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[PMID]:28720331
[Au] Autor:Park BG; Shin WS; Oh S; Park GM; Kim NI; Lee S
[Ad] Endereço:Department of Physiology, Catholic Kwandong University College of Medicine, Gangneung 25601, Republic of Korea; Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung 25601, Republic of Korea.
[Ti] Título:A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca channel blocker and endothelin A/B receptor antagonist.
[So] Source:Bioorg Med Chem;25(17):4649-4655, 2017 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK )-induced basilar artery contraction with EC values of 3.52±0.42 and 1.62±0.63µM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC =9.8±0.6µM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca channel and endothelin A/B receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension.
[Mh] Termos MeSH primário: Anti-Hipertensivos/química
Benzopiranos/química
Bloqueadores dos Canais de Cálcio/química
Antagonistas do Receptor de Endotelina A/química
Antagonistas do Receptor de Endotelina B/química
Feófitas/química
[Mh] Termos MeSH secundário: Administração Oral
Animais
Anti-Hipertensivos/isolamento & purificação
Anti-Hipertensivos/farmacologia
Artéria Basilar/efeitos dos fármacos
Artéria Basilar/fisiologia
Benzopiranos/isolamento & purificação
Benzopiranos/farmacologia
Pressão Sanguínea/efeitos dos fármacos
Bloqueadores dos Canais de Cálcio/isolamento & purificação
Bloqueadores dos Canais de Cálcio/farmacologia
Canais de Cálcio Tipo L/química
Canais de Cálcio Tipo L/metabolismo
Antagonistas do Receptor de Endotelina A/isolamento & purificação
Antagonistas do Receptor de Endotelina A/farmacologia
Antagonistas do Receptor de Endotelina B/isolamento & purificação
Antagonistas do Receptor de Endotelina B/farmacologia
Masculino
Feófitas/metabolismo
Coelhos
Ratos
Ratos Endogâmicos SHR
Receptor de Endotelina A/química
Receptor de Endotelina A/metabolismo
Receptor de Endotelina B/química
Receptor de Endotelina B/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antihypertensive Agents); 0 (Benzopyrans); 0 (Calcium Channel Blockers); 0 (Calcium Channels, L-Type); 0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 0 (sargachromenol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE


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[PMID]:28134077
[Au] Autor:Soldano S; Paolino S; Pizzorni C; Trombetta AC; Montagna P; Brizzolara R; Corallo C; Giordano N; Sulli A; Cutolo M
[Ad] Endereço:Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS AOU San Martino Hospital, Genoa, Italy.
[Ti] Título:Dual endothelin receptor antagonists contrast the effects induced by endothelin-1 on cultured human microvascular endothelial cells.
[So] Source:Clin Exp Rheumatol;35(3):484-493, 2017 May-Jun.
[Is] ISSN:0392-856X
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To evaluate the ability of dual endothelin (ET) receptor antagonists (ETA/ETB -ETA/BRAs) to contrast the ET-1-induced effects on cultured human microvascular endothelial cells (HMVECs). METHODS: Some cultured HMVECs were untreated, or treated with ET-1 (100nM) or transforming growth factor ß1 (TGFß1, 10ng/mL) alone for 6 days, in order to induce the endothelial-to-mesenchymal transition (EndoMT). Other cultured HMVECs were pre-treated for 1hr with ETA/BRAs bosentan (10µM) or macitentan (1µM, 10µM) before the stimulation with ET-1 for 6 days. At the end of treatments, a mechanical injury was induced to cultured HMVECs (by scratching the cell monolayer with a sterile tip), and then the cell ability to re-fill the damaged area was determined after 24hrs. EndoMT phenotype markers and monocyte chemoattractant protein-1 (MCP-1) were evaluated by qRT-PCR and Western blotting. Statistical analysis was performed using Mann-Whitney-U non-parametric test. RESULTS: Both ET-1 and TGFß1 induced EndoMT and the MCP-1 over-expression in cultured HMVECs, as well as reduced the process of endothelial cell damage repair. Pre-treatment with ETA/BRAs let cultured HMVECs to significantly restore the in vitro damage of the cell monolayer and antagonised the EndoMT process as well as the MCP-1 over-expression (range p<0.05 - p<0.001). Conversely, untreated or TGFß1-treated HMVECs were found unaffected by the ETA/BRAs treatments. CONCLUSIONS: The treatment with dual ETA/BRAs seems to partially restore the altered cell function induced by ET-1 in cultured endothelial cells, and might justify their therapeutic efficiency in clinical conditions characterised by increased concentrations of ET-1.
