article{4ac00774-2f85-4776-9b6d-b14fe0384556, abstract = {Antisense oligodeoxynucleotides to endothelin ETA receptor mRNA were used to characterize vascular smooth muscle receptors. The concentration-response curve showed a significant attenuation of endothelin-1-induced contraction in circular segments of the human superficial temporal artery. Endothelin ETB receptor antisense or mismatch oligodeoxynucleotides showed no alteration of the endothelin-1-induced contraction. Complementary experiments with the selective endothelin ETA receptor antagonist FR139317 demonstrated a shift of the concentration-response curve to the right in a competitive manner (pA2 = 6.93). The specific method of using the receptor antisense oligodeoxynucleotides approach revealed the presence of endothelin ETA receptors mediating contraction in the human superficial temporal artery.}, author = {Adner, Mikael and Erlinge, David and Salford, Leif and Yee, Frances and Wahlestedt, Claes and Edvinsson, Lars}, issn = ...

Tezosentan is a potent, specific, and highly water-soluble ET receptor antagonist. It binds with a high affinity to human ETA receptors. The lower inhibitory potency observed for the human ETA receptors expressed in baculovirus-infected insect cells compared with CHO cells is likely to be due to a different glycosylation pattern, a modified receptor conformation due to the marked overexpression, or an abnormal G protein coupling of the receptor in this expression system. The high-affinity binding of tezosentan on ETA receptors is also confirmed in functional assays. Tezosentan also has a high affinity for ETB receptors and is about 30-fold more potent on ETA receptors than on ETBreceptors. It is a competitive antagonist, and therefore its inhibitory activity will depend on the agonist concentration. It is a very specific antagonist for ET receptors.. The in vivo pharmacological properties of tezosentan have been evaluated by its inhibition of the pressor effect of big ET-1 and by the increase in ...

Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death (16,35). Thus, ET antagonists are of great clinical interest as mortality remains high in patients with CHF in spite of currently available drugs. Endothelin-1 exerts its vasoconstrictive effects through activation of ETA and ETB receptors on vascular smooth muscle cells. The ETA receptor also mediates proliferation of vascular smooth muscle cells (9). In contrast, ETB receptors on endothelial cells mediate the release of vasodilating and antiproliferative NO and prostaglandins (10-12) and are involved in the clearance of ET-1 (22-25). Indeed, selective ETB antagonism exerts unfavorable hemodynamic effects (36,37). Therefore, there is particular interest in selective ETA receptor antagonists as therapeutic agents in chronic heart failure. As in previous studies with other ET-1 receptor antagonists, ET-1 plasma levels increased significantly after administration of the selective ETA receptor antagonist ...

TY - JOUR. T1 - Bosentan ameliorates cyclosporin A-induced hypertension in rats and primates. AU - Bartholomeusz, Briony. AU - Hardy, Kenneth J.. AU - Nelson, Angela S.. AU - Phillips, Paddy A.. PY - 1996/6/1. Y1 - 1996/6/1. N2 - Cyclosporine-induced hypertension is a major problem in transplant therapy. The pathophysiology of this disease is unclear. Cyclosporine increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of chronic endothelin receptor blockade with the novel nonpeptide endothelin receptor antagonist bosentan in two animal models of cyclosporine-induced hypertension. Cyclosporine was administered daily to female Wistar rats (10 mg/kg per day SC for 30 days) and marmosets (30 mg/kg per day PP for 20 days). Control rats received vehicle. Tail-cuff systolic pressure was significantly elevated in the cyclosporine-treated animals before the last week of treatment. Bosentan (100 mg/kg) in arabic gum or arabic gum alone was given ...

Macitentan may be the lately approved dual endothelin-receptor antagonist (Period) for the treating symptomatic pulmonary arterial hypertension. hypertension sufferers with macitentan resulted in statistically significant improvements in useful class, workout tolerance, and hemodynamic variables, and a decrease in morbidity within an event-driven long-term trial. solid course=kwd-title Keywords: endothelin, endothelin receptor antagonists, macitentan, pulmonary arterial hypertension Pulmonary arterial hypertension Pulmonary arterial hypertension (PAH) is normally a intensifying and BRL-15572 supplier lethal disease seen as a remodeling from the pulmonary arterioles with consequent enhance from the pulmonary vascular level of resistance (PVR) with eventual best ventricular failing and ultimately loss of life. Furthermore, despite targeted remedies, the disease continues to be fatal.1 The organic history of PAH as well as the survival prices for patients experiencing this disease had been ...

TY - JOUR. T1 - Determination of the endothelin-1 recognition sites of endothelin receptor type A by the directed-degeneration method. AU - Han, Seong Gu. AU - Ko, Sanghwan. AU - Lee, Won Kyu. AU - Jung, Sang Taek. AU - Yu, Yeon Gyu. PY - 2017/12/1. Y1 - 2017/12/1. N2 - G-protein coupled receptors (GPCRs) play indispensable physiological roles in cell proliferation, differentiation, and migration; therefore, identifying the mechanisms by which ligands bind to GPCRs is crucial for developing GPCR-targeting pharmaceutics and for understanding critical biological functions. Although some structural information is available regarding the interactions between GPCRs and their small molecule ligands, knowledge of how GPCRs interact with their corresponding macromolecule ligands, such as peptides and proteins, remains elusive. In this study, we have developed a novel strategy to investigate the precise ligand recognition mechanisms involved in the interaction of endothelin receptor type A (ETA) with its ...

Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.

Endothelin 1 may have a role in the development of acute airway narrowing in asthma. Blockade of the endothelin system may thereby protect against airway narrowing. Two receptors exist for endothelin 1, Endothelin A & B. Both can be blocked by Bosentan, and the A receptor by ambrisentan. Both medications are currently in use for the treatment of pulmonary arterial hypertension. The investigators will endeavour to examine the potential role of endothelin 1 in the development of airway narrowing in asthma through blockade of the endothelin receptors A&B through the use of bosentan and ambrisentan ...

