which stimulate inducible nitric oxide synthase (iNOS) to produce nitric oxide (NO). Together with IL-2, they also intensify the release of IL-1 and TNF-α from macrophages (Roth and De Souza; Sagy et al.; Zhang et al. ). Furthermore, septic shock is also associated with an increased level of platelet-activating factor, thromboxane A2, leukotrienes, macrophage inflammatory protein-1, prostaglandin E2 (PGE2), cyclooxygenase (COX)-2 mRNA and endothelin-1 (ET-1) (Dilshara et al.; Jesmin et al.; Keller et al.; Roth and De Souza ). Under pathological conditions, endotoxin stimulates endothelin systems to release large amounts of endothelin into the blood stream. Likewise, the levels of ETA and ETB receptor mRNA are also elevated in some tissues (Forni et al. ). LPS-induced sepsis impairs the integrity of the endothelial barrier resulting in endothelial cell injury, which contributes to greater permeability of endothelial cells and impaired homeostasis, and induces the release of cytokines and reactive oxygen species (ROS). Plasma levels of ET-1 are elevated in septic patients and are associated with the severity of the illness. Some authors indicate a clear correlation between endothelin plasma level and morbidity and mortality in septic patients (Pan et al. ).

The Endothelin System

The endothelins are a family of 21 amino acid peptides with three distinct isoforms: ET-1, ET-2 and ET-3. ET-1 is the most abundant and the best described isoform. ET-2 and ET-3 were identified later and are not as well-studied (Motte et al.; Yanagisawa et al. ). ET-1 is produced in a variety of cells (Table 1) and there are many factors which regulate its secretion (Table 2). Physical and chemical stimulants activate ET-1 gene expression in endothelial cells by the DNA binding of transcription factors such as activator protein-1, GATA-2, smad, hypoxia inducible factor-1 and NF-κB (Rodriguez-Pascual et al.; Wanecek et al.; Wort et al. ).

Two types of endothelin receptors are found in mammals, ETA and ETB receptors, which belong to the G protein-coupled receptors family. ETA receptors are located mostly in vascular smooth muscle cells (VSMC), where they are responsible for potent vascular contraction (Fig. 1), cell proliferation and a proinflammatory effect. ETB receptors include two subtypes: ETB1, which is expressed on endothelial cells and evokes NO-mediated vasodilation, and ETB2, also present in VSMC, which causes contraction (Hynynen and Khalil; Yanagisawa et al. ). Stimulation of ETB1 receptors also results in the release of other vasodilatory factors such as prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor. Furthermore, it is suggested that endothelial ETB receptors take part in ET-1 clearance, but findings are not unequivocal (Hynynen and Khalil; Kawanabe and Nauli; Ohkita et al. ).

So far, ETA and ETB receptors have been detected in many cell types other than blood vessels (Table 1), but predominantly in cardiovascular tissues (Hynynen and Khalil ). Endothelins, through their receptors, exert an influence on the function of many organs like the heart, the kidneys, the lungs and the liver (Lima et al.; Rodriguez et al. ). Apart from participating in the regulation of vascular tone, endothelins take part in vascular, myocardial and bone remodelling, inhibition of apoptosis and salt-water retention. Furthermore, endothelins can contribute to bronchoconstriction, angiogenesis and neuropathic pain (Rodriguez et al.; Thakkar et al. ).

ET-1 and ROS

It is known that ET-1 stimulates the production of ROS, primarily superoxide anions (O2 −), and consequently leads to the development of oxidative stress. When given intravenously, the peptide initially causes vasodilation of blood vessels followed by their subsequent long lasting contraction, resulting in ischemia of internal organs and the dysfunction of the endothelium. These changes can lead to abundant ROS generation (Dong et al.; Loomis et al.; López-Sepúlveda et al.; Thakali et al. ). Some studies have shown the oxidative stress caused by ET-1 to be associated with augmentation of lipid peroxidation and reduction of intracellular GSH (glutathione) and SH groups (Scalera et al.; Viswanatha Swamy et al. ). According to the literature, both the ETA (Elmarakby et al. ) and ETB receptors (Dong et al. ) mediate ROS generation. Callera et al. demonstrated that elevated concentrations of ET-1 induce the synthesis of O2 − through ETA receptors. Xu et al. report a significant reduction in lipid peroxidation products content in the ischemic myocardium after applying BQ123, a blocker of the ETA receptor. Other authors note a reduction of lipid peroxidation in various organs during oxidative stress when using this blocker (Briyal et al. ). BQ123 has been found to block increased production of O2 − in ET-1-induced oxidative stress in the arteries and veins of patients with coronary artery disease (Cerrato et al. ), has been associated with a significant increase in the concentration of total glutathione and superoxide dismutase (SOD) activity after application (Briyal et al. ), as well as a significant increase in the activity of the antioxidant enzymes SOD and catalase in cases of ET-1-induced oxidative stress (Ozdemir et al. ).

Studies on blocking ETB receptors are ambiguous. Wedgwood et al. note that the ETB receptor antagonist (Res-701-3) increased the production of H2O2 in the smooth muscle cell culture from the pulmonary artery, but not in endothelial cells. However, other studies indicate that the ETB receptor blockade reduces the ROS production in various tissues (Dai et al. ). Moreover, Piechota-Polanczyk et al. report a significant increase in the concentration of GSH, but insignificant increase in the ratio of GSH/GSSG in the rat heart after application of BQ788. On the other hand, Leonard et al. did not observe any changes in the concentration of glutathione in rats after administration of BQ788.

The Proinflammatory Effect of ET-1

Several studies have demonstrated that ET-1 contributes to the development of inflammatory processes in the vascular wall. ET-1 has been found to be associated with an inflammatory response involving activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1 and IL-6 (Yeager et al. ). These transcription factors and proinflammatory cytokines in turn stimulate ET-1 production (Virdis and Schiffrin ). Bellisai et al. report that ET-1 increases the synthesis of TNF-α in macrophages and monocytes. This cytokine enhances the inflammatory response by stimulating the chemotaxis and phagocytosis of macrophages, monocytes and neutrophils. Increased production of ROS in different types of cells occurs via the NF-κB, COX and NADPH oxidase-dependent pathways (Donate et al.; Kleniewska et al.; Piechota and Goraca ).

Recent studies have shown that the ETA receptor antagonist BQ123 has a beneficial influence on the concentration of TNF-α (Ozdemir et al. ). Ford et al. note that the ETA receptor blockade lowered the concentration of TNF-α in patients after bypass grafting via the antagonist BQ123. Chen et al. confirmed that BQ123 inhibited the expression of TNF-α and IL-1β in the lungs of rats during oxidative stress induced by intraperitoneal administration of an extract from the cigarette smoke. Moreover, an ETB receptor blockade may also have an influence on TNF-α synthesis. In a recent study by Tonari et al., BQ788 showed significant inhibition of the expression of TNF-α when applied to patients with damage to the optic nerve. However, Piechota-Polanczyk et al. report no significant reduction in the concentrations of TNF-α in the rat heart following the application of BQ788.

