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1.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445301

RESUMO

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-ß and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.


Assuntos
Aminobutiratos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência da Valva Mitral/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Compostos de Bifenilo/farmacologia , Células Cultivadas , Combinação de Medicamentos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Valva Mitral/efeitos dos fármacos , Valva Mitral/patologia , Valva Mitral/fisiologia , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/fisiopatologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Neprilisina/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Valsartana/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
2.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443591

RESUMO

The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial benefits of resveratrol with sacubitril/valsartan alongside an active comparator valsartan in MI-induced male Sprague Dawley rats. MI-induced and sham-operated animals received vehicle, resveratrol, sacubitril/valsartan, valsartan alone or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint to assess cardiac structure and function. Cardiac oxidative stress, inflammation, fibrosis, brain natriuretic peptide (BNP), creatinine and neutrophil gelatinase associated lipocalin were measured. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented left ventricular (LV) dilatation and improved LV ejection fraction in MI-induced rats. All treatments also significantly reduced myocardial tissue oxidative stress, inflammation and fibrosis, as well as BNP. Treatment with the combination of sacubitril/valsartan and resveratrol did not show additive effects. In conclusion, resveratrol, sacubitril/valsartan, and valsartan significantly prevented cardiac remodeling and dysfunction in MI-induced rats. The reduction in cardiac remodeling and dysfunction in MI-induced rats was mediated by a reduction in cardiac oxidative stress, inflammation and fibrosis.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Resveratrol/farmacologia , Valsartana/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Combinação de Medicamentos , Interações Medicamentosas , Fibrose , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacos
3.
J Biochem Mol Toxicol ; 35(9): e22842, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34273911

RESUMO

Doxorubicin (DOX) treatment has been associated with cardiotoxicity. Therefore, it is crucial to search for a therapeutic that can effectively mitigate DOX-induced cardiotoxicity. This study was conducted to investigate the protective effects of valsartan (VAL) against DOX-induced cardiotoxicity. Sprague-Dawley rats were divided into four treatment groups: Group I: Control, Group II: VAL (30 mg/kg, ip), Group III: DOX (15 mg/kg, ip), and Group IV: VAL + DOX (30 + 15 mg/kg, ip). All groups were treated every other day for 14 days. Blood was isolated for biochemical and metabolomics studies, and sections of the heart were also analyzed for histopathological and immunohistochemical alterations to detect changes in P53, BAX, BCL-2, and P62 expression. The combination of VAL + DOX resulted in a marked decrease in cardiac biomarker enzymes (aminotransferase and creatine phosphokinase) compared to DOX monotherapy. In addition, the histopathological examination of the VAL + DOX combination revealed a low percentage of fibrosis and inflammation. Immunohistochemical expression of p53 and BAX was significantly reduced, whereas BCL-2 expression was significantly increased in the VAL + DOX treatment group compared to DOX monotherapy. Also, the combination of VAL + DOX reverses the negative effect of DOX on nuclear p62 expression. Analysis of serum metabolites showed that DOX monotherapy reduced the number of several amino acids, whereas the combination of VAL + DOX restored these metabolic pathways. This study revealed the potential cardioprotective effect of VAL, which may provide novel and promising approaches for managing cardiotoxicity induced by DOX.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxicidade , Doxorrubicina/administração & dosagem , Metabolômica , Valsartana/farmacologia , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiotoxicidade/prevenção & controle , Doxorrubicina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
4.
Life Sci ; 280: 119692, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102189

