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1
Kelland, Nicholas. "The role of the endothelial cell endothelin B receptor in cardiovascular function." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/1899.
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Endothelin-1 (ET-1) binds to endothelin A (ETA) and B (ETB) receptors on vascular smooth muscle cells, resulting in profound vasoconstriction and cellular proliferation. In contrast, activation of endothelial cell (EC) ETB receptors releases nitric oxide (NO) and prostacyclin (PGI2), which are anti-mitotic and mediate vasodilatation. ETB receptors are also responsible for the clearance of ET-1 from the circulation and renal ETB receptors contribute to sodium and water balance. Pharmacological blockade and genetic models featuring total ETB ablation, demonstrate salt sensitive hypertension. However, these do not allow the role of the EC ETB in cardiovascular homeostasis to be determined. Mice featuring loxP sites flanking exons 3 and 4 of the ETB gene (floxed ETB mice: FF/--) were crossed with Tie2-Cre mice (WW/Tie2-Cre), in which the expression of a Cre recombinase cDNA transgene is limited to EC, to generate EC-specific ETB down-regulated mice (FF/Tie2-Cre). Having demonstrated EC-specific down-regulation of ETB receptors using autoradiography, the role and relative contribution of the EC ETB to the regulation of systemic BP, to the clearance of ET-1 from the plasma, as well as to the development of pulmonary arterial hypertension were investigated. Autoradiography revealed significant down-regulation of ETB in EC-rich tissues such as lung of FF/Tie2-Cre animals (8 ± 3 amol.mm-2) compared to controls (80 ± 21 amol.mm-2) (n=4; p<0.05). Levels of ETA expression were preserved despite higher concentrations of plasma ET-1 in the FF/Tie2-Cre samples (12.4 ± 3.0 pg.ml-1) compared to controls (3.0 ± 0.8 pg.ml-1) (n=6; p<0.001). Using radiotelemetry, mean arterial blood pressure of FF/Tie2 mice was not significantly different to that of FF/- controls on low salt (FF/Tie2-Cre: 122.7 ± 1.52 mmHg, n=10; FF/--: 125.7 ± 0.58 mmHg, n=12), normal salt (FF/Tie2-Cre: 133.8 ± 4.0 mmHg, n=10; FF/--: 131.5 ± 3.33 mmHg, n=12) or high salt diet (FF/Tie2-Cre: 149.2 ± 2.71 mmHg, n=10; FF/--: 143.9 ± 2.97 mmHg, n=12). Similarly no differences in SBP, DBP or HR were seen between genotypes. The clearance of an intravenous bolus of radiolabelled ET-1 was significantly impaired in FF/Tie2-Cre mice (0.054 ± 0.006 ml.sec-1) compared to control mice (0.175 ± 0.032 ml.sec-1) (n=5; p<0.01). ETB blockade of control mice reduced ET-1 clearance to that of untreated FF/Tie2-Cre animals (n=4). Two weeks of hypobaric hypoxia induced an exaggerated increase in systolic right ventricular pressure in FF/Tie2-Cre mice (34.4 ± 1.2 mmHg, n=10) compared with FF/-- mice (24.6 ± 1.4mmHg, n=10; p<0.05), associated with an increased right ventricular/ left ventricular + septum ratio in FF/Tie2-Cre mice (normoxia: 0.224 ± 0.009; hypoxia: 0.285 ± 0.017; p<0.01), but not in FF/-- mice. Hypoxia increased the percentage of remodeled vessels in FF/-- mice (normoxia: 5.6 ± 0.6%; hypoxia: 11.4 ± 0.6%; n=6; p<0.001), and this was augmented in FF/Tie2-Cre mice (normoxia: 7.1 ± 0.5%; hypoxia: 18.5 ± 1.2%; n=6; p<0.001). The EC ETB receptor does not play a significant role in the BP response to salt, suggesting that ETB signalling on other cell types is responsible for ETB mediated natriuresis. However, the EC ETB receptor is crucial to the elimination of ET-1 from the circulation and is protective against the development of pulmonary arterial hypertension, most likely by preventing remodeling of small pulmonary arteries.
2
Van, der Walle Christopher Frederick. "Synthesis and characterisation of an endothelin receptor fragment and an endothelin analogue." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301137.
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Swire, Matthew. "Investigating endothelin receptor B signalling during myelination." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28912.
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A key process enabling the correct functioning of neural circuits involves the formation of multi‐layered membranous myelin sheaths around axons. Myelin sheaths, made by specialised glial cells called oligodendrocytes in the central nervous system (CNS), metabolically support underlying axons and speed up electrical impulse conduction, aiding efficient communication between neurons. As only a subset of axons in the CNS are myelinated, with unique patterns developed therein, it raises the questions: how does an oligodendrocyte choose which axon to myelinate and what regulates the amount of myelin made? The production of myelin sheaths by the oligodendrocyte, is under strong influence from of a range of signals including those mediated by G protein‐coupled receptor (GPR) superfamily members. One GPR, Endothelin receptor B (EDNRB), best known for regulating blood flow, had previously been demonstrated to both positively and negatively influence myelination. I have investigated how EDNRB regulates myelination using an in vitro myelination assay, alongside in vivo analysis in zebrafish and mice. These systems identified a direct signalling role for EDNRB in the promotion of myelin sheath number. Furthermore, profiling the protein signalling cascade downstream of this receptor identified a range of known and novel factors involved in the regulation of myelin sheath number including the MAPK pathway, Src family kinases, ErbB receptors, protein kinase C ε, NMDAR and AMPAR. Functional analyses of a subset of these factors elucidate how EDNRB signalling, potentially connecting signals from a range of cell types, ensures correct adequate myelination in the CNS.
4
Fukuroda, Takahiro. "STUDIES ON ENDOTHELIN RECEPTOR SUBTYPES MEDIATING ENDOTHELIN ACTION AND CLEARANCE IN THE LUNGS." Kyoto University, 1999. http://hdl.handle.net/2433/182431.
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Zhang, Yufeng. "Characteristics of a truncated human endothelin receptor A." Thesis, St George's, University of London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300418.
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Cid, Graciela Mariana. "Expression and characterization of human endothelin receptor A." Thesis, Birkbeck (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395809.
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Bagnall, Alan. "Role of the endothelin B receptor in cardiovascular homeostasis." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/24786.
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The aim of this project was to precisely determine the role of the endothelial cell (EC) ETB receptor in the regulation of vascular tone, blood pressure and clearance of ET-1. Cre-loxP recombination was utilised to conditionally regulate ETB receptor expression in vivo. Mice featuring loxP sites flanking exons 2 and 3 of the ETB receptor gene (floxed ETB receptor mice) were generated by standard gene targeting techniques in embryonic stem cells. Floxed ETB mice were crossed with Tie2-Cre transgenic mice to produce mice in which recombination-mediated removal of ETB receptor coding regions was limited to EC (Flox/Flox Tie2). EC ETB receptor binding of 125I ET-1 and in vitro aortic and tracheal ring myography were performed to assess endothelial function and the response to selective ETB receptor agonists. Pulmonary EC ET-1 binding was decreased by ~80% in EC-specific ETB receptor knockout mice (cpm/50μg membrane protein ± SEM; Flox/Flox Tie2 581 ± 67; W/W -/- 3175 ± 268; n=3; p<0.001). Cell-specificity of ETB receptor down-regulation was demonstrated by maintenance of normal ETB receptor-mediated tracheal constriction. Blood pressure was increased in Flox/Flox Tie2 mice (MAP 137.2 ± 6.4mmHg (n=5); W/W -/-, 113.7 ± 4.7mmHg (n=6; p<0.05) but was not affected by dietary salt. Plasma ET-1 was increased ~4 fold following EC ETB receptor down-regulation (mean plasma [ET-1] pg/ml ± SEM; Flox/Flox Tie2 12.40 ± 2.95; W/W -/- 2.94 ± 0.83; n=6; p<0.001). Aortic rings from Flox/Flox Tie2 mice demonstrated impaired endothelium-dependant vasodilatation to ETB receptor selective agonists and acetylcholine but normal endothelium-independent vasodilatation. Recombination-mediated removal of exons 2 and 3 of the ETB receptor is sufficient to prevent expression of functional ETB receptors. The ‘floxed’ ETB receptor mouse thereby facilitates the cell type-specific down-regulation of ETB receptor expression in vivo. The EC ETB receptor plays an important role in the determination of blood pressure under normal physiological conditions. The mechanism underlying this effect may involve loss of EC ETB receptor-mediated vasodilatation or impaired clearance of ET-1 with a consequent increase in ETA receptor activity.
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Peter, Markus Guenter. "Endothelin receptor expression in human, rat and porcine heart." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627471.
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Leslie, Stephen James. "The effect of endothelin A and endothelin B receptor ligands on the cardiovascular system of man." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/29221.
