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1.
Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242

RESUMO

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.


Assuntos
Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
2.
Front Immunol ; 12: 641874, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33828553

RESUMO

The endothelin-A receptor antagonist BQ123 is an effective treatment agent for hypertension and obese cardiomyopathy. However, the role of BQ123 in controlling acute inflammatory diseases and its underlying mechanisms are not well understood. Here, we showed that BQ123 activated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice and that the IL13/STAT6/Arg1 signaling pathway is involved in this process. Importantly, both treatment with BQ123 and the transfer of BQ123-induced PMN-MDSCs (BQ123-MDSCs) were effective in relieving inflammation, including dextran sulfate sodium (DSS)-induced colitis, papain-induced pneumonia, and concanavalin A (ConA)-induced hepatitis, in mice. The treatment effects were mediated by the attenuation of the inflammation associated with the accumulation of PMN-MDSCs in the colon, lung, and liver. However, concurrent injection of Gr1 agonistic antibody with BQ123 induced PMN-MDSC aggravated the observed acute inflammation. Interestingly, no remission of inflammation was observed in Rag2 knockout mice administered BQ123-MDSCs, but co-injection with CD3+ T cells significantly relieved acute inflammation. In summary, BQ123-induced PMN-MDSCs attenuated acute inflammation in a T cell-dependent manner, providing a novel potential strategy to prevent the occurrence of acute inflammation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Colite/tratamento farmacológico , Antagonistas do Receptor de Endotelina A/farmacologia , Granulócitos/imunologia , Células Supressoras Mieloides/imunologia , Peptídeos Cíclicos/farmacologia , Pneumonia/tratamento farmacológico , Linfócitos T/imunologia , Doença Aguda , Animais , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Colite/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/induzido quimicamente , Pneumonia/imunologia
3.
Am J Pathol ; 191(5): 829-837, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33617784

RESUMO

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ETAR) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ETAR with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ETAR antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin.


Assuntos
Atrasentana/farmacologia , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Antagonistas do Receptor de Endotelina A/farmacologia , Fibrose/patologia , Trombomodulina/metabolismo , Animais , Endotélio/patologia , Humanos , Inflamação/patologia , Rim/patologia , Glomérulos Renais/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Trombomodulina/efeitos dos fármacos , Trombomodulina/genética
4.
J Therm Biol ; 95: 102804, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33454036

RESUMO

Previous studies have demonstrated that endothelin-1 (ET-1) is involved in the febrile response induced by lipopolysaccharide (LPS) in male and female rats. This peptide induces fever acting on ETB receptors in the central nervous system. However, during sepsis, endothelinergic ETA receptors in the brain also exert an important role reducing the mortality of the animals. The present study evaluated the participation of ETA receptors in the febrile response induced by different doses LPS in rats. Male Wistar rats were treated with the ETA receptor antagonist BQ123 before or after the injection of a low dose (10 µg/kg) or a high dose (200 µg/kg) of LPS intraperitoneally. The febrile response was evaluated. The treatment with BQ123, in both protocols did not change the febrile response induced by the lower dose of LPS. The pre-treatment with BQ123 also did not significantly change the febrile response induced by a higher dose of LPS but the post-treatment with the antagonist abolished the febrile response induced by this dose of LPS. These results suggest that even though ETA receptors are not recruited in the febrile response induced by lower doses of LPS, they are involved in the febrile response induced by high doses of this stimulus.


Assuntos
Febre/metabolismo , Lipopolissacarídeos/toxicidade , Receptor de Endotelina A/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/farmacologia , Febre/etiologia , Febre/fisiopatologia , Masculino , Peptídeos Cíclicos/farmacologia , Ratos , Ratos Wistar
5.
Biochem Biophys Res Commun ; 540: 56-60, 2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445111