Furthermore, an excess amount of proinflammatory cytokines activates prostaglandin production during inflammatory responses in a number of cell types such as vascular endothelial and smooth muscle cells. Prostaglandins are synthetized by COX, which is also known as prostaglandin endopeptidase synthase. In this process, phospholipase A2 catalyses the release of arachidonic acid (AA) from membrane phospholipids, while COX catalyzes the conversion of AA into prostaglandins. There are two COX isoforms: COX-1 is constitutively expressed under normal conditions in the most tissues. This isoform takes part in regulating normal physiological responses and controls vascular homeostasis. COX-2 is not detectable in most normal cells and tissues, but its expression increases in inflammatory cells. Thus, COX-2 may play a crucial role in the development of various inflammatory responses including vascular inflammation. Recent studies have indicated that ET-1 induces COX-2 expression and PGE2 release by MAPKs and NF-κB (Lin et al. ).

ET-1 enhances the expression of adhesion molecules on vascular endothelial cells and stimulates the aggregation of polymorphonuclear neutrophils (PMNs) contributing to inflammation and endothelial dysfunction. Li et al. postulate that ET-1 stimulates the arterial vascular adhesion molecule-1 (VCAM-1) in hypertensive patients. VCAM-1 and the intracellular adhesion molecule-1 induce firm adhesion of inflammatory cells at the vascular surface (Blankenberg et al. ). PMNs may contribute to myocardial damage by releasing ROS, proteases and arachidonic acid metabolites (Hansen ). Oktar et al. indicate that ET-1 causes an accumulation of PMNs, oxidative stress, and mucosal dysfunction in the rat small intestine. Gonon et al. showed that the ET receptor blockade attenuates the accumulation of neutrophils and myeloperoxidase activity in the ischemic myocardium. It has been shown that the vascular injury caused by carotid artery ligation results in vascular inflammation and neointima formation. This action is attenuated in vascular endothelial ET-1-knockout mice (Anggrahini et al. ).

Increased ROS release contributes to endothelium dysfunction. Endothelial dysfunction occurs in cardiovascular diseases such as atherosclerosis. Increased expression of ET-1 was observed both in experimental models of atherosclerosis as well as in human atherosclerosis (Barton et al. ) and its level correlated with the severity of the atherosclerotic lesion. Haug et al. identify a higher expression of ET-1 in human VSMC harvested from human atherosclerotic coronary arteries than in cells from non-atherosclerotic arteries. ET-1 was associated with regions of the atherosclerotic plaque, particularly in regions with high macrophage content (Dashwood and Tsui ). It was shown that overexpression of ET-1 significantly increased the atherosclerotic lesion size in apolipoprotein E gene deleted mice (ApoE−/−) fed a high-fat diet. In this case, increased endothelial ET-1 expression enhances an increase in expression of genes associated with lipid synthesis in the vasculature and accelerates the progression of atherosclerosis (Simeone et al. ).

Li et al. have reported that ET-1 plays a role in the development of atherosclerosis and abdominal aortic aneurysm by decreasing high-density lipoprotein, increasing oxidative stress and monocyte/macrophage infiltration in both the aorta and aneurysms. So, plaque formation and endothelial function can be restored in the atherosclerosis model by the administration of ETA or dual ETA/ETB receptor antagonists. Moreover, it has been noted that tissue ET-1 concentration is more important than serum ET-1 in predicting atherosclerosis in patients with chronic kidney disease (Noshad et al. ). Recently, a study indicated that ethanolic extract of propolis inhibits atherosclerotic lesion formation in ApoE−/− mice fed a high-fat diet, probably by regulating the inflammatory reaction and inhibiting ET-1 (Fang et al. ). Overexpression of ET-1, particularly in the endothelium of mice with atherosclerosis, is accompanied by a decrease in endothelial signalling pathways responsible for endothelium-dependent relaxation and an increase in the activity of sensitive voltage-dependent potassium channels (Mian et al. ). ROS are important physiological messengers in vascular cells and their overproduction contributes to the progression of atherosclerosis (Freund-Michel et al. ). ET-1 receptor antagonists may be useful for prevention of various vascular diseases (Kitada et al., ).

ET-1 and Endothelin Receptor Antagonists in Sepsis

Recently, studies have addressed the role of endothelins and blockers of their receptors in the development of sepsis. During endotoxaemia, plasma endothelin level is increased in various species (Kaszaki et al.; Pan et al.; Piechota-Polańczyk and Gorąca ). In experimental models, endotoxin induces the expression of preproendothelin-1 mRNA in the lung and heart (Kaddoura et al. ). Infusion of ET-1 in septic shock contributed to the dysfunction of several vital organs such as liver, lung, heart and kidney (Fenhammar et al.; Piechota-Polanczyk et al. ). It has been indicated that the infusion of ET-1 in humans causes cardiovascular changes in part resembling those observed during sepsis i.e. decreased cardiac output, vasoconstriction in the pulmonary artery, impairment of renal and splanchnic circulation (Bomberg et al.; Ross; Schuuring et al. ). It has been demonstrated in animal experiments that dual ETA/ETB endothelin blockade during endotoxaemia improves cardiopulmonary function, reduces pulmonary hypertension and lung injury and attenuates intestinal and liver microcirculatory dysfunction (Kuklin et al.; Sánchez-Etayo et al. ). Also ETA receptor blockade alone improves the function of the lungs (Mercier et al. ), kidney (Rullman et al. ), heart (Vanêcková et al. ) and aorta (Tirapelli et al. ).

Endothelin receptor antagonists (ERAs) are a new, promising class of medicines which block the ETA and ETB endothelin receptors with varying degrees of selectivity. They form a large group consisting of nearly 40 or more compounds, and part of them is currently under investigation (Hynynen and Khalil; Khalil; Motte et al. ) as potential therapeutic objects in clinical trials (see Table 3). ERAs act on various pathophysiological mechanisms (Table 4), three of which recommended for treatment of pulmonary arterial hypertension, bosentan, ambrisentan and macitentan, are already on the world pharmaceutical market (Motte et al.; Patel and McKeage ). However, the nonselective ERAs, bosentan and tezosentan, and selective antagonists, BQ123 and BQ788, are currently receiving the most attention with regard to the effect of ERAs on the progression of sepsis.

Bosentan

In 2001, bosentan (Tracleer®) became the first ERA to be registered in the USA as an oral medicine for patients with pulmonary arterial hypertension of functional class III/IV (Dupuis and Hoeper; Motte et al. ). Many studies have shown a significant improvement in functional class and exercise capacity, as well as haemodynamic, Doppler and echocardiographic parameters after treatment with bosentan. Despite having side effects such as increases in liver transaminase content, headache, peripheral oedema, dizziness, nasal congestion and nausea, bosentan therapy is generally regarded as beneficial (Montani et al.; Motte et al. ). Bosentan also has been found to exert a positive therapeutic influence on the treatment of systemic sclerosis (scleroderma) and other disorders (Cozzi et al. ) (Table 3).