[Mh] Termos MeSH primário: Células Endoteliais/efeitos dos fármacos
Antagonistas do Receptor de Endotelina A/farmacologia
Antagonistas do Receptor de Endotelina B/farmacologia
Endotelina-1/farmacologia
Microvasos/efeitos dos fármacos
Pirimidinas/farmacologia
Receptor de Endotelina A/efeitos dos fármacos
Receptor de Endotelina B/efeitos dos fármacos
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Forma Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Quimiocina CCL2/genética
Quimiocina CCL2/metabolismo
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Seres Humanos
Microvasos/metabolismo
Microvasos/patologia
Miofibroblastos/efeitos dos fármacos
Miofibroblastos/metabolismo
Miofibroblastos/patologia
Fenótipo
Receptor de Endotelina A/metabolismo
Receptor de Endotelina B/metabolismo
Fatores de Tempo
Fator de Crescimento Transformador beta1/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCL2 protein, human); 0 (Chemokine CCL2); 0 (EDNRB protein, human); 0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Endothelin-1); 0 (Pyrimidines); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 0 (Sulfonamides); 0 (Transforming Growth Factor beta1); Q326023R30 (bosentan); Z9K9Y9WMVL (macitentan)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170824
[Lr] Data última revisão:
170824
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170131
[St] Status:MEDLINE


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[PMID]:27671974
[Au] Autor:Mehta S; Sastry BK; Souza R; Torbicki A; Ghofrani HA; Channick RN; Delcroix M; Pulido T; Simonneau G; Wlodarczyk J; Rubin LJ; Jansa P; Hunsche E; Galiè N; Perchenet L; Sitbon O
[Ad] Endereço:London Health Sciences Centre, Victoria Hospital, Western University, London, ON, Canada. Electronic address: sanjay.mehta@lhsc.on.ca.
[Ti] Título:Macitentan Improves Health-Related Quality of Life for Patients With Pulmonary Arterial Hypertension: Results From the Randomized Controlled SERAPHIN Trial.
[So] Source:Chest;151(1):106-118, 2017 Jan.
[Is] ISSN:1931-3543
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in patients with PAH in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) study. The association between baseline HRQoL and long-term outcomes was also investigated. METHODS: Patients were randomized to placebo, macitentan 3 mg, or macitentan 10 mg once daily. Patients aged 14 years or older completed the 36-Item Short Form Survey (SF-36) at baseline, at month 6 and month 12, and at the end of treatment (EOT). The absolute change from baseline to month 6 in SF-36 scores was calculated. The time to a clinically meaningful deterioration in the SF-36 physical component summary and mental component summary (PCS and MCS) scores and associations between baseline PCS/MCS scores and time to morbidity/mortality events were also assessed. RESULTS: At month 6, macitentan 10 mg significantly improved seven of eight SF-36 domains and the PCS and MCS scores vs placebo. Macitentan 10 mg significantly reduced the risk of a three-point or greater deterioration in PCS (hazard ratio [HR], 0.60; 95% CI, 0.47-0.76; P < .0001) and MCS scores (HR, 0.76; 95% CI, 0.61-0.95; P = .0173) until EOT vs placebo. Patients with a baseline PCS score greater than the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score less than the median; a similar result was observed for the MCS score. CONCLUSIONS: Macitentan significantly improved HRQoL in patients with PAH compared with placebo and significantly reduced the risk of a clinically meaningful HRQoL deterioration. An association between better baseline HRQoL and improved long-term outcomes was shown. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00660179; URL: clinicaltrials.gov.
