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1.
Gen Physiol Biophys ; 39(3): 203-204, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32525813

RESUMO

Renin-angiotensin system (RAS) inhibition supposedly increases the expression of angiotensin converting enzyme 2, serving as a binding site for SARS-CoV-2. Concerns arose regarding therapy with RAS inhibition during the COVID-19 pandemic. However, the pharmacological restraining the classical RAS axis might be beneficial due to the reduction of deleterious effects of angiotensin II and enhancement of the anti-inflammatory angiotensin 1-7 pathway. Unless large controlled studies are performed, RAS inhibition remains the cornerstone therapy in populations with cardiovascular disorders.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Sistema Renina-Angiotensina , Angiotensina II/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Doenças Cardiovasculares/complicações , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos
2.
Ann Endocrinol (Paris) ; 81(2-3): 63-67, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32370986

RESUMO

With the multiplication of COVID-19 severe acute respiratory syndrome cases due to SARS-COV2, some concerns about angiotensin-converting enzyme 1 (ACE1) inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) have emerged. Since the ACE2 (angiotensin-converting enzyme 2) enzyme is the receptor that allows SARS COV2 entry into cells, the fear was that pre-existing treatment with ACEi or ARB might increase the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection. The present article discusses these concerns. ACE2 is a membrane-bound enzyme (carboxypeptidase) that contributes to the inactivation of angiotensin II and therefore physiologically counters angiotensin II effects. ACEis do not inhibit ACE2. Although ARBs have been shown to up-regulate ACE2 tissue expression in experimental animals, evidence was not always consistent in human studies. Moreover, to date there is no evidence that ACEi or ARB administration facilitates SARS-COV2 cell entry by increasing ACE2 tissue expression in either animal or human studies. Finally, some studies support the hypothesis that elevated ACE2 membrane expression and tissue activity by administration of ARB and/or infusion of soluble ACE2 could confer protective properties against inflammatory tissue damage in COVID-19 infection. In summary, based on the currently available evidence and as advocated by many medical societies, ACEi or ARB should not be discontinued because of concerns with COVID-19 infection, except when the hemodynamic situation is precarious and case-by-case adjustment is required.


Assuntos
Aldosterona/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Betacoronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Aldosterona/metabolismo , Pressão Sanguínea/fisiologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Guias de Prática Clínica como Assunto , Índice de Gravidade de Doença , Suspensão de Tratamento
3.
Eur J Intern Med ; 76: 14-20, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32336612

RESUMO

Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the 'adverse' ACE→Angiotensin II→AT1 receptor axis and the 'protective' ACE2→Angiotensin1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7. In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Betacoronavirus , Infecções por Coronavirus , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Receptores Virais/metabolismo , Angiotensinas/metabolismo , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/epidemiologia , Descoberta de Drogas , Insuficiência Cardíaca/epidemiologia , Humanos , Hipertensão/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Proteínas Recombinantes/farmacologia , Fatores de Risco
4.
Life Sci ; 252: 117629, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32247619

RESUMO

AIMS: To analyze the prostatic compartments, extracellular matrix, microvascularization, transforming growth factor-beta (TGF-ß) and angiotensin II receptors type 1 (AT1) levels, and histopathology of the ventral prostate in a rat model for rheumatoid arthritis, and to evaluate the effect of angiotensin II AT1 receptor blocker (ARB) in the disease. MAIN METHODS: Fifteen male rats (90 days old) were divided into three groups (n = 5/group): control, adjuvant-induced arthritis without (AIA) or with AT1 receptor blocker (AIA + ARB). Animals were euthanized 60 days after immunization. The ventral prostate was collected, weighed, and processed for histological and immunohistochemical analysis. KEY FINDINGS: Our results show that AIA increases production of the prostatic epithelium and extracellular matrix, accompanied by a reduction in the number of tissue capillaries. ARB treatment promotes decreased production of extracellular matrix and increased TGF-ß and AT1 receptor immunostaining. SIGNIFICANCE: AIA may activate specific mechanisms that modify the prostatic environment; the use of ARB attenuates some altered prostate parameters in a rat model for arthritis.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Artrite Experimental/complicações , Artrite Reumatoide/complicações , Próstata/patologia , Doenças Prostáticas/prevenção & controle , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/fisiopatologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Matriz Extracelular/patologia , Masculino , Doenças Prostáticas/etiologia , Ratos , Ratos Wistar
5.
Life Sci ; 252: 117650, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32294475

