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1.
Eur Heart J ; 41(48): 4580-4588, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33206176

RESUMO

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.


Assuntos
/genética , Anti-Hipertensivos/farmacologia , Hipertensão , Túbulos Renais/metabolismo , Pulmão/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Fatores Etários , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Diuréticos/farmacologia , Feminino , Perfilação da Expressão Gênica , Taxa de Filtração Glomerular , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Túbulos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Endogâmicos SHR , Análise de Sequência de RNA , Fatores Sexuais , Transcriptoma/efeitos dos fármacos
2.
Pediatr Cardiol ; 41(7): 1301-1318, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32915293

RESUMO

Alterations in blood pressure are common during the perioperative period in infants and children. Perioperative hypertension may be the result of renal failure, volume overload, or activation of the sympathetic nervous system. Concerns regarding end-organ effects or postoperative bleeding may mandate regulation of blood pressure. During the perioperative period, various pharmacologic agents have been used for blood pressure control including sodium nitroprusside, nitroglycerin, ß-adrenergic antagonists, fenoldopam, and calcium channel antagonists. The following manuscript outlines the commonly used pharmacologic agents for perioperative BP including dosing regimens and adverse effect profiles. Previously published clinical trials are discussed and efficacy in the perioperative period reviewed.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Adolescente , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Criança , Pré-Escolar , Fenoldopam/efeitos adversos , Fenoldopam/farmacologia , Fenoldopam/uso terapêutico , Humanos , Hipertensão/etiologia , Lactente , Masculino , Nitroprussiato/efeitos adversos , Nitroprussiato/farmacologia , Nitroprussiato/uso terapêutico , Período Perioperatório , Insuficiência Renal/complicações , Resultado do Tratamento
3.
Arch Oral Biol ; 118: 104865, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32801034

RESUMO

OBJECTIVE: The aim of this study was to verify ß2-AR expression in oral squamous cell carcinoma cell lines (SCC-9 and SCC-25), and to investigate the role of this receptor in migration and invasion of these neoplastic cells. DESIGN: SCC-9 and SCC-25 cells were investigated for gene and protein expression of ß2-AR. Cell migration and invasion were analyzed by wound healing assay and transwell invasion camera system. Different concentrations (0.1, 1 and 10 µM) of norepinephrine were used to stimulate, and 1 µM propranolol was used to block the beta-adrenergic receptors on cancer cells. Differences in median values of SCC-9 and SCC-25 and ß2-AR protein expression were analyzed by Friedman test and in case of significant differences; pairwise comparisons were performed using Bonferroni correction. RESULTS: The results showed that the ß2-AR gene and protein expression were observed in both oral cancer cell lines. The concentration of 10 µM of norepinephrine significantly inhibited (p ≤ 0.05) migration of SCC-9 and SCC-25 cell lines. Furthermore, there was a significant reduction (p ≤ 0.05) in the effect of norepinephrine on cell migration when the ß2-AR was inhibited by propranolol. The blockade by propranolol showed a tendency to reverse the effect of norepinephrine on the invasiveness of SCC-9 and SCC-25. CONCLUSIONS: The use of beta-adrenergic receptor agonists could become an adjuvant therapeutic target in the treatment of this malignancy.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Invasividade Neoplásica , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Neoplasias Bucais/tratamento farmacológico , Propranolol/farmacologia
4.
Am J Surg ; 220(5): 1312-1318, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32741547

RESUMO

INTRODUCTION: Propranolol has been shown to improve erythroid progenitor cell growth and anemia following trauma and this study sought to investigate the mechanisms involved by evaluating the effects of selective beta blockade. METHODS: Male Sprague-Dawley rats were subjected to lung contusion, hemorrhagic shock and chronic stress (LCHS/CS) ± daily selective beta-1, beta-2, or beta-3 blockade (B1B, B2B, B3B). Bone marrow cellularity and growth of erythroid progenitor colonies, hemoglobin, plasma granulocyte colony-stimulating factor (G-CSF), hematopoietic progenitor cell mobilization, and daily weight were assessed. RESULTS: Selective beta-2 and beta-3 blockade improved bone marrow cellularity, erythroid progenitor colony growth and hemoglobin levels, while decreasing plasma G-CSF, progenitor cell mobilization and weight loss following LCHS/CS. CONCLUSIONS: Attenuating the neuroendocrine stress response with the use of selective beta-2 and 3 adrenergic blockade may be an alternative to improve bone marrow erythroid function following trauma.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Medula Óssea/efeitos dos fármacos , Contusões/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico , Propranolol/farmacologia , Choque Hemorrágico/tratamento farmacológico , Estresse Fisiológico/efeitos dos fármacos , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Biomarcadores/metabolismo , Medula Óssea/metabolismo , Medula Óssea/patologia , Medula Óssea/fisiopatologia , Contusões/fisiopatologia , Lesão Pulmonar/fisiopatologia , Masculino , Propranolol/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Choque Hemorrágico/fisiopatologia
5.
Bioessays ; 42(11): e2000094, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32815593