This is the first study to investigate the effects of tezosentan, a non-selective endothelin receptor antagonist, in LPS challenged rats with cirrhosis. LPS was administered intravenously, followed by intravenous administration of tezosentan or placebo one hour later. Thus the study design mimics the occurrence of severe endotoxaemia by intravenous administration of a Gram negative bacterial product. In this study, normal rats were not investigated as we observed that 1 mg/kg LPS intravenously had only minor effects on serum transaminase activities and had no lethal effects (unpublished results, Moreau and Lebrec, 2001). Similar findings have been previously observed.6,7. In this series of rats with cirrhosis, LPS administration induced a significant decrease in arterial pressure and an increase in plasma endothelin levels associated with elevated serum transaminase activities and high mortality indicating endotoxin induced liver injury. These results were similar to those previously observed ...

INTRODUCTION: The purpose of this study was to determine whether prolonged oral therapy with sitaxsentan, a potent selective ET(A) endothelin receptor antagonist, normalizes systolic blood pressure in spontaneously hypertensive hamsters, a new rodent

At the cell surface, βARs and endothelin receptors can regulate nitric oxide (NO) production. β-adrenergic receptors (βARs) and type B endothelin receptors (ETB) are present in cardiac nuclear membranes and regulate transcription. The present study investigated the role of the NO pathway in the regulation of gene transcription by these nuclear G protein-coupled receptors. Nitric oxide production and transcription initiation were measured in nuclei isolated from the adult rat heart. The cell-permeable fluorescent dye 4,5-diaminofluorescein diacetate (DAF2 DA) was used to provide a direct assessment of nitric oxide release. Both isoproterenol and endothelin increased NO production in isolated nuclei. Furthermore, a β3AR-selective agonist, BRL 37344, increased NO synthesis whereas the β1AR-selective agonist xamoterol did not. Isoproterenol increased, whereas ET-1 reduced, de novo transcription. The NO synthase inhibitor l-NAME prevented isoproterenol from increasing either NO production or de ...

OBJECTIVE: Endothelins (ETs) are involved in several inflammatory events. The present study investigated the efficacy of bosentan, a dual ETA/ETB receptor antagonist, in collagen-induced arthritis (CIA) in mice. TREATMENT: CIA was induced in DBA/1J mice. Arthritic mice were treated with bosentan (100 mg/kg) once a day, starting from the day when arthritis was clinically detectable. METHODS: CIA progression was assessed by measurements of visual clinical score, paw swelling and hypernociception. Histological changes, neutrophil infiltration and pro-inflammatory cytokines were evaluated in the joints. Gene expression in the lymph nodes of arthritic mice was evaluated by microarray technology. PreproET-1 mRNA expression in the lymph nodes of mice and in peripheral blood mononuclear cells (PBMCs) was evaluated by real-time PCR. The differences were evaluated by one-way ANOVA or Students t test. RESULTS: Oral treatment with bosentan markedly ameliorated the clinical aspects of CIA (visual clinical score,

TY - JOUR. T1 - Endothelin receptor alterations in equine airway hyperreactivity. AU - Venugopal, Changaram S.. AU - Polikepahad, Sumanth. AU - Holmes, Earnestine P.. AU - Vanden Heuvel, John Patrick. AU - Leas, Tara L.. AU - Moore, Rustin M.. PY - 2006/1/1. Y1 - 2006/1/1. N2 - The purpose of this study was to evaluate the role of endothelin-1 (ET-1) and its receptors in the airway hyperreactivity of horses with obstructive pulmonary disease associated with summer pasture (SPAOPD). The right diaphragmatic lobe of the lung of 8 clinically healthy (unaffected) and 8 SPAOPD-affected horses was collected immediately after euthanasia. Bronchial rings (4 mm wide) were prepared and mounted in organ baths and attached to force transducers interfaced with a polygraph. Four rings were used to study each ET-1 receptor; 1 ring served as the control, and the other 3 were incubated with 10-9, 10-7, or 10-5 M of either BQ-123, an ETA-receptor antagonist, or IRL-1038, an ETB-receptor antagonist. Cumulative ...

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Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin-angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET-1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ETA) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors

Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ETA-receptor antagonists over mixed or dual receptor antagonists has depended on a range of receptor binding assays, second messenger assays and functional blood vessel assays. This study compared the 3 clinically-approved endothelin receptor antagonists in assays of human isolated pulmonary and radial arteries in vitro. METHODS: Human isolated pulmonary (i.d. 5.5mm) and human radial (i.d. 3.23mm) artery ring segments were mounted in organ baths for isometric force measurement. Single concentration-contraction curves to endothelin-1 were constructed in the absence or presence of bosentan (1-10µM), macitentan (0.03-0.3µM) or ambrisentan (0.1-1µM). RESULTS: All 3 endothelin antagonists caused competitive rightward shifts in the endothelin-1 concentration-response curves in both arteries. The Clark plot and analysis gave the following pKB values: bosentan, pulmonary artery 6.28±0.13 and ...

Introduction. Endothelin-1 (ET-1), together with its cognate receptors endothelin receptor subtype A (ET-RA) and endothelin receptor subtype B (ET-RB), is known to be one of the many mediators that play a role in angiogenesis.1 For example, it has been shown that ET-1, acting via ET-RB and in concert with vascular endothelial growth factor (VEGF), promotes proliferation, migration and invasion of umbilical vein endothelial cells (HUVECs).2 The ET axis has also been found to be over-expressed by cancer cells and there is evidence that it is involved, in association with VEGF and other factors, in tumour angiogenesis.3 For example, in ovarian cancer, ET-1 stimulates early neovascularisation (proliferation and migration of endothelial cells) via ET-RB receptors.4 The ET system also plays a less direct role in angiogenesis by, for example, breaking down the extracellular matrix.3,5 Studies have linked increased tumour vascularity to ET-1 in brain tumours, ovarian and colorectal cancer,4,6,7 and in a ...

Introduction. Endothelin-1 (ET-1), together with its cognate receptors endothelin receptor subtype A (ET-RA) and endothelin receptor subtype B (ET-RB), is known to be one of the many mediators that play a role in angiogenesis.1 For example, it has been shown that ET-1, acting via ET-RB and in concert with vascular endothelial growth factor (VEGF), promotes proliferation, migration and invasion of umbilical vein endothelial cells (HUVECs).2 The ET axis has also been found to be over-expressed by cancer cells and there is evidence that it is involved, in association with VEGF and other factors, in tumour angiogenesis.3 For example, in ovarian cancer, ET-1 stimulates early neovascularisation (proliferation and migration of endothelial cells) via ET-RB receptors.4 The ET system also plays a less direct role in angiogenesis by, for example, breaking down the extracellular matrix.3,5 Studies have linked increased tumour vascularity to ET-1 in brain tumours, ovarian and colorectal cancer,4,6,7 and in a ...

