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1.
Medicine (Baltimore) ; 100(18): e25559, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950930

RESUMO

ABSTRACT: Background: Atrial fibrillation (AF) is a type of arrhythmia that represents a severe health hazard. The current therapies for AF have achieved success in some conditions. However, because the mechanisms underlying the occurrence and development of this disease remain unclear, the current treatment for AF often does not achieve the desired outcomes. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which exert robust effects on specific cardiovascular diseases, are widely used in the clinic. Several studies are focusing on the effect of ACEIs/ARBs on the prevention and cure of AF. Some systematic reviews have obtained different and even opposite results. An overview is required to obtain a conclusion and provide strong evidence to guide clinical work.Methods: We searched 5 databases, including MEDLINE, EMBASE, Cochrane Library, Web of Science, and CNKI (Chinese), and selected relevant reviews that passed the assessment we performed. Then, we synthesized the data for each result from the included reviews and obtained conclusions.Results: ACEIs/ARBs prevented new-onset AF and AF after heart failure. ACEIs/ARBs performed well in the prevention of secondary AF, especially postoperative AF. However, for patients suffering from hypertension and myocardial infarction, ACEIs/ARBs were not the right choices for preventing AF.Conclusions: We suggest that physicians select ACEIs/ARBs as an anti-AF therapy for patients with heart failure due to their additional benefits. Moreover, for patients who have suffered AF, ACEIs/ARBs may be a routine drug for secondary prevention.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Fibrilação Atrial/prevenção & controle , Insuficiência Cardíaca/tratamento farmacológico , Prevenção Secundária/métodos , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Insuficiência Cardíaca/complicações , Humanos , Incidência , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Revisões Sistemáticas como Assunto , Resultado do Tratamento
2.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808232

RESUMO

The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Valsartana/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Conectina/metabolismo , GMP Cíclico/sangue , Diástole/efeitos dos fármacos , Diástole/fisiologia , Modelos Animais de Doenças , Combinação de Medicamentos , Eletrocardiografia , Feminino , Fibrose , Hemoglobina A Glicada/análise , Músculo Esquelético/fisiologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/fisiopatologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fosforilação/efeitos dos fármacos , Ratos Mutantes , Função Ventricular Esquerda/efeitos dos fármacos
3.
Anticancer Res ; 41(4): 2093-2100, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813419

RESUMO

BACKGROUND/AIM: The Renin-Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies. PATIENTS AND METHODS: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PD-L1 antibodies monotherapy as second- or later-line treatment. We classified patients into those with or without use of RASi. RESULTS: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59, 95%CI=0.40-0.88). The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0.71, 95%CI=0.45-1.11). CONCLUSION: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Sinergismo Farmacológico , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Japão/epidemiologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
4.
Cells ; 10(3)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804069

RESUMO

Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1-7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Peptidil Dipeptidase A/metabolismo , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , /genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Receptores de Angiotensina/genética , Regeneração/efeitos dos fármacos , Regeneração/genética , Regeneração/fisiologia , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Vulvodinia/imunologia , Vulvodinia/fisiopatologia
5.
Circ Res ; 128(7): 1062-1079, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33793331

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19-related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.


Assuntos
/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Antagonistas de Receptores de Angiotensina/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , /metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Humanos , Hipertensão/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco
6.
Eur J Pharmacol ; 899: 173981, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33689706

RESUMO

Gestational diabetes mellitus (GDM) affects 5-10% of pregnancies and increases the risk of fetal and maternal adverse outcomes. Interestingly, the vascular response to AngII is decreased by pregnancy while the response is increased by diabetes. It remains unclear how GDM affects vascular tone and how angiotensin II receptors contribute to these changes. In this work, we sought to establish the vascular impact of a hypercaloric diet-induced GDM through changes in AT1 and AT2 receptor's expression. Female rats fed for 7 weeks with standard (SD) or hypercaloric (HD) diet were divided at week 4. Half of the rats of each group were mated to become pregnant and those fed with a HD developed GDM. AngII-induced vasoconstriction was measured in thoracic or abdominal aorta rings using a conventional isolated organ bath and AT1 and AT2 receptors were searched by immunohistochemistry. Experiments where conducted on the pregnant standard diet group (PSD) and the pregnant hypercaloric-gestational diabetes mellitus group (PHD-GDM). Vasoconstriction was reduced in the thoracic aorta (P < 0.05 vs PSD) but increased in the abdominal aorta of PHD-GDM rats (P < 0.05 vs PSD). Blockade of AT2 receptors using PD123319 decreased vasoconstriction, particularly in the abdominal aorta of PHD-GDM animals (P < 0.05 vs PSD). PHD-GDM increased AT1 receptors expression (P < 0.05 vs PSD). Also, PHD-GDM reverted physiologic hypoglycemia and hypotension of healthy pregnancy. Findings provide new insight into the hypercaloric diet induced damage on the vasculature during pregnancy.