RESUMO

More than 15 million people have been affected by coronavirus disease 2019 (COVID-19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID-19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin-angiotensin-aldosterone system (RAAS) is focused in COVID-19 and a vicious circle consisting of the Adrenergic system-RAAS-Angiotensin converting enzyme 2 (ACE2)-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (which is referred to as the "ARAS loop") is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID-19, and beta-adrenergic blockers are proposed as a potential treatment option. Beta-adrenergic blockers may decrease the SARS-CoV-2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta-adrenergic blockers may decrease the morbidity and mortality in COVID-19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Carvedilol/farmacologia , Carvedilol/uso terapêutico , Infecções por Coronavirus/epidemiologia , Reposicionamento de Medicamentos/métodos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pandemias , Papaína/antagonistas & inibidores , Papaína/metabolismo , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Embolia Pulmonar/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Insuficiência Respiratória/prevenção & controle , Choque Séptico/prevenção & controle , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus/efeitos dos fármacos
6.
Nat Commun ; 11(1): 3881, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753572

RESUMO

Cells typically respond to chemical or physical perturbations via complex signaling cascades which can simultaneously affect multiple physiological parameters, such as membrane voltage, calcium, pH, and redox potential. Protein-based fluorescent sensors can report many of these parameters, but spectral overlap prevents more than ~4 modalities from being recorded in parallel. Here we introduce the technique, MOSAIC, Multiplexed Optical Sensors in Arrayed Islands of Cells, where patterning of fluorescent sensor-encoding lentiviral vectors with a microarray printer enables parallel recording of multiple modalities. We demonstrate simultaneous recordings from 20 sensors in parallel in human embryonic kidney (HEK293) cells and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and we describe responses to metabolic and pharmacological perturbations. Together, these results show that MOSAIC can provide rich multi-modal data on complex physiological responses in multiple cell types.


Assuntos
Técnicas Biossensoriais/métodos , Células-Tronco Pluripotentes Induzidas/metabolismo , Microscopia de Fluorescência/métodos , Miócitos Cardíacos/metabolismo , Imagem Óptica/métodos , Potenciais de Ação/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacologia , Técnicas Biossensoriais/instrumentação , Cálcio/química , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Peróxido de Hidrogênio/farmacologia , Concentração de Íons de Hidrogênio , Células-Tronco Pluripotentes Induzidas/citologia , Mitocôndrias/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Imagem Óptica/instrumentação , Oxidantes/farmacologia , Oxirredução/efeitos dos fármacos , Propanolaminas/farmacologia
7.
J Vis Exp ; (160)2020 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-32628173

RESUMO

The electrocardiogram is a valuable tool for evaluating the cardiac conduction system. Animal research has helped generate novel genetic and pharmacological information regarding the electrocardiogram. However, making electrocardiogram measurements in small animals in vivo, such as mice, has been challenging. To this end, we used an electrocardiogram recording method in anesthetized mice with many advantages: it is a technically simple procedure, is inexpensive, has short measuring time, and is affordable, even in young mice. Despite the limitations with using anesthesia, comparisons between control and experimental groups can be performed with enhanced sensitivity. We treated mice with agonists and antagonists of the autonomic nervous system to determine the validity of this protocol and compared our results with previous reports. Our ECG protocol detected increased heart rates and QTc intervals on treatment with atropine, decreased heart rates and QTc intervals after carbachol treatment, and higher heart rates and QTc intervals with isoprenaline but did not note any change in ECG parameters on administration of propranolol. These results are supported by previous reports, confirming the reliability of this ECG protocol. Thus, this method can be used as a screening approach to making ECG measurements that otherwise would not be attempted due to high cost and technical difficulties.


