ETB receptor dependent alteration in aortic responses to ET-1 in the cardiomyopathic hamsterThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.

2006 ◽  
Vol 84 (7) ◽  
pp. 787-794 ◽  
Author(s):  
Johny Al-Khoury ◽  
Ghassan Bkaily ◽  
Mirna Chahine ◽  
Danielle Jacques ◽  
Pedro D'Orléans-Juste
Keyword(s):  
Receptor Antagonist ◽  
Second Messengers ◽  
Receptor Density ◽  
Special Issue ◽  
Cardiomyopathic Hamster ◽  
Cardiomyopathic Hamsters ◽  
Etb Receptor ◽  
Pre Treatment ◽  
Dose Dependent ◽  
Selection Of

The aim of this study was to verify whether an alteration in the aortic endothelin-1 (ET-1) response takes place in UM-X7.1 cardiomyopathic hamsters. Our results showed that ET-1 (10−12 – 10−5 mol/L) induces dose-dependent sustained increases in tension in the intact and endothelium denuded aortas from both normal and cardiomyopathic hamsters. The EC50 values of ET-1 of both intact and endothelium denuded aortas of normal hamsters were similar (2.2 × 10−9 mol/L and 1.8 × 10−9 mol/L, respectively). However, in cardiomyopathic hamsters, the EC50 of ET-1 in intact aortas was higher (1.5 × 10−8 mol/L) than that of the endothelium denuded preparations (2.7 × 10−9 mol/L). The EC50 of ET-1 in normal and cardiomyopathic hamster denuded aortas were similar. However, the EC50 of ET-1 in intact aortas of cardiomyopathic hamster was higher (1.5 × 10−8 mol/L) than that of normal hamsters (2.2 × 10−9 mol/L). Pre-treatment with the ETA receptor antagonist ABT-627 (10−5 mol/L) of intact and endothelium denuded aortas from both normal and cardiomyopathic hamsters significantly prevented ET-1 (10−7 mol/L) from inducing an increase in tension. Pre-treatment with the ETB receptor antagonist A-192621 (10−5 mol/L) had no effect on the ET-1-induced increase in tension in endothelium denuded aortas of both normal and cardiomyopathic hamsters, as well as in intact preparations of normal animals. However, blockade of the ETB receptors in intact aortas of cardiomyopathic hamsters significantly (p < 0.001) potentiated the ET-1-induced increase in tension. In summary, an attenuation of the contraction response to ET-1 was found in UM-X7.1 cardiomyopathic hamsters when compared with normal age-matched hamsters. This alteration of the ET-1 effect in the aortas of cardiomyopathic hamsters seems to be dependent on the presence of the endothelium and could be due, in part, to an increase in the contribution of endothelial ETB receptors to relaxation, which in turn acts as a physiological depressor of ET-1 vasoconstriction. Our results suggest that an increase in the endothelium ETB receptor density may play a role in the development of hypotension in UM-X7.1 cardiomyopathic hamsters.

PTP1B and TC-PTP: novel roles in immune-cell signalingThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.

2006 ◽  
Vol 84 (7) ◽  
pp. 667-675 ◽  
Author(s):  
Paul D. Simoncic ◽  
C. Jane McGlade ◽  
Michel L. Tremblay
Keyword(s):  
Immune Response ◽  
Cell Signaling ◽  
Protein Tyrosine Phosphatase ◽  
Immune Cell ◽  
Second Messengers ◽  
Tyrosine Phosphatase ◽  
Special Issue ◽  
Substrate Specificities ◽  
Myeloid Development ◽  
Selection Of

It has recently been demonstrated that the protein tyrosine phosphatase (PTP) PTP1B and the T-cell PTP (TC-PTP) target several substrates involved in immune cell signaling. Recent data have furthered the view of these 2 PTP members as key regulators of the immune response. This review will focus on the substrate specificities of PTP1B and TC-PTP and their roles in immune cell signaling, and will discuss some new data implicating PTP1B and TC-PTP in myeloid development.