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ET-1 vasoconstricts in the skin microcirculation and it appears that endothelin converting enzyme (ECE) activity is present as big ET-1 also vasoconstricts. ECE and neutral endopeptidase (NEP) blockade both cause vasodilatation suggesting skin basal resting ET tone. ET-1 (1-31) is also a vasoconstrictor in the skin microcirculation. Plasma concentrations of ET-1(1-31) are not elevated in patients with CHF. ETARA improves systemic haemodynamics in patients with CHF while concomitant ETBRA attenuates this effect. In the isolated human myocardium ET is positively inotropic but there is no resting ET inotropy with no effect on basal twitch force with ETRA. In addition, ET attenuates beta-adrenergic activation in isolated human myocardium. In hypercholesterolaemia, forearm vascular effects are similar to those previously reported in healthy volunteers. Treatment with statin therapy for 8 weeks caused a trend towards an increase in ETA mediated vasodilatation. Conclusions: The novel finding that ET(1-31) is a vasoconstrictor in the skin microcirculation may represent a novel pathway of ET production. The haemodynamic benefits of selective ETARA over dual ETA/BRA is a unique finding with considerable importance and supports the development of selective ETARAs as clinical therapies in CHF. The finding of antagonism between the ET system and the beta-adrenergic stimulation may represent a protective adaptation in conditions where there beta-adrenergic stimulation is detrimental and there is activation of the ET system, such as CHF.
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Elez, Danka. "Production of recombinant human endothelin B receptor in different hosts and its subsequent solubilization and purification." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=970794746.
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Somell, Anna. "Endothelin receptor antagonism and hypertonic solutions in experimental endotoxin shock /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-209-5/.
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Doerr, Megan Jane. "A Human Genome Epidemiology Systematic Review of Endothelin Receptor-A." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1228773764.
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Haque, S. "The contribution of endothelin-1 in colorectal cancer & the efficacy of the novel endothelin receptor antagonist ZD4054." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1418516/.
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The overall aims of this thesis are: to determine the cellular response to ET-1 and effects of receptor antagonism on proliferation, migration and contraction of colonic fibroblasts and cancer cell lines. At the molecular level to identify novel genes that are regulated by ET-1 and whether antagonists including ZD4054 have potentially beneficial effects by blocking expression of these genes. Finally to determine ET-1 binding distribution by autoradiography in patient tumour sections and delineate binding characteristics of ET-1 and its receptor antagonists (Bmax, Kd and IC50). To investigate ET-1 and its antagonistic effects at the cellular level, colorectal cancer cell lines and colonic fibroblasts (isolated from patient colorectal cancer specimens) were studied. They were incubated with ET-1 with/without BQ123, zibotentan (ETAR antagonists) and/or BQ788 (ETBR antagonist). Growth was measured by methylene blue uptake; migration by scratch wound assay and contraction in collagen gels. To identify novel key genes regulated by ET-1, Illumina micro-arrays determined differential gene expression post-ET-1 stimulation of 3 colorectal cancer cell lines and the 4 human colonic fibroblast strains. To confirm expression of genes of interest, we examined time point induction mRNA levels (conventional RT-PCR; quantitative real-time RT-PCR). ETA (Zibotentan, BQ123) and ETB (BQ788) antagonistic effects were measured at the mRNA and protein levels (Immunoblotting). Silencing (SiRNA) was also used to confirm receptor involvement in regulation of these key genes. ET-1 receptor distribution and binding characteristics (Kd; Bmax) were determined using in vitro autoradiography on patient sections, tissue homogenates, CRC cell lines and colonic fibroblasts. Effects of the ETAR specific antagonist zibotentan (ZD4054) on ET-1 receptor binding (IC50) were evaluated against laboratory-standard compounds. Immunohistochemistry (IHC) was used to identify stromal structures and receptor distribution (vascular CD31; Thy-1 fibroblasts; collagen type XI; ETA and ETB). Study was awarded ethical approval, REC No. 08/H0720/162, University College London Hospitals.
14
Mickley, Emma J. "Vascular endothelin-1 production and receptor subtypes in chronic heart failure." Thesis, University of Edinburgh, 1998. http://hdl.handle.net/1842/21415.
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The aims of this thesis were i). to characterise the ET receptors on the smooth muscle of normotensive rats, ii). investigate any changes of the ET receptor subtypes in a CHF rat model and in CHF patients and iii). investigate whether there is increased ET-1 synthesis in CHF by measuring plasma ET-1 and big ET-1 levels and if there is an altered localisation of ET-1 and ECE in the wall of the arteries. Firstly, the ET-1 receptor subtypes responsible for ET-1-induced vasoconstriction in endothelium-denuded mesenteric arteries from normotensive Wistar rats were investigated. Arteries were mounted in a perfusion myograph and ET-1 or sarafotoxin S6c (SRTX S6c) concentration-response curves (CRC) were performed. The relative roles of the ETA and ETB receptors in the ET-1 induced vasoconstrictions were evaluated by using either the ETA receptor antagonist, BQ-123; the ETB receptor antagonist, BQ-788; the ETB receptor agonist, SRTX S6c or the non-selective ETA/ETB antagonist, TAK-044. Both ETA and ETB receptors were found to mediate ET-1 vasoconstriction and that ETA receptors could compensate for the inhibition of ETB receptors. The results suggested a potential crosstalk mechanism between the two receptor subtypes. Any changes in vascular smooth muscle ET receptor responses and subtypes mediating ET-1 vasoconstriction in resistance arteries in CHF were then investigated. Two sources of arteries were used; i). mesenteric arteries from rats at two different time points after the induction of heart failure by left coronary artery ligation or sham-operation and ii). gluteal arteries dissected from buttock biopsies obtained from Grade II & III CHF patients and age-matched controls.
15
Montgomery, Jennifer Pielstick Zinn Kai George Patterson Paul H. "The effects of behavioral stress and endothelin receptor antagonists on cancer /." Diss., Pasadena, Calif. : California Institute of Technology, 2007. http://resolver.caltech.edu/CaltechETD:etd-05222007-105207.
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Wener, Avraham Dov. "Transcriptional regulation of the endothelin A receptor, possible developmental and pathophysiological implications." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0027/MQ50440.pdf.
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Chin, Nikeisha L. "The Role of Endothelin 3 in Melanoma Progression and Metastasis." FIU Digital Commons, 2015. http://digitalcommons.fiu.edu/etd/2286.
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Endothelin receptor b (Ednrb) and its ligand Endothelin 3 (Edn3) have been implicated in melanoma. Several studies have shown an upregulation of EDNRB and EDN3 at both the protein and mRNA levels, as melanoma becomes more aggressive. This study investigated the putative role played by Edn3 over-expression in melanoma progression and angiogenesis in vivo. We crossed Tg(Grm1)Epv transgenic mice that aberrantly express metabotropic glutamate receptor1 under the Dopachrome tautomerase promoter, leading to spontaneous melanocytic lesions in the ears and tails that do not metastasize, with transgenics that overexpress Edn3 under the Keratin 5 promoter (K5-Edn3) or overexpress Ednrb in melanocytes (Tg(Ednrb)1Lk). In both the Tg(Grm1)Epv/K5-Edn3 and Tg(Grm1)Epv/Tg(Ednrb)1Lk mice, tumors appeared earlier and grew significantly larger and faster when compared to Tg(Grm1)Epv mice. Approximately eighty-one percent of Tg(Grm1)Epv/ K5-Edn3 mice and 76% of Tg(Grm1)Epv/Tg(Ednrb)1Lk mice had pigmented lesions in distant organs such as the lung and brain. Real-Time PCR analysis showed higher expression levels of genes involved in cell-cell and cell-matrix interactions and angiogenesis in lesions of Tg(Grm1)Epv/K5-Edn3 when compared to controls. Considering the rapid tumor growth rate of in the Tg(Grm1)Epv/K5-Edn3 mice, differences in the angiogenic response compared to control mice were investigated. Immunofluorescence analysis with the endothelial cell marker CD31 showed that there were more endothelial cells per tumor area in the Tg(Grm1)Epv/K5-Edn3 mice than the controls. Proteome analysis showed that the Dct-Grm1/K5-Edn3 mice had significant increases in other angiogenic related genes such as Angiogenin, CXCL 16 and Endoglin, when compared to controls, while real time PCR analysis of tail tumors also showed higher expression levels of angiogenic related genes such as Hif-1α. The results of this study showed that the EDNRB/EDN3 axis is sufficient to alter the kinetics of melanocytic tumors’ progression, lead them to a fully malignant state, and increase the tumor angiogenic response.
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Dawas, K. I. "Selective endothelin receptor involvement in the development of colorectal cancer and liver metastases." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445484/.