Assuntos
Adjuvantes Anestésicos/farmacologia , Sistema Nervoso Autônomo/fisiologia , Eletrocardiografia/métodos , Sistema de Condução Cardíaco/fisiologia , Frequência Cardíaca/fisiologia , Monitorização Fisiológica/métodos , Antagonistas Adrenérgicos beta/farmacologia , Animais , Atropina/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Propranolol/farmacologia , Reprodutibilidade dos Testes
8.
Am J Cardiol ; 130: 152-156, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32680673

RESUMO

Impairments in heart rate (HR) reserve and HR recovery are associated with mortality, and the combination of these two, termed exercise HR gradient (EHRG), is a better predictor than either alone. However, the confounding effect of beta-blockade on chronotropic impairment to exercise has not been fully explored; the aim of the present study was to evaluate the effect of beta blockade on EHRG. Participants were 2769 Veterans (58.7 ± 11.6 years) who underwent a maximal exercise test for clinical reasons. HR reserve and HR recovery were acquired and divided into quintiles and summed to provide an EHRG score. Net reclassification improvement (NRI) was performed to evaluate the impact of HR reserve, HR recovery and EHRG on all-cause mortality for patients with and without beta-blocker use. During a mean follow up of 10.9 ± 4.1 years, 657 patients died. Among patients without beta-blocker therapy, adding EHRG score to an established model including multiple baseline risk factors and exercise capacity resulted in an NRI of 14.3% (p <0.001). Adding HR recovery instead of EHRG score yielded an NRI of 11.5% (p <0.001), whereas HR reserve had no significant NRI among patients without beta-blocker therapy. In contrast, among participants on beta-blocker therapy, the addition of HR reserve, HR recovery, or EHRG score did not result in any significant reclassification. In conclusion, EHRG was superior to both HR reserve and HR recovery in predicting mortality and provides significant reclassification of risk but only among patients not taking beta-blockers.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Teste de Esforço/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Mortalidade , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco
9.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(4): 582-586, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32691572

RESUMO

History and clinical findings: A 76 year-old woman with 8-year history of diabetes mellitus and hypertension was admitted with gangrene of left great toe, 3rd, 4th and 5th toes. Twenty months ago, She started to receive hemodialysis due to end-stage renal disease. She did not have any history of reactive airway disease nor bradycardia that would contraindicate the use of topical beta-blocker. The X-ray of left lower limb and foot showed calcification of left superficial femoral artery, popliteal artery, anterior tibial artery, posterior tibial artery, dorsal foot artery and digital artery, as well as osteolytic destruction at distal end of metatarsal bone, and lateral dislocation of the 4th and 5th toes. Color Doppler ultrasound of bilateral lower extremity arteries showed obvious calcification of bilateral superficial femoral arteries, thrombosis of left popliteal artery, severe stenosis of left anterior tibial artery, occlusion of left posterior tibial artery, right anterior tibial artery and posterior tibial artery. Computed tomographic angiography (CTA) of bilateral lower limb arteries revealed moderate stenosis of left superficial femoral artery, occlusion of left popliteal artery, left posterior tibial artery and dorsal pedal artery, occulusion of right posterior tibial artery, but right dorsal pedal artery was visible. Diagnosis, treatment and follow-up: Diagnosis of diabetic foot (left, grade 4) and diabetic lower extremity arterial occlusion (left, stage 4) was made. Based on multidisciplinary team (MDT) discussion, the patient was unable to undergo vascular bypass surgery, and left lower extermity amputation also was not suitable because of right atrial thrombosis. Therefore, conservative treatment was recommended. The specific scheme used clopidogrel for antiplatelet agglutination, Low Molecular Weight Heparin (Clexane) and warfarin for anticoagulation, lipo-alprostadil for vasodilation, as well as local debridement and ultrasonic debridement. The treatments were given for up to 9 weeks, but with no significant clinical response. So the patient was treated with vacuum-assisted closure and autologous platelet-rich gel therapy for the next 7 weeks, then applied with 1 drop of timolol maleate 0.5% ophthalmic solution per cm 2 wound area every other day for another 6 weeks, the wound rapidly healed and re-epithelialized basically. The follow-up for 5 weeks showed that the wound healed completely without any discomfort. No side effect was found.