RESUMO

AIMS: This study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome. MATERIALS AND METHODS: Mice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h. KEY FINDINGS: Compared to controls, abdominal aortic ligation significantly increased plasma NT-proBNP and urine neutrophil gelatinase-associated lipocalin (NGAL), which were associated with reduced renal length and velocity time integral on ultrasonography. Histology revealed wrinkling of the glomerular capillary wall and sclerosis of the glomerulus, dilatation of the Bowman's capsule, accompanied by diffuse renal tubular atrophy and fibrosis, accompanied by lower kidney index and higher percentage area of fibrosis. Increases in NGAL and decreased ANP protein and mRNA expression levels were observed. These abnormalities were significantly prevented by LCZ696 and to a lesser extent by valsartan. Cellular experiments demonstrated a central role of Ang II/transforming growth factor-ß1/Smad2/3/connective tissue growth factor-dependent signaling leading to type IV collagen deposition. This upregulation was reversed by LCZ696 in a greater extent than valsartan treatment alone, accompanied by a significant improvement in NGAL. SIGNIFICANCE: LCZ696 can reduce kidney injury to a level beyond valsartan therapy alone in mice with cardiorenal syndrome, which can be speculated by effects on epithelial-mesenchymal transition and fibrosis through downregulating the TGF-ß1/Smad2/3/CTGF/Collagen IV pathway.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Síndrome Cardiorrenal/tratamento farmacológico , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Compostos de Bifenilo/farmacologia , Síndrome Cardiorrenal/patologia , Linhagem Celular , Combinação de Medicamentos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Ratos , Valsartana/farmacologia
5.
Aging (Albany NY) ; 13(7): 9582-9591, 2021 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-33839697

RESUMO

Lipopolysaccharide (LPS)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. LCZ696, the dual-acting angiotensin receptor blocker, and neprilysin inhibitor has been used for the treatment of heart failure with reduced ejection fraction. Recent work suggests that LCZ696 therapy might have an anti-inflammatory effect in cardiovascular tissue. In the current study, we show that LCZ696 attenuates LPS-induced oxidative stress by reducing the production of intracellular reactive oxygen species (ROS) and the measurements of malonyl dialdehyde (MDA) level in human umbilical vascular endothelial cells (HUVECs). LCZ696 inhibits LPS-induced expressions and secretions of the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-1α (IL-1α), and tumor necrosis factor ß (TNF-ß) as well as the chemokines, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-X-C motif) ligand 1 protein (CXCL1). Additionally, we found that LCZ696 reduces LPS-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin and the attachment of U937 monocytes to HUVECs. Mechanistically, LCZ696 prevents LPS-induced activation of the TLR4/Myd88 pathway and nuclear translocation of nuclear factor kappa-B (NF-κB) p65 factor. Based on these findings, we conclude that LCZ696 is capable of ameliorating LPS-induced endothelial dysfunction via anti-inflammatory properties.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Valsartana/farmacologia , Citocinas/metabolismo , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Malondialdeído/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
6.
Am J Physiol Renal Physiol ; 320(6): F1133-F1151, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33870733

RESUMO

Although renin-angiotensin blockade has shown beneficial outcomes in patients with diabetes, renal injury progresses in most of these patients. Therefore, there remains a need for new therapeutic targets in diabetic kidney disease. Enhancement of vasoactive peptides, such as natriuretic peptides, via neprilysin inhibition, has been a new approach. A first-in-class drug, sacubitril/valsartan (Sac/Val), a combination of the angiotensin II receptor blocker Val and neprilysin inhibitor prodrug Sac, has been shown to be more effective than renin-angiotensin blockade alone in the treatment of heart failure with reduced ejection fraction. In this study, we tested the effects of Sac/Val in diabetic kidney disease. We administered Sac/Val or Val to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3 mo of treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Val shared a similar improvement but to a lesser degree in some parameters compared with Sac/Val. Sac/Val but not Val decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on antioxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self-DNA-activated cGMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, which was activated in diabetic kidneys and prevented by Sac/Val or Val treatment. The present data suggest that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease, and its effectiveness could be better than Val alone.NEW & NOTEWORTHY The first-in-class drug sacubitril/valsartan, a combination of the angiotensin II receptor blocker valsartan and neprilysin inhibitor sacubitril, was tested for its effects in diabetic kidney disease using db/db mice and KKAy mice. We found that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease. We further revealed a new mechanism to cause inflammation, self-DNA-activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by sacubitril/valsartan or valsartan treatment.