AMP-activated protein kinase — the fat controller of the energy railroadThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.

2006 ◽  
Vol 84 (7) ◽  
pp. 655-665 ◽  
Author(s):  
Gregory R. Steinberg ◽  
S. Lance Macaulay ◽  
Mark A Febbraio ◽  
Bruce E. Kemp
Keyword(s):  
Protein Kinase ◽  
Energy Demand ◽  
Second Messengers ◽  
Metabolic Stress ◽  
Special Issue ◽  
Endocrine Control ◽  
Fatty Acid Triglyceride ◽  
Amp Activated Protein Kinase ◽  
Major Mediator ◽  
Selection Of

AMP-activated protein kinase plays an important role in the regulation of lipid metabolism in response to metabolic stress and energy demand. It is also under endocrine control. AMPK acts at multiple steps and has a central role controlling fatty acid, triglyceride, and cholesterol synthesis, as well as the oxidation of fatty acids through direct phosphorylation effects and the control of gene transcription. As such, it can be considered to be the fat controller of the energy railroad. It is thought that AMPK may be a major mediator of the health benefits of exercise in mitigating the development of obesity and age-onset diseases.

scholarly journals Role of Endothelin-1 in the Migration of Human Olfactory Gonadotropin-Releasing Hormone-Secreting Neuroblasts

Endocrinology ◽  
2005 ◽  
Vol 146 (10) ◽  
pp. 4321-4330 ◽  
Author(s):  
Roberto G. Romanelli ◽  
Tullio Barni ◽  
Mario Maggi ◽  
Michaela Luconi ◽  
Paola Failli ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Migratory Pattern ◽  
Biochemical Analyses ◽  
Eta Receptor Antagonist ◽  
Dose Dependent

FNC-B4 neuroblasts that express both neuronal and olfactory markers have been established and cloned. These cells express GnRH and both the endothelin-1 (ET-1) gene and protein and respond in a migratory manner to GnRH in a dose-dependent manner. Previous research has shown that FNC-B4 cells produce and respond to ET-1 by regulating the secretion of GnRH through endothelin type A receptors and by stimulating their proliferation through endothelin type B (ETB) receptors. In this study, we found that FNC-B4 cells are able to migrate in response to ET-1 through the involvement of ETB receptors. Combined immunohistochemical and biochemical analyses showed that ET-1 triggered actin cytoskeletal remodeling and a dose-dependent increase in migration (up to 6-fold). Whereas the ETB receptor antagonist (B-BQ788) blunted the ET-1-induced effects, the ETA receptor antagonist (A-BQ123) did not. Moreover, we observed that FNC-B4 cells were independently and selectively stimulated by ET-1 and GnRH. We suggest that ET-1, through ETB receptor activation, may be required to maintain an adequate proliferative stem cell pool in the developing olfactory epithelium and the subsequent commitment to GnRH neuronal migratory pattern. The coordinate interaction between ET receptors and GnRH receptor participates in the fully expressed GnRH-secreting neuron phenotype.

ETA receptors are present in human aortic vascular endothelial cells and modulate intracellular calciumThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (8) ◽  
pp. 817-829 ◽  
Author(s):  
Levon Avedanian ◽  
Julie Riopel ◽  
Ghassan Bkaily ◽  
Moni Nader ◽  
Pedro D’Orleans-Juste ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Receptor Antagonist ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Blot Technique ◽  
Intracellular Ca ◽  
Envelope Membranes ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Selection Of