RESUMO

It has been described that the cardiac dysfunction in the obesity model is because of collagen imbalance and that angiotensin II (Ang II) contributes to myocardial fibrosis. However, it remains undefined if changes in collagen I and III metabolism in obesity is due to the renin-angiotensin system (RAS) dysregulation from myocardium or excessive adipose tissue. AIM: This study aimed to verify whether the changes in myocardial collagen metabolism result from RAS deregulation of cardiac or adipose tissue in an obesity model. MAIN METHODS: Wistar rats were fed with control (CD) and high-fat (HFD) diets for 30 weeks. After the dietary intervention, animals were assigned to be treated with losartan at the 30 mg/kg/day dosage or kept untreated for an additional five weeks. KEY FINDINGS: HFD induced obesity, comorbidities, and cardiac collagen overexpression. The HFD group presented an increase in Ang II levels in both adipose tissue and plasma, as well as AT1 receptor expression in cardiac tissue. Of note, the myocardial Ang II was not changed in the HFD group. Losartan administration reduced some obesity-induced comorbidities regardless of weight loss. The AT1 receptor blockade also decreased the release of Ang II from adipose tissue and myocardial AT1 receptor and collagen. SIGNIFICANCE: It was seen that excessive adipose tissue is responsible for the exacerbated circulating Ang II, which induced cardiac fibrosis development.


Assuntos
Tecido Adiposo/metabolismo , Angiotensina II/metabolismo , Miocárdio/patologia , Obesidade/fisiopatologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fibrose , Losartan/farmacologia , Masculino , Miocárdio/metabolismo , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/fisiologia
6.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(4): 520-525, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32344475

RESUMO

Objective: To understand the current status of anti-hypertensive drug use in patients with hypertension in the Southwest areas of China. Methods: Based on the Program of Screening and Intervention Subjects with High Risk Cardiovascular Diseases, this study presented information on adults aged 35-75 in Southwest China by convenient sampling method, from January 2016 to November 2018. Basic information and cardiovascular related data were collected. Data on hypertensive patients were recorded, including names, doses and frequency of anti-hypertensive drugs they used. Information on the use of anti-hypertensive drugs among different hypertension subgroups, potential related characteristics, types and combination patterns of drugs, etc., were analyzed. Results: A total of 394 957 subjects were included in the study, with 159 014 identified as being hypertensive [mean age (58.8±9.5) years, 40.2% male]. 29.8% of them ever received antihypertensive drugs. A total of 30 445 of the patients reported detailed information of the drugs they ever used and 22.5% of them received therapy of combined drugs. Rates of using combination therapy were consistent among subgroups with different age, gender, blood pressure level and history of cardiovascular and cerebrovascular diseases. Results from the multivariate logistic regression analysis showed that patients with previous cardiovascular and cerebrovascular events, obesity or diabetes were more likely to have received combined therapy, while patients with less education or lower income were in the opposite. Calcium antagonists (58.6%) were the main drugs being used in single drug therapy, while traditional fixed-dose combination drugs (31.4%) were the most common ones in the drug-combination therapy, followed by angiotensin converting enzyme inhibitor/angiotensin receptor blocker combined with calcium antagonists (22.4%). Angiotensin converting enzyme inhibitor/angiotensin receptor blocker combined with beta blocker was the main drug used in patients with coronary heart disease. Conclusions: Treatment programs using the antihypertensive drugs for hypertensive patients in Southwest China needs to be improved, since the irrational use of antihypertensive drugs still exists. However, we would encourage the use of combination therapy for hypertensive patients.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Adulto , Idoso , Pressão Sanguínea , China/epidemiologia , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
7.
Emerg Microbes Infect ; 9(1): 757-760, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32228222

RESUMO

The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown. COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors. We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood. In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs. This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Infecções por Coronavirus/complicações , Hipertensão/tratamento farmacológico , Pneumonia Viral/complicações , Sistema Renina-Angiotensina , Idoso , Betacoronavirus , Proteína C-Reativa/análise , Complexo CD3 , Linfócitos T CD8-Positivos/citologia , China , Infecções por Coronavirus/tratamento farmacológico , Feminino , Humanos , Hipertensão/complicações , Hipertensão/virologia , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Carga Viral
9.
Hypertension ; 75(6): 1382-1385, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32208987

