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Lars Edvinsson - One of the best experts on this subject based on the ideXlab platform.
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Myocardial ischemia-reperfusion enhances transcriptional expression of endothelin-1 and vasoconstrictor ETB receptors via the protein kinase MEK-ERK1/2 signaling pathway in rat - Fig 4
2017Co-Authors: Gry Freja Skovsted, Lars Schack Kruse, Lukas Adrian Berchtold, Anne-sofie Grell, Karin Warfvinge, Lars EdvinssonAbstract:Concentration-response curves show the effect of increasing concentrations of Sarafotoxin 6c (S6c) in the left anterior descending artery (LAD) upstream of the ligature, LAD downstream of the ligature, and non-ischemic septal coronary artery (SCA) after treatment with (A) IR and vehicle or (B) U0126. The results are shown as mean values ± SEM (n = 6–7), ***P < 0.001; two-way ANOVA with repeated measurements; LAD downstream vs. upstream. Concentration-response curves show the effect of increasing concentrations of endothelin-1 (ET-1) after ETB receptor desensitization and BQ788 treatment in the LAD upstream of the ligature, LAD downstream of the ligature, and non-ischemic SCA after treatment with (C) the vehicle or (D) U0126. The results are shown as mean values ± SEM (n = 4–7), ***P < 0.001; two-way ANOVA with repeated measurements; LAD downstream vs. upstream.
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cigarette smoke extracts promote vascular smooth muscle cell proliferation and enhances contractile responses in the vasculature and airway
Basic & Clinical Pharmacology & Toxicology, 2010Co-Authors: Ying Lei, Qingwen Chen, Christina Pehrson, Lennart Larsson, Lars EdvinssonAbstract:Cigarette smoke exposure is a strong risk factor for cardiovascular and respiratory diseases. However, the knowledge about how cigarette smoke induces damage to vasculature and airway is limited. The present study was designed to examine the effects of cigarette smoke particles extracted by heptane (heptane-soluble smoke particles, HSP), by water (water-soluble smoke particles, WSP) and by DMSO (DMSO-soluble smoke particles, DSP), which represent lipophilic, hydrophilic and ambiphoteric constituents from the cigarette smoke, respectively. Human aortic smooth muscle cell (HASMC) proliferation was assessed in cell culture. Rat resistance artery and airway contractile responses to serotonin, U46619, phenylephrine, noradrenaline, acetylcholine, des-Arg(9)-bradykinin, bradykinin, Sarafotoxin 6c and endothelin-1 were monitored by a sensitive myograph system. Immunocytochemistry and cell-based phosphoELISA assay were used to demonstrate activation of extracellular signal-regulated kinases 1/2 (ERK1/2). For the first time, our results demonstrate that although all the three extracts promote HASMC proliferation, the HSP and DSP effects occur earlier. HSP and DSP, but not WSP, increase the contractile responses to Sarafotoxin 6c, U46619 or bradykinin in rat mesenteric artery and/or in bronchi. ERK1/2 is activated by HSP and DSP in HASMCs and inhibition of ERK1/2 abrogated the smoke extracts-induced HASMC proliferation, while blockage of nicotinic receptors had no effects, suggesting that the toxic effects of the smoke extracts occur via activation of intracellular ERK1/2 signalling, but not nicotinic receptors.
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Up-regulation of endothelin type B receptors in the human internal mammary artery in culture is dependent on protein kinase C and mitogen-activated kinase signaling pathways
BMC Cardiovascular Disorders, 2008Co-Authors: David Nilsson, Angelica Wackenfors, Per Paulsson, Lotta Gustafsson, Bodil Gesslein, Richard Ingemansson, Lars Edvinsson, Malin MalmsjoAbstract:Background Up-regulation of vascular endothelin type B (ET_B) receptors is implicated in the pathogenesis of cardiovascular disease. Culture of intact arteries has been shown to induce similar receptor alterations and has therefore been suggested as a suitable method for, ex vivo , in detail delineation of the regulation of endothelin receptors. We hypothesize that mitogen-activated kinases (MAPK) and protein kinase C (PKC) are involved in the regulation of endothelin ET_B receptors in human internal mammary arteries. Methods Human internal mammary arteries were obtained during coronary artery bypass graft surgery and were studied before and after 24 hours of organ culture, using in vitro pharmacology, real time PCR and Western blot techniques. Sarafotoxin 6c and endothelin-1 were used to examine the endothelin ET_A and ET_B receptor effects, respectively. The involvement of PKC and MAPK in the endothelin receptor regulation was examined by culture in the presence of antagonists. Results The endohtelin-1-induced contraction (after endothelin ET_B receptor desensitization) and the endothelin ET_A receptor mRNA expression levels were not altered by culture. The Sarafotoxin 6c contraction, endothelin ET_B receptor protein and mRNA expression levels were increased after organ culture. This increase was antagonized by; (1) PKC inhibitors (10 μM bisindolylmaleimide I and 10 μM Ro-32-0432), and (2) inhibitors of the p38, extracellular signal related kinases 1 and 2 (ERK1/2) and C-jun terminal kinase (JNK) MAPK pathways (10 μM SB203580, 10 μM PD98059 and 10 μM SP600125, respectively). Conclusion In conclusion, PKC and MAPK seem to be involved in the up-regulation of endothelin ET_B receptor expression in human internal mammary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin ET_B receptor changes in cardiovascular disease.