Assuntos
Aorta Abdominal/metabolismo , Aorta Torácica/metabolismo , Diabetes Gestacional/metabolismo , Endotélio Vascular/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Vasoconstrição , Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/fisiopatologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Diabetes Gestacional/fisiopatologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Gravidez , Ratos Wistar , Receptor Tipo 1 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/agonistas , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
7.
Nat Commun ; 12(1): 1660, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712587

RESUMO

In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs and a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, viral, and microbial profiling. We applied these methods to clinical specimens gathered from 669 patients in New York City during the first two months of the outbreak, yielding a broad molecular portrait of the emerging COVID-19 disease. We find significant enrichment of a NYC-distinctive clade of the virus (20C), as well as host responses in interferon, ACE, hematological, and olfaction pathways. In addition, we use 50,821 patient records to find that renin-angiotensin-aldosterone system inhibitors have a protective effect for severe COVID-19 outcomes, unlike similar drugs. Finally, spatial transcriptomic data from COVID-19 patient autopsy tissues reveal distinct ACE2 expression loci, with macrophage and neutrophil infiltration in the lungs. These findings can inform public health and may help develop and drive SARS-CoV-2 diagnostic, prevention, and treatment strategies.


Assuntos
/genética , /genética , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/farmacologia , /epidemiologia , Interações Medicamentosas , Feminino , Perfilação da Expressão Gênica , Genoma Viral , Antígenos HLA/genética , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Cidade de Nova Iorque/epidemiologia , Técnicas de Amplificação de Ácido Nucleico , Pandemias , RNA-Seq , /efeitos dos fármacos
8.
JAMA Netw Open ; 4(3): e213594, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33787911

RESUMO

Importance: The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes. Objective: To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19. Data Sources: PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020. Study Selection: The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs. Data Extraction and Synthesis: Three authors independently extracted data on mortality and severe AEs associated with COVID-19. Severe AEs were defined as intensive care unit admission or the need for assisted ventilation. For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs. Main Outcomes and Measures: Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19. Results: A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation. Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101 949 total patients, of whom 26 545 (26.0%) were receiving ACEIs or ARBs. When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P < .001) and severe AEs (aOR, 0.68; 95% CI, 0.53-0.88; P < .001) were found. Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 0.66 [95% CI, 0.49-0.91]; P = .01; aOR, 0.51 [95% CI, 0.32-0.84]; P = .008) and severe AEs (unadjusted OR, 0.70 [95% CI, 0.54-0.91]; P = .007; aOR, 0.55 [95% CI, 0.36-0.85]; P = .007). Conclusions and Relevance: In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to establish causality.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Comorbidade , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade
9.
Kidney Blood Press Res ; 46(2): 245-249, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33756485

RESUMO

BACKGROUND: Preclinical studies suggested that pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) may increase local angiotensin-converting enzyme 2 (ACE2) expression. METHODS: In this study, we evaluated the effect of ACEi or ARB treatment on expression of ACE2, ACE, and AGTR1 in 3-month protocol kidney allograft biopsies of stable patients using RT-qPCR (n = 48). Protein ACE2 expression was assessed using immunohistochemistry from paraffin sections. RESULTS: The therapy with RAAS blockers was not associated with increased ACE2, ACE, or ATGR1 expression in kidney allografts and also ACE2 protein immunohistochemistry did not reveal differences among groups. CONCLUSIONS: ACEis or ARBs in kidney transplant recipients do not affect local ACE2 expression. This observation supports long-term RAAS treatment in kidney transplant recipients, despite acute complications such as COVID-19 where ACE2 serves as the entry protein for infection.


Assuntos
Aloenxertos/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Adulto , Idoso , Aloenxertos/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , /antagonistas & inibidores , Anti-Hipertensivos/farmacologia , /genética , Feminino , Humanos , Rim/metabolismo , Transplante de Rim , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , RNA Mensageiro/genética , Sistema Renina-Angiotensina/efeitos dos fármacos
10.
Am J Physiol Renal Physiol ; 320(4): F644-F653, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33615887