Using immunofluorescence and real 3-D confocal microscopy, our results showed the presence of ET-1, ETA, and ETB receptors in isolated human aortic vascular endothelial cells (hVECs). The level of the peptide and its receptors was significantly higher in the nucleus (including the nuclear envelope membranes) than in the cytosol (including the cell membrane). Furthermore, using the Western blot technique we demonstrated the presence of both ETA and ETB receptors. Using intact and isolated human hVECs and the Fura-2 calcium (Ca2+) measurement technique, we showed that ET-1 induced a dose-dependent increase of total intracellular free Ca2+, with an EC50 of 1.3 × 10−10 mol/L. The specific ETA receptor antagonist ABT-627 (10−7 mol/L), but not the ETB receptor antagonist A-192621 (10−7 mol/L), prevented the ET-1 (10−9 mol/L) induced increase of total intracellular Ca2+. In conclusion, these results clearly show that similar to ETB receptors, ETA receptors are also present in human aortic vascular endothelial cells and their levels are higher than ETB in the nucleus when compared with the cytosol. Furthermore, we suggest that ETA, but not ETB, receptors mediate the effect of ET-1 on total intracellular Ca2+ of human aortic vascular endothelial cells.

Endothelial cell-specific ETB receptor knockout: autoradiographic and histological characterisation and crucial role in the clearance of endothelin-1This article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (6) ◽  
pp. 644-651 ◽  
Author(s):  
N.F. Kelland ◽  
R.E. Kuc ◽  
D.L. McLean ◽  
A. Azfer ◽  
A.J. Bagnall ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Genetic Mutation ◽  
Special Issue ◽  
Rt Pcr ◽  
Similar Extent ◽  
Relative Contribution ◽  
Liver And Kidney ◽  
Etb Receptor ◽  
Endothelin B ◽  
Selection Of

Inactivation of endothelin B receptors (ETB), either through selective pharmacological antagonism or genetic mutation, increases the circulating concentration of endothelin-1 (ET-1), suggesting ETB plays an important role in clearance of this peptide. However, the cellular site of ETB-mediated clearance has not yet been determined. We have used a novel mouse model of endothelial cell-specific knockout (KO) of ETB (EC ETB–/–) to evaluate the relative contribution of EC-ETB to the clearance of ET-1. Phenotypic evidence of EC-specific ETB KO was confirmed by immunocytochemistry and autoradiography. Binding of the radiolabelled selective ETB ligand BQ3020 was significantly and selectively decreased in EC-rich tissues of EC ETB–/– mice, including the lung, liver, and kidney. By contrast, ETA binding was unaltered. RT-PCR confirmed equal expression of ET-1 in tissue from EC ETB–/– mice and controls, despite increased concentration of plasma ET-1 in EC ETB–/–. Clearance of an intravenous bolus of [125I]ET-1 was impaired in EC ETB–/– mice. Pretreatment with the selective ETB antagonist A192621 impaired [125I]ET-1 clearance in control animals to a similar extent, but did not further impair clearance in EC ETB–/– mice. These studies suggest that EC-ETB are largely responsible for the clearance of ET-1 from the circulation.

scholarly journals Perampanel, a potent AMPA receptor antagonist, protects against tetramethylenedisulfotetramine-induced seizures and lethality in mice: comparison with diazepam

2021 ◽  
Author(s):  
Dorota Zolkowska ◽  
Ashish Dhir ◽  
Michael A. Rogawski
Keyword(s):  
Receptor Antagonist ◽  
Ampa Receptor ◽  
High Dose ◽  
Parallel Testing ◽  
Ampa Receptor Antagonist ◽  
Chemically Induced ◽  
Dose Dependent Fashion ◽  
Clonic Seizures ◽  
Pre Treatment ◽  
Dose Dependent