[Mh] Termos MeSH primário: Hipertensão Pulmonar
Pirimidinas
Qualidade de Vida
Sulfonamidas
[Mh] Termos MeSH secundário: Adulto
Relação Dose-Resposta a Droga
Monitoramento de Medicamentos/métodos
Antagonistas do Receptor de Endotelina B/administração & dosagem
Antagonistas do Receptor de Endotelina B/efeitos adversos
Feminino
Seres Humanos
Hipertensão Pulmonar/diagnóstico
Hipertensão Pulmonar/tratamento farmacológico
Hipertensão Pulmonar/fisiopatologia
Hipertensão Pulmonar/psicologia
Masculino
Meia-Idade
Gravidade do Paciente
Pirimidinas/administração & dosagem
Pirimidinas/efeitos adversos
Sulfonamidas/administração & dosagem
Sulfonamidas/efeitos adversos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Endothelin B Receptor Antagonists); 0 (Pyrimidines); 0 (Sulfonamides); Z9K9Y9WMVL (macitentan)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160928
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE


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[PMID]:27810862
[Au] Autor:Valero-Munoz M; Li S; Wilson RM; Boldbaatar B; Iglarz M; Sam F
[Ad] Endereço:From the Whitaker Cardiovascular Institute (M.V.-M., S.L., R.M.W., B.B., F.S.) and Cardiovascular Section and Evans Department of Medicine (F.S.), Boston University School of Medicine, MA; and Actelion Pharmaceuticals Ltd., Allschwil, Switzerland (M.I.).
[Ti] Título:Dual Endothelin-A/Endothelin-B Receptor Blockade and Cardiac Remodeling in Heart Failure With Preserved Ejection Fraction.
[So] Source:Circ Heart Fail;9(11), 2016 Nov.
[Is] ISSN:1941-3297
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension. METHODS AND RESULTS: In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF. CONCLUSIONS: These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF.
[Mh] Termos MeSH primário: Antagonistas do Receptor de Endotelina A/uso terapêutico
Antagonistas do Receptor de Endotelina B/uso terapêutico
Insuficiência Cardíaca/tratamento farmacológico
Hipertrofia Ventricular Esquerda/tratamento farmacológico
Pirimidinas/uso terapêutico
Volume Sistólico
Sulfonamidas/uso terapêutico
Disfunção Ventricular Esquerda/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso
Animais
Estudos de Casos e Controles
Colágeno Tipo I/efeitos dos fármacos
Colágeno Tipo I/genética
Conectina/efeitos dos fármacos
Conectina/genética
Diástole
Ecocardiografia
Antagonistas do Receptor de Endotelina A/farmacologia
Antagonistas do Receptor de Endotelina B/farmacologia
Endotelina-1/sangue
Feminino
Coração/efeitos dos fármacos
Insuficiência Cardíaca/sangue
Insuficiência Cardíaca/diagnóstico por imagem
Insuficiência Cardíaca/fisiopatologia
Seres Humanos
Hipertrofia
Hipertrofia Ventricular Esquerda/diagnóstico por imagem
Hipertrofia Ventricular Esquerda/fisiopatologia
Técnicas In Vitro
Fatores de Transcrição MEF2/efeitos dos fármacos
Fatores de Transcrição MEF2/metabolismo
Masculino
Camundongos
Meia-Idade
Miócitos Cardíacos/efeitos dos fármacos
Pirimidinas/farmacologia
RNA Mensageiro/efeitos dos fármacos
RNA Mensageiro/metabolismo
Sulfonamidas/farmacologia
Disfunção Ventricular Esquerda/diagnóstico por imagem
Disfunção Ventricular Esquerda/fisiopatologia
Remodelação Ventricular/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Collagen Type I); 0 (Connectin); 0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Endothelin-1); 0 (MEF2 Transcription Factors); 0 (Pyrimidines); 0 (RNA, Messenger); 0 (Sulfonamides); 0 (TTN protein, human); Z9K9Y9WMVL (macitentan)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:27274200
[Au] Autor:Monaco TJ; Davila CD
[Ad] Endereço:Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA.
[Ti] Título:Safety, efficacy, and clinical utility of macitentan in the treatment of pulmonary arterial hypertension.
[So] Source:Drug Des Devel Ther;10:1675-82, 2016.