RESUMO

BACKGROUND/AIMS: Sex dependent differences in coronary artery vasoregulation may be due to variations in responses to endogenous vasoactive compounds including endothelin (ET-1) and nitric oxide (NO). METHODS: Septal coronary arteries (<200 µm) from healthy, sexually mature male, female and ovariectomized (i.e. surgical menopause) Sprague-Dawley rats were used. Myogenic tone, measured by pressure myography, was initially determined for all vessel segments studied before and after exposure to the nonselective ETA/ETB receptor blocker, bosentan (1 µM). Vasoconstrictor responses (vascular endothelium intact) to cumulative ET-1 (10-12 - 10-9 M) were assessed in a separate set of septal coronary vessels. Additional studies, examined the vasoconstrictor effects of ET-1 after NO blockade with L-NAME (200 µM). RESULTS: Myogenic tone was 26 ± 7% in male, 20 ± 7% in female (p = 0.04 versus male) and 24 ± 3% in ovariectomized (p = NS versus male/female) vessels. Antagonism of ET-1 receptors produced a greater reduction in myogenic tone in male, compared to female rats over a similar range of intraluminal pressure (20-80 mmHg). Robust constrictor responses to cumulative concentrations of ET-1 were observed in all vessels; however, male rats exhibited greater sensitivity to vasoconstrictor effects of ET-1. After exposure to L-NAME vessel responses to ET-1 were normalized in male and female (not studied in ovariectomized) groups. CONCLUSIONS: These findings confirm marked sex differences for myogenic tone and vessel constrictor responses to ET-1 in coronary resistance vessels. Results also suggest greater sensitivity to vasoconstrictor effects of ET-1 in male coronary resistance vessels.


Assuntos
Vasos Coronários/efeitos dos fármacos , Endotelina-1/farmacologia , Caracteres Sexuais , Resistência Vascular , Vasoconstrição/efeitos dos fármacos , Animais , Bosentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Feminino , Masculino , Miografia , Óxido Nítrico/metabolismo , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo , Resistência Vascular/efeitos dos fármacos
6.
Expert Opin Investig Drugs ; 30(3): 253-262, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33356648

RESUMO

Introduction: Selective antagonists of Endothelin-1 receptors (ERA) have been tested in diabetic and nondiabetic chronic kidney disease (CKD). The SONAR trial (Study Of diabetic Nephropathy with AtRasentan) was the first randomized, phase 3, study assessing the long-term effect of ERA on CKD progression.Areas covered: We examine the ERA effects in proteinuric CKD. We discuss the results of the main clinical studies on ERA in CKD and offer an opinion on the findings of SONAR study and future perspectives in this field. We searched in PubMed and ISI Web of Science databases for including experimental and clinical studies that evaluated ERA in proteinuric CKD.Expert opinion: The SONAR study demonstrated that ERA confers protection against risk for CKD progression. This trial stimulated clinical research on ERA, to expand the therapeutic opportunities in CKD patients. Two novel phase 3 studies testing ERA in patients with glomerular disease are ongoing. Within the context of personalized medicine, we think it would be relevant to evaluate the effect of multiple treatments, including ERA, in proteinuric CKD patients. Testing ERA in clinical trials of novel design will also help at identifying the patients who would more benefit from these drugs.


Assuntos
Antagonistas do Receptor de Endotelina A/farmacologia , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Atrasentana/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Progressão da Doença , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/metabolismo , Insuficiência Renal Crônica/fisiopatologia
7.
Sci Rep ; 10(1): 22314, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339902

RESUMO

Prevalence of major depression in people with chronic heart failure is higher than in normal populations. Depression in heart failure has become a major issue. Psilocybin-containing mushrooms commonly known as magic mushrooms, have been used since ancient times for their mind healing properties. Their safety in cardiovascular disease conditions is not fully known and may pose as a risk for users suffering from these illnesses. Study investigates the effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushrooms use from genus Psilocybe and Panaeolus respectively, in a pathological hypertrophy conditions in which endothelin-1 disorder is a contributor to pathogenesis. We examined the effects of the mushrooms extracts on endothelin-1-induced hypertrophy and tumor necrosis factor-α (TNF- α)-induced cell injury in H9C2 cardiomyocytes. Mushrooms were oven dried and extracted with cold and boiling-hot water. H9C2 cardiomyocytes were induced with endothelin-1 prior to treatment with extracts over 48 h. Cell injury was stimulated with TNF-α. Results proposed that the water extracts of Panaeolus cyanescens and Psilocybe cubensis did not aggravate the pathological hypertrophy induced by endothelin-1 and also protected against the TNF-α-induced injury and cell death in concentrations used. Results support medicinal safe use of mushrooms under controlled conditions and cautioned use of higher concentrations.