AbstractTetramethylenedisulfotetramine (TETS), a noncompetitive GABAA receptor antagonist, is a potent, highly lethal convulsant that is considered to be a chemical threat agent. Here, we assessed the ability of the AMPA receptor antagonist perampanel to protect against TETS-induced seizures and lethality in mice when administered before or after treatment with the toxicant. For comparison, we conducted parallel testing with diazepam, which is a first-line treatment for chemically induced seizures in humans. Pre-treatment of mice with either perampanel (1–4 mg/kg, i.p.) or diazepam (1–5 mg/kg, i.p.) conferred protection in a dose-dependent fashion against tonic seizures and lethality following a dose of TETS (0.2 mg/kg, i.p.) that rapidly induces seizures and death. The ED50 values for protection against mortality were 1.6 mg/kg for perampanel and 2.1 mg/kg for diazepam. Clonic seizures were unaffected by perampanel and only prevented in a minority of animals by high-dose diazepam. Neither treatment prevented myoclonic body twitches. Perampanel and diazepam also conferred protection against tonic seizures and lethality when administered 15 min following a 0.14 mg/kg, i.p., dose of TETS and 5 min following a 0.2 mg/kg, i.p., dose of TETS. Both posttreatments were highly potent at reducing tonic seizures and lethality in animals exposed to the lower dose of TETS whereas greater doses of both treatments were required in animals exposed to the larger dose of TETS. Neither treatment was as effective suppressing clonic seizures. In an experiment where 0.4 mg/kg TETS was administered by oral gavage and the treatment drugs were administered 5 min later, perampanel only partially protected against lethality whereas diazepam produced nearly complete protection. We conclude that perampanel and diazepam protect against TETS-induced tonic seizures and lethality but have less impact on clonic seizures. Both drugs could have utility in the treatment of TETS intoxication but neither eliminates all seizure activity.

Endothelin B receptors located on the endothelium provide cardiovascular protection in the hamster

2002 ◽  
Vol 103 (s2002) ◽  
pp. 280S-283S ◽  
Author(s):  
Jean-Claude HONORÉ ◽  
Caroline PROTEAU ◽  
Pedro D'ORLÉANS-JUSTE
Keyword(s):  
Receptor Antagonist ◽  
Pressor Response ◽  
Receptor Activation ◽  
Protective Role ◽  
Pressor Responses ◽  
Cardiomyopathic Hamsters ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B ◽  
Eta Receptor Antagonist

Endothelins (ETs) act through two receptors, namely ETA and ETB. In the cardiovascular system, the activation of both receptors leads to vasoconstriction. However, ETB receptors also mediate endothelium-dependent vasodilatation and clearance of plasma ET-1. With regard to these latter properties, we wanted to assess the contribution of ETB receptors and the effects of selective and mixed ET receptor blockade on vascular tone in control Syrian Golden hamsters and in Bio 14.6 cardiomyopathic hamsters after bolus injection of ET-1 and IRL-1620, a selective ETB agonist. In 12-week-old anaesthetized control hamsters, ET-1 (0.5nmol/kg) induced a sustained pressor response which was only partly reduced by the selective ETA receptor antagonist BQ-123, suggesting a contribution of ETB receptor activation to the vasoconstrictive effects of ET-1. This was confirmed by injection of the selective ETB receptor agonist IRL-1620 (1 nmol/kg). However, the pressor response to this agonist was always preceded by a transient vasodilatation, indicating activation of endothelium-located ETB receptors. When the selective ETB receptor antagonist BQ-788 was administered, the hypotensive phase following IRL-1620 injection was abolished. Interestingly, BQ-788 or a mixture of BQ-788 and BQ-123 significantly potentiated the pressor responses to ET-1. In 12-week-old Bio 14.6 cardiomyopathic hamsters, ET-1 and IRL-1620 induced haemodynamic responses similar to those observed in control hamsters, although the IRL-1620-induced pressor increase was lower. No difference in cardiac prepro ET-1 mRNA expression was observed between the two strains of hamsters. In conclusion, we suggest that endothelium-located ETB receptors are involved in the physiological antagonism of ET-dependent protracted pressor effects, and thus may play a protective role in both normal hamsters and those with cardiomyopathy.