A common feature of sepsis is microcirculatory dysfunction. However, Krejci et al. note improved microcirculatory blood flow in the pancreas, gastric, skeletal muscle and colon mucosa of septic pigs treated with bosentan. Further, Iskit et al. report that bosentan at a dose of 30 mg/kg b.w. decreases caecal ligation and reduce liver, kidney and spleen injury, improving survival (p < 0.05) in a mouse model of polymicrobial sepsis. They also suggest that antagonism of endothelin receptors during the hypodynamic phase of septic shock gives much better results. More detailed data provided by Keller et al. confirm that the administration of LPS results in increased expressions of ET-1, iNOS, and COX-2 mRNA. They also report a significant inhibition of the up-regulation of ET-1, iNOS, and COX-2 mRNA after treatment of rats with 30 mg/kg b.w. bosentan, thus demonstrating its anti-inflammatory and therapeutic properties.

Tezosentan

The first study concerning the effects of tezosentan on the cardiovascular system in sepsis was conducted by Chin et al.. During endotoxaemia, endothelin antagonism with this ERA maintained renal and cardiac functions, preventing decreases in cardiac index, renal blood flow, glomerular filtration rate and increased systemic vascular resistance in neonatal piglets (Chin et al. ). Further research demonstrated that tezosentan (10 mg/kg b.w) prevents mesenteric ischemia in septic mice. It significantly (p = 0.0046) attenuated decreases in mesenteric blood flow and limited injury to organs such as the liver, kidney and spleen. However, in this study, despite what was expected, tezosentan did not reduce ROS generation (Erdem et al. ). Other sepsis studies on pigs have brought similar effects, confirming that application of tezosentan results in improved intestinal and renal microcirculation, contributes to increased portal vein flow and decreased pulmonary capillary wedge pressure, and preserves cardiac index. Moreover, pH and arterial lactate values were better compared to the control (Andersson et al.; Fenhammar et al. ). It is also significant that this dual blocker had no influence on TNF-α, IL-6 or IL-10 plasma levels, nor angiotensin II or aldosterone plasma concentration, in this model of sepsis (Fenhammar et al. ). A recent investigation using tezosentan and the selective ETA antagonist, TBC3711 revealed no improvement in the liver and ileum microvascular blood flow during selective antagonism, but it showed marked amelioration after tezosentan. These findings highlight the special role of the ETB receptor in mediating the microcirculatory failure in this area (Andersson et al. ).

BQ123 and BQ788

Selective endothelin receptor blockers like BQ123 and BQ788 have also been used in sepsis studies: the former being an ETA receptor antagonist and the latter an ETB receptor blocker. Hirata and Ishimaru report that BQ123 does not increase survival in a rat septic shock model, due to lack of improvement in LPS-induced profound hypotension. However, a dual blockade of endothelin receptors helped maintain normal mean arterial pressure. The authors also suggest that this effect does not depend on iNOS-derived NO (Hirata and Ishimaru, ). Similarly, Nitescu et al. note that while BQ123 did not prevent endotoxin-induced hypotension, BQ788 did, by increasing mean arterial pressure in septic rats. Moreover, marked decrease (p < 0.05) of renal blood flow was observed in the group treated with both BQ788 and LPS, which may indicate that the ETB receptor is responsible for renal vasodilation and maintenance of normal renal blood flow (Nitescu et al. ).

Some authors suggest that oxidative stress in sepsis is mediated by ET-1 and ETA receptors. Studies on a rat model have shown that LPS markedly elevates lipid peroxidation products, TNF-α and H2O2 concentration in the lung, and BQ123 administration resulted in a distinct decrease of these parameters (p < 0.05), except for lipid peroxidation products level, which remained elevated. This ETA blocker also reduced TNF-α level in lung and plasma. Furthermore, a lower dose of BQ123 (0.5 mg/kg) was found to be more effective than higher dose of 1 mg/kg, and also prevented lung oedema development (p < 0.01) (Piechota et al.; Piechota-Polańczyk and Gorąca ). On the other hand, the same study based on heart tissue demonstrated a significant reduction in lipid peroxidation products and TNF-α, but not in H2O2 concentration, after BQ123 administration in experimental sepsis (Piechota-Polanczyk et al. ). These performance differences are probably associated with different antioxidant enzymes activities in the lung and heart.

Moreover, ETB receptor antagonism with BQ788 also reduced amplified amount of ROS, lowering lipid peroxidation products and H2O2 concentration. However, BQ788 did not influence increased concentration of TNF-α and neither BQ123 nor BQ788 affected LPS-induced activation of NF-κB pathway. However, Naito et al. note the protective effects of BQ788, including inhibition of neuroblast apoptosis, c-FOS expression, number of reactive microglia and distinctly diminished TNF-α level in mouse brain tissue during sepsis. These findings may suggest that in the heart, the ETA receptor is more involved in secretion of TNF-α than ETB. Furthermore, presumably both endothelin receptors in heart tissue stimulate ROS generation by some other signalling pathways than NF-κB. Nevertheless, the blockage of ETA receptor reduces ROS production and improves tissue antioxidant properties (Piechota-Polanczyk et al. ). These findings also confirm to some extent that ET-1 is strongly involved in the pathogenesis of septic shock, but the close links between factors inducing sepsis and increased production of ET-1 are still unclear.

Towards the End

A very recent study has revealed that the oedema-promoting effects of ET-1 might be related to augmented level of heparin-binding protein (HBP) accompanying sepsis. HBP, also termed CAP37 or azurocidin is a protein released from neutrophils, which induces vascular hyperpermeability and contributes to oedema formation during endotoxaemia. Until now, it was believed that ET-1 induces vascular leakage, but the mechanisms of this action were not established. Using a porcine sepsis model, Persson et al. report a significant decrease of HBP plasma level, as well as reduced pulmonary oedema, in animals treated with tezosentan compared to those who received ET-1 or the ETB receptor agonist sarafotoxin 6c, both of which caused a dose-dependent increase in HBP levels similar to those observed in sepsis. These findings suggest that stimulation of both endothelin receptors activates reactions which lead to augmented secretion of HBP and this process may be abolished by nonselective ERA (Persson et al. ).

More than 20 years ago, ET-1 was identified as the first endothelium-derived contracting factor. Shortly after, two receptor subtypes, ETA and ETB, were discovered, which permitted the development of orally active ET-1 receptor antagonists. One of the first was the nonselective ETA/ETB-receptor antagonist, bosentan (Tracleer®), available to patients in 2001. Since then, although many ERAs have been described, not all of them are in clinical use. A novel ERA, macitentan (Opsumit®), is a very potent nonslective blocker, with high lipophilicity (Montani et al. ) “sustained receptor binding and enhanced tissue penetration properties” (Sidharta et al. ). It is the newest and safest registered ERA (Patel and McKeage ), but its specific properties have not yet been studied in condition of sepsis. Similarly, a potent ETA receptor antagonist, ambrisentan (Letairis®, Volibris®) may present favourable effects in sepsis (Montani et al.; Elshaboury and Anderson ).