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up regulation of endothelin receptor function and mrna expression in airway smooth muscle cells following sephadex induced airway inflammation
Basic & Clinical Pharmacology & Toxicology, 2004Co-Authors: Bengt W Granstrom, Cangbao Xu, E Nilsson, Ursula Hultkvist Bengtsson, Lars EdvinssonAbstract:The hypothesis that up-regulation of bronchial constrictor endothelin receptors in airway smooth muscle cells may contribute to hyperreactivity during airway inflammation was tested in the present study by quantitative endothelin receptor mRNA analysis and functional responses in ring segments of rat trachea and bronchi. Real time reverse transcription polymerase chain reaction was used to quantify endothelin receptor expression in rat airway smooth muscle cells following Sephadex-induced inflammation. Compared with controls, Sephadex-induced airway inflammation caused a significant increase (3.9 times P<0.05) of endothelin receptor type B mRNA expression in bronchial smooth muscle cells, but not in tracheal smooth muscle cells. Functional myograph studies of bronchial and tracheal ring segments without epithelium (mechanically denuded) revealed an increase of the maximum contractile effects of endothelin-1 (a dual agonist for both endothelin type A and B receptors) and Sarafotoxin 6c (a selective agonist for endothelin B receptors) in bronchial smooth muscle cells in Sephadex-induced inflammation, but not in tracheal smooth muscle cells. The enhanced maximal responses of bronchial smooth muscle cells to endothelin-1 and Sarafotoxin 6c in Sephadex-induced inflammation support our molecular findings and hence imply a role for endothelin B receptors in airway hyperreactivity during airway inflammation.
Edvinsson Lars - One of the best experts on this subject based on the ideXlab platform.
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Contractile Responses in Spontaneously Hypertensive Rats after Transient Middle Cerebral Artery Occlusion
'S. Karger AG', 2018Co-Authors: Grell, Anne Sofie, Edvinsson Lars, Mostajeran Maryam, Ansar SaemaAbstract:Stroke is one of the leading causes of mortality and morbidity worldwide, and few therapeutic treatments have shown beneficial effect clinically. One reason for this could be the lack of risk factors incorporated into the preclinical stroke research. We have previously demonstrated phenotypic receptor changes to be one of the injurious mechanisms occurring after stroke but mostly in healthy rats. The aim of this study was to investigate if hypertension has an effect on vasoconstrictive receptor responses to endothelin 1, Sarafotoxin 6c and angiotensin II after stroke by inducing transient middle cerebral artery occlusion in spontaneously hypertensive rats and Wistar-Kyoto rats using the wire-myograph. We demonstrated an increased contractile response to endothelin 1 and extracellular potassium as well as an increased carbachol-induced dilator response in the middle cerebral arteries from hypertensive rats after stroke. This study demonstrates the importance of including risk factors in experimental stroke research
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Nuclear Factor-kappaB-Mediated Endothelin Receptor Up-Regulation Increases Renal Artery Contractility in Rats
'Wiley', 2013Co-Authors: Xie Yan-hua, Edvinsson Lars, Wang Si-wang, Zhang Yaping, Xu Cang-baoAbstract:Increased renal artery contractility leads to renal vasospasm and ischaemia as well as kidney damage. This study was designed to examine the hypothesis that organ culture of renal arteries induces transcriptional up-regulation of endothelin type A (ETA) and type B2 (ETB2) receptors in the smooth muscle cells via activation of nuclear factor-kappaB (NF-B) and subsequently increases renal artery contractility. Rat renal artery segments were organ-cultured for 6 or 24hr to increase endothelin receptor-mediated contraction. To dissect molecular mechanisms involved in this process, inhibitors for NF-B signalling pathway (MG-132 and BMS345541), transcription (actinomycin D) and translation (cycloheximide) were used during organ culture. Endothelin receptors were studied using a sensitive myograph (functional contractility), real-time PCR (mRNA analysis) and immunohistochemistry (protein localization). Compared with fresh segments, contractile responses to endothelin-1 (non-selective endothelin receptor agonist) and Sarafotoxin 6c (selective ETB receptor agonist) were significantly increased in the segments after 24hr of organ culture; ETB2 receptor-mediated maximal contraction increased from 2.7 +/- 0.5 to 135.3 +/- 5.1 (p
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Endothelin receptor-mediated vasodilatation: Effects of organ culture.