Assuntos
Agaricales/química , Endotelina-1/genética , Hipertrofia/tratamento farmacológico , Psilocybe/química , Receptor de Endotelina A/genética , Animais , Antagonistas do Receptor de Endotelina A/farmacologia , Alucinógenos/química , Alucinógenos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Hipertrofia/induzido quimicamente , Hipertrofia/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fenilpropionatos/farmacologia , Psilocibina/química , Psilocibina/farmacologia , Piridazinas/farmacologia , Ratos , Receptor de Endotelina A/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética
8.
Commun Biol ; 3(1): 677, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188287

RESUMO

Identification of regulatory mechanisms underlying the poor prognosis of ovarian cancer is necessary for diagnostic and therapeutic implications. Here we show that endothelin A receptor (ETAR) and ZEB1 expression is upregulated in mesenchymal ovarian cancer and correlates with poor prognosis. Notably, the expression of ETAR and ZEB1 negatively correlates with miR-200b/c. These miRNAs, besides targeting ZEB1, impair ETAR expression through the 3'UTR binding. ZEB1, in turn, restores ETAR levels by transcriptionally repressing miR-200b/c. Activation of ETAR drives the expression of ZEB1 integrating the miR-200/ZEB1 double negative feedback loop. The ETAR-miR-200b/c-ZEB1 circuit promotes epithelial-mesenchymal transition, cell plasticity, invasiveness and metastasis. Of therapeutic interest, ETAR blockade with macitentan, a dual ETAR and ETBR antagonist, increases miR-200b/c and reduces ZEB1 expression with the concomitant inhibition of metastatic dissemination. Collectively, these findings highlight the reciprocal network that integrates ETAR and ZEB1 axes with the miR-200b/c regulatory circuit to favour metastatic progression in ovarian cancer.


Assuntos
MicroRNAs/metabolismo , Metástase Neoplásica/fisiopatologia , Neoplasias Ovarianas/patologia , Pirimidinas/farmacologia , Receptor de Endotelina A/metabolismo , Sulfonamidas/farmacologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Ovarianas/prevenção & controle , Receptor de Endotelina A/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
9.
Sci Rep ; 10(1): 15931, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985601

RESUMO

Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia). Whole transcriptome analysis using RNAseq indicated Ambrisentan's inhibitory effects on the whole transcriptome of resting and PAR2-activated COLO-357 cells, which tended to normalize to an unstimulated profile. Finally, in a pre-clinical murine model of metastatic breast cancer, treatment with Ambrisentan was effective in decreasing metastasis into the lungs and liver. Importantly, this was associated with a significant enhancement in animal survival. Taken together, our work suggests a new therapeutic application for Ambrisentan in the treatment of cancer metastasis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Movimento Celular , Antagonistas do Receptor de Endotelina A/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Anticancer Res ; 40(10): 5539-5544, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988877

RESUMO

BACKGROUND/AIM: Endothelin-1 (ET-1) is overexpressed in many types of cancer, inhibiting the release of the microRNA 15a (miR-15a) and inducing the production of Mxi-2. Our aim was to identify a molecular complex regulating p53 activity in prostate cancer (PCa). MATERIALS AND METHODS: DU145 cells were treated with ET-1, MAPK p38 inhibitor, Endothelin A receptor inhibitor (ETAR inhibitor) and Endothelin B receptor inhibitor (ETBR inhibitor). Extracts were analysed using Western Blot, immunoprecipitation and qRT-PCR. Furthermore, prostate cancer patient samples were analysed using qRT-PCR and ELISA. RESULTS: The hypothesised molecular complex was identified, with miR-15a, microRNA 1285 (miR-1285) and Mxi-2 levels up-regulated in patients in relation to increasing aggressiveness of PCa. CONCLUSION: A complex composed of Argonaut 2 (Ago2)/Mxi-2/miR-1285 is involved in PCa. The expression of Mxi-2 correlates with increasing PCa aggressiveness and might be used as a non-invasive marker for the diagnosis and progression of PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Quinase 14 Ativada por Mitógeno/genética , Neoplasias da Próstata/genética , Proteína Supressora de Tumor p53/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Argonauta/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/farmacologia , Humanos , Masculino , MicroRNAs/genética , Neoplasias da Próstata/patologia , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
11.
Toxins (Basel) ; 12(6)2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32545475