RESUMO

During the spread of the severe acute respiratory syndrome coronavirus-2, some reports of data still emerging and in need of full analysis indicate that certain groups of patients are at risk of COVID-19. This includes patients with hypertension, heart disease, diabetes mellitus, and clearly the elderly. Many of those patients are treated with renin-angiotensin system blockers. Because the ACE2 (angiotensin-converting enzyme 2) protein is the receptor that facilitates coronavirus entry into cells, the notion has been popularized that treatment with renin-angiotensin system blockers might increase the risk of developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection. The present article discusses this concept. ACE2 in its full-length form is a membrane-bound enzyme, whereas its shorter (soluble) form circulates in blood at very low levels. As a mono-carboxypeptidase, ACE2 contributes to the degradation of several substrates including angiotensins I and II. ACE (angiotensin-converting enzyme) inhibitors do not inhibit ACE2 because ACE and ACE2 are different enzymes. Although angiotensin II type 1 receptor blockers have been shown to upregulate ACE2 in experimental animals, the evidence is not always consistent and differs among the diverse angiotensin II type 1 receptor blockers and differing organs. Moreover, there are no data to support the notion that ACE inhibitor or angiotensin II type 1 receptor blocker administration facilitates coronavirus entry by increasing ACE2 expression in either animals or humans. Indeed, animal data support elevated ACE2 expression as conferring potential protective pulmonary and cardiovascular effects. In summary, based on the currently available evidence, treatment with renin-angiotensin system blockers should not be discontinued because of concerns with coronavirus infection.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/tratamento farmacológico , Receptores Virais/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Humanos , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia , Receptores Virais/antagonistas & inibidores
10.
Vasc Health Risk Manag ; 16: 41-51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021227

RESUMO

This review aims to elucidate the optimal dosing of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in the heart failure (HF) treatment paradigm through examination of the trial population characteristics and the mortality benefit observed in the Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; NCT01035255) trial. Considerations regarding the initiation and titration of sacubitril/valsartan, a first-in-class ARNI, will also be addressed. The approval of sacubitril/valsartan heralded the first novel pharmacological class in over a decade for the treatment of heart failure with reduced ejection fraction (HFrEF). The PARADIGM-HF trial showed that treatment with valsartan/valsartan reduced the risk of first occurrence of either cardiovascular death or HF-related hospitalization (composite primary endpoint) by 20% compared with enalapril in patients with HFrEF. The incremental benefits of treatment with valsartan/valsartan over enalapril demonstrated in the PARADIGM-HF trial led to strong recommendations for its use over ACEIs or angiotensin receptor blockers to further reduce morbidity and mortality in the 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America updates to the guidelines for the management of HF. Although the optimal timing for the initiation of valsartan/valsartan has yet to be determined, its early use is likely to have a positive impact on patient outcomes.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Tetrazóis/uso terapêutico , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Ensaios Clínicos como Assunto , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/efeitos adversos , Fatores de Risco , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
13.
Lancet ; 394(10216): 2263-2270, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31836196

RESUMO

BACKGROUND: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. METHODS: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. FINDINGS: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking ß blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. INTERPRETATION: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. FUNDING: British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Aorta/diagnóstico por imagem , Irbesartana/administração & dosagem , Síndrome de Marfan/tratamento farmacológico , Adolescente , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Aorta/efeitos dos fármacos , Criança , Método Duplo-Cego , Esquema de Medicação , Ecocardiografia , Feminino , Humanos , Irbesartana/farmacologia , Masculino , Síndrome de Marfan/diagnóstico por imagem , Resultado do Tratamento , Reino Unido , Adulto Jovem
14.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 38-48, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31836883