Assuntos
Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Valsartana/farmacologia , Albuminúria/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Estresse Oxidativo , Valsartana/administração & dosagem
7.
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
8.
Oxid Med Cell Longev ; 2021: 5575545, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763167

RESUMO

Valsartan belongs to angiotensin II type 1 (AT1) receptor blockers (ARB) used in cardiovascular diseases like heart failure and hypertension. Except for its AT1-antagonism, another mechanism of drug action has been suggested in recent research. One of the supposed actions refers to the positive impact on redox balance and reducing protein glycation. Our study is aimed at assessing the antiglycooxidant properties of valsartan in an in vitro model of oxidized bovine serum albumin (BSA). Glucose, fructose, ribose, glyoxal (GO), methylglyoxal (MGO), and chloramine T were used as glycation or oxidation agents. Protein oxidation products (total thiols, protein carbonyls (PC), and advanced oxidation protein products (AOPP)), glycooxidation products (tryptophan, kynurenine, N-formylkynurenine, and dityrosine), glycation products (amyloid-ß structure, fructosamine, and advanced glycation end products (AGE)), and albumin antioxidant activity (total antioxidant capacity (TAC), DPPH assay, and ferric reducing antioxidant power (FRAP)) were measured in each sample. In the presence of valsartan, concentrations of protein oxidation and glycation products were significantly lower comparing to control. Moreover, albumin antioxidant activity was significantly higher in those samples. The drug's action was comparable to renowned antiglycation agents and antioxidants, e.g., aminoguanidine, metformin, Trolox, N-acetylcysteine, or alpha-lipoic acid. The conducted experiment proves that valsartan can ameliorate protein glycation and oxidation in vitro in various conditions. Available animal and clinical studies uphold this statement, but further research is needed to confirm it, as reduction of protein oxidation and glycation may prevent cardiovascular disease development.


Assuntos
Antioxidantes/farmacologia , Valsartana/farmacologia , Acetilcisteína/farmacologia , Animais , Captopril/farmacologia , Cloraminas , Cromanos/farmacologia , Frutose , Glucose , Glicosilação , Humanos , Metformina/farmacologia , Oxirredução , Aldeído Pirúvico , Soroalbumina Bovina/metabolismo , Ácido Tióctico/farmacologia , Compostos de Tosil
9.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786624

RESUMO

The therapeutic effect of sacubitril/valsartan (S/V) on heart failure has been confirmed, while its role in atherosclerosis remains largely unexplored. The present study aimed to investigate the effects of S/V on the expression of metastasis­associated lung adenocarcinoma transcript 1 (MALAT1), inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) induced by oxidized low­density lipoprotein (ox­LDL) and to elucidate its possible mechanism. Cell Counting Kit­8 assay was used to detect cell viability. Reverse transcription­quantitative PCR was performed to detect the MALAT1 expression. ELISA was performed to detect the levels of IL­1ß, IL­6 and TNF­α. Flow cytometry was conducted to detect the apoptotic rate of cells. A nitric oxide (NO) detection kit was used to determine the concentration of NO. Western blotting analysis was performed to determine the levels of intercellular cell adhesion molecule (ICAM)­1, vascular cell adhesion molecule (VCAM)­1, endothelin­1, caspase­3, Bax, Bcl­2, Toll­like receptor 4 (TLR4), p65 and p­p65. Compared with the ox­LDL group, S/V treatment significantly increased the cell viability, NO concentration and Bcl­2 expression, decreased the levels of IL­1ß, IL­6 and TNF­α and reduced the expressions of MALAT1, ICAM­1, VCAM­1, cleaved­caspase­3, Bax, TLR4 and p­p65. Overall, the findings suggested that S/V could downregulate the expression of MALAT1, inhibit inflammation and apoptosis and improve endothelial function in ox­LDL­induced HUVECs via inactivating the TLR4/NF­κB signaling pathway. Therefore, S/V might be utilized as a promising therapeutic strategy for the prevention and treatment of atherosclerosis.