New applications for this group of medicines still remain an interesting subject of study. Antibiotics, fluids and vasopressors are most commonly used in the treatment of sepsis. Recent anti-inflammatory strategies such as high-dose corticosteroids, anti-TNF-α, IL-1-based therapies or activated protein C, have proved to be disappointing (Xie et al. ). Effective clinical applications of endothelin receptor antagonists need a more thorough understanding of the physiology and pathophysiology of the ET-1 system. Endothelins, HBP and other, yet unidentified, factors involved in the bacterial toxin activation of the endothelin system might represent the main target for sepsis therapy in the future.

References 138

  1. 1.

    Andersson A, Fenhammar J, Frithiof R, et al. Mixed endothelin receptor antagonism with tezosentan improves intestinal microcirculation in endotoxemic shock. J Surg Res. 2008;149:138-147.

    Not in our library10.1016/j.jss.2007.12.751

  2. 2.

    Andersson A, Fenhammar J, Weitzberg E, et al. Endothelin-mediated gut microcirculatory dysfunction during porcine endotoxaemia. Br J Anaesth. 2010;105:640-647.

    Not in our library10.1093/bja/aeq217

  3. 3.

    Anggrahini DW, Emoto N, Nakayama K, et al. Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation. Cardiovasc Res. 2009;82:143-151.

    Not in our library10.1093/cvr/cvp026

  4. 4.

    Barton M, Traupe T, Haudenschild CC. Endothelin, hypercholesterolemia and atherosclerosis. Coron Artery Dis. 2003;14:477-490.

    Not in our library10.1097/00019501-200311000-00002

  5. 5.

    Bellisai F, Morozzi G, Scaccia F, et al. Evaluation of the effect of bosentan treatment on proinflammatory cytokine serum levels in patients affected by systemic sclerosis. Int J Immunopathol Pharmacol. 2011;24:261-264.

    Not in our library10.1177/039463201102400134

  6. 6.

    Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis. 2003;170:191-203.

    Not in our library10.1016/s0021-9150(03)00097-2

  7. 7.

    Bomberg H, Bierbach B, Flache S, et al. Endothelin and vasopressin influence splanchnic blood flow distribution during and after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2013;145:539-547.

    Not in our library10.1016/j.jtcvs.2012.03.014

  8. 8.

    Braun L, Sood V, Hogue S, et al. High burden and unmet patient needs in chronic kidney disease. Int J Nephrol Renovasc Dis. 2012;5:151-163.

    Not in our library10.2147/ijnrd.s37766

  9. 9.

    Briyal S, Philip T, Gulati A. Endothelin-A receptor antagonists prevent amyloid-β-induced increase in ETA receptor expression, oxidative stress, and cognitive impairment. J Alzheimers Dis. 2011;23:491-503.

    Not in our library10.3233/jad-2010-101245

  10. 10.

    Callera GE, Touyz RM, Teixeira SA, et al. ETA receptor blockade decreases vascular superoxide generation in DOCA-salt hypertension. Hypertension. 2003;42:811-817.

    Not in our library10.1161/01.hyp.0000088363.65943.6c

  11. 11.

    Carducci MA, Saad F, Abrahamsson PA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110:1959-1966.

    Not in our library10.1002/cncr.22996

  12. 12.

    Cerrato R, Cunnington C, Crabtree MJ, et al. Endothelin-1 increases superoxide production in human coronary artery bypass grafts. Life Sci. 2012;91:723-728.

    Not in our library10.1016/j.lfs.2012.03.024

  13. 13.

    Chen Y, Hanaoka M, Droma Y, et al. Endothelin-1 receptor antagonists prevent the development of pulmonary emphysema in rats. Eur Respir J. 2010;35:904-912.

    Not in our library10.1183/09031936.00003909

  14. 14.

    Chin A, Radhakrishnan J, Fornell L, et al. Effects of tezosentan, a dual endothelin receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxic shock. J Pediatr Surg. 2002;37:482-487.

    Not in our library10.1053/jpsu.2002.30871

  15. 15.

    Chouaid C, Nathan F, Pemberton K, et al. A phase II, randomized, multicenter study to assess the efficacy, safety, and tolerability of zibotentan (ZD4054) in combination with pemetrexed in patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2011;67:1203-1208.

    Not in our library10.1007/s00280-010-1538-z

  16. 16.

    Cognetti F, Bagnato A, Colombo N, et al. A Phase II, randomized, double-blind study of zibotentan (ZD4054) in combination with carboplatin/paclitaxel versus placebo in combination with carboplatin/paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy (AGO-OVAR 2.14). Gynecol Oncol. 2013;130:31-37.

    Not in our library10.1016/j.ygyno.2012.12.004

  17. 17.

    Corte TJ, Keir GJ, Dimopoulos K, et al. Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia (BPHIT). Am J Respir Crit Care Med. 2014;190:208-217.

    Not in our library10.1164/rccm.201403-0446oc

  18. 18.

    Cozzi F, Pigatto E, Rizzo M, et al. Low occurrence of digital ulcers in scleroderma patients treated with bosentan for pulmonary arterial hypertension: a retrospective case-control study. Clin Rheumatol. 2013;32:679-683.

    Not in our library10.1007/s10067-013-2172-z

  19. 19.

    Dai X, Galligan JJ, Watts SW, et al. Increased O2•_ production and upregulation of ETB receptors by sympathetic neurons in DOCA-salt hypertensive rats. Hypertension. 2004;43:1048-1054.

    Not in our library10.1161/01.hyp.0000126068.27125.42

  20. 20.

    Dashwood MR, Tsui JC. Further evidence for a role of endothelin-1 (ET-1) in critical limb ischaemia. J Cell Commun Signal. 2011;5:45-49.

    Not in our library10.1007/s12079-010-0109-8

  21. 21.

    Denault AY, Pearl RG, Michler RE, et al. Tezosentan and right ventricular failure in patients with pulmonary hypertension undergoing cardiac surgery: the TACTICS trial. J Cardiothorac Vasc Anesth. 2013;27:1212-1217.

    Not in our library10.1053/j.jvca.2013.01.023

  22. 22.

    Dilshara MG, Lee KT, Jayasooriya RG, et al. Downregulation of NO and PGE2 in LPS-stimulated BV2 microglial cells by trans-isoferulic acid via suppression of PI3 K/Akt-dependent NF-κB and activation of Nrf2-mediated HO-1. Int Immunopharmacol. 2014;18:203-211.

    Not in our library10.1016/j.intimp.2013.11.020

  23. 23.

    Donate PB, Cunha TM, Verri WA, et al. Bosentan, an endothelin receptor antagonist, ameliorates collagen-induced arthritis: the role of TNF-α in the induction of endothelin system genes. Inflamm Res. 2012;61:337-348.

    Not in our library10.1007/s00011-011-0415-5

  24. 24.

    Dong F, Zhang X, Wold LE, et al. Endothelin-1 enhances oxidative stress, cell proliferation and reduces apoptosis in human umbilical vein endothelial cells: role of ETB receptor, NADPH oxidase and caveolin-1. Br J Pharmacol. 2005;145:323-333.

    Not in our library10.1038/sj.bjp.0706193

  25. 25.