Proliferation and migration of endothelial cells is promoted by endothelins via activation of ETB receptors

1995 ◽  
Vol 269 (2) ◽  
pp. H686-H695 ◽  
Author(s):  
L. Morbidelli ◽  
C. Orlando ◽  
C. A. Maggi ◽  
F. Ledda ◽  
M. Ziche
Keyword(s):  
Endothelial Cells ◽  
Receptor Antagonist ◽  
Cell Lines ◽  
Receptor Activation ◽  
Cell Number ◽  
Dependent Manner ◽  
Etb Receptor ◽  
And Migration ◽  
Dose Dependent ◽  
Proliferation And Migration

The growth and migration of endothelial cells are the prerequisites for vascular remodeling. The effects of endothelin (ET)-1 and -3 (ET-1, ET-3) on the proliferation and migration of endothelial cells isolated from bovine adrenal capillaries (BACE) and human umbilical veins (HUVEC) have been investigated. Cell proliferation (measured as DNA synthesis and as total cell number) and migration were significantly increased by ET-1 and ET-3. Dose-dependent proliferation was produced by ET-1 and ET-3 in both cell lines, with maximal effects at 0.1 nM concentration. ET-1 and ET-3 also stimulated BACE and HUVEC mobilization in a dose-dependent manner. The maximal responses were obtained at 10 nM concentration in both BACE and HUVEC. The full agonist for the ETB receptor, ET-(16--21), was able to reproduce the effects of ET on proliferation and migration of both cell lines. Modification of ET-(16--21) at Leu17 and Ile19 and amidation of the COOH-terminal were accompanied by loss of activity. The ETB-receptor antagonist IRL-1038 blocked the migration induced by ET-3 and ET-(16--21), whereas the ETA-receptor antagonist BQ-123 was not effective. We conclude that ETs, by favoring endothelial cell growth and mobilization, can contribute to neovascularization through an autocrine mechanism that requires ETB-receptor activation.

Effects of 17 beta-estradiol on coronary microvascular responses to endothelin-1

1996 ◽  
Vol 271 (3) ◽  
pp. H1117-H1124 ◽  
Author(s):  
K. G. Lamping ◽  
D. W. Nuno
Keyword(s):  
Nitric Oxide ◽  
Left Ventricle ◽  
Receptor Antagonist ◽  
Male And Female ◽  
Small Arteries ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist ◽  
Dose Dependent

The objective of this study was to examine the effects of 17 beta-estradiol on responses of coronary microvessels to endothelin-1 (ET-1). With the use of isolated pressurized coronary microvessels from the left ventricle of male or female dogs, constrictions to ET-1 were similar in vessels from male and female dogs. 17 beta-Estradiol (1 microM) attenuated constriction to ET-1 of small arteries from both male (percent constriction at 10 microM control: 39 +/- 9%, estradiol: 3 +/- 2%; P < 0.05) and female (percent constriction at 10 microM control: 39 +/- 8%, estradiol: 6 +/- 3%; P < 0.05) dogs similarly. In contrast, testosterone (1 microM) had no effect on constriction to ET-1. Constrictions to ET-1 were completely abolished by BQ-123 (1 microM), a selective ETA-receptor antagonist, and enhanced by BQ-788 (1 microM), a selective ETB-receptor antagonist. Constrictions to ET-1 alone were not altered by indomethacin (Indo, 10 microM) or NG-nitro-L-arginine (L-NNA, 100 microM). 17 beta-Estradiol produced dose-dependent relaxation of coronary microvessels preconstricted with ET-1 that was similar to the response to testosterone and progesterone. Indo or L-NNA alone had no effect on relaxation to 17 beta-estradiol. However, the combination of Indo and L-NNA attenuated Taxation to 17 beta-estradiol (percent dilation at 1 microM control: 64 +/- 13%; Indo plus L-NNA: 21 +/- 6%; P < 0.05) but did not affect relaxation to testosterone. Thus 17 beta-estradiol attenuated constrictions of coronary microvessels to ET-1 more than did similar concentrations of testosterone. The ability of 17 beta-estradiol to modulate responses to endothelin may involve release of vasodilator prostaglandins and/or nitric oxide by 17 beta-estradiol.

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