RESUMO

Obstructive sleep apnea is characterized by chronic intermittent hypoxia (CIH), which is a risk factor for renal peritubular capillary (PTC) loss, and angiotensin II receptor blockers can alleviate PTC loss. However, the mechanism by which losartan (an angiotensin II receptor blocker) reduces CIH-induced PTC loss and attenuates kidney damage is still unknown. Thus, in this study, we examined the protective effects of losartan against CIH-induced PTC loss and explored the underlying mechanisms in rat CIH model. The immunohistochemical staining of CD34 and morphological examination showed that CIH reduced PTC density and damaged tubular epithelial cells. Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR, and western blot analysis results revealed that CIH increased the expression of hypoxia inducible factor-1α (HIF-1α), angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R), pro-angiogenesis factor vascular endothelial growth factor (VEGF), and anti-angiogenesis factor thrombospondin-1 (TSP-1) in the renal cortex of rats. CIH may up-regulate VEGF expression and simultaneously increase TSP-1 production. By histopathological, immunohistochemistry, ELISA, RT-qPCR, and western blot analysis, we found that the expressions of renal renin-angiotensin system (RAS), HIF-1α, VEGF, and TSP-1 were decreased, and PTC loss and tubular epithelial cell injury were attenuated with losartan treatment. Losartan ameliorated CIH-induced PTC loss by modulating renal RAS to improve the crosstalk between endothelial cells and tubular epithelial cells and subsequently regulate the balance of angiogenesis factors. Our study provided novel insights into the mechanisms of CIH-induced kidney damage and indicated that losartan could be a potential therapeutic agent for renal protection by alleviating CIH-induced PTC loss.


Assuntos
Indutores da Angiogênese/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Capilares/patologia , Hipóxia/complicações , Losartan/farmacologia , Substâncias Protetoras/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/sangue , Animais , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Células Epiteliais/efeitos dos fármacos , Hipóxia/etiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Córtex Renal/irrigação sanguínea , Córtex Renal/metabolismo , Masculino , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Apneia Obstrutiva do Sono/complicações , Trombospondina 1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Am J Respir Crit Care Med ; 201(3): 313-324, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613648

RESUMO

Rationale: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca2+-activated and voltage-dependent K+ (BK) channels, critical for mucociliary function in the absence of CFTR (CF transmembrane conductance regulator).Objectives: To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CF-like airway disease.Methods: Losartan's antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested in vitro using primary, fully redifferentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacologic sheep model of CF-like, inflammation-associated mucociliary dysfunction.Measurements and Main Results: Nasal scrapings from patients with CF showed that neutrophilic inflammation correlated with reduced expression of LRRC26 (leucine rich repeat containing 26), the γ subunit mandatory for BK function in the airways. TGF-ß1 (transforming growth factor ß1), downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression), ciliary beat frequency and airway surface liquid volume improved, and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic, CF-like sheep model, ewes inhaled CFTRinh172 and neutrophil elastase for 3 days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration, and increased TGF-ß1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-ß1.Conclusions: Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Fibrose Cística/fisiopatologia , Losartan/farmacologia , Depuração Mucociliar/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Brônquios/citologia , Células Cultivadas , Fibrose Cística/tratamento farmacológico , Modelos Animais de Doenças , Células Epiteliais , Feminino , Humanos , Inflamação/fisiopatologia , Losartan/uso terapêutico , Ovinos
17.
Int J Cardiovasc Imaging ; 36(2): 271-278, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31583499

RESUMO

Increased vascular stiffness is known to be an independent predictor of mortality in patients with heart failure with reduced ejection fraction (HFrEF). The effects of sacubitril-valsartan on vascular structure and function have not been systematically studied in this patient population. We hypothesized that aortic distensibility (AD) and fractional area change (AFAC), as assessed by 2D transthoracic echocardiography (TTE), would improve over time in HFrEF patients on sacubitril-valsartan therapy, due to the vasodilatory properties of the medication. We prospectively studied 30 patients with HFrEF (25 < EF < 40%) on optimal guideline-directed medical therapy who were subsequently started on sacubitril-valsartan. Patients underwent serial 2D TTE imaging at baseline, 3 and 6 months following therapy initiation. Ascending aortic diameters were measured 3 cm above the aortic valve in the parasternal long-axis view and used to calculate AD and AFAC, two markers of vascular compliance. For reference, we also measured AD and AFAC in 30 healthy, age and gender-matched controls at a single time point. Normal controls had significantly higher values of AD and AFAC than HFrEF patients at baseline (AD: 4.0 ± 1.1 vs. 2.2 ± 0.9 cm2dyne-110-3, p < 0.0001 and AFAC: 18.8 ± 3.7% vs. 10.3 ± 4.3%, p < 0.0001). In HFrEF patients on sacubitril-valsartan, both indices of aortic compliance progressively improved towards normal from baseline to 6 months: AD from 2.2 ± 0.9 to 3.6 ± 1.5 cm2dyne-110-3 (p < 0.0001) and AFAC from 10.3 ± 4.3 to 13.7 ± 4.1% (p < 0.0001). In conclusion, AD and AFAC are decreased in patients with HFrEF and gradually improve with sacubitril-valsartan treatment. The echocardiographic markers used in this study may become a useful tool to assess the effectiveness of sacubitril-valsartan therapy in HFrEF patients.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Ecocardiografia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Tetrazóis/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto , Idoso , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Estudos de Casos e Controles , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Valor Preditivo dos Testes , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
18.
Int Heart J ; 61(1): 1-6, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31875616