Assuntos
Plaquetas , Diabetes Mellitus , Pé Diabético , Géis , Timolol , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Artérias/patologia , Pé Diabético/complicações , Pé Diabético/terapia , Feminino , Géis/farmacologia , Géis/uso terapêutico , Humanos , Isquemia/terapia , Timolol/farmacologia , Timolol/uso terapêutico , Resultado do Tratamento , Cicatrização/efeitos dos fármacos
10.
Sci Rep ; 10(1): 10465, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591592

RESUMO

Standard chemotherapy for soft tissue sarcomas has shown limited efficacy. Here, we sought to evaluate whether ß-adrenergic receptor (ß-AR) signalling contributed to the progression of sarcomas and therapy resistance. To assess the translational potential of ß-adrenergic receptors, we performed immunohistochemical detection of ß1-AR, ß2-AR and ß3-AR in leiomyosarcoma, liposarcoma and angiosarcoma tissue specimens, reporting the results scored for the intensity. By using established and patient-derived sarcoma cells, we demonstrated the antitumour potential of the pharmacological targeting of ß-ARs with the nonselective ß-blocker propranolol in such sarcomas. Of note, pharmacological ß-AR inhibition synergized with doxorubicin in inhibiting the cell viability of liposarcoma and leiomyosarcoma cells and increased the response to docetaxel in angiosarcoma- and solitary fibrous tumour (SFT)-patient-derived cells. Notably, the SFT patient was treated with the combination of propranolol and docetaxel, reporting prolonged disease control. Mechanistically, we found that propranolol reduced the activity of the multidrug resistance efflux pump P-gp, thereby increasing the intracellular doxorubicin concentration and antitumour activity. In addition, propranolol attenuated the Akt-dependent survival signal induced by doxorubicin and strongly reduced the activation of the NF-kB/COX-2 pathway, increasing cell sensitivity to docetaxel. Overall, our study highlighted the therapeutic potential of propranolol, alone or in rational combination therapies, for sarcoma treatment.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Propranolol/farmacologia , Sarcoma/tratamento farmacológico , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Doxorrubicina/farmacologia , Humanos , NF-kappa B/metabolismo , Projetos Piloto , Receptores Adrenérgicos beta/metabolismo , Sarcoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/metabolismo
11.
Life Sci ; 256: 118014, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32593712

RESUMO

The age and strength of fear memory are two potential parameters that can be influenced by the impairing effects of pharmacological agents on reconsolidation of fear memory. In reconsolidation, stored information is rendered labile again after being reactivated. Pharmacological manipulations at this stage result in an inability to retrieve the fear memories, suggesting that they are erased or persistently inhibited. This fear memory impairment phenomenon can be valuable to treat post-traumatic stress disorders (PTSD). Previously ß-adrenergic antagonist propranolol has been repeatedly reported to impair fear memory in the treatment of PTSD. Atropine has also shown to disrupt memory formation. The present study was therefore designed to compare the effects of atropine and propranolol on reconsolidation of older fear memory in rat model of PTSD using Pavlovian fear conditioning apparatus. For this purpose 18 rats were taken and divided into control, atropine and propranolol groups and subjected to Pavlovian fear conditioning trials in order to develop animal model of PTSD. To evaluate the reconsolidation impairment of fear memory by atropine and propranolol, short term and long term memory was tested after reactivation of fear memory in rats. The present findings demonstrate that atropine significantly decreases fear expression. These results suggest that atropine significantly reduces the strength of fear memories and may be effective in the treatment of psychiatric disorders especially in PTSD.


Assuntos
Atropina/farmacologia , Medo/efeitos dos fármacos , Propranolol/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Memória/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Ratos , Ratos Wistar , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia
12.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R123-R131, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32491938