RESUMO

Elevated levels of endothelin-1 (ET-1) were recorded in sera of scorpion sting patients. However, no studies focused on the mechanism of ET-1 involvement in the pathogenesis of scorpion envenomation, particularly in the cardiovascular system which is seriously affected in severe cases of scorpion stings. Inflammation induced by Androctonus australis hector (Aah) scorpion venom in the heart together with the aorta was studied in mice pretreated with a specific endothelin A receptor (ETA-R) inhibitor. ETA-R inhibition resulted in the attenuation of the high amounts of cytokine (tumor necrosis factor alpha (TNF-α) and interleukin-17 (IL-17)) recorded in the sera of envenomed mice. The recovery of the oxidative stress marker balance and matrix metalloproteinase (MMP) expression were also observed, concomitantly with the reduction of tissular neutrophil infiltration. Additionally, the cardiac and the aortic tissue alterations, and the metabolic enzymes (creatine kinase (CK) and muscle-brain isoform creatine kinase (CK-MB)) overspread into sera were significantly attenuated. Obtained results suggest the implication of endothelin throughout its ETA receptors in the inflammatory response observed in the cardiovascular components during scorpion envenomation. Further knowledge is needed to better understand the implication of the endothelin axis and to improve the therapeutic management of severe scorpion sting cases.


Assuntos
Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Endotelina-1/metabolismo , Inflamação/metabolismo , Receptor de Endotelina A/metabolismo , Picadas de Escorpião/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina A/farmacologia , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Peptídeos Cíclicos/farmacologia , Receptor de Endotelina A/efeitos dos fármacos , Picadas de Escorpião/tratamento farmacológico , Venenos de Escorpião , Transdução de Sinais
12.
Biochem Biophys Res Commun ; 527(2): 568-573, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32423820

RESUMO

Pancreatic adenocarcinoma is currently one of the leading causes of cancer-related death worldwide. The high rate of mortality in pancreatic cancer patients is due to the inability to detect early-stage disease and the disease being highly refractory to therapy. Gemcitabine has been the standard chemotherapy for advanced pancreatic cancer patients for the last two decades. However, gemcitabine resistance develops within a few weeks of treatment, and the associated mechanism remains poorly understood. Therefore, a novel therapeutic strategy is needed to overcome the limited clinical efficacy of gemcitabine in pancreatic adenocarcinoma. In this study, we demonstrated that ET-1/ETAR axis gene expression was upregulated in pancreatic cancer cells after treatment with gemcitabine. Additionally, ETAR expression was significantly higher in tumor tissues than in normal tissues, and patients with high ETAR expression had a notably worse overall survival rate than those with low ETAR expression. Furthermore, our results revealed that bosentan, an ETAR antagonist, enhanced the growth-inhibiting and proapoptotic effects of gemcitabine on pancreatic cancer cells. Thus, our findings indicate that blockade of the ET-1/ETAR axis signaling pathway promotes the antiproliferative effect of gemcitabine on pancreatic cancer. Therefore, combination of ETAR blockade and gemcitabine serves as an effective therapeutic approach to achieve clinical benefits in pancreatic adenocarcinoma patients.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Bosentana/farmacologia , Desoxicitidina/análogos & derivados , Antagonistas do Receptor de Endotelina A/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptor de Endotelina A/metabolismo
14.
Am J Physiol Renal Physiol ; 318(5): F1295-F1305, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249614

RESUMO

Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ETAR) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ETAR antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ETAR antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Atrasentana/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/farmacologia , Losartan/farmacologia , Podócitos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Camundongos , Fosforilação , Podócitos/metabolismo , Podócitos/patologia , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/prevenção & controle , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo
15.
J Alzheimers Dis ; 73(3): 1185-1199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31903990