RESUMO

Chronic heart failure (CHF) seriously affects the quality of patients' lives. Sacrubitril/valsartan is a combination angiotensin receptor-neprilysin inhibitor, a new therapeutic drugs to treat CHF.This study aims to observe the impact of sacrubitril/valsartan on clinical treatment and high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-brain natriuretic peptide (NT-ProBNP) serum levels, the improvement of the left atrial diameter (LAD) and left ventricular end diastolic dimension (LVEDD), and the left ventricular ejection fraction (LVEF) in patients with CHF.120 patients were randomly divided into a sacrubitil/valsartan group and a valsantan group, with 60 cases in each. Patients in the sacrubitil/valsartan group were administered sacrubitril/valsartan; while in the valsantan group, they were administered valsartan. The clinical effects, adverse reactions, and rehospitalization were observed eight weeks later, and hs-cTnT and NT-ProBNP serum levels and LAD, LVEDD, and LVEF were assayed.There were 53 cases of positive effect in the sacrubitil/valsartan group and 42 in the valsartan group (P < 0.05). Eight participants demonstrated adverse reactions in the sacrubitil/valsartan group, while 17 in the control group (P < 0.05). Hs-cTnT and NT-ProBNP serum levels, the measurements of LAD, LVEDD, and LVEF in the sacrubitil/valsartan group before the treatments were (24.47 ± 7.54) pg/mL, (10,356.94 ± 5,447.68) pg/mL, (49.41 ± 5.22) mm, (68.06 ± 6.20) mm and (31.12 ±6.65) %; in the valsartan group were (29.752 ± 10.03) pg/mL, (9,518.17 ± 5,905.17) pg/mL, (49.65 ± 4.91) mm, (67.06 ± 3.97) mm, and (30.41 ± 6.11) % (P > 0.05), while in the sacrubitil/valsartan group, the values decreased after the treatments to (17.92 ± 4.74) pg/mL, (3,881.59 ± 2,087.79) pg/mL, (42.18 ± 4.87) mm, (60.35 ± 7.12) mm and (45.35 ± 4.49) %; in the valsartan group to (25.81 ± 7.36) pg/mL, (6,278.35 ± 2,643.11) pg/mL, (46.53 ± 4.80) mm, (64.51 ± 4.34) mm, and (36.47 ± 5.21) % (P < 0.05). There were significant differences within the same group, before and after treatments (P < 0.05).Sacrubitril/valsartan treatment of patients with CHF improves their symptoms and is deserving of clinical application. This is also evident from significantly improved levels of serum hs-cTnT and NT-ProBNP and the left ventricular function.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Troponina T/sangue , Valsartana/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Biomarcadores/sangue , Doença Crônica , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Valsartana/farmacologia
19.
J Ethnopharmacol ; 248: 112306, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31626909