Endothelin-1 (ET-1) is a potent mitogen and modulator of vascular tone. It is synthesized and released from endothelial cells and acts upon two receptor subtypes designated as ETA and ETB. In this study, a series of potent dipeptide sulfonamide dual-

TY - JOUR. T1 - Endothelin antagonism reduces circulating galectin-3 in patients with proteinuric chronic kidney disease. AU - Farrah, Tariq E. AU - Anand, Atul. AU - Miller-Hodges, Eve. AU - Mills, Nicholas L. AU - Webb, David J. AU - Dhaun, Neeraj. PY - 2018/1. Y1 - 2018/1. KW - Endothelin Receptor Antagonists. KW - Endothelins. KW - Galectin 3. KW - Humans. KW - Proteinuria. KW - Renal Insufficiency, Chronic. U2 - 10.1016/j.kint.2017.10.009. DO - 10.1016/j.kint.2017.10.009. M3 - Letter. C2 - 29291821. VL - 93. SP - 270. JO - Kidney International. JF - Kidney International. SN - 0085-2538. IS - 1. ER - ...

It is established that peptidemimetic drugs, such as renin inhibitors, somatostatin analogs, and endothelin antagonists, are often efficiently excreted into the bile in an unchanged form, resulting in their low bioavailability (Bertrams et al., 1991a,b;Greenfield et al., 1989; Nakamura et al., 1996). However, the present study shows that both the CLtotal andCLbile, p differ between various endothelin antagonist. Compound A has a 4-fold lowerCLtotal than that of BQ-485 (Table 1).CLbile, p also differs between each compound, with an 8-fold difference between compound A and BQ-485 (Table 1). The inhibition constant of compound A for binding to ETA is in the nanomolar range, as in the case of BQ-485 and BQ-123 (22, 3.4, and 13 nM for BQ-123, BQ-485, and compound A, respectively) (Fukami et al., 1996; Itoh et al., 1993; Moreland et al., 1994). This means that it is possible to construct a small peptide, like compound A, that exhibits relatively lower hepatic extraction but still has potent antagonist ...

Since its discovery in 1988, endothelin (ET) has been widely implicated in the pathophysiology of cardiovascular disease. ET antagonists have favourable effects in experimental models of these...

TY - JOUR. T1 - β-adrenergic and endothelin receptor interaction in dilated human cardiomyopathic myocardium. AU - Walker, C. A.. AU - Ergul, A.. AU - Grubbs, A.. AU - Zile, M. R.. AU - Zellner, J. L.. AU - Crumbley, A. J.. AU - Spinale, F. G.. PY - 2001. Y1 - 2001. N2 - Background: Although end-stage dilated cardiomyopathy (DCM) is characterized by defects in β-adrenergic receptor (β-AR) activity and increased endothelin-1 (ET-1), possible interactions between these 2 systems remain to be defined. Accordingly, the goal of this study was to determine the effects of ET receptor activation on β-AR signaling through measurement of cyclic adenosine monophosphate (cAMP) in normal and DCM myocardium. Methods and Results: Myocardial sarcolemmal preparations were prepared from normal human (n = 6), dilated cardiomyopathic (n = 10), and ischemic cardiomyopathic (ICM, n = 10) tissue. Basal cAMP production was measured in the presence of ET-1 alone (10−6 to 0−9 mol/L) as well as after ...

The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ETA) and endothelin B (ETB) receptors including those in the vasculature. Previous studies demonstrated that sex and sex hormones evoke discrepancies in ET-1-mediated control of vascular tone in different vascular beds. However, little is known about sex- and sex hormone-related differences in ET-1-dependent renal microvascular reactivity. Accordingly, we hypothesized that loss of sex hormones impairs afferent arteriole reactivity to ET-1. Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery (n = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ETA and ETB agonist, 10−12 to 10−8 M) and sarafotoxin 6c (S6c, ETB agonist, 10−12 to 10−8 M) using the

The IUPHAR/BPS Guide to Pharmacology. ETA receptor - Endothelin receptors. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.

Fingerprint Dive into the research topics of Affinity labelling of endothelin receptor and characterization of solubilized endothelin-endothelin‐receptor complex. Together they form a unique fingerprint. ...

We are interested in developing an airway explant culture system using sheep bronchi in which to establish respiratory viral infection and from which tissue can be used for functional, biochemical and immunohistochemical studies involving the endothelins (ETs). Freshly harvested sheep bronchial airway smooth muscle contains a homogeneous population of the ETA receptor. However, the potency of ET-1 and maximum contractile response of sheep bronchial explants to ET-1 increased with time in culture, despite these parameters remaining constant for carbachol in explants maintained for up to 48h. The possibility that this was caused by changes in ET receptor density was assessed using light microscopic quantitative autoradiography. In view of the increased responsiveness to ET-1 in cultured explants, it was surprising to demonstrate a significant decrease in total ET receptor (59±6% compared with the initial value, n = 4-5; P,0.01) and ETA receptor (51±2% compared with the initial value, n = 4-5, ...

AIM: Peripheral artery disease results in impaired blood flow to the extremities, most often as a consequence of atherosclerotic disease. The hallmark of atherosclerosis is chronic inflammation in the vessel wall. The renin-angiotensin and endothelin systems are considered important pathophysiological effectors. Midkine, a multifunctional cytokine, fulfils different roles in inflammation and promotion of neoangiogenesis. The aim of this study was to assess whether circulating midkine serum levels in patients with peripheral artery disease correlate with established atherosclerosis risk factors, as well as titers of functional autoantibodies directed against receptors of the renin-angiotensin and endothelin system ...

The contribution of the endothelin system to BP regulation in the SHR is controversial, but the present work appears to be the first in which BP was measured by radiotelemetry. We found that bosentan per se failed to induce any change in BP in both rat strains. The bosentan was active because it antagonized the effects of exogenous administration of ET-1 in conscious rats (Fig 2⇑) and the tension responses to ET-1 in ring preparations of rat aorta (Table 2⇑) in a competitive fashion. These results parallel those of other researchers.6 7 In contrast to our findings with bosentan, both BQ-123, an ETA antagonist, and SB 209670, a nonselective ETA/ETB antagonist, have been reported to reduce BP in SHR8 9 and transgenic rats10 when infused over prolonged periods. On the other hand, other researchers have reported no change of BP with BQ-123 and bosentan in SHR.11 12 Pressure in these previous studies was monitored with exteriorized catheters or by the tail-cuff method. Control BP values are ...