    Duan J, Xu H, Dai S, et al. Phytoestrogen alpha-zearalanol inhibits homocysteine-induced endothelin-1 expression and oxidative stress in human umbilical vein endothelial cells. Atherosclerosis. 2008;197:549-555.

    Not in our library10.1016/j.atherosclerosis.2007.08.018

  26. 26.

    Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J. 2008;31:407-415.

    Not in our library10.1183/09031936.00078207

  27. 27.

    Ehrenreich H, Burd PR, Rottem M, et al. Endothelins belong to the assortment of mast cell-derived and mast cell-bound cytokines. New Biol. 1992;4:147-156.

    Not in our library

  28. 28.

    Elmarakby AA, Loomis ED, Pollock JS, et al. NADPH oxidase inhibition attenuates oxidative stress but not hypertension produced by chronic ET-1. Hypertension. 2005;45:283-287.

    Not in our library10.1161/01.hyp.0000153051.56460.6a

  29. 29.

    Elshaboury SM, Anderson JR. Ambrisentan for the treatment of pulmonary arterial hypertension: improving outcomes. Patient Prefer Adherence. 2013;7:401-409.

    Not in our library10.2147/ppa.s30949

  30. 30.

    Endo T, Uchida Y, Matsumoto H, et al. Regulation of endothelin-1 synthesis in cultured guinea pig airway epithelial cells by various cytokines. Biochem Biophys Res Commun. 1992;186:1594-1599.

    Not in our library10.1016/s0006-291x(05)81590-6

  31. 31.

    Erdem A, Meltem Sevgili A, Akbiyik F, et al. Tezosentan attenuates organ injury and mesenteric blood flow decrease in endotoxemia and cecal ligation and puncture. J Surg Res. 2007;141:211-219.

    Not in our library10.1016/j.jss.2006.08.028

  32. 32.

    Fang Y, Sang H, Yuan N, et al. Ethanolic extract of propolis inhibits atherosclerosis in ApoE-knockout mice. Lipids Health Dis. 2013;12:123.

    Not in our library10.1186/1476-511x-12-123

  33. 33.

    Fenhammar J, Andersson A, Frithiof R, et al. The endothelin receptor antagonist tezosentan improves renal microcirculation in a porcine model of endotoxemic shock. Acta Anaesthesiol Scand. 2008;52:1385-1393.

    Not in our library10.1111/j.1399-6576.2008.01768.x

  34. 34.

    Fenhammar J, Andersson A, Forestier J, et al. Endothelin receptor A antagonism attenuates renal medullary blood flow impairment in endotoxemic pigs. PLoS ONE. 2011;6:e21534.

    Not in our library10.1371/journal.pone.0021534

  35. 35.

    Ford RL, Mains IM, Hilton EJ, et al. Endothelin-A receptor inhibition after cardiopulmonary bypass: cytokines and receptor activation. Ann Thorac Surg. 2008;86:1576-1583.

    Not in our library10.1016/j.athoracsur.2008.06.076

  36. 36.

    Forni M, Mazzola S, Ribeiro LA, et al. Expression of endothelin-1 system in a pig model of endotoxic shock. Regul Pept. 2005;131:89-96.

    Not in our library10.1016/j.regpep.2005.07.001

  37. 37.
    Reactive oxygen species as therapeutic targets in pulmonary hypertension · 2013
    Not checked
  38. 38.

    Gonon AT, Gourine AV, Middelveld RJ, et al. Limitation of infarct size and attenuation of myeloperoxidase activity by an endothelin A receptor antagonist following ischaemia and reperfusion. Basic Res Cardiol. 2001;96:454-462.

    Not in our library10.1007/s003950170027

  39. 39.

    Grassi G. Selective endothelin receptor blockade in resistant hypertension: results of the DORADO trial. Expert Opin Pharmacother. 2011;12:153-155.

    Not in our library10.1517/14656566.2011.535812

  40. 40.

    Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation. 1995;91:1872-1885.

    Not in our library10.1161/01.cir.91.6.1872

  41. 41.

    Haque SU, Dashwood MR, Heetun M, et al. Efficacy of the specific endothelin A receptor antagonist zibotentan (ZD4054) in colorectal cancer: a preclinical study. Mol Cancer Ther. 2013;12:1556-1567.

    Not in our library10.1158/1535-7163.mct-12-0975

  42. 42.

    Haug C, Voisard R, Lenich A, et al. Increased endothelin release by cultured human smooth muscle cells from atherosclerotic coronary arteries. Cardiovasc Res. 1996;31:807-813.

    Not in our library10.1016/0008-6363(96)00012-0

  43. 43.

    Hirata Y, Ishimaru S. Effects of endothelin receptor antagonists on endothelin-1 and inducible nitric oxide synthase genes in a rat endotoxic shock model. Clin Sci. 2002;103(Suppl 48):332S-335S.

    Not in our library10.1042/cs103s332s

  44. 44.

    Hukovic N, Hadziselimovic R. Endothelin 1 action on isolated rat stomach and the role of calcium ions in ET 1 induced depolarization of smooth muscle cells BC3H1. Biochem Mol Biol Int. 1998;46:877-886.

    Not in our library10.1080/15216549800204422

  45. 45.

    Hynynen MM, Khalil RA. The vascular endothelin system in hypertension–recent patents and discoveries. Recent Pat Cardiovasc Drug Discov. 2006;1:95-108.

    Not in our library10.2174/157489006775244263

  46. 46.

    Imhof AK, Glück L, Gajda M, et al. Potent anti-inflammatory and antinociceptive activity of the endothelin receptor antagonist bosentan in monoarthritic mice. Arthritis Res Ther. 2011;13:R97.

    Not in our library10.1186/ar3372

  47. 47.

    Iskit AB, Senel I, Sokmensuer C, et al. Endothelin receptor antagonist bosentan improves survival in a murine caecal ligation and puncture model of septic shock. Eur J Pharmacol. 2004;506:83-88.

    Not in our library10.1016/j.ejphar.2004.10.038

  48. 48.

    Jesmin S, Shimojo N, Yamaguchi N, et al. Effects of protease activated receptor (PAR)2 blocking peptide on endothelin-1 levels in kidney tissues in endotoxemic rat mode. Life Sci. 2014;102:127-133.

    Not in our library10.1016/j.lfs.2014.03.013

  49. 49.

    Kaddoura S, Curzen NP, Evans TW, et al. Tissue expression of endothelin-1 mRNA in endotoxaemia. Biochem Biophys Res Commun. 1996;218:641-647.

    Not in our library10.1006/bbrc.1996.0115

  50. 50.

    Kaszaki J, Wolfárd A, Boros M, et al. Effects of antiendothelin treatment on the early hemodynamic changes in hyperdynamic endotoxemia. Acta Chir Hung. 1997;36:152-153.

    Not in our library

  51. 51.

    Kawanabe Y, Nauli SM. Endothelin. Cell Mol Life Sci. 2011;68:195-203.

    Not in our library10.1007/s00018-010-0518-0

  52. 52.