[Is] ISSN:1177-8881
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Pulmonary arterial hypertension is a progressive, debilitating disease caused by a dysregulation of the pulmonary vascular tone that inevitably leads to right heart failure and death without treatment. Until relatively recently, the treatment options for those afflicted by pulmonary arterial hypertension were limited; today, a greater understanding of the pathophysiology behind this disease has led to several evidence-based therapies that can improve pulmonary function and quality of life for these patients. One of the primary mediators of pulmonary vascular tone is endothelin-1, which is a potent and long-lasting vasoconstrictor. Macitentan is a second-generation endothelin receptor antagonist that acts selectively as a pulmonary vasodilator without the significant side effects noted with previous endothelin receptor antagonists. This review focuses on the mechanism of action and pharmacokinetics of macitentan, as well as the adverse effects, efficacy, and clinical uses of macitentan in the clinical trials to date. In addition, the authors briefly review clinical trials currently underway to illustrate possible future directions for the use of macitentan.
[Mh] Termos MeSH primário: Anti-Hipertensivos/uso terapêutico
Pressão Arterial/efeitos dos fármacos
Antagonistas do Receptor de Endotelina A/uso terapêutico
Antagonistas do Receptor de Endotelina B/uso terapêutico
Hipertensão Pulmonar/tratamento farmacológico
Artéria Pulmonar/efeitos dos fármacos
Pirimidinas/uso terapêutico
Sulfonamidas/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Anti-Hipertensivos/efeitos adversos
Anti-Hipertensivos/farmacocinética
Antagonistas do Receptor de Endotelina A/efeitos adversos
Antagonistas do Receptor de Endotelina A/farmacocinética
Antagonistas do Receptor de Endotelina B/efeitos adversos
Antagonistas do Receptor de Endotelina B/farmacocinética
Seres Humanos
Hipertensão Pulmonar/diagnóstico
Hipertensão Pulmonar/fisiopatologia
Artéria Pulmonar/fisiopatologia
Pirimidinas/efeitos adversos
Pirimidinas/farmacocinética
Sulfonamidas/efeitos adversos
Sulfonamidas/farmacocinética
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antihypertensive Agents); 0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Pyrimidines); 0 (Sulfonamides); Z9K9Y9WMVL (macitentan)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170328
[Lr] Data última revisão:
170328
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160609
[St] Status:MEDLINE
[do] DOI:10.2147/DDDT.S88612


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[PMID]:27062279
[Au] Autor:Chang F; Flavahan S; Flavahan NA
[Ad] Endereço:Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.
[Ti] Título:Immature endothelial cells initiate endothelin-mediated constriction of newborn arteries.
[So] Source:J Physiol;594(17):4933-44, 2016 Sep 01.
[Is] ISSN:1469-7793
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:KEY POINTS: Endothelial expression and the release of endothelin-1 (ET-1) in levels sufficient to initiate vasoconstriction is considered to be a hallmark feature of pathological endothelial dysfunction. During the immediate postnatal period, arterial endothelial cells undergo remarkable structural and functional changes as they transition to a mature protective cell layer, which includes a marked increase in NO dilator activity. The present study demonstrates that endothelial cells lining newborn central arteries express high levels of ET-1 peptides and, in response to endothelial stimulation, rapidly release ET-1 and initiate powerful ET-1-mediated constriction. This activity is lost as the endothelium matures in the postnatal period. Heightened activity of ET-1 in the neonatal endothelium might contribute to inappropriate responses of immature arteries to stress or injury. Indeed, the immature endothelium resembles dysfunctional endothelial cells, and retention or re-emergence of this phenotype may contribute to the development of vascular disease. ABSTRACT: Endothelial cells lining fetal and newborn arteries have an unusual phenotype, including reduced NO activity, prominent actin stress fibres and poorly developed cellular junctions. Experiments were performed to determine whether the immature endothelium of newborn arteries also expresses and releases endothelin-1 (ET-1) and initiates endothelium-dependent constriction. Carotid arteries were isolated from newborn (postnatal day 1; P1), postnatal day 7 (P7) and postnatal day 21 (P21) mice and assessed in a pressure myograph system. Endothelial stimulation with A23187 or thrombin caused constriction in P1 arteries, no significant change in diameter of P7 arteries, and dilatation in P21 arteries. In P1 arteries, constriction to thrombin or A23187 was inhibited by endothelial-denudation, by ET-1 receptor antagonists (BQ123 plus BQ788) or by inhibition of endothelin-converting enzyme (phosphoramidon or SM19712). ET-1 receptor antagonism did not affect responses to thrombin or A23187 in more mature arteries. Exogenous ET-1 caused similar concentration-dependent constrictions of P1, P7 and P21 arteries. Endothelial stimulation with thrombin rapidly increased the endothelial release of ET-1 from P1 but not P21 aortas. Endothelial expression of ET-1 peptides, as assessed by immunofluorescence analysis, was increased in P1 compared to P21 arteries. Therefore, newborn endothelial cells express high levels of ET-1 peptides, rapidly release ET-1 in response to endothelial stimulation, and initiate ET-1-mediated endothelium-dependent constriction. This activity is diminished as the endothelium matures in the immediate postnatal period. Heightened activity of ET-1 in neonatal endothelium probably reflects an early developmental role of the peptide, although this might contribute to inappropriate responses of immature arteries to stress or injury.