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Endothelin-1 (ET-1), a vasoactive peptide with mitogenic qualities, is over-expressed in the plasma of patients with colorectal cancer (CRC) and liver metastases. Its actions are mediated via two G-protein linked receptors, ETA and ETB. This study (i) examined the effect of ET-1 and its receptor antagonists as well as a G-protein blocker on CRC cell line growth (ii) investigated tET receptor distribution in human CRC and liver metastases by autoradiography (iii) recorded the effect on tumour growth of an oral ETA receptor antagonist to an in vivo model of colorectal cancer liver metastases. ET-1 stimulated significant growth in the cancer cells. This effect was reversed by the ETA, but not the ETB, receptor antagonist. Apoptosis was similar in controls and ET-1 antagonist treated cells. BrDU staining demonstrated an ET-1 dependent increase in mitosis, reversed by the ETA receptor antagonist. Blocking the G-protein subunits also reversed growth. In human cancer tissues ETA was over-expressed while ETB was under- expressed compared to controls. There was no significant difference in weight or number of liver metastases between control and experimental rats in vivo. In summary, ET-1 stimulates human CRC growth in vitro via ETA receptors by mechanisms that include stimulation of mitosis but not alteration of apoptosis. Thi signal is transduced via the G-protein subunits Go or Gi. Human CRC liver metastases tissue over-express ETA receptors compared to normal tissue. ET receptor antagonists may have a therapeutic role in primary and metastatic CRC.
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Schipper, Mitchell. "Expression of the endothelin-A receptor gene during differentiation, analysis of promoter function." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq29780.pdf.
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Schipper, Mitchell. "Expression of the endothelin-A receptor gene during differentiation : analysis of promoter function." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=27404.
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ET sc A is expressed predominantly in myocardium and smooth muscle. Fusion plasmids of luciferase and the 5$ sp prime$ flanking region of the human ET sc A gene were transfected into rat vascular smooth muscle cells (A10), primary cultures of porcine aortic smooth muscle cells (PSMC), a pluripotential embryonal cell (P19) induced to differentiate to a myocyte lineage, and COS7 cells. Binding studies showed no ET receptors in COS7 while the others expressed high levels of ET sc A. Mock transfected cells expressed negligible levels of luciferase activity (RLU). Transfection with the region $-$848 to +92 bp of ETA (relative to transcriptional initiation) resulted in several hundred fold increase in activity with the highest levels seen in cells expressing ET sc A (Mean $ pm$ SEM: PSMC = 4748 $ pm$ 521 RLU, A10 = 6670 $ pm$ 304 RLU, COS7 = 1268 $ pm$ 212; PSMC vs. COS7 p = 0.0035, A10 vs. COS7 p = 0.001). Deletion from $-$848 to $-$625 (including a CARG box) resulted in a 20-60% loss of promoter activity (p = 0.01). Further deletions to $-$116 increased activity 2 fold (p = 0.05) suggesting the presence of a weak negative regulatory element. Two strong positive regulatory elements: the first one whose deletion led to a loss of 80% of promoter activity, was identified between $-$116 and $-$38; and the second one was identified between +90 and +200 in an area which exhibited $>$80% homology between the human and the murine gene. In conclusion: (1) The region between $-$848 bp and +92 bp of the human ET sc A directs the expression of a reporter gene to significantly higher levels in myocytes normally expressing the receptor compared to non-expressing cells, (2) weak negative and strong positive regulatory cis-acting elements have been identified in this region.
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Yu, Julie C.-M. "Endothelin peptide secretion and receptor expression in human cultured vascular smooth muscle cells." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242935.
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Kirkby, Nicholas S. "Investigating the role of endothelin receptor subtypes in the response to vascular injury." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4440.
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Neointimal hyperplasia, the proliferative growth of the innermost layer of the blood vessel wall, is a key process in the response to vascular injury, underlying conditions such as post-interventional restenosis and vein/arterial graft disease. One of the many mediators implicated in this process is endothelin-1 (ET-1), a potent vasoconstrictor with pro-inflammatory and pro-mitogenic actions, which acts through ETA and ETB receptor subtypes. It is well established that ET-1 increases, and ETA blockade reduces, neointima formation following vascular injury. The role of ETB is less clear because these receptors mediate potentially beneficial actions in endothelial cells (EC; such as nitric oxide production, and ET-1 clearance) but detrimental effects elsewhere (such as vascular smooth muscle) and it has been recently reported that non-cell-specific ETB deficiency is associated with increased neointimal lesion size following injury. The work described in this thesis addressed the hypothesis that endogenous ET-1 contributes to neointimal hyperplasia by activation of the ETA receptor, and that this action is moderated by concurrent activation of the ETB receptor expressed in EC. The role of ET receptors in neointimal lesion development was assessed using two models of femoral arterial injury in the mouse: (i) an established method of intraluminal wire-injury, and (ii) adaptation of a model of ligation injury that induces robust neointimal lesion formation without physical damage to the endothelium. Lesion development was assessed using standard histological techniques and this was augmented by development of quantitative optical projection tomography (OPT) to allow three-dimensional analysis of lesions. The role of ETA and ETB receptors in these models was addressed using suitable pharmacological ET receptor antagonists. Following wire-injury, selective ETB blockade (A192621; 30mg.kg-1.day-1; 35 days) increased lesion size and blood pressure without significant altering lesion composition. In contrast, selective ETA blockade (atrasentan; 10mg.kg-1.day-1; 35 days) reduced lesion size and blood pressure. Combined ETA+ETB antagonism had no effect on lesion size, despite reducing blood pressure, and reducing collagen content of the lesions. In the ligation model, neither ETA selective, ETB selective nor ETA+ETB blockade altered lesion size as assessed by standard histology but analysis by OPT indicated that ETA blockade, with or without concurrent ETB blockade, reduced lesion volume. The influence of ETB receptors expressed by ECs on lesion formation was addressed using EC-specific ETB knockout mice. Small vessel myography indicated that endothelium-dependent relaxation was unaltered in femoral arteries from these mice. In addition, no effect on lesion size or rate of development was observed in either wire- or ligation-injury models of neointima formation (although subtle effects on lesion and medial composition were apparent after intra-luminal injury). These results indicate that ETB receptor activation can moderate the detrimental actions of the ETA receptor on neointimal lesion progression, and that this role is dependent on the mode of vascular injury. Furthermore, in this setting, this beneficial action is not primarily mediated by ETB expressed by EC, suggesting that ETB in other cell types can reduce lesion development through another, unidentified mechanism. Therefore, while both ETA selective and non-selective ETA/B antagonists are currently in clinical use, in conditions where similar arterial remodelling processes occur, selective ETA receptor antagonists might be preferred.
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Picken, Paula. "The synthesis of endothelin analogues : potential application to immunoassay and receptor antagonist development." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318826.
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Adner, Mikael. "Altered expression of contractile endothelin receptors in the vascular bed." Lund : Dept. of Internal Medicine, University of Lund, 1998. http://catalog.hathitrust.org/api/volumes/oclc/39103326.html.
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Neder, Thomas Harry [Verfasser], and Charlotte [Akademischer Betreuer] Wagner. "The endothelin-A and endothelin-B receptor as potential factors to control synthesis and secretion of renin / Thomas Harry Neder ; Betreuer: Charlotte Wagner." Regensburg : Universitätsbibliothek Regensburg, 2018. http://d-nb.info/1155360753/34.
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Wu, Sumin [Verfasser]. "Structural and functional basis of Endothelin-1 type A receptor (ETAR) activation / Sumin Wu." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1179779118/34.
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Lee, G. R. "Alterations in endothelin receptor subtypes in the pathogenesis of hypertension induced ventricular cell hypertrophy." Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246339.
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Lowenstein, Marcia. "Interactions between Endothelin Receptor B and Transcription Factors Sox10 and Pax3 in the Melanocyte Lineage." FIU Digital Commons, 2009. http://digitalcommons.fiu.edu/etd/117.