    Keller S, Karaa A, Paxian M, et al. Inhibition of endothelin-1-mediated up-regulation of iNOS by bosentan ameliorates endotoxin-induced liver injury in cirrhosis. Shock. 2006;25:306-313.

    Not in our library10.1097/01.shk.0000196549.18258.6a

  53. 53.

    Khalil RA. Modulators of the vascular endothelin receptor in blood pressure regulation and hypertension. Curr Mol Pharmacol. 2011;4:176-186.

    Not in our library10.2174/1874467211104030176

  54. 54.

    Kim SJ, Kim JS, Kim SW, et al. Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist, enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer. Neoplasia. 2011;13:167-179.

    Not in our library10.1593/neo.10806

  55. 55.

    Kim SJ, Kim JS, Kim SW, et al. Antivascular therapy for multidrug-resistant ovarian tumors by macitentan, a dual endothelin receptor antagonist. Transl Oncol. 2012;5:39-47.

    Not in our library10.1593/tlo.11286

  56. 56.

    Kitada K, Yui N, Matsumoto C, et al. Inhibition of endothelin ETB receptor system aggravates neointimal hyperplasia after balloon injury of rat carotid artery. J Pharmacol Exp Ther. 2009;331:998-1004.

    Not in our library10.1124/jpet.109.157065

  57. 57.

    Kitada K, Ohkita M, Matsumura Y. Pathological importance of the endothelin-1/ET(B) receptor system on vascular diseases. Cardiol Res Pract. 2012;2012:731970.

    Not in our library10.1155/2012/731970

  58. 58.

    Kleniewska P, Piechota-Polanczyk A, Michalski L, et al. Influence of block of NF-kappa B signaling pathway on oxidative stress in the liver homogenates. Oxid Med Cell Longev. 2013;2013:308358.

    Not in our library10.1155/2013/308358

  59. 59.

    Kohan DE, Pollock DM. Endothelin antagonists for diabetic and non-diabetic chronic kidney disease. Br J Clin Pharmacol. 2013;76:573-579.

    Not in our library10.1111/bcp.12064

  60. 60.

    Kohan DE, Pritchett Y, Molitch M, et al. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol. 2011;22:763-772.

    Not in our library10.1681/asn.2010080869

  61. 61.

    Konieczka K, Meyer P, Schoetzau A, et al. Effect of avosentan (SPP-301) in porcine ciliary arteries. Curr Eye Res. 2011;36:118-124.

    Not in our library10.3109/02713683.2010.529982

  62. 62.

    Krejci V, Hiltebrand LB, Erni D, et al. Endothelin receptor antagonist bosentan improves microcirculatory blood flow in splanchnic organs in septic shock. Crit Care Med. 2003;31:203-210.

    Not in our library10.1097/00003246-200301000-00031

  63. 63.

    Kuklin V, Kirov M, Sovershaev M, et al. Tezosentan-induced attenuation of lung injury in endotoxemic sheep is associated with reduced activation of protein kinase C. Crit Care. 2005;9:R211-R217.

    Not in our library10.1186/cc3497

  64. 64.

    Leonard MG, Briyal S, Gulati A. Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats. Brain Res. 2011;1420:48-58.

    Not in our library10.1016/j.brainres.2011.08.075

  65. 65.

    Leonard MG, Briyal S, Gulati A. Endothelin B receptor agonist, IRL-1620, provides long-term neuroprotection in cerebral ischemia in rats. Brain Res. 2012;1464:14-23.

    Not in our library10.1016/j.brainres.2012.05.005

  66. 66.

    Li L, Chu Y, Fink GD, et al. Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. Hypertension. 2003;42:997-1003.

    Not in our library10.1161/01.hyp.0000095980.43859.59

  67. 67.

    Li W, Sachidanandam K, Ergul A. Comparison of selective versus dual endothelin receptor antagonism on cerebrovascular dysfunction in diabetes. Neurol Res. 2011;33:185-191.

    Not in our library10.1179/016164111x12881719352417

  68. 68.

    Li MW, Mian MO, Barhoumi T, et al. Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2013;33:2306-2315.

    Not in our library10.1161/atvbaha.113.302028

  69. 69.

    Lima VV, Giachini FR, Hardy DM, et al. O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature. Am J Physiol Regul Integr Comp Physiol. 2011;300:R236-R250.

    Not in our library10.1152/ajpregu.00230.2010

  70. 70.

    Lin CC, Hsieh HL, Shih RH, et al. Up-regulation of COX-2/PGE2 by endothelin-1 via MAPK-dependent NF-κB pathway in mouse brain microvascular endothelial cells. Cell Commun Signal. 2013;11:8.

    Not in our library10.1186/1478-811x-11-8

  71. 71.

    Liu B, Zhou J, Chen H, et al. Expression and cellular location of endothelin-1 mRNA in rat liver following endotoxemia. Chin Med J. 1997;110:932-935.

    Not in our library

  72. 72.

    Loomis ED, Sullivan JC, Osmond DA, et al. Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther. 2005;315:1058-1064.

    Not in our library10.1124/jpet.105.091728

  73. 73.

    López-Sepúlveda R, Gómez-Guzmán M, Zarzuelo MJ, et al. Red wine polyphenols prevent endothelial dysfunction induced by endothelin-1 in rat aorta: role of NADPH oxidase. Clin Sci. 2011;120:321-333.

    Not in our library10.1042/cs20100311

  74. 74.

    Macdonald RL, Higashida RT, Keller E, et al. Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2). Acta Neurochir Suppl. 2013;115:27-31.

    Not in our library10.1007/978-3-7091-1192-5_7

  75. 75.

    Maemura K, Kurihara H, Morita T, et al. Production of endothelin-1 in vascular endothelial cells is regulated by factors associated with vascular injury. Gerontology. 1992;38(Suppl 1):29-35.

    Not in our library10.1159/000213360

  76. 76.

    Maron BA, Waxman AB, Opotowsky AR, et al. Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials). Am J Cardiol. 2013;112:720-725.

    Not in our library10.1016/j.amjcard.2013.04.051

  77. 77.

    Mercier O, Sage E, Izziki M, et al. Endothelin A receptor blockade improves regression of flow-induced pulmonary vasculopathy in piglets. J Thorac Cardiovasc Surg. 2010;140:677-683.

    Not in our library10.1016/j.jtcvs.2010.01.004

  78. 78.

    Mian MO, Idris-Khodja N, Li MW, et al. Preservation of endothelium-dependent relaxation in atherosclerotic mice with endothelium-restricted endothelin-1 overexpression. J Pharmacol Exp Ther. 2013;347:30-37.

    Not in our library10.1124/jpet.113.206532

  79. 79.

    Miller K, Moul JW, Gleave M, et al. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2013;16:187-192.

    Not in our library10.1038/pcan.2013.2

  80. 80.
    Pulmonary arterial hypertension · 2013
    No notice
  81. 81.

    Motte S, McEntee K, Naeije R. Endothelin receptor antagonists. Pharmacol Ther. 2006;110:386-414.

    Not in our library10.1016/j.pharmthera.2005.08.012

  82. 82.