Principal Investigator：NINOMIYA Haruaki, Project Period (FY)：1998 - 2001, Research Category：Grant-in-Aid for Scientific Research (C), Section：一般, Research Field：General pharmacology

units with a pulmonary capillary wedge pressure < 15 mmHg 8,10. TREATMENT SSc-associated PAH previously had a poor prognosis with a one-year survival rate of 45%. Poor survival has significantly increased with modern treatments such as prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Drugs used in PAH 1) Prostanoids a)Epoprostenol: Starting dose of infusion is 1-2 ng/kg per minute, gradually increased up to 25-40 ng/kg per minute b) Treprostinil: given as a continuous subcutaneous or intravenous infusion in patients with PAH from functional class II, III and IV Dose:1.25 ng/kg per minute 2).Endothelin receptor antagonists a)Bosentan: It is indicated for PAH functional classes II, III and IV. Dose: 62.5 mg bid for 4 weeks before titration up to 125-250 mg bid b) Ambrisentan: Dose: 2.5-10 mg Ambrisentan in combination with tadalafil reduces the risks of disease progression and hospitalization for worsening PAH and improves exercise ability. 3)PDE inhibitors a) ...

Name: Beta-blockers and ace inhibitors as combination therapy for heart failure or endothelin receptor antagonist and ace inhibitors as combination therapy for heart failure Course: Lecturer: Date Table of Content ABSTRACT 2 INTRODUCTION 3 Background to the Study 3 Purpose of the Study 4 Research Questions 4 Significance of the Study 4 LITERATURE REVIEW 5 Literature Search Approach 5 Current trend in cases of heart failure 6 Systolic Dysfunction in Heart Failure: Neurohormonal Theory 7 Beta blocks and their functions 8 ACE inhibitors and their functions 9 Endothelin receptor antagonists and their functions 10 RESULTS 11 Selection of Patients for Beta-Blockers and ACE Inhibitor combination 12 ...

Results Ninety-eight patients (initial ERA=24, initial PDE5=59, initial ERA/PDE5=15) were included; no significant differences in baseline variables existed. TTCW was significantly worse in patients initially started on ERA compared to PDE5 or ERA/PDE5 (p=0.0001). Baseline factors independently associated with shorter TTCW were initial ERA (HR 2.63, p=0.009), lower DLCO (HR 0.69 per 10% change, p=0.04), and higher PVR (HR 1.10 per Wood unit change, p=0.007). Three year survival was significantly worse in the initial ERA group (52.9%) compared to the PDE5 (91.5%) or ERA/PDE5 group (92.9%, p=0.004). The only baseline factor independently associated with risk for death in this cohort was initial ERA therapy (HR 4.55, p=0.004). ...

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The current understanding of the mechanisms of action of insulin and cellular interactions of insulin with endothelin supports an expectation for both vascular and nonvascular effects of endothelin antagonism on insulin action. The discovery of endothelin as a vasoconstrictor agent produced by the endothelium prompted initial explorations of its role as a modulator of vascular function (39). The net tissue actions of insulin in skeletal muscle depend in part on the capacity of the vasculature to vasodilate in response to insulin (12,40,41), with this vasodilation actively redistributing blood flow in support of the increased metabolism (13). This vascular action of insulin is impaired in states of insulin resistance (9,42,43), and we and others have previously shown that increased endogenous endothelin contributes to vascular dysfunction in obesity and diabetes (7,8). Based on these observations, we had an a priori expectation that endothelin antagonism would improve insulin-stimulated ...

Endothelin A Receptor: A subtype of endothelin receptor found predominantly in the VASCULAR SMOOTH MUSCLE. It has a high affinity for ENDOTHELIN-1 and ENDOTHELIN-2.

Biological Description: Macitentan(ACT064992) is an orally active, non-peptide dual endothelin ETA and ETB receptor antagonist for the potential treatment of idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).IC50 value: Target: ETA/ETB ...

Ambrisentan belongs to the group of medications called endothelin receptor antagonists. These medications block the action of endothelin in the arteries of the lung that causes blood vessels to tighten or constrict. Ambrisentan is used to treat the symptoms of primary pulmonary arterial hypertension (PAH), or high blood pressure in the arteries of the lungs.

Supplementary MaterialsSupplementary Information 41467_2020_16637_MOESM1_ESM. Small RNA profiling reveals that miR2118-dependent 21-nucleotide (nt) phasiRNAs in the anther wall are?U-rich, distinct from the phasiRNAs in germ cells. Furthermore, the miR2118-dependent biogenesis of 21-nt phasiRNAs may involve the Argonaute proteins OsAGO1b/OsAGO1d, which are abundant in anther wall NRAS cell layers. Our study highlights the site-specific differences of phasiRNAs […]. ...

Principal Investigator：SHIGEMATSU Kazuto, Project Period (FY)：1997 - 1998, Research Category：Grant-in-Aid for Scientific Research (C), Section：一般, Research Field：Experimental pathology

Learn more about OPSUMIT® (macitentan), an endothelin receptor antagonist, including PAH (WHO Group 1) disease education, and more.

GPR37 antibody (G protein-coupled receptor 37 (endothelin receptor type B-like)) for IHC-P. Anti-GPR37 pAb (GTX85872) is tested in Human samples. 100% Ab-Assurance.

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I had a few other issues to discuss with him but overall the neurologist felt that Dear Son had deteriorated significantly and that his disease is progressing. In light of that, he asked me what I wanted to do regarding the surgery and I said that I didnt want to drive that issue. We talked some more and I asked him if we were to do the surgery, is this something we need to do now or later and he felt if we did it, we should do it now since he wont be able to manage it later. He told me that there is a chance Dear Son would need to be intubated after the surgery and that the intubation could be quite lengthly. He explained that Dear Son will die of respiratory issues. I did not get the sense that he felt Dear Son would really make it through the surgery even though the ENT thought the surgery was doable. I also had some difficulty in doing a surgery so soon after we had been released. My gut tells me that Dear Son would not survive this surgery. I saw how hard it was in November for him to ...