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Genetic interactions that underlie developmental processes such as cell differentiation and pattern formation are complex and difficult to elucidate. Neural Crest (NC) cells and their derivatives offer an optimal system in which to probe for these complex interactions as they acquire different cell fates and constitute a variety of structures. The transcription factors Sox10 and Pax3 as well as the transmembrane receptor Endothelin receptor b (Ednrb) are temporally and spatially co-expressed early in NC cells and mutations in these genes lead to similar hypopigmentation phenotypes due to a reduced number of NC-derived melanocyte precursors, the melanoblasts. The goal of this study was to establish whether Sox10 and Ednrb or Pax3 and Ednrb interact to promote normal murine melanocyte development. Crosses of Sox10 or Pax3 with Ednrb heterozygous mutants showed that the double heterozygous hypopigmentation phenotype was significantly more pronounced than phenotypes of single heterozygotes, implying that a synergistic interaction exists between Sox10 and Ednrb and Pax3 and Ednrb. This interaction was further explored by the attempt to rescue the Sox10 and Pax3 hypopigmentation phenotypes by the transgenic addition of Ednrb to melanoblasts. Pigmentation was completely restored in the Sox10 and partially restored in the Pax3 mutant mice. The comparison of the number of melanoblasts in transgenic and non-transgenic Sox10 mutant embryos showed that the transgenic rescue occurred as early as E11.5, a critical time for melanoblast population expansion. Cell survival assays indicated that the rescue was not due to an effect of the transgene on melanoblast survival. A novel phenotype arose when studying the interaction between Ednrb and Pax3. Newborns appeared normal but by 3.5 weeks of age, the affected pups were smaller than normal littermates and developed a dome-shaped head; some also developed thoracic kyphosis. Affected pups were dead by 4 weeks of age: 80% were Pax3Sp/+ and 75% were female. When compared to normal littermates, affected mice had brains with enlarged 4th ventricles and more glia while skeletal staining showed kyphosis, wider rib cages and pelvic differences. An epistatic interaction resulting from the mixing of genetic backgrounds that is exacerbated in the presence of Pax3 heterozygosity is suspected.
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Docherty, Cheryl Catherine. "Endothelin-receptor mediated responses in pulmonary resistance arteries : effect of developmental age and left ventricular dysfunction." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241867.
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Dyukova, Elena [Verfasser]. "The calcium-sensing receptor in heart physiology and development of endothelin-1-dependent hypertrophy / Elena Dyukova." Gießen : Universitätsbibliothek, 2017. http://d-nb.info/1144148111/34.
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Pino, Javier. "Transgneic Endothelin 3 Regulates Murine Pigment Production and Coat Color." FIU Digital Commons, 2017. https://digitalcommons.fiu.edu/etd/3533.
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Pigmentation plays a protective role against damage caused by ultraviolet (UV) irradiation. Humans with fair skin and light hair have a higher susceptibility to UV-induced DNA damage that can lead to the development of skin cancers. The melanocytes found in the skin and hair follicles depend on different signaling molecules for their proper development and pigment production. α-Melanocyte Stimulating Hormone (α-msh) binds to the Melanocortin 1 receptor (Mc1r) to regulate pigment production and the switch between eumelanin and pheomelanin. Lethal yellow mice (Ay) overexpress the agouti signaling protein, which inhibits the binding of α-msh, resulting in a yellow coat color phenotype. Endothelin 3 (Edn3) encodes for a ligand involved in melanocyte development by regulating the differentiation, proliferation and migration of melanocyte precursors. A tetracycline inducible transgenic mouse in which Edn3 was placed under the keratin 5 promoter (K5-tTA;TRE-Edn3-lacZ) displays a hyperpigmentation phenotype due to the accumulation of melanocytes in the skin and an increase in hair pigment. Comparative analysis of dorsal hairs from Ay and Ay; K5-tTA;TRE-Edn3-lacZ mice using high performance liquid chromatography showed that transgenic Edn3 expression significantly increased both eumelanin and pheomelanin. No significant difference in the number of follicular melanocytes between Edn3 transgenic and non-transgenic mice was evidenced by immunofluorescence using an antibody against Tyrosinase related protein 1. Gene expression analysis of hair follicles showed that Edn3 upregulates the expression of melanogenic genes. Deactivation of transgenic Edn3 is possible with doxycycline (dox) treatment. To test if transgenic Edn3 expression is required to rescue and maintain a dark pigmentation phenotype in Ay mice, dox was administered during embryonic and postnatal development to manipulate transgenic Edn3 expression. Results showed that transgenic Edn3 expression is required to maintain a dark pigmentation phenotype after birth but is independent of a developmental requirement. Transgenic Edn3 expression in Mc1re/e mice also resulted in a darkened coat color. Our results indicate that the paracrine expression of Edn3 from keratinocytes is capable of generating and maintaining a dark coat color by the regulation of melanogenic genes independent of Mc1r signaling. The results of this study may open new approaches to the treatment of hypopigmentation disorders.
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Xu, Zhengshuang, and 許正雙. "Studies toward the total synthesis of biologically active agents I: yanucamide a and apratoxin a from marinecyanobacteria, II: nonpeptide endothelin receptor antagonist SB-209670." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B31244981.
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Cullen, John Patrick. "Receptor subtypes and associated mechanisms in the stimulation of ventricular cell hypertrophy by angiotensin II and endothelin-1." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287435.
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Franzén, Stephanie. "The role of hypoxia for the development of diabetic nephropathy : Temporal relationship and involvement of endothelin receptor signaling." Doctoral thesis, Linköpings universitet, Avdelningen för läkemedelsforskning, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-125522.
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Diabetic nephropathy is one of the most common causes of end stage renal disease and develops in approximately one third of all diabetes patients. Disease progression is characterized by deteriorating glomerular filtration rate and escalating urinary albumin/protein excretion; both are used as clinical markers for disease progression. Recently, it has been proposed that intrarenal hypoxia is a unifying mechanism for chronic kidney disease, including diabetic nephropathy. Several mechanistic pathways have been linked to the development of intrarenal hypoxia and diabetic nephropathy including increased angiotensin II signaling, oxidative stress and hyperglycemia per se. Furthermore, pathological endothelin signaling has recently immerged as a possible contributing factor for chronic kidney disease and diabetic nephropathy. The overall aims of this thesis were therefore to determine the temporal relationship between development of intrarenal hypoxia and kidney disease as well as elucidate the potential link between endothelin signaling, intrarenal hypoxia and kidney disease in experimental insulinopenic diabetes. It is well established that different mouse strains have different susceptibility for kidney and cardiovascular disease. The first step was therefore to compare four commonly used mouse strains with regards to development of kidney disease after onset of insulinopenic diabetes. From the results of this study, we concluded that the NMRI mouse strain has a disease progression closest to the human disease and this strain was chosen in the subsequent studies in mice. The next step was to adapt and optimize a suitable method for repetitive measurements of intrarenal oxygen tension during the course of disease development. Electron paramagnetic resonance (EPR) oximetry had previously been used in tumor biology and was now adapted and optimized for measurements of kidney oxygenation in our diabetic mouse model. EPR oximetry in normoglycemic control mice recorded cortical oxygen tension values similar to previous reports using invasive techniques. Surprisingly, intrarenal hypoxia developed already within the first 72h after induction of hyperglycemia and persisted throughout the two-week study period. Importantly, this was well before albuminuria developed. The final part of this thesis was to investigate the role of endothelin signaling for the intrarenal hypoxia in a diabetic rat model. Endothelin 1 signals via two distinctly different receptor-mediated pathways. In normal physiology, endothelin 1 binding to endothelin receptor type A (ETA) induces vasoconstriction, which can be blocked by the specific ETA antagonist BQ123, whereas endothelin 1 binding to endothelin receptor type B (ETB) induces nitric oxide-dependent vasodilation. ETB receptors can be selectively activated by Sarafotoxin 6c. The results from blocking ETA and activating ETB receptors demonstrated that endothelin 1 signaling via ETA receptors contributes to intrarenal hypoxia in the rat diabetic kidney, and that ETB stimulation significantly reduces the diabetes-induced intrarenal hypoxia. The beneficial effects on kidney oxygen availability in diabetes by ETA blockade or ETB stimulation were mainly linked to hemodynamic improvements rather than direct effects on kidney oxygen consumption or oxidative stress status. In conclusion, by applying EPR oximetry in a mouse model of insulinopenic diabetes mimicking the human disease, we demonstrated intrarenal hypoxia already within the first couple of days after the onset of hyperglycemia, which is well before detectable signs of kidney disease development. Furthermore, blockade of ETA or activation of ETB receptors significantly reduced intrarenal hypoxia in the diabetic kidney. These results demonstrate involvement of ETA receptor signaling in diabetes-induced intrarenal hypoxia and ETA blockade or ETB activation might provide new therapeutical targets to reduce kidney hypoxia and disease progression in diabetes.
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Moraes, Maria Nathália de Carvalho Magalhães. "Efeito da endotelina sobre a expressão gênica das melanopsinas (Opn4x e Opn4m) e do receptor de endotelina, subtipo ETc, em melanóforo de Xenopus laevis." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/41/41135/tde-18022011-104223/.