    Naito Y, Yoshioka K, Tanaka K et al (2014) Endothelin B receptor-mediated encephalopathic events in mouse sepsis model. Life Sci. doi:10.1016/j.lfs.2014.03.012

    Not in our library10.1016/j.lfs.2014.03.012

  83. 83.

    Nelson JB, Fizazi K, Miller K, et al. Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer. 2012;118:5709-5718.

    Not in our library10.1002/cncr.27674

  84. 84.

    Nitescu N, Grimberg E, Ricksten SE, et al. Endothelin B receptors preserve renal blood flow in a normotensive model of endotoxin-induced acute kidney dysfunction. Shock. 2008;29:402-409.

    Not in our library10.1097/shk.0b013e3181454118

  85. 85.

    Noshad H, Argani H, Nezami N, et al. Arterial atherosclerosis in patients with chronic kidney disease and its relationship with serum and tissue endothelin-1. Iran J Kidney Dis. 2009;3:203-209.

    Not in our library

  86. 86.

    Ohkita M, Tawa M, Kitada K, et al. Pathophysiological roles of endothelin receptors in cardiovascular diseases. J Pharmacol Sci. 2012;119:302-313.

    Not in our library10.1254/jphs.12r01cr

  87. 87.

    Oktar BK, Coşkun T, Bozkurt A, et al. Endothelin-1-induced PMN infiltration and mucosal dysfunction in the rat small intestine. Am J Physiol Gastrointest Liver Physiol. 2000;279:G483-G491.

    Not in our library10.1152/ajpgi.2000.279.3.g483

  88. 88.

    Ozdemir R, Parlakpinar H, Polat A, et al. Selective endothelin A (ETA) receptor antagonist (BQ-123) reduces both myocardial infarct size and oxidant injury. Toxicology. 2006;219:142-149.

    Not in our library10.1016/j.tox.2005.11.022

  89. 89.

    Pan C, Wang J, Liu W, et al. Low tidal volume protects pulmonary vasomotor function from “second-hit” injury in acute lung injury rats. Respir Res. 2012;13:77.

    Not in our library10.1186/1465-9921-13-77

  90. 90.

    Patel T, McKeage K. Macitentan: first global approval. Drugs. 2014;74:127-133.

    Not in our library10.1007/s40265-013-0156-6

  91. 91.

    Persson BP, Halldorsdottir H, Lindbom L, et al. Heparin-binding protein (HBP/CAP37): a link to endothelin-1 in endotoxemia-induced pulmonary oedema? Acta Anaesthesiol Scand. 2014;58:549-559.

    Not in our library10.1111/aas.12301

  92. 92.

    Piechota A, Goraca A. Influence of nuclear factor-κB inhibition on endothelin-1 induced lung edema and oxidative stress in rats. J Physiol Pharmacol. 2011;62:183-188.

    Not in our library

  93. 93.

    Piechota A, Polańczyk A, Goraca A. Protective effects of endothelin-A receptor antagonist BQ123 against LPS-induced oxidative stress in lungs. Pharmacol Rep. 2011;63:494-500.

    Not in our library10.1016/s1734-1140(11)70516-3

  94. 94.

    Piechota-Polańczyk A, Gorąca A. Influence of specific endothelin-1 receptor blockers on hemodynamic parameters and antioxidant status of plasma in LPS-induced endotoxemia. Pharmacol Rep. 2012;64:1434-1441.

    Not in our library10.1016/s1734-1140(12)70941-6

  95. 95.

    Piechota-Polanczyk A, Kleniewska P, Gorąca A. The influence of ETA and ETB receptor blockers on LPS-induced oxidative stress and NF-κB signaling pathway in heart. Gen Physiol Biophys. 2012;31:271-278.

    Not in our library10.4149/gpb_2012_031

  96. 96.

    Quinn DI, Tangen CM, Hussain M, et al. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013;14:893-900.

    Not in our library10.1016/s1470-2045(13)70294-8

  97. 97.

    Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158:641-649.

    Not in our library10.7326/0003-4819-158-9-201305070-00003

  98. 98.

    Raghu G, Million-Rousseau R, Morganti A, et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013;42:1622-1632.

    Not in our library10.1183/09031936.00104612

  99. 99.

    Reriani M, Raichlin E, Prasad A, et al. Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis. Circulation. 2010;122:958-966.

    Not in our library10.1161/circulationaha.110.967406

  100. 100.

    Rodriguez MR, Soria LR, Ventimiglia MS, et al. Endothelin-1 and -3 induce choleresis in the rat through ETB receptors coupled to nitric oxide and vagovagal reflexes. Clin Sci. 2013;125:521-532.

    Not in our library10.1042/cs20120633

  101. 101.

    Rodriguez-Pascual F, Redondo-Horcajo M, Lamas S. Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-β-mediated induction of endothelin- 1 expression. Circ Res. 2003;92:1288-1295.

    Not in our library10.1161/01.res.0000078491.79697.7f

  102. 102.

    Ross EA. Congestive renal failure: the pathophysiology and treatment of renal venous hypertension. J Card Fail. 2012;18:930-938.

    Not in our library10.1016/j.cardfail.2012.10.010

  103. 103.

    Roth J, De Souza GE. Fever induction pathways: evidence from responses to systemic or local cytokine formation. Braz J Med Biol Res. 2001;34:301-314.

    Not in our library10.1590/s0100-879x2001000300003

  104. 104.

    Rullman E, Gustafsson T, Ahlborg G. The impact of the endothelin type A receptor on regional endothelin-1 turnover, in particular renal endothelin-1 release, in humans. J Appl Physiol. 2010;108:1625-1630.

    Not in our library10.1152/japplphysiol.00881.2009

  105. 105.

    Ryu SM, Kim HJ, Cho KR, et al. Myocardial protective effect of tezosentan, an endothelin receptor antagonist, for ischemia-reperfusion injury in experimental heart failure models. J Korean Med Sci. 2009;24:782-788.

    Not in our library10.3346/jkms.2009.24.5.782

  106. 106.

    Sagy M, Al-Qaqaa Y, Kim P. Definitions and pathophysiology of sepsis. Curr Probl Pediatr Adolesc Health Care. 2013;43:260-263.

    Not in our library10.1016/j.cppeds.2013.10.001

  107. 107.

    Sánchez-Etayo G, Borrat X, Escobar B, et al. Effect of intra-abdominal pressure on hepatic microcirculation: implications of the endothelin-1 receptor. J Dig Dis. 2012;13:478-485.

    Not in our library10.1111/j.1751-2980.2012.00613.x

  108. 108.

    Scalera F, Dittrich R, Beckmann MW, et al. Effect of endothelin-1 on intracellular glutathione and lipid peroxide availability and on the secretion of vasoactive substances by human umbilical vein endothelial cells. Eur J Clin Invest. 2002;32:556-562.

    Not in our library10.1046/j.1365-2362.2002.01040.x

  109. 109.

    Schelman WR, Liu G, Wilding G, et al. A phase I study of zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer. Invest New Drugs. 2011;29:118-125.