RESUMO

Cerebral blood flow is reduced in Alzheimer's disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-ß (Aß) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in brain tissue correlates positively with Aß load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of Aß40 exacerbated pre-existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of Aß40 on blood pressure and heart rate and their variability; carotid flow; endothelin-1; and markers of cerebral oxygenation, in the (normotensive) Wistar rat, and the modulatory influence of the endothelin A receptor antagonist Zibotentan (ZD4054). Cerebral infusion of Aß caused progressive rise in blood pressure (p < 0.0001) (paired t-test: increase of 3 (0.1-5.6) mmHg (p = 0.040)), with evidence of reduced baroreflex responsiveness, and accumulation of Aß and elevated endothelin-1 in the vicinity of the infusion. Oral Zibotentan (3 mg/kg/d, administered for 31 d) abrogated the effects of Aß40 infusion on baroreflex responsiveness and blood pressure, which declined, although without reduction in carotid blood flow, and Zibotentan caused uncoupling of the positive linear relationship between endothelin-1 and vascular endothelial growth factor, which as a sensor of tissue oxygenation would be expected to increase if there were hypoperfusion.


Assuntos
Peptídeos beta-Amiloides/efeitos adversos , Circulação Cerebrovascular/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/farmacologia , Hipertensão/prevenção & controle , Pirrolidinas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Endotelina-1/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Ratos , Ratos Endogâmicos Dahl , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Kidney Blood Press Res ; 44(6): 1493-1505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31770762

RESUMO

INTRODUCTION: Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ETA receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD. METHODS: The treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks. RESULTS: The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance - all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. CONCLUSION: These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.


Assuntos
Antagonistas do Receptor de Endotelina A/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Insuficiência Renal Crônica/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Hipertensão , Masculino , Nefrectomia , Ratos , Ratos Transgênicos , Receptor de Endotelina A
17.
Clin Sci (Lond) ; 133(13): 1475-1486, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31273050

RESUMO

Hyperfiltration, highly prevalent early in sickle cell disease (SCD), is in part driven by an increase in ultrafiltration coefficient (Kf). The increase in Kf may be due to enlarged filtration surface area and/or increased glomerular permeability (Palb). Previous studies have demonstrated that endothelin-1 (ET-1) contributes to Palb changes in models of diabetes and SCD. Thus, we performed longitudinal studies of renal function to determine the relationship between ET-1 and glomerular size and Palb that may contribute to hyperfiltration in humanized sickle cell (HbSS) and control (HbAA) mice at 8-32 weeks of age. HbSS mice were characterized by significant increases in plasma and glomerular ET-1 expression in both sexes although this increase was significantly greater in males. HbSS glomeruli of both males and females presented with a progressive and significant increase in glomerular size, volume, and Kf During the onset of hyperfiltration, plasma and glomerular ET-1 expression were associated with a greater increase in glomerular size and Kf in HbSS mice, regardless of sex. The pattern of Palb augmentation during the hyperfiltration was also associated with an increase in glomerular ET-1 expression, in both male and female HbSS mice. However, the increase in Palb was significantly greater in males and delayed in time in females. Additionally, selective endothelin A receptor (ETA) antagonist prevented hyperfiltration in HbSS, regardless of sex. These results suggest that marked sex disparity in glomerular hyperfiltration may be driven, in part, by ET-1-dependent ultra-structural changes in filtration barrier components contributing to glomerular hyperfiltration in HbSS mice.


Assuntos
Anemia Falciforme/metabolismo , Endotelina-1/metabolismo , Taxa de Filtração Glomerular , Nefropatias/metabolismo , Glomérulos Renais/metabolismo , Anemia Falciforme/genética , Anemia Falciforme/patologia , Anemia Falciforme/fisiopatologia , Animais , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemoglobina A/genética , Hemoglobinas/genética , Humanos , Nefropatias/etiologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Masculino , Camundongos Transgênicos , Mutação , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Fatores de Risco , Fatores Sexuais , Transdução de Sinais
18.
Clin Hemorheol Microcirc ; 73(4): 497-522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156142