Assuntos
Aminobutiratos/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , RNA Longo não Codificante/genética , Tetrazóis/farmacologia , Valsartana/farmacologia , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
10.
Blood Press Monit ; 26(4): 251-256, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33734121

RESUMO

OBJECTIVE: In a substudy of a randomized controlled trial, we investigated the effects of the valsartan/amlodipine single-pill combination and nifedipine gastrointestinal therapeutic system (GITS) monotherapy on brachial pulse pressure (bPP) and radial augmentation index (rAI) in patients with previously uncontrolled hypertension. METHODS: We performed measurements of clinic blood pressure (BP) and pulse rate and rAI (n = 63) and ambulatory BP monitoring (n = 42) at baseline and 12-week of follow-up. Analysis of covariance was performed to calculate the least square mean change from baseline and between-group differences [95% confidence interval (CI)]. Correlation analysis was performed to study the interrelationship between the changes in bPP and rAI and in pulse rate. RESULTS: After 12-week treatment, clinic and ambulatory SBP/DBP and pulse rate were not differently changed between the valsartan/amlodipine (n = 29) and nifedipine GITS groups (n = 34, P ≥ 0.06) except daytime SBP (P = 0.01). The reductions in 24-h and daytime ambulatory bPP were significantly greater in the former than the latter group (P ≤ 0.04). rAI increased slightly by 3.5% (P = 0.20) and 5.2% (P = 0.06) in the valsartan/amlodipine and nifedipine groups, respectively, with a between-group difference of -1.7% (95% CI -9.6 to 6.1%, P = 0.66). In the two groups combined, the changes in clinic and ambulatory bPP were not or weakly associated with that in clinic or ambulatory pulse rate (r = -0.14 to 0.36, P = 0.02-0.95), while the changes in rAI were more strongly or significantly associated with that in clinic or ambulatory pulse rate (r = -0.39 to -0.23, P = 0.02-0.16). CONCLUSIONS: Antihypertensive drug-induced changes in rAI but not bPP were dependent on pulse rate.


Assuntos
Hipertensão , Nifedipino , Anlodipino , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Humanos , Hipertensão/tratamento farmacológico , Nifedipino/farmacologia , Tetrazóis , Resultado do Tratamento , Valsartana/farmacologia
11.
Clin Sci (Lond) ; 135(2): 259-274, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33404046

RESUMO

Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6-8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97 ± 0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation.


Assuntos
Angiotensina II/metabolismo , Hipertensão/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensinogênio/sangue , Animais , Encéfalo/metabolismo , Tronco Encefálico/metabolismo , Acetato de Desoxicorticosterona/administração & dosagem , Hipertensão/induzido quimicamente , Masculino , Ratos Sprague-Dawley , Renina/sangue , Cloreto de Sódio na Dieta/administração & dosagem , Valsartana/farmacologia
12.
Clin Hemorheol Microcirc ; 77(4): 425-433, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33386797

RESUMO

OBJECTIVE: The aim of the present study was to observe the effect of sacubitril valsartan on cardiac function and vascular endothelial function in patients with chronic heart failure with reduced ejection fraction (HFrEF). METHODS: A total of 80 patients with HFrEF were randomly divided into an observation group and a control group, with 40 patients in each group. Sacubitril valsartan was added to the conventional treatment in the observation group, and perindopril was added to the conventional treatment in the control group. Both groups were treated continuously for 12 weeks. The left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), flow-mediated vasodilatory function (FMD) of the brachial artery, and levels of plasma Ang II, endothelin 1 (ET-1), and calcitonin gene-related peptide (CGRP), together with the serum nitric oxide (NO) and NO synthase (NOS) were compared before and after treatment in the groups. RESULTS: Before the treatment, the levels of LVEF, LVEDD, FMD, Ang II, ET-1, CGRP, NO, and NOS in the observation group were not significantly different from those in the control group (P > 0.05). However, the levels of LVEF, FMD, CGRP, NO, and NOS in both groups were significantly higher after the treatment than those before the treatment (P < 0.05) and significantly higher in the observation group than those in the control group. The difference was statistically significant (P < 0.05). Meanwhile, the levels of LVEDD, Ang II, and ET-1 in both groups decreased significantly after the treatment (P < 0.05) and were significantly lower in the observation group than those in the control group. The difference was statistically significant (P < 0.05). CONCLUSION: Sacubitril valsartan might improve endothelial function while increasing cardiac function in HFrEF patients.