RESUMO

Fetal heart rate (FHR) variability (FHRV) and ST segment morphology are potential clinical indices of fetal well-being during labor. ß-Adrenergic stimulation by circulating catecholamines has been hypothesized to contribute to both FHRV and ST segment morphology during labor, but this has not been tested during brief repeated fetal hypoxemia that is characteristic of labor. Near-term fetal sheep (0.85 gestation) received propranolol (ß-adrenergic blockade; n = 10) or saline (n = 7) 30 min before being exposed to three 2-min complete umbilical cord occlusions (UCOs) separated by 3-min reperfusions. T/QRS ratio was calculated throughout UCOs and reperfusion periods, and measures of FHRV (RMSSD, SDNN, and STV) were calculated between UCOs. During the baseline period, before the start of UCOs, propranolol was associated with reduced FHR, SDNN, and STV but did not affect RMSSD or T/QRS ratio. UCOs were associated with rapid FHR decelerations and increased T/QRS ratio; propranolol significantly reduced FHR during UCOs and was associated with a slower rise in T/QRS ratio during the first UCOs, without affecting the maximal rise or T/QRS ratio during the second and third UCO. Between UCOs propranolol reduced FHR and T/QRS ratio but did not affect any measure of FHRV. These data demonstrate that circulating catecholamines do not contribute to FHRV during labor-like hypoxemia. Furthermore, circulating catecholamines did not contribute to the major rise in T/QRS ratio during labor-like hypoxemia but may regulate T/QRS ratio between brief hypoxemia.


Assuntos
Catecolaminas/fisiologia , Frequência Cardíaca Fetal/fisiologia , Carneiro Doméstico/fisiologia , Cordão Umbilical/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Animais , Catecolaminas/sangue , Eletrocardiografia , Feminino , Hipóxia Fetal/fisiopatologia , Humanos , Hipóxia/fisiopatologia , Trabalho de Parto , Gravidez , Propranolol/farmacologia
13.
Nat Chem Biol ; 16(7): 749-755, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32483378

RESUMO

Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the ß2-adrenergic receptor (ß2AR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E1223.41 and the backbone carbonyls of V2065.45 and S2075.46. The AS408 binding site is adjacent to a previously identified molecular switch for ß2AR activation formed by I3.40, P5.50 and F6.44. The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/química , Antagonistas Adrenérgicos beta/química , Alprenolol/química , Norepinefrina/química , Receptores Adrenérgicos beta 2/química , Xinafoato de Salmeterol/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Regulação Alostérica , Sítio Alostérico , Alprenolol/farmacologia , Células HEK293 , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Norepinefrina/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Receptores Adrenérgicos beta 2/metabolismo , Xinafoato de Salmeterol/farmacologia , Termodinâmica , Água/química
14.
Am J Physiol Heart Circ Physiol ; 319(1): H192-H202, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502375

RESUMO

Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise, increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of inactive skeletal muscle and active skeletal muscle during cycle exercise in healthy humans. In ten male participants (18-35 yr), mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during cycle exercise (60% total peak workload) alone and during combined cycle exercise + handgrip exercise (HGE) before and after intra-arterial blockade of α- and ß-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR, +81.7 ± 84.6 vs. +9.7 ± 30.7%; P = 0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE, +139.3 ± 67.0 vs. cycle exercise: +81.9 ± 66.3 ml·min-1·100 mmHg-1; P = 0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, nonadrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise.NEW & NOTEWORTHY Sympathetic restraint of vascular conductance to inactive skeletal muscle is critical to maintain blood pressure during moderate- to high-intensity whole body exercise. This investigation shows that cycle exercise-induced restraint of inactive skeletal muscle vascular conductance occurs primarily because of activation of α-adrenergic receptors. Furthermore, exercise-induced vasoconstriction restrains the subsequent vasodilatory response to hand-grip exercise; however, the restraint of active skeletal muscle vasodilation was in part due to nonadrenergic mechanisms. We conclude that α-adrenergic receptors are the primary but not exclusive mechanism by which sympathetic vasoconstriction restrains blood flow in humans during whole body exercise and that metabolic activity modulates the contribution of α-adrenergic receptors.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Exercício Físico , Músculo Esquelético/fisiologia , Sistema Nervoso Simpático/fisiologia , Adulto , Pressão Sanguínea , Humanos , Masculino , Contração Muscular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Fentolamina/farmacologia , Propranolol/farmacologia , Fluxo Sanguíneo Regional , Sistema Nervoso Simpático/efeitos dos fármacos , Vasoconstrição , Vasodilatação
15.
Biochem Biophys Res Commun ; 528(1): 78-84, 2020 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-32451082