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The aim of this study was to characterize endothelin receptor subtypes of the detrusor muscle of the human urinary bladder. The receptor subtypes mediating endothelin (ET)-1-induced activity in the human detrusor smooth muscles have been characterized using isometric contraction and reverse transcription-polymerase chain reaction (RT-PCR). ET-1 (a non-selective ET receptor agonist; 10-10 M to 10-6 M) exhibited concentration-dependent contractions in human urinary bladder with a plateau at concentrations above 3×10-7 M. Neither IRL1620 nor sarafotoxin S6c (both ETB-selective agonists; 10-10 M to 10-6 M) elicited contractile activity in the human urinary bladder detrusor smooth muscle. FR139317 (an ETA-selective antagonist; 10-7 M to 10-5 M) produced a marked shift to the right of the ET-1 concentration-response curve in human urinary bladder detrusor smooth muscle (from the Schild plot TpA2 = 7.96; slope = 0.95). In contrast, RES701-1 (an ETB-selective antagonist; 10-7 M to 10-5 M) had no effect ...

article{b53dd734-d576-42ed-8e0f-a70425b980ab, abstract = {The aim of this study was to examine if endothelin ETB receptor-mediated contraction occurred in isolated segments of rat coronary arteries during organ culture. Presence of contractile endothelin ETB receptors was studied by measuring the change in isometric tension in rings of left anterior descending coronary arteries isolated from hearts of rats as response to application of the selective endothelin ETB receptor agonist, Sarafotoxin 6c and endothelin-1. In segments cultured 1 day in serum free Dulbeccos Modified Eagles Medium, Sarafotoxin 6c induced a concentration dependent contraction with pEC(50) value of 10.4 +/- 0.21 and a maximal response of 3.9 +/- 0.25 mN/mm (n = 15). The maximal contraction was significantly larger than the responses measured in fresh tissue, where the mean value of the maximal contractions was 0.22 +/- 0.03 mN/mm (n = 17). The increased contraction to Sarafotoxin 6c, after culturing could be eliminated ...

About one third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (Sarafotoxin 6c for 30-40 min; 0.78 pmol h-1 directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague Dawley rats ...

About one third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (Sarafotoxin 6c for 30-40 min; 0.78 pmol h-1 directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague Dawley rats ...

TY - JOUR. T1 - Endothelin receptor blockade during hypothermic perfusion preservation mitigates the adverse effect of preretrieval warm ischemic injury on posttransplant glomerular filtration rate. AU - Inman, Sharon R.. AU - Burns, Thomas E.. AU - Plott, Wanda K.. AU - Pomilee, Ray A.. AU - Antonelli, Jodi A.. AU - Lewis, Richard M.. PY - 2002/7/27. Y1 - 2002/7/27. N2 - Background. Preretrieval warm ischemic injury predisposes to both short-term and long-term dysfunction of cadaveric renal allografts. We previously reported that the excretion of the vasoactive peptide, endothelin (ET), is significantly increased during hypothermic perfusion preservation (HPP) of kidneys subjected to preretrieval warm ischemia compared with nonischemic controls. As such, the purpose of this study was to determine if endothelin receptor (ET-R) blockade during HPP would improve glomerular filtration rate (GFR) of kidneys subjected to preretrieval warm ischemia when measured in situ at 2 weeks after ...

TY - JOUR. T1 - Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure. AU - Fratz, Sohrab. AU - Meyrick, Barbara. AU - Ovadia, Boaz. AU - Johengen, Michael J.. AU - Reinhartz, Olaf. AU - Azakie, Anthony. AU - Ross, Greg. AU - Fitzgerald, Robert. AU - Oishi, Peter. AU - Hess, John. AU - Black, Stephen M.. AU - Fineman, Jeffrey R.. PY - 2004/9/1. Y1 - 2004/9/1. N2 - Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in ...

TY - JOUR. T1 - Renal vasoconstriction to endothelin-1 is enhanced with blockade of endothelin-B receptors or nitric oxide production. AU - Stacy, D. L.. AU - Martinez, R.. AU - Tilton, Ronald. PY - 1996. Y1 - 1996. N2 - Endothelin (ET-1) is a potent renal vasoconstrictor causing an initial transient vasodilation due to activation of ETB receptors and a long-lasting vasoconstriction thought to be due to ETA and ETB receptors. In anesthetized rats ET-1 was infused intravenously {i.V., 1 nmole/kg) after BQ-123 (an ETA receptor antagonist), BQ-788 (an ETB receptor antagonist), or vehicle. Left renal artery flow and mean arterial pressure (MAP) were measured. Resistance was calculated as MAP/flow. ET-1 increased renal resistance by 248% (26±2 to 90±13 mmHg/ml/min.). After pretreatment with BQ-123 (1 mg/kg, i.V.), the increase in renal resistance with ET-1 was reduced by 77% (29±5 to 43±7 mmHg/ml/min.), due to a reduction in the increase in MAP by 81% and decrease in flow by 61%. Pretreatment ...

295329207 - EP 1009741 A1 2000-06-21 - NOVEL CARBOXYLIC ACID DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MIXED ET A?/ET B? ENDOTHELIN-RECEPTOR ANTAGONISTS - [origin: WO9911629A1] The invention relates to carboxylic acid derivatives of formula (I) wherein the radicals are defined in the description, and to the use of these derivatives as ETA/ETB endothelin-receptor antagonists.[origin: WO9911629A1] The invention relates to carboxylic acid derivatives of formula (I) wherein the radicals are defined in the description, and to the use of these derivatives as ETA/ETB endothelin-receptor antagonists.

A highly selective peptide agonist of the endothelin-B receptor. Endothelin B receptor agonist SPI-1620 binds to endothelin-B receptors on endothelial cells in tumor blood vessels, which, unlike the angioarchitecture of normal blood vessels, are relatively devoid of smooth muscle. This agent may induce a transient, selective increase in blood flow to a tumor, which may result in an increase in the delivery of anticancer agents to the tumor and, so, an increase in anticancer agent efficacy.. ...

United States Endothelin Receptor Antagonist Market Report 2016 is a market research report available at US $3800 for a Single User PDF License from RnR Market Research Reports Library.