Assuntos
Aminobutiratos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Valsartana/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Aminobutiratos/farmacologia , Compostos de Bifenilo/farmacologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Valsartana/farmacologia
13.
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 , Comprometimento Cognitivo Relacionado à Quimioterapia/metabolismo , Combinação de Medicamentos , Humanos , Valsartana/efeitos adversos , Valsartana/farmacologia
14.
J Clin Hypertens (Greenwich) ; 23(2): 392-397, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33455076

RESUMO

We examined the effects of a fixed-dose single-pill combination of cilnidipine (10 mg), an L-/N-type calcium channel blocker, and valsartan (80 mg) (SPC of Cil/Val) on the day-by-day variability of morning home systolic blood pressure (MHSBP) in 616 patients with treated hypertension for 12 months as a sub-analysis of the HOPE-Combi survey, multicentral, post-marketing, and prospective observational survey. The SPC of Cil/Val was administrated once a day in the morning. The SPC of Cil/Val decreased the standard deviation (SD, from 6.3 ± 4.8 to 5.1 ± 3.8 mmHg, p < .01), coefficient of variation (from 4.3 ± 3.2 to 3.8 ± 2.9%, p < .05), average real variability (ARV, from 7.9 ± 6.6 to 6.3 ± 5.1 mmHg, p < .01), and the difference between maximum and minimum (MMD, from 11.9 ± 9.2 to 9.7 ± 7.2 mmHg, p < .01) of MHSBP. The variability of MHSBP increased with age; however, this was not increased in patients ≥70 years at the baseline. In elderly patients (≥70 years, N = 283), the SPC of Cil/Val decreased the SD (from 6.9 ± 5.6 to 5.6 ± 4.4 mmHg, p < .01), ARV (from 8.6 ± 7.7 to 6.9 ± 5.7 mmHg, p < .05), and MMD (from 13.2 ± 10.7 to 10.7 ± 8.3 mmHg, p < .01) of MHSBP at 12 months; the reduction in these MHSBP variability parameters was comparable to that in adults <70 years. These results suggest that the SPC of Cil/Val is effective in reducing day-by-day variability of MHSBP in elderly patients.


Assuntos
Bloqueadores dos Canais de Cálcio , Hipertensão , Adulto , Idoso , Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/farmacologia , Canais de Cálcio Tipo L/uso terapêutico , Di-Hidropiridinas , Humanos , Hipertensão/tratamento farmacológico , Tetrazóis/farmacologia , Valsartana/farmacologia
15.
J Clin Hypertens (Greenwich) ; 23(3): 687-691, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33497537

RESUMO

We tested our hypothesis that, in hypertensive patients with higher nocturnal home systolic blood pressure (HSBP) at baseline, a valsartan/cilnidipine (80/10 mg) combination would reduce nocturnal HSBP more markedly than a valsartan/hydrochlorothiazide (80/12.5 mg) combination. Patients measured their nocturnal HSBP over three nights prior to study randomization and at the end of treatment. Sixty-three and 66 patients comprised the valsartan/cilnidipine and valsartan/hydrochlorothiazide groups; their respective baseline nocturnal HSBP values were 124.3 ± 15.6 and 125.8 ± 15.2 mm Hg (P = .597). Nocturnal HSBPs were significantly reduced from baseline in both groups. Although the valsartan/hydrochlorothiazide group exhibited a significantly greater reduction in nocturnal HSBP compared to the valsartan/cilnidipine group (-5.0 vs. -10.0 mm Hg, P = .035), interaction between the treatment groups and the baseline nocturnal HSBP levels for the changes in nocturnal HSBP after the treatment periods was significant (P = .047). The BP-lowering effect of valsartan/cilnidipine was more dependent on baseline nocturnal HSBP than that of valsartan/hydrochlorothiazide.