'Elsevier BV', 2008Co-Authors: Nilsson David, Edvinsson Lars, Wackenfors Angelica, Gustafsson Lotta, Ugander Martin, Paulsson Per, Ingemansson Richard, Malmsjö MalinAbstract:Culture of intact arteries is a frequently employed experimental model for investigating the mechanisms governing the regulation of vascular endothelin receptors. Endothelin type A (ETA) and type B (ETB) receptors on vascular smooth muscle cells are up-regulated in organ culture and the enhanced vasoconstriction mimics the changes that occur in cardiovascular disease. The effect of organ culture on endothelial dilatory endothelin ETB receptors is not known. We hypothesize that organ culture decreases the endothelin receptor-mediated dilatation and that this is one possible mechanism by which the effects of the endothelin in blood vessels are altered during culture. Porcine coronary arteries were studied before and after 24 h of culture, using in vitro pharmacology and immunofluorescence. Sarafotoxin 6c and endothelin-1 were used to examine the endothelin ETA and ETB receptor effects, and the antagonists, Nω-nitro-l-arginine (l-NOARG) for nitric oxide (NO), indomethacin for prostaglandins and charybdotoxin in combination with apamin for endothelium-derived hyperpolarizing factor (EDHF), were used to study the endothelium-derived dilatory mediators. Organ culture induced up-regulation of the Sarafotoxin 6c (ETB receptor agonist) and endothelin-1 (ETA receptor agonist) elicited vasoconstriction. The Sarafotoxin 6c contraction was stronger after endothelium denudation, suggesting endothelium-dependent dilatation. The endothelin-1 contraction was not affected by endothelium denudation. The increase in Sarafotoxin 6c contraction after removal of the endothelium was more pronounced before than after organ culture, suggesting down-regulated endothelial endothelin ETB receptors. Also, the immunofluorescence staining intensities for endothelial endothelin ETB receptors were higher before than after organ culture. Pre-incubation with inhibitors for dilatory mediators suggested that both NO and EDHF play a vasodilatory role, while prostaglandins are not involved. In conclusion, endothelial endothelin ETB receptors induce NO and EDHF mediated vasodilatation in porcine coronary arteries. In organ culture, endothelial endothelin ETB receptors are down-regulated, mimicking the changes that occur in cardiovascular disease. Down-regulation of endothelial endothelin ETB receptors may in part explain the increased endothelin ETB receptor-mediated vasoconstriction frequently studied in organ culture
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Enhanced expression of contractile endothelin ET(B) receptors in rat coronary artery after organ culture.