RESUMO

Growing evidence suggests that inflammation is crucially involved in the pathogenesis of pulmonary hypertension (PH) and consecutive right heart failure. The present study analyzed the inflammatory response in lung and right ventricle in a rat model of PH and evaluated the effects of the dual endothelin receptor antagonist (ERA) Macitentan. PH was induced by monocrotalin (60 mg/kg body weight s.c.) in Sprague-Dawley rats (PH, n = 10) and compared to healthy controls (CON, n = 10) as well as monocrotalin-induced, macitentan-treated rats (THER, n = 10). Detection of Dendritic cells (DCs), regulatory T cells (Tregs) and others as well as RT-PCR based inflammatory gene expression analysis were performed. Circulating DCs and Tregs were quantified by flow cytometry in the rat model and in PH patients (n = 70) compared to controls (n = 52). Inflammatory cells were increased in lung and right ventricular tissue, whereas DCs and Tregs were decreased in blood. Expression of 17 genes in the lung and 20 genes in the right ventricle were relevantly (>2.0 fold) regulated in the PH group. These effects were, at least in part, attenuated in response to Macitentan treatment. In humans as well as rats, immune cells showed significant correlations to clinical, echocardiographic, and haemodynamic parameters. PH is accompanied by a distinct inflammatory response in lung and right but not left ventricular tissue attenuated by Macitentan. Correlations of circulating DCs as well as tissue resident immune cells with parameters reflecting right ventricular function raise the idea of both, promising biomarkers and novel treatment strategies.


Assuntos
Antagonistas do Receptor de Endotelina A/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Pulmão/patologia , Animais , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina A/farmacologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
19.
Ann N Y Acad Sci ; 1448(1): 30-41, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30937921

RESUMO

Endothelin-A receptor (ETAR) is overexpressed in cancers and can function through transactivation of the epidermal growth factor receptor. We explored ETAR in gastric cancer and investigated the antitumor effect of trastuzumab in combination with the ETAR antagonist ZD4054. The expression of ETAR was significantly correlated with the expression of vascular endothelial growth factor. Univariate and multivariate analyses further showed that ETAR expression correlated with reduced survival in gastric cancer patients. In vitro, ZD4054 increased the antiproliferative effect of trastuzumab in gastric cancer cell lines. Moreover, the addition of ZD4054 to trastuzumab significantly increased apoptosis in gastric cancer cell lines. In vivo, tumor growth was considerably inhibited by treatment with ZD4054 and trastuzumab, and the tumor volume in the trastuzumab and ZD4054 combination group was smaller than in the other groups. The detection of ETAR could help predict the prognosis of gastric cancer patients. Additionally, this study provides support for the therapeutic use of the combination of ZD4054 and trastuzumab as an anticancer treatment, especially for gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Pirrolidinas/farmacologia , Receptor de Endotelina A/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Antagonistas do Receptor de Endotelina A/farmacologia , Receptores ErbB/metabolismo , Feminino , Mucosa Gástrica/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Receptor de Endotelina A/genética , Neoplasias Gástricas/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Life Sci ; 222: 133-139, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844374

RESUMO

BACKGROUND: Cigarette smoke is exogenous modifiable factors to changes the neurovascular complication. The chronic exposure of cigarette smoke enhances neurocognitive dysfunction. AIMS: The present study is focused on evaluating the role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke-induced cognitive impairment in Danio rerio. MAIN METHODS: The cognitive dysfunction was developed by cigarette smoke exposure (CSE; 10 min in 25 ml of CSE per day) for five days. The selective endothelin-A receptor antagonist i.e., ambrisentan (2.5 to 5 mg/kg; i.p. for five consecutive days) was used for testing of CSE induced cognitive dysfunction. In addition, treatment of reference drug i.e., donepezil (10 mg/kg; i.p. for five consecutive days) was used for this cognitive function study. The cognitive functions were assessed by light and dark chamber; color recognition; partition preference; horizontal compartment; and T-Maze tests. Further, the CSE induced biomarkers changes of the zebrafish brain samples were estimated. KEY FINDINGS: The treatment of ambrisentan showed a potential ameliorative effect against the CSE induced cognitive functions along with attenuation of biochemical changes. The results are comparable to donepezil-treated groups. SIGNIFICANCE: Therefore, ambrisentan can be considered for the attenuation of CSE induced impairment neurocognitive functions due to its reduction of free radical scavenging and neuroinflammatory actions as well as regulation of cholinergic neurotransmitter functions.


Assuntos
Fumar Cigarros/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Fumar Cigarros/tendências , Disfunção Cognitiva/psicologia , Antagonistas do Receptor de Endotelina A/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Fumaça/efeitos adversos , Peixe-Zebra
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