RESUMO

The kidneys are an important target for angiotensin II (ANG II). In adult kidneys, the effects of ANG II are mediated mainly by ANG II type 1 (AT1) receptors. AT1 receptor expression has been reported for a variety of different cell types within the kidneys, suggesting a broad spectrum of actions for ANG II. Since there have been heterogeneous results in the literature regarding the intrarenal distribution of AT1 receptors, this study aimed to obtain a comprehensive overview about the localization of AT1 receptor expression in mouse, rat, and human kidneys. Using the cell-specific and high-resolution RNAscope technique, we performed colocalization experiments with various cell markers to specifically discriminate between different segments of the tubular and vascular system. Overall, we found a similar pattern of AT1 mRNA expression in mouse, rat, and human kidneys. AT1 receptors were detected in mesangial cells and renin-producing cells. In addition, AT1 mRNA was found in interstitial cells of the cortex and outer medulla. In rodents, late afferent and early efferent arterioles expressed AT1 receptor mRNA, but larger vessels of the investigated species showed no AT1 expression. Tubular expression of AT1 mRNA was species dependent with a strong expression in proximal tubules of mice, whereas expression was undetectable in human tubular cells. These findings suggest that the (juxta)glomerular area and tubulointerstitium are conserved expression sites for AT1 receptors across species and might present the main target sites for ANG II in adult human and rodent kidneys.NEW & NOTEWORTHY Angiotensin II (ANG II) type 1 (AT1) receptors are essential for mediating the effects of ANG II in the kidneys. This study aimed to obtain a comprehensive overview about the cell-specific localization of AT1 receptor expression in rodent and human kidneys using the novel RNAscope technique. We found that the conserved AT1 receptor mRNA expression sites across species are the (juxta)glomerular areas and tubulointerstitium, which might present main target sites for ANG II in adult human and rodent kidneys.


Assuntos
Angiotensina II/farmacologia , Expressão Gênica/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Angiotensina I/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Ratos , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Roedores/genética , Roedores/metabolismo
11.
Life Sci ; 270: 119118, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33548284

RESUMO

Pancreatic cancer is among the most lethal malignancies with poor prognosis and patients become chemoresistant to current therapies, supporting further investigations to identify new therapeutic regimens in the treatment of this condition. Preclinical and clinical studies now appear to support the role of the renin-angiotensin system (RAS) in the regulation of tumor growth, angiogenesis, and metastasis in different malignancies including pancreatic cancer. These studies suggest that RAS blockers; Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); could have anti-carcinogenic effects and improve clinical outcomes in the management of pancreatic cancer. Here we provided an overview of ACE inhibitors and ARBs as a potential therapeutic option in the treatment of pancreatic cancer.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Quimioterapia Combinada , Humanos , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos
14.
Clin Pharmacol Ther ; 109(4): 1092-1103, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33506503

RESUMO

ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are standard-of-care treatments for hypertension and diabetes, common comorbidities among hospitalized patients with coronavirus disease 2019 (COVID-19). Their use in the setting of COVID-19 has been heavily debated due to potential interactions with ACE2, an enzyme that links the pro-inflammatory and anti-inflammatory arms of the renin angiotensin system, but also the entryway by which severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) invades cells. ACE2 expression is altered by age, hypertension, diabetes, and the virus itself. This study integrated available information about the renin angiotensin aldosterone system (RAAS) and effects of SARS-CoV-2 and its comorbidities on ACE2 into a mechanistic mathematical model and aimed to quantitatively predict effects of ACEi/ARBs on the RAAS pro-inflammatory/anti-inflammatory balance. RAAS blockade prior to SARS-CoV-2 infection is predicted to increase the mas-AT1 receptor occupancy ratio up to 20-fold, indicating that in patients already taking an ACEi/ARB before infection, the anti-inflammatory arm is already elevated while the pro-inflammatory arm is suppressed. Predicted pro-inflammatory shifts in the mas-AT1 ratio due to ACE2 downregulation by SARS-CoV-2 were small relative to anti-inflammatory shifts induced by ACEi/ARB. Predicted effects of changes in ACE2 expression with comorbidities of diabetes, hypertension, or aging on mas-AT1 occupancy ratio were also relatively small. Last, predicted changes in the angiotensin (Ang(1-7)) production rate with ACEi/ARB therapy, comorbidities, or infection were all small relative to exogenous Ang(1-7) infusion rates shown experimentally to protect against acute lung injury, suggesting that any changes in the ACE2-Ang(1-7)-mas arm may not be large enough to play a major role in COVID-19 pathophysiology.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Receptor Tipo 1 de Angiotensina/fisiologia , Sistema Renina-Angiotensina/fisiologia , Fatores Etários , Envelhecimento/fisiologia , Diabetes Mellitus/fisiopatologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Mediadores da Inflamação/metabolismo , Modelos Teóricos
15.
Eur J Pharmacol ; 894: 173851, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33422508