In the present study, chronic administration of bosentan, an antagonist of both ETA and ETB receptors, had no significant effect on the systolic BP level reached after 6 weeks of L-NAME treatment, confirming the observation that acute (60 minutes) administration of the selective ETA receptor antagonist BQ-123 could not lower BP in rats treated for 3 weeks with an l-arginine analogue.21 However, the delay in the BP elevation occurring when bosentan was added to L-NAME would suggest that ET is involved in the early hypertensive response to the l-arginine analogue. This observation is in line with studies showing a blunted hypertensive effect of acute L-NAME administrations by ET receptor antagonists12 13 14 and provides experimental evidence to explain the discrepancy in the efficacy of ET receptor antagonists in acute and chronic L-NAME-induced hypertension.. Chronic administration of L-NAME leads to eutrophic remodeling of the basilar artery, as we previously reported.15 The structural ...

There are no specific protocols for Recombinant Human Endothelin B Receptor protein (ab114259). Please download our general protocols booklet

In the RITZ-4 trial, the effect of tezosentan in patients with acute decompensated heart failure associated with acute coronary syndromes was evaluated.43 In this multicenter, randomized, double-blind trial, 193 patients were randomized to receive intravenous 25 mg tezosentan per hour for the first hour and then 50 mg per hour up to 48 hours or placebo. The primary end point was a composite of death, worsening heart failure, recurrent ischemia, and recurrent or new myocardial infarction within 72 hours. No significant differences were observed between the group receiving tezosentan and placebo in the composite primary end point. Symptomatic hypotension was more frequent in the treatment group.. The RITZ-5 trial evaluated the addition of intravenous tezosentan to standard therapy for patients presenting with acute pulmonary edema.44 In this trial, all patients received oxygen through a face mask, intravenous morphine, furosemide, and a continuous drip of isosorbide dinitrate according to their ...

The vascular effects of the endothelin B (ETB) receptor agonist IRL 1620 were investigated in the rat P22 carcinosarcoma and a range of normal tissues in BDIX rats. Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine. A comparison of vascular effects in the P22 tumour and the HSN sarcoma growing in CBH/CBi rats was made using laser Doppler flowmetry, showing similar effects of IRL 1620, with red cell flux rapidly decreasing by 50-60% and then returning to control levels within approximately 30 min. This corresponded to similar levels but different spatial organisation of ETB binding sites in the two tumours, as measured by autoradiography. The decrease in tumour blood flow and an increase in vascular resistance suggest that the vascular component of ETB receptors in the P22 tumour is localised on contractile elements rather than on endothelial cells. ETA receptors were also identified. Vasoconstriction occurred uniformly throughout the P22 ...

BioAssay record AID 66868 submitted by ChEMBL: Inhibition of (125 I)-endothelin 1 binding to endothelin B receptor in rat cerebellum.

Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

METHODS AND RESULTS Experiments were performed on rats at 1 through 16 weeks after sham operation or coronary artery ligation. Rats with left ventricular end-diastolic pressures , 15 mm Hg were considered to have chronic heart failure (CHF), while the others were considered to have uncomplicated myocardial infarction (MI). There were increased ET-1 concentrations in CHF rats at weeks 1 to 16 (Sham, 20 +/- 0.5 pg/mL, n = 45; CHF, 31 +/- 2 pg/mL, n = 50; P , .001) and transient increases in ET-3 concentrations at week 1 in both the MI and CHF groups. There were no significant increases in big ET-1 concentrations, suggesting an increased conversion of ET-1 from big ET-1 in the CHF group. At weeks 2 through 8, oral administration of the mixed (ETA and ETB) endothelin receptor antagonist bosentan significantly decreased mean arterial pressure in conscious CHF rats, an effect that increased over time. Furthermore, bosentan had an additive effect to the angiotensin-converting enzyme inhibitor ...

EDNRB - EDNRB (Myc-DDK-tagged)-Human endothelin receptor type B (EDNRB), transcript variant 3 available for purchase from OriGene - Your Gene Company.

Recent gene targeting studies have revealed unexpected roles for endothelins in the development of neural crest-derived tissues. Endothelin converting enzyme-1 (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to endothelin-1(ET-1) in vitro. However, the importance of ECE-1 cleavage in the multiple endothelin pathways in vivo is unknown. Here we generated a targeted null mutation in the mouse ECE-1 gene. ECE-1−/− term embryos exhibited craniofacial and cardiac abnormalities virtually identical to the defects seen in ET-1 and endothelin A receptor (ETA)-deficient embryos. Epidermal melanocytes as well as enteric neurons of the distal gut were also absent in ECE-1−/− embryos, reproducing the developmental phenotype seen in ET-3−/− and endothelin B receptor (ETB)−/− mice. Surprisingly, large amounts of mature ET-1 peptide are found in ECE-1−/− embryos, indicating that non-ECE-1 protease(s) can activate ET-1 at certain sites. However, these enzymes cannot produce ...

Microvascular dysfunction originating during a preeclamptic pregnancy persists postpartum and probably contributes to increased CVD risk in these women. One putative mechanism contributing to this dysfunction is increased vasoconstrictor sensitivity to endothelin-1 (ET-1), mediated by alterations in ET-1 receptor type-B (ETBR). We evaluated ET-1 sensitivity, ETAR, and ETBR contributions to ET-1-mediated constriction, and the mechanistic role of ETBR in endothelium-dependent dilation in vivo in the microvasculature of postpartum women who had preeclampsia (PrEC, n=12) and control women who had a healthy pregnancy (HC, n=12). We hypothesized that (1) PrEC would have a greater vasoconstrictor response to ET-1, and (2) reduced ETBR-mediated dilation. We further hypothesized that ETBR-blockade would attenuate endothelium-dependent vasodilation in HC, but not PrEC. Microvascular reactivity was assessed by measurement of cutaneous vascular conductance responses to graded infusion of ET-1 ...

LifeSpan BioSciences currently sells 33 antibodies , 5 peptides , 11 ELISA Kits , 4 proteins specific for EDNRB / Endothelin B Receptor.

Buy our Endothelin B Receptor peptide. Ab109654 is a blocking peptide for ab95911 and has been validated in BL. Abcam provides free protocols, tips and expert…

Endothelin B Receptor Polyclonal Antibody from Invitrogen for Western Blot and Immunohistochemistry (Paraffin) applications. This antibody reacts with Human, Mouse, Rat samples. Supplied as 100 µL purified antibody (1 mg/ml) in PBS with 50% glycerol and 0.01% thimerosal; pH 7.