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Os relógios biológicos são fundamentais para a sincronização do comportamento dos organismos a mudanças no fotoperíodo. Todas as alterações rítmicas são determinantes para a sobrevivência da espécie uma vez que elas prevêem que os ajustes internos coincidam com a fase mais propícia do ciclo ambiental, permitindo aos organismos a capacidade de sincronizar esses eventos internos com os ciclos ambientais. Muitos desses ritmos biológicos são claramente associados ao ciclo claro-escuro, sendo este ciclo de grande importância para as espécies que possuem algum tipo de pigmento fotossensível. Os melanóforos de Xenopus laevis são fotossensíveis, respondendo à luz com dispersão dos grânulos de melanina, devido à presença de duas melanopsinas, Opn4x e Opn4m. As células pigmentares dos vertebrados heterotérmicos respondem com migração pigmentar a uma variedade de agentes, incluindo as endotelinas. Em peixes teleósteos, ETs induzem a agregação pigmentar em melanóforos, enquanto que em anfíbios, ET-3 induz a dispersão de grânulos de pigmentos em melanóforos de Xenopus laevis e de Rana catesbeiana, através da ativação de receptores ETc. Propusemos determinar o padrão temporal de expressão dos genes das melanopsinas e do receptor ETc em melanóforos dérmicos de X. laevis em cultura, bem como os efeitos temporais e dose- dependentes da endotelina sobre essa expressão. Demonstramos, através de ensaios de PCR quantitativo, que o tratamento de 12C:12E , somado a uma troca de meio, assim como o de endotelina-3 10-9 e 10-8M em escuro constante, foi capaz de sincronizar a expressão de Opn4x e Opn4m. Entretanto, o receptor ETc parece não ser sincronizado pelo ciclo claro-escuro, ou pelo tratamento hormonal. Dependendo da dose utilizada e do ZT analisado, ET-3 pode promover um aumento ou inibição da expressão gênica de Opn4x, Opn4m e ETc, indicando uma modulação de forma dose-dependente. Além disso, pode atuar como um agente sincronizador da expressão dos transcritos das melanopsinas.The biological clocks are critical for synchronizing the behavior of organisms to changes in photoperiod. All rhythmic changes are crucial to the survival of the species since they provide for internal adjustments to coincide with the phase of the cycle most favorable. Many of these biological rhythms are clearly associated with the light-dark cycle, of major importance for species that have some type of photosensitive pigment. Melanophores of Xenopus laevis are photosensitive, responding to light with dispersion of melanin granules, due to the presence of two melanopsins, Opn4x and Opn4m. The pigment cells of ectothermic vertebrates respond with pigment migration to a variety of agents including the endothelins. In teleost fish, ETs induce pigment aggregation in melanophores, whereas in amphibians, ET-3 induces the dispersion of pigment granules in melanophores of Xenopus laevis and Rana catesbeiana, by activation of ETc. We proposed to determine the temporal pattern of gene expression of the ETc receptor and melanopsins in dermal melanophores of X. laevis in culture as well as the effects of endothelin-3 on the temporal expression of the 3 genes. Using quantitative PCR, we demonstrated that 12L: 12D regimen, combined with medium changes, as well as the treatment with 10-9 and 10-8M endothelin-3, was able to synchronize the expression of Opn4x and Opn4m. However, ETc receptor seems not to be synchronized by light-dark cycle, or hormone treatment. Depending on the dose and the ZT, ET-3 may promote an increase or inhibition of gene expression of Opn4x, Opn4m and ETc, indicating a dose-dependent modulatory effect. In addition, endothelin-3 may also act as a synchronizing agent of the melanopsins transcripts.
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Casare, Fernando Augusto Malavazzi. "Efeito da interação de angiotensina II e o receptor AT1 ou endotelina 3 e os receptores ETA e ETB na função e morfologia renal de ratos." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-15042016-105127/.
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Para avaliar os efeitos de angiotensina II (Ang II) ou endotelina-3 (ET-3), ratos Wistar foram organizados nos grupos: controle, tratados com Ang II ou ET-3 por 42 dias, tratados com losartan, atrasentan ou BQ788 ou co-tratados com Ang II e losartan ou ET-3 e atrasentan ou BQ 788. Foram avaliados: pressão arterial, concentrações plasmáticas e intrarrenais das Angs e ETs, morfologia e função renal. A Ang II induziu hipertensão arterial, aumentou as concentrações plasmáticas das ETs e das Angs e a expressão de RNAm para renina; induziu injuria glomerular e remodelamento das arteríolas renais. O tratamento com losartan reverteu a maioria dos efeitos da Ang II. A ET-3 induziu hipertensão arterial, injúria glomerular, alteração da função renal e aumento de RNAm intrarrenal para os componentes do SRA. O bloqueio do receptor ETA atenuou os efeitos de ET-3 na hipertensão, enquanto o bloqueio de ETB foi melhor nos parâmetros renais. Nossos resultados sugerem uma interação entre os sistemas SRA e endotelinas, induzindo mudanças na estrutura e função renal.To evaluate the chronic effects of angiotensin II (Ang II) and /or losartan or endothelin-3 (ET-3) and /or atrasentan or BQ788, Wistar rats were organized as: control, treated with Ang II, or ET-3 for 42 days, losartan-treated, co-treated with Ang II and losartan. Treated with ET-3, treated with BQ788 or atrasentan, co-treated with ET-3 and antagonists. Were evaluated: blood pressure, plasma and intrarenal concentrations of Angs and ETs, protein expression, renal morphology and function. Ang II induced hypertension, increased plasma levels of ETs and Angs; increased mRNA for renin; induced glomerular injury and renal arterioles remodeling. Treatment with losartan restored most of the changes induced by Ang II. ET-3 induced hypertension, glomerular injury, renal dysfunction and increased intrarenal mRNA for SRA components. The ETA receptor blockage reverted the ET-3 effects on hypertension, while ETB blockage reverted renal parameters. Our results suggest a crosstalk of renin-angiotensin and endothelin systems, inducing renal structural and functional changes.
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Darrah, Rebecca J. "Genetic Modifiers of Cystic Fibrosis Pulmonary Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270133199.
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Guyonnet, Léa. "Rôle du récepteur myéloïde à l’endothéline (ETB) au cours de l’hypertension artérielle." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB018.
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L’hypertension artérielle (HTA) est un problème de santé publique. Largement répandue dans le monde, elle touchait 40% des adultes âgés de plus de 25 ans et causait 9.4 millions de décès en 2008. Cette pathologie est la cause la plus commune de décès dans les pays développés et constitue un facteur de risque majeur d’atteintes cardiaques, rénales et cérébrales. Bien qu'étudiés depuis maintenant plus d'un demi-siècle, les mécanismes des atteintes systémiques liées à l'hypertension restent encore peu connus. L'augmentation de la pression artérielle est multifactorielle et découle aussi du dérèglement de certains systèmes tels le système rénine-angiotensine et le système endothéline. De récentes études ont suggéré un rôle de l’immunité innée dans le développement de l’HTA et des lésions qui y sont associées. L’endothéline-1 est un puissant vasoconstricteur. Sa production est déclenchée par différents stimuli dont l’AngII et des cytokines pro-inflammatoires. L’ET-1 agit via deux récepteurs : ETAR et ETBR. Pour ce projet, nous avons généré des souris ne possédant pas le récepteur ETB myéloïde (LysM-Cre Ednrb lox/lox). Ces souris ont été soumises à une perfusion chronique d’AngII associée à un régime hyper-sodé. Nous avons observé que les deux groupes de souris développent la même hypertension et les mêmes atteintes cardiaques. En revanche les atteintes des organes cibles sont moins importantes chez les souris LysM-Cre Ednrb lox/lox. La fonction rénale de ces dernières est préservée et, histologiquement, moins de lésions sont observées. Cette protection semble être due à l’incapacité des cellules myéloïdes à infiltrer les reins. En effet, la chimioattraction des cellules myéloïdes vers ET-1 est dépendante du récepteur ETB myéloïde. De plus, les cellules inflammatoires qui sont observées dans les reins des souris LysM-Cre Ednrb lox/lox présentent un phénotype anti-inflammatoire contrairement à leur contrôlesArterial hypertension is a major risk factor for atherosclerosis, coronary artery disease, stroke, and chronic kidney disease (CKD) and is one of the most prominent contributors to death worldwide. However, despite the frequency of hypertension, its cause in the majority of adults is unknown. Hypertension is complex, with no single mechanism entirely explaining the blood pressure (BP) rise in any given model. The past 50 years have seen growing evidence implicating the immune system. Recent data suggest that macrophages (M)/monocytes contribute to, and protect from, hypertension and its associated end organ injury. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor. Its production is triggered by multiple stimuli including Ang II and pro-inflammatory cytokines. ET-1 acts by binding to two distinct receptors, the endothelin-A (ETA) and the endothelin-B (ETB) receptors. Interestingly, ET antagonism can blunt BP elevation in an Ang II model suggesting that ET-1 largely mediates the effects of Ang II. Here, we have generated mice specifically lacking ETB receptors on myeloid cells. We have shown that the development of hypertension associated with Ang II infusion is not dependent on these cells. Similarly, the cardiac dysfunction seen after 6 weeks of Ang II was similar between knockout and control mice. Interestingly, mice deficient of ETB receptors on myeloid cells alone were protected from Ang II induced vascular dysfunction and kidney injury. This protection appeared to relate to an inability for ETB receptor deficient Mto infiltrate the kidneys due to impaired chemokinesis towards ET-1. Furthermore, the Minfiltrating he kidney in response to Ang II in myeloid ETB receptor deficient mice overwhelmingly possessed an anti-inflammatory phenotype
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Sedkaoui, Melissa. "Single-chain variable fragments and molecularly imprinted polymers directed against endothelin receptors – type B for cancer cells targeting." Thesis, Compiègne, 2021. http://www.theses.fr/2021COMP2636.