RESUMO

Sacubitril/valsartan (Entresto™; LCZ696) is the first angiotensin receptor-neprilysin inhibitor (ARNI) drug approved by the US and EU for heart failure (HF) and especially recommended for hypertensive HF (HHF). Sacubitril inhibits the enzyme neprilysin (NEP) which produces both beneficial and adverse effects in the human body. While LCZ696 causes beneficial cardiovascular effects, it may induce memory and cognitive dysfunction, or even exacerbate Alzheimer's disease (AD). This article reviewed data reported by experimental and clinical studies that examined NEP inhibitors and their dementia-related side effects. Based on the literature, LCZ696 increases the risk of memory and cognitive dysfunctions, and clinical trials failed to show compelling evidence for LCZ696 safety for the brain. Together, it was concluded that more experimental and clinical studies with particular focus on LCZ696 side effects on ß-amyloid (Aß) degradation are needed to assess LCZ696 safety for the cognitive function, especially in case of long-term administration.


Assuntos
Encefalopatias/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Aminobutiratos/efeitos adversos , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacologia , Combinação de Medicamentos , Humanos , Valsartana/efeitos adversos , Valsartana/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-33461698

RESUMO

Irbesartan, (2-butyl-3-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one), is a member of non-peptide angiotensin II receptor antagonists used worldwide in the treatment of hypertension and diabetic nephropathy in hypertensive patients with type 2 diabetes, elevated serum creatinine, and proteinuria. Irbesartan can be used alone or in combination with other antihypertensive agents (e.g., hydrochlorothiazide). These combination products are indicated for hypertension in patients with uncontrolled hypertension with monotherapy or first line in patients not expected to be well controlled with monotherapy. Irbesartan is also indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria. Irbesartan exerts its action mainly via a selective blockade action on AT1 receptors and the consequent reduced pressor effect of angiotensin II. This article discusses, by a critical comprehensive review of the literature on irbesartan in terms of its description, names, formulae, elemental composition, appearance, and therapeutic uses. The article also discusses the methods for preparation of irbesartan, its physical-chemical properties, analytical methods for its determination, pharmacological-toxicological properties, and dosing information.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Hipertensão , Irbesartana/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Tipo 2 , Humanos , Hipertensão/tratamento farmacológico , Irbesartana/uso terapêutico
17.
Life Sci ; 266: 118877, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310048

RESUMO

AIMS: Pulmonary hypertension (PH) is a fatal disease identified by progressive elevated pulmonary arterial pressure, which neurohormonal activation is a notable contributor to its development. Sacubitril/valsartan is a complex of sacubitril [via enhancing the natriuretic peptide (NP) system] and valsartan [via blocking the renin-angiotensin-aldosterone system (RAAS)]. Regulation of the two neurohormonal system had been shown to attenuate PH. This study was to explore the role of sacubitril/valsartan in both monocrotaline (MCT)-induced and hypoxia-induced rat models and the underlying mechanism. MAIN METHODS: The rats were treated with MCT or hypoxic environment for 14 days, after that sacubitril/valsartan were given for another 14 days. Hemodynamic measurements and histological assessments were performed. The expression of NPs was measured using RT-PCR and ELISA, while the protein level of natriuretic peptide receptors (NPRs) and AT1 receptor were detected by western blot, the concentrations of cGMP, IL-1ß, IL-6, TNF-α and TGF-ß1 were tested by ELISA. KEY FINDINGS: We found that sacubitril/valsartan significantly improved the hemodynamic and histological data of two PH models. Sacubitril/valsartan suppressed the protein expression of AT1 receptor (P < 0.05). The intervention increased the expression of ANP and CNP (P< 0.05) and therefore upregulated the protein expression of NPRs (P < 0.05), raised the concentration of cGMP (P < 0.05). In addition, the treatment reduced the concentration of IL-1ß, IL-6 and TNF-α (P < 0.05) but have no effects on TGF-ß1. SIGNIFICANCE: Sacubitril/valsartan alleviated PH in MCT-induced and hypoxia-induced rat models by inhibiting the activated RAAS, promoting ANP/NPR-A/cGMP and CNP/NPR-B/cGMP pathway, restoring the NPR-C signaling and the anti-inflammatory effects.