[Mh] Termos MeSH primário: Artérias Carótidas/fisiologia
Células Endoteliais/fisiologia
Endotelina-1/fisiologia
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Artérias Carótidas/efeitos dos fármacos
Antagonistas do Receptor de Endotelina A/farmacologia
Antagonistas do Receptor de Endotelina B/farmacologia
Feminino
Masculino
Camundongos Endogâmicos C57BL
Oligopeptídeos/farmacologia
Peptídeos Cíclicos/farmacologia
Piperidinas/farmacologia
Vasoconstrição/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Endothelin-1); 0 (Oligopeptides); 0 (Peptides, Cyclic); 0 (Piperidines); 44OLL8XEJ4 (BQ 788); S2A8YZM151 (cyclo(Trp-Asp-Pro-Val-Leu))
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160411
[St] Status:MEDLINE
[do] DOI:10.1113/JP272176


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[PMID]:26999111
[Au] Autor:Wang X; Zhang Y; Liu Q; Ai Z; Zhang Y; Xiang Y; Qiao Y
[Ad] Endereço:Beijing Key Lab of Traditional Chinese Medicine (TCM) Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China. wangxing@ccmu.edu.cn.
[Ti] Título:Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening.
[So] Source:Int J Mol Sci;17(3):389, 2016 Mar 16.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Endothelin-1 receptors (ETAR and ETBR) act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA) was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 µM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.
[Mh] Termos MeSH primário: Ácidos Aristolóquicos/farmacologia
Antagonistas do Receptor de Endotelina A/farmacologia
Antagonistas do Receptor de Endotelina B/farmacologia
Plantas Medicinais/química
Receptor de Endotelina A/efeitos dos fármacos
Receptor de Endotelina B/efeitos dos fármacos
[Mh] Termos MeSH secundário: Simulação por Computador
Avaliação Pré-Clínica de Medicamentos
Células HEK293
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aristolochic Acids); 0 (EDNRB protein, human); 0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 94218WFP5T (aristolochic acid I)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160322
[St] Status:MEDLINE


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[PMID]:26930122
[Au] Autor:Harvey TW; Engel JE; Chade AR
[Ad] Endereço:Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss., USA.
[Ti] Título:Vascular Endothelial Growth Factor and Podocyte Protection in Chronic Hypoxia: Effects of Endothelin-A Receptor Antagonism.
[So] Source:Am J Nephrol;43(2):74-84, 2016.
[Is] ISSN:1421-9670
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Podocytes are major components of the filtration barrier and a renal source of vascular endothelial growth factor (VEGF). Chronic renovascular disease (RVD) progressively degrades the renal function, accompanied by podocyte damage and a progressive reduction in VEGF. We showed that the endothelin (ET) pathway contributes to this pathological process and ET-A (but not ET-B) receptor antagonism protects the kidney in RVD. We hypothesize that ET-A-induced renoprotection is largely driven by the protection of podocyte integrity and function. METHODS: To mimic the renal environment of chronic RVD, human podocytes were incubated under chronic hypoxia for 96 h and divided in untreated or treated with an ET-A or ET-B receptor antagonist. Cells were quantified after 96 h. Cell homogenates and media were obtained after 1, 24 and 96 h to quantify production of VEGF, anti-VEGF soluble receptor s-Flt1, and the expression of apoptotic mediators. A separate set of similar experiments was performed after addition of a VEGF-neutralizing antibody (VEGF-NA). RESULTS: Hypoxia decreased podocyte number, which was exacerbated by ET-B but improved after ET-A antagonism. Production of VEGF was preserved by ET-A antagonism, whereas s-Flt1 increased in hypoxic cells after ET-B antagonism only, accompanied by a greater expression of pro-apoptotic mediators. On the other hand, treatment with VEGF-NA diminished ET-A-induced protection of podocytes. CONCLUSION: ET-A antagonism preserves podocyte viability and integrity under chronic hypoxia, whereas ET-B antagonism exacerbates podocyte dysfunction and death. Enhanced bioavailability of VEGF after ET-A antagonism could be a pivotal mechanism of podocyte protection that significantly contributes to ET-A receptor blockade-induced renal recovery in chronic RVD.