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Les récepteurs aux endothélines sont des récepteurs couples aux protéines G desquels deux variants existent, type A (ETAR) et type B (ETBR). Ils sont principalement décrits pour leur rôle physiologique de régulation du flux sanguin dans tous les types de vaisseaux via les mécanismes de vasoconstriction et de dilatation, respectivement. Cependant, les récepteurs aux endothélines sont impliqués dans plusieurs désordres physiologiques dont le cancer ou l’expression de l’un ou des deux récepteurs aux endothélines est dérégulée. Nous avons développé deux stratégies complémentaires pour le ciblage des récepteurs ETB, visant à inhiber son action quand il est surexprimé : la sélection de single-chain variable fragment (scFv) à partir d’une banque large et naïve par la technologie du phage-display, et la synthèse sur mesure, assistée par une matrice de polymères à empreintes moléculaires (MIP) comme « anticorps en plastique ». La sélection de scFv a été réalisée par biopanning sur cellules transfectées entières afin de maintenir la conformation native de ETBR. Phage-scFv qui se lient uniquement à la cible et ceux qui sont internalisés suite à l’interaction scFv- récepteur ont été isolés séparément. Après confirmation de la reconnaissance des cellules CHO-ETBR par rapport aux cellules CHO-WT par les phages-scFv polyclonaux en utilisant un test ELISA et la microscopie électronique à balayage (MEB), nous avons sélectionné au total 17 clones qui ont montré une capacité de liaison augmentée par phage-ELISA monoclonal sur cellules transfectées entières, mais également sur UACC-257, une lignée cellulaire de mélanome avec une surexpression de ETBR. Des résultats préliminaires obtenus par cryométrie en flux ont montré une reconnaissance augmentée de CHO-ETBR par l’un des clones sélectionnés. La viabilité cellulaire a été affectée par certains de ces clones. Des MIP nanoparticules ont été synthétisées en utilisant un peptide synthétique comme molécule matrice qui mime un « épitope » de ETBR. Nous avons réalisé la synthèse sur une phase solide afin d’obtenir une exposition orientée de la matrice, résultant en la production de MIP avec des cavités homogènes. Les particules MIP d’une taille de l’ordre du nanomètre ont été obtenus et ont par la suite été testés pour leur capacité à reconnaitre le récepteur entier exprimé sur la surface cellulaire par imagerie cellulaire. Des nano-MIP fluorescents ont montré une reconnaissance sélective des cellules transfectées par rapport à leurs homologues non transfectéesEndothelin receptors are G-protein coupled receptors of which two variants exist, type A (ETAR) and type B (ETBR). They are mainly described for their physiological role of regulating the blood flow in all vessel types via vasoconstriction and vasodilatation mechanisms, respectively. However, endothelin receptors are involved in several physiological disorders including cancer in which the expression of one or both endothelin receptors are deregulated.We have developed two complementary strategies for targeting ETB receptors, aiming to inhibit its action when it is overexpressed: selection of single-chain variable fragments (scFv) from a large naive library by phage-display technology as « biologic antibodies », and tailor-made template-assisted synthesis of Molecularly Imprinted Polymers (MIP) as « plastic antibodies ». The selection of scFv was performed by biopanning on whole transfected cells in order to maintain the native conformation of ETBR. Phage-scFv that only bind to the target and the ones that are internalized subsequently to scFv-receptor interaction were isolatedseparately. After confirming the recognition of CHO-ETBR cells over CHO-WT cells by polyclonal phage-scFv using an ELISA assay and Scanning Electron Microscopy (S.E.M), we have selected in total 17 clones that showed increased binding ability by monoclonal phage-ELISA on whole transfected cells but also to UACC-257, a melanoma cell line with an overexpression of ETBR. Preliminary results obtained by flow cytometry showed an enhanced recognition of CHO-ETBR by one of the selected clones. Cell viability was shown to be affected by some of these clones. MIP nanoparticles were synthesized using a synthetic peptide as template molecule that mimics an « epitope » of ETBR. We performed the synthesis on a solid phase in order to obtain an oriented exposition of the template resulting in the production of MIPs with homogenous cavities. MIP particles of a size in the nanometer range were obtained and were subsequently tested for their ability to recognize the whole receptor expressed oncell surface by cell imaging. Fluorescent nano-MIPs were shown to recognize selectively transfected cells with regard to their non-transfected counterparts
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Böhm, Felix. "The importance of endothelin-1 for vascular function in patients with atherosclerosis and healthy controls /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-293-0.
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Sandqvist, Anna. "Vardenafil and methylarginines in pulmonary hypertension." Doctoral thesis, Umeå universitet, Klinisk farmakologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-113903.
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Background: Pulmonary hypertension (PH) is a rare condition characterized by endothelial dysfunction and vascular remodelling, leading to increased pulmonary vascular resistance (PVR) and right ventricular heart failure. Endothelial dysfunction is associated with an imbalance between vasoconstrictor compounds, such as endothelin and thromboxane A2, and vasodilator compounds, such as prostacyclin and nitric oxide (NO). Asymmetric dimethylarginine (ADMA), a methyl derivate of L-arginine, inhibits synthesis of NO. Vardenafil, a phosphodiesterase type 5 inhibitor (PDE5-inhibitors), causes vasodilation through the NO/cGMP pathway. Aim: This thesis investigates the pharmacological effects and diagnostic utility of vardenafil in PH patients. In addition, to evaluate the change of L-arginine and dimethylarginines before and during PAHspecific therapy in PAH patients compared to patients with left ventricular heart failure (LVHF) and healthy subjects. Methods: The pharmacokinetics and hemodynamic effects of vardenafil were examined during right heart catheterization (RHC) in 16 PH patients and plasma concentrations were measured for up to nine hours after oral administration. In 20 PH patients, acute vasoreactivity test with vardenafil was performed during RHC. Hemodynamic responses were recorded, responders were defined and followed for up to seven years. Additionally, plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, L-citrulline and L-ornithine levels before and after PAH drug treatment were monitored in 21 PAH patients and compared to values measured in 14 LVHF patients and 27 healthy subjects. Results: Vardenafil concentrations increased rapidly to maximum plasma concentration (tmax 1h) and elimination half-life was 3.4 h. Patients co-medicated with bosentan had reduced vardenafil concentration. Significant acute hemodynamic responses were observed for mean pulmonary artery pressure (mPAP) (p<0.001), pulmonary vascular resistance (PVR) (p<0.001), cardiac output (CO) (p=0.015), cardiac index (CI) (p=0.010), systemic vascular resistance (SVR) (p<0.001) and PVR/SVR (p=0.002) and were related to plasma vardenafil concentrations. PAH patients had significantly higher ADMA and SDMA levels and significantly lower L-arginine levels and L-arginine/ADMA ratio compared with healthy subjects (p<0.001). L-arginine was also lower in PAH patients compared to patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to Larginine and L-arginine/ADMA ratio in PAH at baseline (p<0.05). At follow-up, patients on mono- or combinationtherapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on PDE5-inhibitors had higher ADMA levels compared to patients without PDE5-inhibitors (p<0.05). Conclusion: Vardenafil is safe in acute vasoreactivity test in PH patients. Cardiopulmonary hemodynamic response was related to plasma drug concentrations. There was a high inter-individual variability of vardenafil pharmacokinetics and co-medication with bosentan caused a pharmacokinetic drug interaction. Baseline L-arginine and dimethylarginines levels were different in PAH patients compared to LVHF patients and healthy controls. PAH-specific treatment influenced L-arginine and dimethylarginines. Our data suggest that L-arginine might be useful for differentiating PAH from LVHF, and L-arginine/ADMA ratios were related to the severity of PAH and might be useful for follow-up evaluations of PAH patients.
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Drozd, Katarzyna. "The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/32066.