'Elsevier BV', 2008Co-Authors: Johnsson Evelina, Wackenfors Angelica, Maddahi Aida, Edvinsson LarsAbstract:Endothelin-1 is a potent vasoconstrictor mediating its effects via two receptor subtypes, the endothelin type A (ET(A)) preferentially situated on smooth muscle cells, mediating vasoconstriction and endothelin type B (ET(B)) mainly located on endothelial cells, mediating vasodilatation. In cardiovascular disease and in organ culture in vitro, endothelin ET(B) receptors are up-regulated on smooth muscle cells. The objectives of the present study were to characterise the endothelin receptor-induced vasoconstriction and quantify the endothelin receptor mRNA levels and immunoreactivity in fresh and cultured rat coronary arteries. We demonstrate that endothelin-1 induces strong and equal concentration-dependent contractions in fresh and cultured segments from the left anterior descending coronary artery. Sarafotoxin 6c, an endothelin ET(B) receptor agonist, had negligible effect in fresh arteries but produced significant vasoconstriction after organ culture. The endothelin ET(B) receptor mRNA level and the receptor protein immunoreactivity were increased, whereas the level of endothelin ET(A) receptor mRNA was down-regulated but not its receptor protein immunoreactivity after organ culture. Pharmacological inhibition of endothelium-derived dilatory mediators did not influence endothelin ET(A) or ET(B) receptor-mediated vasoconstriction in fresh segments. In cultured arteries, inhibition of endothelial vasodilators potentiated the effect of Sarafotoxin 6c. In conclusion, endothelin ET(B) receptor stimulation in cultured coronary arteries elicits vasoconstriction. This is likely not related to endothelial dysfunction with putative loss of its vasodilator components, but rather explained by the up-regulation of contractile endothelin ET(B) receptors on smooth muscle cells
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Upregulation of endothelin ETB receptor-mediated vasoconstriction in rat coronary artery after organ culture
'Elsevier BV', 2006Co-Authors: Eskesen K, Edvinsson LarsAbstract: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 Dulbecco's Modified Eagle's 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 with addition of the transcriptional blocker, actinomycin D, to the culture medium or be significantly attenuated by application of the translational inhibitor, cycloheximide. The vasoconstrictor effect of endothelin-1 or to depolarisation by high K+-solution was not modified after 1 day in culture medium. The experiments indicate that organ culture of rat coronary arteries upregulate endothelin ETB receptor-mediated contraction by inducing synthesis of new protein. (c) 2006 Elsevier B.V. All rights reserved
Mordechai Sokolovsky - One of the best experts on this subject based on the ideXlab platform.
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structure function relationships of endothelins Sarafotoxins and their receptor subtypes
Journal of Neurochemistry, 1992Co-Authors: Mordechai SokolovskyAbstract:: In brain synaptic membranes not extensively washed, (+)-5-[3H]methyl-10,1 l-dihydro-5H-dibenzo[a, d]-cyclohepten-5,10-imine ([3H]MK-801) binding was markedly inhibited in a concentration-dependent manner (at concentrations above 1 μM) by several compounds having antagonistic activity at the Ca2+-binding protein calmodulin. Scatchard analysis revealed that N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) inhibited the binding through a significant decrease in the density of binding sites without affecting the affinity at 10 μM. In membranes extensively washed and treated with a low concentration of Triton X-100, L-glutamic acid (Glu) drastically accelerated the initial association rate of [3H]MK-801 binding with glycine (Gly), almost doubling the initial association rate found in the presence of Glu alone. The addition of W-7 invariably reduced the initial association rate observed in the presence of either Glu alone or both Glu and Gly, without significantly altering the dissociation rate of bound [3H]-MK-801, irrespective of the presence of the two stimulatory amino acids. The maximal potencies of Glu, Gly, and spermidine in potentiating the binding were all attenuated by W-7. These results suggest that calmodulin antagonists may interfere with opening processes of an ion channel associated with an N-methyl-D-aspartate-sensitive subclass of excitatory amino acid receptors in rat brain.
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endothelins and Sarafotoxins physiological regulation receptor subtypes and transmembrane signaling
Pharmacology & Therapeutics, 1992Co-Authors: Mordechai SokolovskyAbstract:The endothelins and Sarafotoxins are two structurally related families of potent vasoactive peptides. Although the physiological functions of these peptides are not entirely clear, the endothelins are probably involved in pathophysiological conditions such as hypertension and heart failure. This review summarizes the state of the art in some areas of this intensively studied subject, including: (1) structure-function relationships of ET/SRTX, (2) ET concentrations in plasma, (3) ET/SRTX receptor subtypes and (4) signaling events mediated by the activation of ET/SRTX receptors.
Xu Cangbao - One of the best experts on this subject based on the ideXlab platform.