When Yanagisawa et al.1 first identified endothelin (ET), a novel polypeptide vasoconstrictor for which numerous other functions were identified later,2 there was early widespread enthusiasm and great expectation for therapeutic opportunities. ET-1 is the most powerful vasoconstrictor in this peptide family; the ET system is complex with a converting enzyme and two receptors, ETA-R and ETB-R. The receptors offer an opportunity for selective blockade. ETA-R primarily mediates vasoconstriction and plays a role in the genesis of hypertension, states of endothelial dysfunction, insulin resistance, inflammation, and fibrosis. From a renal perspective, it is important to note that both ETA-R and ETB-R are found in the kidney, ETA-R in vessels and ETB-R mainly in the medulla3 but also in glomeruli.4 Of note, collecting duct ETB-R null mice develop elevated BP, pointing to a potential causal role in the genesis of hypertension.5 It was immediately perceived that such a multifunctional system might ...

Since its discovery in 1988 the powerful vasoconstrictor endothelin-1 (ET-1) has been widely implicated in the pathophysiology of chronic kidney disease (CKD) as well as the cardiovascular disease with which it is associated. ET receptor antagonists have favourable effects in experimental models of these conditions and orally acting antagonists are now licensed for the treatment of pulmonary arterial hypertension. However, there is a paucity of human data regarding the role of ET-1 in CKD. In this thesis, I have therefore explored the utility of ET-1 as a biomarker in CKD, and, using selective ET receptor antagonists, the beneficial renal and cardiovascular effects of ET receptor antagonism in CKD. I have shown that as glomerular filtration rate (GFR) declines plasma ET-1 increases linearly whereas urinary ET-1 shows an exponential increase. Furthermore, urinary ET-1 may be a useful marker of disease activity in patients with lupus nephritis. Its levels are high in those with biopsy-proven ...

TY - JOUR. T1 - Elevated urinary excretion of endothelin in insulin-dependent diabetes mellitus. T2 - No influence of physical exercise. AU - Mattyus, I.. AU - Zimmerhackl, L. B.. AU - Schwarz, A.. AU - Brandis, M.. AU - Miltényi, M.. AU - Tulassay, T.. PY - 1996/1/1. Y1 - 1996/1/1. N2 - The urinary excretion of endothelin was measured by radioimmunoassay in children with diabetes mellitus in metabolically stable condition before and after ergometric exercise. Apparently healthy children served as normal controls. The excretion of endothelin, calculated for 24h and the ratio of endothelin/creatinine in urine were also significantly higher in diabetic children compared to normal controls. Physical exercise had no influence on renal endothelin excretion. In-diabetic children the volume of diuresis was higher compared to controls. Physical exercise had no influence on diuresis. In a previous study we found a positive correlation between diureses and endothelin excretion. Therefore, the increased ...

Endothelins are potent endothelium-derived vasoconstrictors 1. The endothelin system has been reported to be activated in various types of experimental or clinical pulmonary hypertension 1. However, whether endogenous endothelins play a role in the control of systemic and pulmonary vascular tone in vivo remains uncertain. Endothelin receptor antagonists have been shown to increase forearm blood flow in humans 2, 3, to reduce brachial artery pressure in patients with essential hypertension 4 and to decrease pulmonary artery pressure in patients with primary pulmonary hypertension 5, 6. However, some investigators have been unable to demonstrate pulmonary or systemic vascular effects of these compounds in vivo 7-17. The failure to show a vasoconstrictor effect of endogenous endothelins appears related, at least in part, to the release of nitric oxide (NO) by the endothelium, which either counteracts the effect and/or inhibits the synthesis of endothelins 16-19.. Endothelins have been hypothesised ...

The current in vitro studies demonstrate an enhanced vasoconstrictor response of small coronary arteries to ET-1 and S6c in pigs with experimental hypercholesterolemia. This response is mediated mainly through the ETB receptor. These alterations in the coronary responsiveness occurred in the setting of long-term elevation of circulating ET-1. These studies support a role for both the ETA and ETB receptors in the regulation of coronary tone in the presence and absence of hypercholesterolemia.. Seo and colleagues12 previously demonstrated that the contractile response of porcine epicardial arteries to endothelins is biphasic; the first phase attained at low concentrations is primarily mediated by the endothelin ETB receptor, whereas both endothelin receptors mediate contraction in the latter, more pronounced phase attained at high concentrations. Takase and colleagues32 found similar results in noncoronary resistance vessels. The current studies extend these previous observations and demonstrate ...

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Object. The disturbed balance between nitric oxide and endothelin (ET)-1 in the cerebrovasculature seems to play a major role in the development of cerebral vasospasm after subarachnoid hemorrhage. Endothelin-1 represents the contractile part in this balance. In addition to the prevailing ETA receptor-dependent contractile effect, ET-1 also has ETB receptor-mediated vasodilatory attributes. The aim of the present study was to define the actual selectivity of clazosentan, the first putative highly ETA receptor-selective antagonist clinically proven to be effective in the treatment of vasospasm in the cerebrovasculature.. Methods. Rat basilar artery ring segments with endothelial function were used for the measurement of isometric force. Concentration effect curves were constructed by cumulative application of sarafotoxin S6c, ET-1, or big ET-1 in the presence or absence of clazosentan (10−9 to 10−6 M) after a precontraction was induced by prostaglandin F2α. The inhibition by clazosentan was ...

The present invention relates to new pyridine sulfonamide modulators of endothelin-A receptor, pharmaceutical compositions thereof, and methods of use thereof. |p||chemistry id=CHEM-US-00001 num=00

Endothelins are potent peptide vasoconstrictors which were discovered two decades back. Their role in cardiovascular diseases, cancer, glaucoma, diabetes mellitus and many other diseases have been studied. Inspite of a lot of research many questions regarding their pathophysiological roles still remain unanswered. Though many endothelin receptor antagonists showed promising results in animal studies they failed to show significant improvement in clinical practice. The limitations of receptor antagonists lead to the research on synthesis inhibitors and their combinations with ACE inhibitors. This article summarizes the path of endothelins from their discovery to their current status and future prospects.. ...