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Background-Pulmonary artery hypertension (PAH) is characterized by progressive vascular changes causing increased pulmonary resistance and eventual right heart failure (HF). It has been suggested that altered myocardial substrate utilization may be associated with right HF, however these changes have not yet been well characterized. The aim of this study was to evaluate in vivo right ventricular (RV) function and RV glucose and fatty acid metabolism in an experimental model of PAH using non-invasive positron emission tomography (PET) imaging and to investigate the effect of a novel endothelin receptor antagonist, Macitentan, on the development of PAH and RV energetics. Methods and Results-Severe PAH was induced in a total of 11 male Sprague-Dawley rats using a single injection of Sugen5416 followed by chronic hypoxia. The rats were then randomized to treatment or no treatment with Macitentan (30 mg/kg daily) Five and eight weeks post injection, substrate utilization was serially assessed with 2-[18F]fluoro-2-deoxyglucose (FDG) and 4-[18F]fluoro-6-thia-heptadecanoate (FTHA) PET scans for glucose and fatty acid metabolism respectively, and reported as a standardized uptake value (SUV). This data was correlated with in vivo functional measurements with echocardiography and multi gated acquisition scans. The Sugen-hypoxia (SuHx) model resulted in an increase in RV FDG uptake over 8 weeks (SUV control: 1.56 ± 0.38, week 5 SuHx: 4.06 ± 1.90, week 8 SuHx: 4.00 ± 1.60, p<0.005 between control and week 5 SuHx). RV FTHA data showed a trend towards increased uptake with onset of PAH at week 5 SuHx (SUV control: 1.50 ± 0.40, week 5 SuHx: 3.06 ± 1.10, p>0.05). Macitentan significantly decreased RV FDG uptake (SUV week 8 SuHx: 4.00 ± 1.60, week 8 SuHx +ERA: 2.54 ± 0.90, p<0.05). This was associated with improved RV ejection fraction (PAH week 8 untreated: 53.15 ± 9.9% vs PAH week 8 treated: 73.22 ± 4.8%, p<0.01) and improved pulmonary artery pressures measured by pulmonary artery acceleration time (PAH week 8 untreated: 17.32 ± 2.30 ms vs. PAH week 8 treated: 24.38 ± 3.90 ms, p<0.001). There was a strong correlation between increased pulmonary artery pressures and increased RV FDG uptake (r=0.87, p=0.001) as well as a significant inverse relationship between improved RV ejection fraction and decreased RV FDG uptake (r=-0.72, p=0.01). Conclusion-PAH is associated with metabolic changes in the RV, characterized by increased glucose uptake and a trend towards increased RV fatty acid uptake with onset of PAH. Macitentan attenuated RV FDG uptake and significantly increased RV function as well as hemodynamics compared to untreated group.
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Lin, Yingfeng [Verfasser], Andrea [Gutachter] Koch, and Juris [Gutachter] Meier. "The role of human airway smooth muscle cells in chronic airway inflammation and putative therapeutic potential of endothelin receptor antagonism / Yingfeng Lin ; Gutachter: Andrea Koch, Juris Meier ; Medizinische Fakultät." Bochum : Ruhr-Universität Bochum, 2018. http://d-nb.info/1161942076/34.
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Ajne, Gunilla. "Endothelin and the regulation of peripheral and uteroplacental vascular tone during pregnancy /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-144-X/.
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Олешко, Тетяна Богданівна, Татьяна Богдановна Олешко, and Tetiana Bohdanivna Oleshko. "Зв’язок поліморфізму генів ендотеліну та ендотелінового рецептора з механізмами основних проявів ішемічного інсульту." Thesis, Сумський державний університет, 2017. http://essuir.sumdu.edu.ua/handle/123456789/65432.
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Дисертація присвячена вивченню впливу Lys198Asn- і C+70G- поліморфних варіантів генів EDN1 та EDNRA на розвиток ішемічного атеротромботичного інсульту (ІАТІ). Однонуклеотидний поліморфізм гена
EDN1 є самостійним незалежним фактором ризику ІАТІ. У осіб, що є гомозиготами за мінорним алелем, ризик розвитку ІАТІ більший у 4 рази, ніж у гомозигот за основним алелем (Р = 0,007; OR = 4,046). Зазначений ризик зростає в осіб чоловічої статі, пацієнтів із надмірною масою тіла, артеріальною
гіпертензією та без звички курити. Урахування поправки на інші коваріанти, що характеризують дані про стать, вік, ІМТ пацієнтів, наявність або відсутність у них АГ та звички курити дозволило виявити збільшення ймовірності настання ІАТІ у носіїв Asn/Asn-генотипу у 8,1 раза (Рпопр = 0,001; ORпопр = 8,059), порівняно з гомозиготами за основним алелем. Щодо поліморфного локусу C+70G гена EDNRA, то статистично значущого зв'язку його генотипів із розвитком ішемічного інсульту не виявлено.
Аналіз поєднаного впливу засвідчив, що співпадіння гомозиготи за мінорним алелем за Lys198Asn-поліморфізмом та одного із трьох можливих генотипів за C+70G-сайтом асоціюється із високим ризиком розвитку ІАТІ. При цьому збіг гетерозигот за двома сайтами також призводить до значного збільшення ризику розвитку ішемічного інсульту. Також виявлено, що поєднання в однієї особи артеріальної гіпертензії з носійством Asn-алеля за поліморфізмом гена EDN1 пов’язане з високим ризиком настання ІАТІ.Диссертация посвящена изучению влияния Lys198Asn- и C+70G-полиморфных вариантов генов EDN1 и EDNRA на развитие ишемического атеротромботического инсульта (ИАТИ). Однонуклеотидный полиморфизм гена EDN1 является самостоятельным независимым фактором риска ИАТИ. У лиц, являющихся гомозиготами по минорному аллелю, риск развития ИАТИ больше в 4 раза, чем у гомозигот по основному аллелю (Р = 0,007; OR = 4,046). Указанный риск возрастает у лиц мужского пола, пациентов с избыточной массой тела, артериальной гипертензией и без привычки курить. Учет поправки на другие коварианты, характеризующие данные о поле, возрасте, ИМТ пациентов, наличие или отсутствие в них АГ и привычки курить, позволил выявить увеличение вероятности развития ИАТИ у носителей Asn/Asn-генотипа у 8,1 раза (Рпопр = 0,001; ORпопр = 8,059) по сравнению с гомозиготами по основному аллелю. Относительно полиморфного локуса C+70G гена EDNRA, то статистически значимой связи его генотипов с развитием ишемического инсульта не обнаружено. Анализ сочетанного воздействия показал, что совпадение гомозигот по минорному аллелю Lys198Asn-полиморфизма и одного из трех возможных генотипов по C+70G-сайту ассоциируется с высоким риском развития ИАТИ. При этом совпадение гетерозигот по двум сайтам также приводит к значительному увеличению риска развития ишемического инсульта. Также выявлено, что сочетание у одного человека артериальной гипертензии с носительством Asn-аллеля по полиморфизму гена EDN1 связано с высоким риском развития ИАТИ.
Thesis is dedicated to the study of the effect of Lys198Asn- and C+70G- polymorphic variants of EDN1 and EDNRA genes impact on the development of ischemic atherothrombotic stroke (IAS). The study group included 170 unrelated Ukrainian patients with a mean age of 64.7 ± 0.73 years who had IAS. The control group consisted of 124 individuals with the absence of cardio-vascular pathologies. Genotyping of EDN1 (Lys198Asn (rs5370)) and EDNRA (C+70G (rs5335)) gene polymorphisms was performed using PCR-RFLP (polymerase chain reaction with following restriction fragment length polymorphism analysis) method. Most statistical analyses were performed using Statistical Package for Social Science software (SPSS, version 17.0, Chicago, IL, USA). Multifactorial dimensionality reduction was used for modelling the interactions between loci. All statistical tests were two-sided, P < 0.05 was considered significant. The single nucleotide polymorphism of the EDN1 gene is an independent risk factor for the development of ischemic atherothrombotic stroke – in the homozygote for the minor allele, the probability of the onset of IAS is significantly higher than that of the homozygote for the main allele (ORcorrec = 8.059; Рcorrec = 0.001). The influence of the polymorphic site of the EDN1 gene on the development of ischemic atherothrombotic stroke has sexual characteristics. The risk of stroke is higher in women who are carriers of the minor Asn-allele than in the carriers of the main Lys-allele (OR = 2.800; P = 0.009), and in males – the homozygote in the minor allele compared to homozygotes in the main allele (OR = 3.534; Р = 0.034). It was found that the risk of IAS development is greater in the homozygote for the minor allele (Asn/Asn) with BMI ≥ 25 kg/m2 than in the homozygote for the main allele (OR = 4.583; P = 0.020); in heterozygote C/G with BMI < 25 kg/m2 than in C/C-genotype carriers (OR = 3.684; P = 0.049); in patients with arterial hypertension – carriers of the heterozygous Lys/Asn-genotype (OR = 1.951; P = 0.034) and homozygote in the minor allele (Asn/Asn) (OR = 4.107; P = 0.033) compared to homozygotes in the main allele; in the Asn/Asn carriers that do not smoke compared to Lys/Lys-genotype carriers (OR = 3.379; Р = 0.041). Dependence of IAS characteristics from Lys198Asn- and C+70G-polymorphic variants of EDN1 and EDNRA genes was established. For carriers of the Asn/Asn-genotype with BMI ˂ 25 kg/m2, simultaneous damage to the anterior, middle, posterior brain arteries and arteries of the vertebro-basilar basin is more frequent characteristic (P = 0.002). The association of the G/G-genotype with the predominant damage of vertebral and basilar arteries in persons with normal arterial pressure (P = 0.050) was revealed. The clinical course of moderate severity IAS is more frequent in the homozygote for the minor G/G-allele with BMI ≥ 25 kg/m2 (P = 0.020). In persons with arterial hypertension and non-smokers who are carriers of the Asn/Asn-genotype, IAS is more likely to be severe (P = 0.024 and P = 0.023 respectively). Analysis of the combined effect of polymorphic sites of endothelin route genes and other known risk factors for atherosclerosis on the IAS development allowed to create a classification model including the polymorphic site of Lys198Asn of the EDN1 gene and arterial hypertension (prognostic significance 62% by MDR method, P = 0.043). The combination of hypertension and carriage of minor Asnallele in one person is a significant predictor of an increased risk of ischemic atherothrombotic stroke.