[Mh] Termos MeSH primário: Anticorpos Neutralizantes/farmacologia
Hipóxia Celular/efeitos dos fármacos
Antagonistas do Receptor de Endotelina A/farmacologia
Antagonistas do Receptor de Endotelina B/farmacologia
Fator A de Crescimento do Endotélio Vascular/metabolismo
Fator A de Crescimento do Endotélio Vascular/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Contagem de Células
Hipóxia Celular/fisiologia
Sobrevivência Celular/efeitos dos fármacos
Endotelina-1/metabolismo
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas de Membrana/metabolismo
Podócitos
Fatores de Proteção
Receptor de Endotelina A/metabolismo
Receptor de Endotelina B/metabolismo
Fator A de Crescimento do Endotélio Vascular/imunologia
Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Endothelin-1); 0 (Intracellular Signaling Peptides and Proteins); 0 (Membrane Proteins); 0 (NPHS2 protein); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 0 (Vascular Endothelial Growth Factor A); 0 (nephrin); EC 2.7.10.1 (FLT1 protein, human); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170302
[Lr] Data última revisão:
170302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160302
[St] Status:MEDLINE
[do] DOI:10.1159/000444719


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[PMID]:26861196
[Au] Autor:Forner S; Martini AC; Andrade EL; Rae GA
[Ad] Endereço:Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Brazil. Electronic address: sforner@uci.edu.
[Ti] Título:Neuropathic pain induced by spinal cord injury: Role of endothelin ETA and ETB receptors.
[So] Source:Neurosci Lett;617:14-21, 2016 03 23.
[Is] ISSN:1872-7972
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Spinal cord injury (SCI) is a devastating neurologic disorder that often inflicts neuropathic pain, which further impacts negatively on the patient's quality of life. Endothelin peptides, which exert their effects via endothelin A (ETAR) and endothelin B (ETBR) receptors, can contribute to sensory changes associated with inflammatory and neuropathic pain, but their role in nociception following SCI is unknown. At different time points after subjecting male Wistar rats to surgery for compression-induced T10 level SCI, the spinal cord levels of ETAR and ETBR were assessed by Western blot and immunohistochemistry, and the corresponding mRNAs by real-time PCR, alongside recordings of behavioural responses to mechanical stimulation of the hind paws with von Frey hairs. SCI was associated with development of hind paw mechanical allodynia from day 14 onwards, and up-regulation of ETAR and ETBR mRNA in the spinal cord and dorsal root ganglia, and of ETAR protein in the spinal cord. SCI increased ETAR protein expression in spinal grey matter. Treatment on day 21 after surgery with the ETAR selective antagonist BQ-123 (40 and 90 pmol, intrathecally) or the dual ETAR/ETBR antagonist bosentan (30 and 100mg/kg, orally) transiently reduced SCI-induced mechanical allodynia, but the ETBR antagonist BQ-788 was ineffective. Altogether, these data show that SCI upregulates ETAR expression in the spinal cord, which appears to contribute to the hind paw mechanical allodynia associated with this condition. Therapies directed towards blockade of spinal ETAR may hold potential to limit SCI-induced neuropathic pain.