There is a clear association between air pollution exposure and cardiovascular mortality. However, the mechanisms linking air pollution to cardiovascular events are poorly understood. Inhalation of particulate matter (PM) air pollution has been shown to increase the release of vasoactive cytokines such as endothelin while individuals with vascular disease have augmented vasoconstrictor responses to this peptide. Therefore, diesel exhaust-released endothelin could contribute to air pollution-induced cardiovascular events in sensitized individuals. We propose to use a novel model of endothelin dependent hypertension and endothelial dysfunction, paired with state-of-the-art methods for generating whole diesel exhaust, to investigate cardiovascular effects of PM. Our recent studies demonstrate that simulating sleep apnea by exposing rats to 90 second episodes of intermittent hypoxia/hypercapnia (IH) for 8 hours a day causes hypertension that is reversed by endothelin antagonists and associated with ...

TY - JOUR. T1 - Endothelin mediated contraction of equine laminar veins. AU - Keen, John A.. AU - McGorum, Bruce C.. AU - Hillier, Chris. AU - Nally, Jane E.. N1 - Originally published in: Equine Veterinary Journal (2008), 40 (5), pp.488-492.. PY - 2008/7/1. Y1 - 2008/7/1. N2 - Endothelin-1 (ET-1) may be a key mediator in the pathogenesis of laminitis, but endothelin-mediated responses in the venous microcirculation of the equine foot have yet to be fully characterised. The aim of this study was to characterise the response of equine laminar veins to ET-1 and evaluate the ET-1 receptor subtypes that mediate this response. Small veins (150-500 µm) draining the equine digital laminae from healthy horses and ponies subjected to euthanasia at an abattoir were investigated using wire myography. Concentration response curves were constructed for ET-1 in the presence of ETA (BQ123) and ETB (BQ788) receptor antagonists, and L-NAME, a nitric oxide synthase blocker. The selective ETB receptor agonist ...

mice on diet-induced hyperinsulinemia and hyperglycemia. The mechanism of insulins enhanced antiatherogenic actions in EC was related to remarkable induction of NO action, which increases endothelin receptor B (EDNRB) expression and intracellular [Ca2+]. Using the mice with knockin mutation of eNOS, which had Ser1176 mutated to alanine (AKI), deleting the only known mechanism for insulin to activate eNOS/NO pathway, we observed that IRS1 overexpression in the endothelia of ...

Ednrb - Ednrb (untagged ORF) - Rat endothelin receptor type B (Ednrb), (10 ug) available for purchase from OriGene - Your Gene Company.

Various tissues including heart express specific binding sites for endothelin. Endothelins have been reported to increase the force of contraction of cardiac muscle, presumably via specific receptors. Specific binding of endothelin to atrial tissue is particularly high. In spontaneously contracting rat atrial cells used in this study, all three isoforms of endothelin (endothelin-1, endothelin-2, and endothelin-3) decreased the rate of beating and caused an increase in inwardly rectifying K+ current in voltage-clamped whole cells. Endothelin-3 was the most potent isoform, and its effects on beating rate and K+ current were present at a concentration as low as 100 pM (Kd, approximately 1 nM). the atrial cells did not have the hyperpolarization-activated current (the pacemaker current), If. In excised inside-out patches, all three isoforms of endothelin activated a population of K+ channels with kinetic properties identical to those of acetylcholine (muscarinic)-activated K+ channels, and this was ...

Injury to the eye or retina triggers Muller cells, the major glia cell of the retina, to dedifferentiate and proliferate. In some species they attain retinal progenitor properties and have the capacity to generate new neurons. The epidermal growth factor receptor (EGFR) system and extracellular signal-regulated kinase (ERK) signaling are key regulators of these processes in Muller cells. The extracellular signals that modulate and control these processes are not fully understood. In this work we studied whether endothelin receptor signaling can activate EGFR and ERK signaling in Muller cells. Endothelin expression is robustly upregulated at retinal injury and endothelin receptors have been shown to transactivate EGFRs in other cell types. We analyzed the endothelin signaling system in chicken retina and cultured primary chicken Muller cells as well as the human Muller cell line MIO-M1. The Muller cells were stimulated with receptor agonists and treated with specific blockers to key enzymes in ...

Endothelins (ET-1, 2, and 3) are considered to be very powerful vasoconstrictive substances. In humans, endothelins mediate their actions via two…

Activation of the endothelin A receptor (ET(A)) by endothelin-1 (ET-1) mediates events that regulate mitogenesis, apoptosis, angiogenesis and metastasis in tumours. Specific blockade of ET(A) may have anticancer effects, while retaining beneficial endothelin B receptor (ET(B))-mediated effects such …

We previously reported that the in vitro inhibitory effects of several OATP1B1 inhibitors showed remarkable substrate-dependence using prototypical substrates, E2G, E1S, and BSP (Izumi et al., 2013). In addition to the prototypical substrates, clinically used OATP1B1 substrate drugs could also serve as in vitro OATP1B1 probe substrates, for which the potential substrate-dependent inhibition has not been comprehensively evaluated. To identify representative in vitro OATP1B1 probe substrates that could mitigate the risk of false-negative DDI prediction, this study investigated the impact of in vitro substrate selection on OATP1B1 inhibition and the subsequent DDI prediction for 12 clinically used OATP1B1 substrate drugs compared with the prototypical probe substrates.. Twelve OATP1B1 substrate drugs-including statins (pitavastatin, atorvastatin, fluvastatin, rosuvastatin, and pravastatin), antidiabetics (repaglinide, nateglinide, and glibenclamide), a dual endothelin receptor antagonist ...

Endothelin is the most potent constrictor of human blood vessels known to man. In mammals, there are three structurally and pharmacologically separate ET isopeptides: ET-1, ET-2, and ET-3 (Volpe 46). Endothelin-1 is the primary isoform in the human cardiovascular system and is a 21-amino acid peptide produced chiefly by endothelial cells (Lüscher 2434). Endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases are responsible for the synthesis of ET-1 by means of autocrine regulation (Lüscher 2434). ET-1 operates through the initiation of two G-protein coupled receptors: ETA and ETB. Located on vascular smooth muscle cells, ETA receptors regulate vasoconstriction and cell proliferation. ETB receptors, situated on endothelial cells, mediate endothelium-dependent vasodilation through the release of nitric oxide and prostacyclin (Haapaniemi 721). In addition to its cardiovascular and mitogenic effects, endothelin-1 is involved in gastrointestinal and endocrine function, ...