    Not in our library10.1007/s10637-009-9318-5

  110. 110.

    Schuuring MJ, Vis JC, van Dijk AP, et al. Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. Eur J Heart Fail. 2013;15:690-698.

    Not in our library10.1093/eurjhf/hft017

  111. 111.

    Sengul O, Ferah I, Polat B, et al. Blockade of endothelin receptors with bosentan limits ischaemia/reperfusion-induced injury in rat ovaries. Eur J Obstet Gynecol Reprod Biol. 2013;170:458-463.

    Not in our library10.1016/j.ejogrb.2013.06.040

  112. 112.

    Shao D, Park JE, Wort SJ. The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension. Pharmacol Res. 2011;63:504-511.

    Not in our library10.1016/j.phrs.2011.03.003

  113. 113.

    Shen J, Pan JW, Fan ZX, et al. Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials. J Neurosurg. 2013;119:180-189.

    Not in our library10.3171/2013.3.jns121436

  114. 114.

    Sidharta PN, van Giersbergen PL, Dingemanse J. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol. 2013;53:1131-1138.

    Not in our library10.1002/jcph.152

  115. 115.

    Simeone SM, Li MW, Paradis P, et al. Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium. Physiol Genomics. 2011;43:148-160.

    Not in our library10.1152/physiolgenomics.00218.2009

  116. 116.

    Singh G, Sharma B, Jaggi AS, et al. Efficacy of bosentan, a dual ETA and ETB endothelin receptor antagonist, in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats. Pharmacol Biochem Behav. 2014;124C:27-35.

    Not in our library10.1016/j.pbb.2014.05.002

  117. 117.

    Sugiura M, Inagami T, Kon V. Endotoxin stimulates endothelin-release in vivo and in vitro as determined by radioimmunoassay. Biochem Biophys Res Commun. 1989;161:1220-1227.

    Not in our library10.1016/0006-291x(89)91372-7

  118. 118.

    Takatsuki S, Rosenzweig EB, Zuckerman W, et al. Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. Pediatr Pulmonol. 2013;48:27-34.

    Not in our library10.1002/ppul.22555

  119. 119.

    Thakali K, Demel SL, Fink GD, et al. Endothelin-1-induced contraction in veins is independent of hydrogen peroxide. Am J Physiol Heart Circ Physiol. 2005;289:H1115-H1122.

    Not in our library10.1152/ajpheart.00086.2005

  120. 120.

    Thakkar SG, Choueiri TK, Garcia JA. Endothelin receptor antagonists: rationale, clinical development, and role in prostate cancer therapeutics. Curr Oncol Rep. 2006;8:108-113.

    Not in our library10.1007/s11912-006-0045-1

  121. 121.

    Tirapelli CR, Legros E, Brochu I, et al. Chronic ethanol intake modulates vascular levels of endothelin-1 receptor and enhances the pressor response to endothelin-1 in anaesthetized rats. Br J Pharmacol. 2008;154:971-981.

    Not in our library10.1038/bjp.2008.157

  122. 122.

    Tonari M, Kurimoto T, Horie T, et al. Blocking endothelin-B receptors rescues retinal ganglion cells from optic nerve injury through suppression of neuroinflammation. Invest Ophthalmol Vis Sci. 2012;53:3490-3500.

    Not in our library10.1167/iovs.11-9415

  123. 123.

    Vanêcková I, Kramer HJ, Bäcker A, et al. Early endothelin-A receptor blockade decreases blood pressure and ameliorates end-organ damage in homozygous Ren-2 rats. Hypertension. 2005;46:969-974.

    Not in our library10.1161/01.hyp.0000173426.06832.b5

  124. 124.

    Virdis A, Schiffrin EL. Vascular inflammation: a role in vascular disease in hypertension? Curr Opin Nephrol Hypertens. 2003;12:181-187.

    Not in our library10.1097/00041552-200303000-00009

  125. 125.

    Viswanatha Swamy AH, Wangikar U, Koti BC, et al. Cardioprotective effect of ascorbic acid on doxorubicin-induced myocardial toxicity in rats. Indian J Pharmacol. 2011;43:507-511.

    Not in our library10.4103/0253-7613.84952

  126. 126.

    Wanecek M, Weitzberg E, Rudehill A, et al. The endothelin system in septic and endotoxin shock. Eur J Pharmacol. 2000;407:1-15.

    Not in our library10.1016/s0014-2999(00)00675-0

  127. 127.

    Wang RF, Podos SM, Serle JB, et al. Effect of SPP 301, an endothelin antagonist, on intraocular pressure in glaucomatous monkey eyes. Curr Eye Res. 2011;36:41-46.

    Not in our library10.3109/02713683.2010.512695

  128. 128.

    Wedgwood S, Dettman RW, Black SM. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol. 2001;281:L1058-L1067.

    Not in our library10.1152/ajplung.2001.281.5.l1058

  129. 129.

    Wong F, Moore K, Dingemanse J, et al. Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome. Hepatology. 2008;47:160-168.

    Not in our library10.1002/hep.21940

  130. 130.

    Wort SJ, Ito M, Chou PC, et al. Synergistic induction of endothelin-1 by tumor necrosis factor alpha and interferon γ is due to enhanced NF-κB binding and histone acetylation at specific κB sites. J Biol Chem. 2009;284:24297-24305.

    Not in our library10.1074/jbc.m109.032524

  131. 131.

    Xie K, Liu L, Yu Y, et al. Hydrogen gas presents a promising therapeutic strategy for sepsis. Biomed Res Int. 2014;2014:807635.

    Not in our library10.1155/2014/807635

  132. 132.

    Xu H, Lin L, Yuan WJ. Antiarrhythmic effect of endothelin-A receptor antagonist on acute ischemic arrhythmia in isolated rat heart. Acta Pharmacol Sin. 2003;24:37-44.

    Not in our library

  133. 133.

    Yamashita J, Ogawa M, Nomura K, et al. Interleukin 6 stimulates the production of immunoreactive endothelin 1 in human breast cancer cells. Cancer Res. 1993;53:464-467.

    Not in our library

  134. 134.

    Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415.

    Not in our library10.1038/332411a0

  135. 135.

    Yeager ME, Belchenko DD, Nguyen CM, et al. Endothelin-1, the unfolded protein response, and persistent inflammation: role of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 2012;46:14-22.

    Not in our library10.1165/rcmb.2010-0506oc

  136. 136.

    Yoon MH, Reriani M, Mario G, et al. Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis. Int J Cardiol. 2013;168:1316-1321.

    Not in our library10.1016/j.ijcard.2012.12.001

  137. 137.

    Yoshizumi M, Kurihara H, Sugiyama T, et al. Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. Biochem Biophys Res Commun. 1989;161:859-864.

    Not in our library10.1016/0006-291x(89)92679-x

  138. 138.

    Zhang Y, Zhao C, He W, et al. Discovery and evaluation of asymmetrical monocarbonyl analogs of curcumin as anti-inflammatory agents. Drug Des Devel Ther. 2014;8:373-382.

    Not in our library10.2147/dddt.s58168

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