RESUMO

Noradrenaline (NA) suppresses TNF-α production via ß-adrenoceptors (ARs) in brain astrocytes. However, the downstream pathways from ß-ARs, and the involvement of α-ARs, remains unknown. In this study, we investigated the AR-mediated regulation of TNF-α mRNA levels in cultured astrocytes from rat spinal cord. NA, the α1-agonist phenylephrine, and the ß-agonist isoproterenol decreased the TNF-α mRNA level, while the α2-agonist dexmedetomidine increased it. The isoproterenol-induced TNF-α mRNA decrease was accompanied by a decrease in ERK phosphorylation. An adenylyl cyclase activator and an ERK inhibitor mimicked these effects. These results indicate that the transcriptional regulation of TNF-α by ß-ARs is mediated via cAMP pathways followed by the ERK pathway inhibition. The dexmedetomidine-induced TNF-α mRNA increase was accompanied by phosphorylation of JNK and ERK, which was blocked by a JNK inhibitor. Furthermore, the LPS-induced increase in the TNF-α mRNA level was accompanied by NF-κB nuclear translocation, and both these effects were blocked by phenylephrine. An NF-κB inhibitor suppressed the LPS-induced increase in the TNF-α mRNA level. These results suggest that α1-ARs suppress the LPS-induced increase in the TNF-α mRNA level via inhibition of NF-κB nuclear translocation. Taken together, our study reveals that both α- and ß-ARs are involved in the transcriptional regulation of TNF-α in astrocytes.


Assuntos
Astrócitos/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos beta/metabolismo , Medula Espinal/metabolismo , Transcrição Genética , Fator de Necrose Tumoral alfa/genética , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
17.
Proc Natl Acad Sci U S A ; 117(22): 12435-12443, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32414934

RESUMO

A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a ß2-adrenergic receptor (ß2AR) agonist enhances skeletal muscle strength and hypertrophy; however, its clinical utility is limited by side effects such as cardiac arrhythmias mediated by G protein signaling. We recently reported that clenbuterol-induced increases in contractility and skeletal muscle hypertrophy were lost in ß-arrestin 1 knockout mice, implying that arrestins, multifunctional adapter and signaling proteins, play a vital role in mediating the skeletal muscle effects of ß2AR agonists. Carvedilol, classically defined as a ßAR antagonist, is widely used for the treatment of chronic systolic heart failure and hypertension, and has been demonstrated to function as a ß-arrestin-biased ligand for the ß2AR, stimulating ß-arrestin-dependent but not G protein-dependent signaling. In this study, we investigated whether treatment with carvedilol could enhance skeletal muscle strength via ß-arrestin-dependent pathways. In a murine model, we demonstrate chronic treatment with carvedilol, but not other ß-blockers, indeed enhances contractile force in skeletal muscle and this is mediated by ß-arrestin 1. Interestingly, carvedilol enhanced skeletal muscle contractility despite a lack of effect on skeletal muscle hypertrophy. Our findings suggest a potential unique clinical role of carvedilol to stimulate skeletal muscle contractility while avoiding the adverse effects with ßAR agonists. This distinctive signaling profile could present an innovative approach to treating sarcopenia, frailty, and secondary muscle wasting.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Carvedilol/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , beta-Arrestina 1/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/fisiologia , beta-Arrestina 1/genética
18.
BMC Med ; 18(1): 103, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32366251

RESUMO

BACKGROUND: Beta-blockers are widely used for many cardiovascular conditions; however, their efficacy in contemporary clinical practice remains uncertain. METHODS: We performed a prospectively designed, umbrella review of meta-analyses of randomised controlled trials (RCTs) investigating the evidence of beta-blockers in the contemporary management of coronary artery disease (CAD), heart failure (HF), patients undergoing surgery or hypertension (registration: PROSPERO CRD42016038375). We searched MEDLINE, EMBASE and the Cochrane Library from inception until December 2018. Outcomes were analysed as beta-blockers versus control for all-cause mortality, myocardial infarction (MI), incident HF or stroke. Two independent investigators abstracted the data, assessed the quality of the evidence and rated the certainty of evidence. RESULTS: We identified 98 meta-analyses, including 284 unique RCTs and 1,617,523 patient-years of follow-up. In CAD, 12 meta-analyses (93 RCTs, 103,481 patients) showed that beta-blockers reduced mortality in analyses before routine reperfusion, but there was a lack of benefit in contemporary studies where ≥ 50% of patients received thrombolytics or intervention. Beta-blockers reduced incident MI at the expense of increased HF. In HF with reduced ejection fraction, 34 meta-analyses (66 RCTs, 35,383 patients) demonstrated a reduction in mortality and HF hospitalisation with beta-blockers in sinus rhythm, but not in atrial fibrillation. In patients undergoing surgery, 23 meta-analyses (89 RCTs, 19,211 patients) showed no effect of beta-blockers on mortality for cardiac surgery, but increased mortality in non-cardiac surgery. In non-cardiac surgery, beta-blockers reduced MI after surgery but increased the risk of stroke. In hypertension, 27 meta-analyses (36 RCTs, 260,549 patients) identified no benefit versus placebo, but beta-blockers were inferior to other agents for preventing mortality and stroke. CONCLUSIONS: Beta-blockers substantially reduce mortality in HF patients in sinus rhythm, but for other conditions, clinicians need to weigh up both benefit and potential risk.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Humanos , Estudos Prospectivos
19.
Curr Pharm Biotechnol ; 21(13): 1377-1385, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32410562