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Abdel-Samad, Dima. "Regulation of human endocardial endothelial cells' secretion of endothelin-1 by neuropeptide Y." Thèse, Université de Sherbrooke, 2008. http://savoirs.usherbrooke.ca/handle/11143/4271.
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Endocardial endothelial cells (EECs) can exert a significant influence on cardiac function by releasing various factors such as nitric oxide (NO), prostanoids, endothelin-1 (ET-1) and angiotensin II (Ang II). Recently, results obtained in our laboratory demonstrated the presence of NPY and its receptors, Y[subscript 1] and Y[subscript 2], as well as ET-1 and its receptors, ET[subscript A] and ET[subscript B], at the level of endocardial endothelial cells (EECs). We have also shown that NPY induces a sustained rise in the intracellular calcium level of these cells, and that only right ventricular EECs have the capacity of secreting NPY. Moreover, the evidence in the literature has become plentiful about complex interactions existing between ET-1 and other cardioactive mediators, such as NO and Ang II. Based on the above-mentioned data, the objective of this study was to investigate if a dialogue equally exists between the systems of NPY and ET-1 at the level of human right (hREECs) and left (hLEECs) ventricular EECs. Using the technique of indirect immunofluorescence coupled to 3-D confocal microscopy, as well as ELISA, our results show that increasing concentrations of NPY (10[superscript -15], 10[superscript -10] and 10[superscript -5]M) induce the release of ET-1 from REECs and LEECs in a time- and dose-dependent fashion. However, right ventricular EECs seem to have a higher ET-1 secretory capacity as compared to their left counterparts. Upon the use of selective antagonists for the NPY receptors, Y[subscript 1], Y[subscript 2] and Y[subscript 5], and the ET-1 receptors, ET[subscript A] and ET[subscript B], our results demonstrated that in REECs the NPY-induced release of ET-1 seems to be primarily due to Y[subscript 2] receptor activation, with the subsequent activation of the ET[subscript A] and ET[subscript B] receptors by the released ET-1. On the other hand, in LEECs, the NPY-evoked secretion of ET-1 seems to be mainly the result of Y[subscript 5] receptor activation by NPY. Unlike REECs, the ET-1 released by NPY in this type of cells does not seem to be contributing further to its own release by activation of its ET[subscript A] and ET[subscript B] receptors. Therefore, our results suggest that NPY is a regulator of ET-I secretion at the level of human EECs, and that this secretory process of ET-1 is different between the right and left ventricular cells. Moreover, these results serve to highlight and endorse the important sensory and tuning roles that right and left ventricular EECs possess, respectively. The ability of EECs to contribute to the local as well as systemic release of factors, such as NPY and ET-1, can affect not only the excitation-secretion coupling of EECs and the excitation-contraction coupling of cardiomyocytes, but also the physiological and pathophysiological state of the underlying, heart muscle.
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Gregan, Bernd. "Hetero- and homodimerisation of endothelin A and endothelin B receptors." [S.l.] : [s.n.], 2005. http://www.diss.fu-berlin.de/2006/85/index.html.
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Farrar, Charlotte Elizabeth. "Molecular regulation of angiogenesis by protese-activated receptors (PARS): differential utilisaton of cyclooxygenase-2 and peroxisome proliferator-activated receptor." Thesis, Royal Veterinary College (University of London), 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618320.
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Burbank, Matthew. "Altération de la dynamique des canalicules biliaires in vitro : une nouvelle approche de la prédiction de la cholestase intrahépatique d'origine médicamenteuse." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B024/document.
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La cholestase intrahépatique est une manifestation fréquente des lésions hépatiques induites par les médicaments; Cependant, les mécanismes impliqués sont peu connus. Nous avons cherché à étudier les mécanismes de la cholestase induite par les médicaments afin d’améliorer sa détection précoce en utilisant les cellules HepaRG humaines. Tout d'abord, nous avons prouvé que les canalicules biliaires (BC) subissaient des contractions spontanées, essentielles pour l'efflux d’acides biliaires et nécessitaient des séries d’alternance dans la phosphorylation/déphosphorylation de la chaîne légère de myosine (MLC2). La courte exposition à des composés cholestatiques a révélé que la modulation des BC était associée à des perturbations de la voie de signalisation ROCK/MLCK. Afin de confirmer notre étude, 12 médicaments cholestatiques et six non cholestatiques ont été analysés et nous avons démontré que tous les médicaments cholestatiques classés sur la base de résultats cliniques provoquaient des perturbations dans la dynamique des BC (dilatation ou constriction), et altéraient la voie de signalisation ROCK/MLCK, tandis que les composés non cholestatiques n'avaient pas d'effet. Nous avons également prouvé que ces changements étaient plus spécifiques que la mesure de l'inhibition de l’efflux comme marqueurs prédictifs non cliniques de la cholestase induite par les médicaments. Afin de confirmer et d’étendre ces conclusions, nous avons analysé les mécanismes impliqués dans les effets cytotoxiques et cholestatiques induits par 4 médicaments de la famille des antagonistes des récepteurs de l'endothéline: deux ayant un lien avec des cas cliniques d'hépatotoxicité (sitaxentan) et/ou cholestase (bosentan), et deux n’ayant pas été impliqués dans l’élévation de transaminases hépatiques ou de bilirubine (ambrisentan et macitentan). Les résultats montrent que le macitentan récemment commercialisé et ayant une structure chimique similaire à celle du bosentan, était capable de causer, comme ce dernier, des altérations in vitro des BC. En revanche, l'ambrisentan n’était pas hépatotoxique et le sitaxentan qui a été retiré du marché pour des cas d’hépatotoxicité, n’affectait pas la dynamique canaliculaireIntrahepatic cholestasis represents a frequent manifestation of drug-induced liver injuries; however, the mechanisms involved in such injuries are poorly understood. We aimed to investigate mechanisms underlying drug-induced cholestasis and improve its early detection using human HepaRG cells. First, we proved that bile canaliculi (BC) underwent spontaneous contractions, which are essential for bile acid efflux and required alternations in myosin light chain (MLC2) phosphorylation/dephosphorylation. A short exposure to cholestatic compounds revealed that BC dynamics was altered and associated with impairment of the ROCK/MLCK pathway. Then, in order to confirm our study, 12 cholestatic drugs and six noncholestatic drugs were analyzed and we demonstrated that all cholestatic drugs classified on the basis of reported clinical findings caused disturbances of both BC dynamics (dilatation or constriction), and alteration of the ROCK/MLCK signaling pathway, whereas noncholestatic compounds had no effect. We also proved that these changes were more specific than efflux inhibition measurements alone as predictive nonclinical markers of drug-induced cholestasis. To confirm and extend these conclusions, we analyzed the mechanisms involved in cytotoxic and cholestatic effects induced by the 4 main drugs from the endothelin receptor antagonists family: two related to clinical cases of hepatotoxicity (sitaxentan) and/or cholestasis (bosentan), and two that have not been reported to cause elevation of liver transaminases or bilirubin (ambrisentan and macitentan). The results showed that like bosentan, the structurally similar recently marketed drug, macitentan, could cause in vitro major BC alterations. By contrast, ambrisentan appeared as a safe drug and sitaxentan that has been withdrawn from the market for hepatotoxic cases, did not impair BC dynamics
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Vuorela, Piia. "Vascular endothelial growth factor, its receptors, and the Tie receptor in normal and complicated pregnancy." Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/vuorela/.
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