[Mh] Termos MeSH primário: Neuralgia/metabolismo
Receptor de Endotelina A/metabolismo
Receptor de Endotelina B/metabolismo
Traumatismos da Medula Espinal/metabolismo
[Mh] Termos MeSH secundário: Animais
Antagonistas do Receptor de Endotelina A/farmacologia
Antagonistas do Receptor de Endotelina B/farmacologia
Substância Cinzenta/metabolismo
Hiperalgesia/fisiopatologia
Masculino
Atividade Motora
Neuralgia/fisiopatologia
Peptídeos Cíclicos/farmacologia
Estimulação Física
RNA Mensageiro/metabolismo
Ratos Wistar
Receptor de Endotelina A/genética
Receptor de Endotelina B/genética
Medula Espinal/efeitos dos fármacos
Medula Espinal/metabolismo
Traumatismos da Medula Espinal/fisiopatologia
Sulfonamidas/farmacologia
Tato
Substância Branca/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Endothelin A Receptor Antagonists); 0 (Endothelin B Receptor Antagonists); 0 (Peptides, Cyclic); 0 (RNA, Messenger); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 0 (Sulfonamides); Q326023R30 (bosentan); S2A8YZM151 (cyclo(Trp-Asp-Pro-Val-Leu))
[Em] Mês de entrada:1608
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160211
[St] Status:MEDLINE


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[PMID]:26781611
[Au] Autor:Marey MA; Yousef MS; Liu J; Morita K; Sasaki M; Hayakawa H; Shimizu T; Elshahawy II; Miyamoto A
[Ad] Endereço:Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
[Ti] Título:Endothelin-1 downregulates sperm phagocytosis by neutrophils in vitro: A physiological implication in bovine oviduct immunity.
[So] Source:J Reprod Dev;62(2):151-7, 2016 Apr 22.
[Is] ISSN:1348-4400
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:The oviduct is an active contractile tube that provides the proper environment for sperm transport, capacitation and survival. Oviductal contractions are regulated by autocrine/paracrine secretion of several factors, such as prostaglandins (PGs) and endothelin-1 (EDN-1). We have previously shown that during the preovulatory stage, sperm are exposed to polymorphonuclear neutrophils (PMNs) in the bovine oviduct, and the bovine oviduct epithelial cells (BOECs) secrete molecules including PGE2 that suppress sperm phagocytosis by PMNs in vitro. In this study, we investigated the possible effects of EDN-1 on the phagocytic activity of PMNs toward sperm. The local concentrations of EDN-1 in oviduct fluid and BOEC culture medium ranged from 10(-10) to 10(-11) M as determined by EIA. Phagocytosis and superoxide production were assayed by co-incubation of sperm pretreated to induce capacitation with PMNs exposed to EDN-1 (0, 10(-11), 10(-10), 10(-9), and 10(-8) M) for 2 h. EDN-1 suppressed dose dependently (10(-11) to 10(-8) M) the phagocytic activity for sperm and superoxide production of PMNs in response to capacitated sperm. Moreover, this suppression was eliminated by an ETB receptor antagonist (BQ-788). EDN-1 suppressed mRNA expression of EDN-1 and ETB but not ETA receptors in PMNs, suggesting the ETB receptor-mediated pathway. Scanning electron microscopic observation revealed that incubation of PMNs with EDN-1 (10(-9) M) completely suppressed the formation of DNA-based neutrophil extracellular traps for sperm entanglement. The results provide evidence indicating that EDN-1 may be involved in the protection of sperm from phagocytosis by PMNs in the bovine oviduct, supporting sperm survival until fertilization.
[Mh] Termos MeSH primário: Endotelina-1/fisiologia
Neutrófilos/citologia
Oviductos/fisiologia
Fagocitose
Espermatozoides/citologia
[Mh] Termos MeSH secundário: Animais
Bovinos
Meios de Cultura/química
Regulação para Baixo
Antagonistas do Receptor de Endotelina B/farmacologia
Feminino
Fertilização
Masculino
Microscopia Eletrônica de Varredura
Oligopeptídeos/química
Piperidinas/química
RNA Mensageiro/metabolismo
Receptor de Endotelina B/fisiologia
Superóxidos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Culture Media); 0 (Endothelin B Receptor Antagonists); 0 (Endothelin-1); 0 (Oligopeptides); 0 (Piperidines); 0 (RNA, Messenger); 0 (Receptor, Endothelin B); 11062-77-4 (Superoxides); 44OLL8XEJ4 (BQ 788)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170616
[Lr] Data última revisão:
170616
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160120
[St] Status:MEDLINE
[do] DOI:10.1262/jrd.2015-112



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