RESUMO

OBJECTIVE: Heart dysfunctions are the major complications of trastuzumab in patients with Human Epidermal growth factor Receptor-2 (HER2)-positive breast cancers. METHODS: In this study, the cytotoxicity of trastuzumab on H9c2 cardiomyoblasts was demonstrated, and the proteome changes of cells were investigated by a tandem mass tagging quantitative approach. The Differentially Abundant Proteins (DAPs) were identified and functionally enriched. RESULTS: We determined that carvedilol, a non-selective beta-blocker, could effectively inhibit trastuzumab toxicity when administrated in a proper dose and at the same time. The proteomics analysis of carvedilol co-treated cardiomyoblasts showed complete or partial reversion in expressional levels of trastuzumab-induced DAPs. CONCLUSION: Downregulation of proteins involved in the translation biological process is one of the most important changes induced by trastuzumab and reversed by carvedilol. These findings provide novel insights to develop new strategies for the cardiotoxicity of trastuzumab.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Antineoplásicos Imunológicos/toxicidade , Carvedilol/farmacologia , Mioblastos Cardíacos/efeitos dos fármacos , Proteoma/metabolismo , Trastuzumab/toxicidade , Antagonistas Adrenérgicos beta/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Cardiomiopatias/prevenção & controle , Carvedilol/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Regulação para Baixo , Feminino , Humanos , Mioblastos Cardíacos/metabolismo , Mioblastos Cardíacos/patologia , Proteômica , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico
20.
PLoS One ; 15(5): e0226539, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413046

RESUMO

A murine model to study the effect of cold-induced stress (CIS) on Chlamydia muridarum genital infection and immune response has been developed in our laboratory. Previous results in the lab show that CIS increases the intensity of chlamydia genital infection, but little is known about the effects and mechanisms of CIS on the differentiation and activities of CD4+ T cell subpopulations and bone marrow-derived dendritic cells (BMDCs). The factors that regulate the production of T helper 1 (Th1) or T helper 2 (Th2) cytokines are not well defined. In this study, we examined whether CIS modulates the expressions of beta-adrenergic receptor (ß-AR), transcription factors, hallmark cytokines of Th1 and Th2, and differentiation of BMDCs during C. muridarum genital infection in the murine model. Our results show that the mRNA level of the beta2-adrenergic receptor (ß2-AR) compared to ß1-AR and ß3-AR was high in the mixed populations of CD4+ T cells and BMDCs. Furthermore, we observed decreased expression of T-bet, low level of Interferon-gamma (IFN-γ) production, increased expression of GATA-3, and Interleukin-4 (IL-4) production in CD4+ T cells of stressed mice. Exposure of BMDCs to Fenoterol, ß2-AR agonist, or ICI118,551, ß2-AR antagonist, revealed significant ß2-AR stimulation or inhibition, respectively, in stressed mice. Moreover, co-culturing of mature BMDCs and naïve CD4+ T cells increased the production of IL-4, IL-10, L-17, and IL-23 cytokines, suggesting that stimulation of ß2-AR leads to the increased production of Th2 cytokines. Overall, our results show for the first time that CIS promotes the switching from a Th1 to Th2 cytokine environment. This was evidenced in the murine stress model by the overexpression of GATA-3 concurrent with elevated IL-4 production, reduced T-bet expression, and IFN-γ secretion.


Assuntos
Infecções por Chlamydia/imunologia , Resposta ao Choque Frio , Células Th1/imunologia , Células Th2/imunologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Chlamydia muridarum , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Fenoterol/farmacologia , Interferon gama/genética , Interferon gama/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Propanolaminas/farmacologia , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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