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minimally modified ldl upregulates endothelin type b receptors in rat coronary artery via erk1 2 mapk and nf κb pathways
Biochimica et Biophysica Acta, 2012Co-Authors: Li Jie, Cao Yongxiao, Yuan Zuyi, Xu CangbaoAbstract:Minimally modified low density lipoprotein (mmLDL) is a well-known risk factor for coronary artery disease. Upregulation of vascular endothelin type B (ETB) receptors on the vascular smooth muscle cells is predicted to be the molecular mechanism that leads to cardiovascular pathogenesis. The objective of the present study was to examine the hypothesis that mmLDL upregulates ETB receptors in rat coronary artery. The contractile responses to Sarafotoxin 6c (ETB receptor agonist) were studied using a sensitive myograph. ETB receptor mRNA and protein expression was determined using real-time PCR and Western blot analysis. The results showed that organ culture increased the contractile responses induced by Sarafotoxin 6c and the levels of ETB receptor mRNA and protein. This increase was further enhanced by the addition of mmLDL (10 mu g/mL). Specific ERK1/2 inhibitors (SB386023 and U0126) and an NF-kappa B inhibitor (wedelolactone) attenuated the mmLDL-increased ETB receptor-mediated contraction and ETB receptor mRNA and protein levels. Wedelolactone significantly attenuated the mmLDL-decreased I kappa B-alpha protein expression. Consistent with this result, I kappa B-alpha protein expression was significantly decreased by culture with mmLDL compared to the level of expression in the organ culture group. However, the JNK inhibitor, SP600125 or p38 pathway inhibitor, SB203580 did not inhibit mmLDL-enhanced effects. The PKC inhibitor, staurosporine attenuated only culture-alone-increased effects. In conclusion, mmLDL upregulates the ETB receptors in rat coronary arterial smooth muscle cells, mainly via activation of the ERK1/2 MAPK and the downstream transcriptional factor NF-kappa B. (C) 2011 Elsevier B.V. All rights reserved. (Less)
Christian Thuillez - One of the best experts on this subject based on the ideXlab platform.
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selective endothelin a versus combined endothelin a endothelin b receptor blockade in rat chronic heart failure
Circulation, 2000Co-Authors: Paul Mulder, Houssaine Boujedaini, Vincent Richard, Genevieve Derumeaux, Jean Paul Henry, Sylvanie Renet, Jerry Wessale, Terry Opgenorth, Christian ThuillezAbstract:Background—The relative efficacy of endothelin-A (ETA) receptor blockade versus combined ETA-ETB receptor blockade in chronic heart failure (CHF) is still largely unknown. Methods and Results—We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ETA antagonist ABT-627 (5 mg · kg−1 · d−1), the ETB antagonist A-192621 (30 mg · kg−1 · d−1) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ETA blockade) or the depressor responses to Sarafotoxin S6c or ET-1 (for ETB blockade). ETA and combined ETA-ETB blockade reduced systolic blood pressure to the same extent, whereas ETB blockade had no effect. In contrast, only combined ETA-ETB blockade significantly reduced heart rate. Both ETA and combined ETA-ETB blockade, but not ETB blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastol...
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selective eta receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure
Cardiovascular Research, 1998Co-Authors: Paul Mulder, Vincent Richard, Genevieve Derumeaux, Francois Bouchart, Klaus Munter, Christian ThuillezAbstract:Background: Left ventricular (LV) dilation, which is a predictor of survival in humans with chronic heart failure (CHF), is limited by a mixed endothelin ETA–ETB antagonist. Whether selective ETA receptor blockade influences LV dilation is unknown. We determined, in a rat model of CHF, the effects of the ETA receptor blocker LU 135 252 on LV remodeling. Methods and Results: Rats were subjected to coronary artery ligation and treated for ten weeks with placebo or LU 135 252 (LU), at a dose of 10 or 30 mg kg−1 day−1. Systolic blood pressure and heart rate (plethysmography) were determined in conscious animals before and after four and ten weeks of treatment. At these time points, cardiac output and LV dimensions were measured in anesthetized rats by transthoracic echocardiography. LV hemodynamics were determined in anesthetized rats after ten weeks. Pressor responses to ET-1 (1 nmol/kg, i.v.) and Sarafotoxin S6c (0.3 ng/kg, i.v.) were measured, to assess the efficacy of ET receptor antagonism and the lack of blockade of ETB receptor blockade, respectively. The pressor response to ET-1 was significantly reduced by LU (% change in systolic blood pressure: sham: 9±1; CHF: 5±1; CHF LU: 0±3 and −4±2% for the low and high dose, respectively). LU did not affect the response to Sarafotoxin (CHF: −37±3; CHF LU: −29±3 and −28±2% for the low and high dose, respectively). Both doses of LU decreased systolic blood pressure, but only the high dose of LU reduced heart rate. Furthermore, LU restored cardiac output dose-dependently throughout the study. Both doses of LU limited LV dilatation and deterioration of LV fractional shortening to the same extent. After ten weeks, LU normalized LV end-diastolic- and central venous pressures, but did not affect LV d P /d t max or d P /d t min. LU did not prevent the development of cardiac hypertrophy, but reduced LV collagen density. Conclusions: In this rat model, the selective ETA receptor blocker LU, at the dose of 30 mg kg−1 day−1, reduced blood pressure and heart rate, limited progressive left ventricular remodeling and improved cardiac hemodynamics and function. These effects of LU might have important clinical relevance in the treatment of heart failure.