Assuntos
Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Modelos Animais de Doenças , Hipertensão Pulmonar/prevenção & controle , Hipóxia/fisiopatologia , Monocrotalina/toxicidade , Tetrazóis/farmacologia , Animais , Peso Corporal , Progressão da Doença , Combinação de Medicamentos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Masculino , Ratos , Ratos Sprague-Dawley
18.
Biomed Pharmacother ; 133: 110824, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378988

RESUMO

BACKGROUND: LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNi), is reported to play a cardioprotective role after acute myocardial infarction (AMI). Angiotensin-converting enzyme inhibitors(ACEIs) have similar roles. However, it is unclear whether the combination of the two drugs has a better protective effect. The purpose of this study was to investigate the effect of this combination therapy after AMI. METHODS: Male C57BL/6 J mice subjected to ligation of left anterior descending artery were treated for 4 weeks with LCZ696, ACEI(benazepril), or both(combination therapy) after induction of MI. Cardiac function, hemodynamics, and inflammatory factors were evaluated at 1 st day, 14th day, and 28th day. Heart weight and myocardial fibrosis were measured at the end of the experiment. RESULTS: Blood pressure was lower in all treatment groups than in the control group. The combination therapy group had the strongest antihypertensive effect. Compared with LCZ696 or benazepril, treatment with combination therapy increased ejection fraction, fractional shortening, and cardiac output and decreased N-terminal pro-B-type natriuretic peptide(NT-proBNP). The ratios of heart weight to body weight in all treatment groups were less than that in the control group. Compared with the control and LCZ696 group, the fibrotic area in the combination therapy group was suppressed and had a lower level of TGF-ß1 in the left ventricle. The plasma concentration of bradykinin and renin in the combination therapy group were highest among groups at 14th and 28th day. CONCLUSIONS: LCZ696 in combination with benazepril showed better positive effects in modulating heart failure and myocardial fibrosis after acute AMI in mice and affect some inflammatory markers.


Assuntos
Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzazepinas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/complicações , Miocárdio/patologia , Inibidores de Proteases/farmacologia , Tetrazóis/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Quimioterapia Combinada , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Neprilisina/antagonistas & inibidores , Renina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
19.
J Renin Angiotensin Aldosterone Syst ; 21(4): 1470320320981321, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33325306

RESUMO

BACKGROUND: The clinical use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) in patients with COVID-19 infection remains controversial. Therefore, we performed a meta-analysis on the effects of ACEI/ARB on disease symptoms and laboratory tests in hypertensive patients infected with COVID-19 virus and those who did not use ACEI/ARB. METHODS: We systematically searched the relevant literatures from Pubmed, Embase, EuropePMC, CNKI, and other databases during the study period of 31 December 2019 (solstice, 15 March 2020), and analyzed the differences in symptoms and laboratory tests between patients with COVID-19 and hypertension who used ACEI/ARB drugs and those who did not. All statistical analyses were performed with REVMAN5.3. RESULTS: We included a total of 1808 patients with hypertension diagnosed with COVID-19 in six studies. Analysis results show that ACEI/ARB drugs group D-dimer is lower (SMD = -0.22, 95%CI: -0.36 to -0.06), and the chances of getting fever is lower (OR = 0.74, 95%CI: 0.55 to 0.98). Meanwhile, laboratory data and symptoms were not statistical difference, but creatinine tends to rise (SMD = 0.22, 95% CI: 0.04 to 0.41). CONCLUSION: We found that the administration of ACEI/ARB drugs had positive effect on reducing D-dimer and the number of people with fever. Meanwhile it had no significant effect on other laboratory tests (creatinine excepted) or symptoms in patients with COVID-19, while special attention was still needed in patients with renal insufficiency.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , /fisiologia , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Viés de Publicação , Resultado do Tratamento
20.
Bol Med Hosp Infant Mex ; 77(5): 274-281, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33064690

RESUMO

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with hypertension and other cardiovascular comorbidities develop more severe coronavirus disease (COVID)-19 and are at high risk of death, a controversy arose about the use of antihypertensives as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs). Such drugs might increase the expression of the fundamental receptor of this new infectious agent: the angiotensin-converting enzyme 2 (ACE2). Preclinical observations indicate that the increase of ACE2 expression or the activity by ACEis and ARBs leads to a greater transformation of angiotensin (Ang)-II to Ang-(1-7), which is associated with positive effects on cardiovascular and pulmonary pathophysiology. This association has been demonstrated in observational studies in patients with cardiovascular pathology and pneumonia. It has not been possible to confirm whether users of ACEis or ARBs are more infected by the new coronavirus, due to methodological issues in studies with patients infected with SARS-CoV-2. However, the use of such antihypertensive treatments in both children and adults might reduce the virulence of infection. Therefore, changes in the antihypertensive therapy of patients at risk of contracting COVID-19 are not recommended.


Assuntos
Anti-Hipertensivos/administração & dosagem , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Adulto , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Criança , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Humanos , Hipertensão/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores de Risco
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