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Leonurus japonicus Houtt. has a long history in the treatment of cardiovascular diseases. Stachydrine hydrochloride, the main bioactive ingredient extracted from Leonurus japonicus Houtt., has been shown to have cardioprotective effects. However, the underlying mechanisms of stachydrine hydrochloride haven't been comprehensively studied so far. AIM OF THE STUDY: The aim of this study was to investigate the protective role of stachydrine hydrochloride in heart failure and elucidate its possible mechanisms of action. MATERIALS AND METHODS: In vivo, transverse aorta constriction was carried out in C57BL/6J mice, and thereafter, 7.2 mg/kg telmisartan (a selective AT1R antagonist as positive control) and 12 mg/kg stachydrine hydrochloride was administered daily intragastrically for 4 weeks. Cardiac function was evaluated by assessing morphological changes as well as echocardiographic and haemodynamic parameters. In vitro, neonatal rat cardiomyocytes or adult mice cardiomyocytes were treated with stachydrine hydrochloride and challenged with phenylephrine (α-AR agonist). Ventricular myocytes were isolated from the hearts of C57BL/6J mice by Langendorff crossflow perfusion system. Intracellular calcium was measured by an ion imaging system. The length and movement of sarcomere were traced to evaluate the systolic and diastolic function of single myocardial cells. RESULTS: Stachydrine hydrochloride improved the cardiac function and calcium transient amplitudes, and inhibited the SR leakage and the amount of sparks in cardiac myocytes isolated from TAC mice. We also demonstrated that stachydrine hydrochloride could ameliorated phenylephrine-induced enhance in sarcomere contraction, calcium transients and calcium sparks. Moreover, our data shown that stachydrine hydrochloride blocked the hyper-phosphorylation of CaMKII, RyR2, PLN, and prevented the disassociation of FKBP12.6 from RyR2. CONCLUSION: Our results suggest that stachydrine hydrochloride exerts beneficial therapeutic effects against heart failure. These cardioprotective effects may be associated with the regulation of calcium handling by stachydrine hydrochloride through inhibiting the hyper-phosphorylation of CaMKII.


Assuntos
Aorta/fisiopatologia , Pressão Arterial , Sinalização do Cálcio/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Insuficiência Cardíaca/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Prolina/análogos & derivados , Função Ventricular Esquerda/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/cirurgia , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Fosforilação , Prolina/farmacologia , Ratos , Ratos Sprague-Dawley , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Sarcômeros/efeitos dos fármacos , Sarcômeros/metabolismo , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Telmisartan/farmacologia
20.
Am J Physiol Heart Circ Physiol ; 318(2): H461-H469, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31886721

RESUMO

Arteries and arterioles constrict in response to intraluminal pressure to generate myogenic tone, but the molecular nature of the vascular force-sensing mechanism is not fully characterized. Here, we investigated the role of angiotensin II type 1 receptors (AT1Rs) on vascular smooth muscle cells in the development of myogenic tone in cerebral parenchymal arterioles from mice. We found that pretreatment with the AT1R blocker losartan inhibited the development of myogenic tone in these vessels but did not alter the luminal diameter of arterioles with preestablished tone. Rodents express two AT1R isotypes: AT1Ra and AT1Rb. We previously demonstrated that AT1Rb is expressed at much higher levels compared with AT1Ra in cerebral pial arteries and is required for myogenic contractility in these vessels, whereas AT1Ra is unnecessary for this function. Here, we found that AT1Ra and AT1Rb are expressed at similar levels in parenchymal arterioles and that genetic knockout of AT1Ra blunted the ability of these vessels to generate myogenic tone. We also found that AT1Rb and total AT1R expression levels are much lower in parenchymal arterioles compared with pial arteries and that parenchymal arterioles are less sensitive to the vasoconstrictive effects of the endogenous AT1R ligand angiotensin II (ANG II). We conclude that 1) AT1Rs are critical for the initiation, but not the maintenance, of myogenic tone in parenchymal arterioles, and 2) lower levels of AT1Rb and total AT1R in parenchymal arterioles compared with pial arteries result in differences in myogenic and ANG II-induced vasoconstriction between these vascular segments.NEW & NOTEWORTHY Myogenic tone is critical for appropriate regulation of cerebral blood flow, but the mechanisms used by vascular smooth muscle cells to detect changes in intraluminal pressure are not fully characterized. Here, we demonstrate angiotensin II receptor type 1 (AT1R) is indispensable to initiation, but not maintenance, of myogenic tone in cerebral parenchymal arterioles. Furthermore, we demonstrate differences in AT1R expression levels lead to critical differences in contractile regulation between parenchymal arterioles and cerebral pial arteries.


Assuntos
Circulação Cerebrovascular/fisiologia , Microvasos/metabolismo , Receptor Tipo 1 de Angiotensina/biossíntese , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Arteríolas/metabolismo , Regulação da Expressão Gênica , Losartan/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Receptor Tipo 1 de Angiotensina/genética
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