Assuntos
Hidroclorotiazida , Hipertensão , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Di-Hidropiridinas , Quimioterapia Combinada , Humanos , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Tetrazóis/farmacologia , Resultado do Tratamento , Valina/farmacologia , Valina/uso terapêutico , Valsartana/farmacologia
16.
Drug Dev Ind Pharm ; 47(2): 302-307, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33492999

RESUMO

Amorphization is a well-established strategy to enhance the dissolution properties of poorly water-soluble drugs. However, the amorphous state is inherently unstable toward recrystallization. Coamorphous systems of a drug and a small-molecule excipient or of two complementary drugs often show an enhanced stability. Diabetes and hypertension are frequently coexistent. In this paper a study on the coamorphization of the poorly water-soluble antidiabetic drug gliclazide (glz) and the antihypertensive drug valsartan (val) is reported. Amorphous glz recrystallized after 1 d under ambient conditions, whereas coamorphous glz-val containing glz and val in a 1:1 or 1:2 molar ratio was stable for at least four months at 20 °C and 56% relative humidity. The dissolution rate of glz increased in the order crystalline glz < glz-val_1:1 < glz-val_1:2. Furthermore, ternary coamorphous systems of glz, val and an excipient were prepared; glz-val_1:1_PVP, glz-val_1:1_HPC, glz-val_1:1_ALM, glz-val_1:1_MCC (PVP = polyvinylpyrrolidone, HPC = hydroxypropyl cellulose, ALM = α-lactose monohydrate, MCC = microcrystalline cellulose). MCC and HPC did not affect the stability of the coamorphous system, while ALM promoted the recrystallization of glz in glz-val_1:1_ALM during storage and freshly prepared glz-val_1:1_PVP contained small amounts of crystalline glz. Glz-val_1:1_MCC showed enhanced dissolution properties compared to crystalline glz and glz-val_1:1 and is a viable fixed-dose formulation.


Assuntos
Gliclazida , Valsartana/química , Estabilidade de Medicamentos , Excipientes , Solubilidade , Valsartana/farmacologia
17.
Ann Pharmacother ; 55(4): 480-495, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32741197

RESUMO

OBJECTIVE: Discuss the literature and describe strategies to overcome barriers of inpatient initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF). DATA SOURCES: A PubMed, EMBASE, and Google Scholar literature search (January 2014 to June 2020) limited to English language articles was conducted with the following terms: sacubitril/valsartan, initiation, inpatient, hospitalized, B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), diuretic, cost, and cost-effectiveness. STUDY SELECTION AND DATA EXTRACTION: Included articles described inpatient initiation of sacubitril/valsartan or described its impact on BNP, NT-proBNP, diuretic dosing, or cost of care. DATA SYNTHESIS: A total of 20 studies were identified based on included search terms. CONCLUSIONS: Sacubitril/valsartan should be considered for hemodynamically stable patients with HFrEF (New York Heart Association class II or III), potassium <5.2 mmol/L, without a history of angioedema, and after a 36-hour washout from angiotensin-converting enzyme (ACE) inhibitor or aliskiren, if applicable. An appropriate dose can be determined based on the patient's previous ACE inhibitor or angiotensin receptor blocker dose and/or blood pressure along with patient-specific factors. To overcome barriers of use, the following are recommended: NT-proBNP or BNP with establishment of a new baseline 1 month after initiation may be used for prognosis or diagnosis; careful monitoring of diuretic requirements; utilization of multiple strategies to overcome cost barriers; and use of interdisciplinary care.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização/tendências , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Ensaios Clínicos como Assunto/métodos , Combinação de Medicamentos , Insuficiência Cardíaca/sangue , Humanos , Pacientes Internados , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Valsartana/farmacologia
19.
Mol Med Rep ; 22(5): 4151-4162, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33000246

RESUMO

Clinical application of doxorubicin (DOX) is hampered by its potential cardiotoxicity, however angiotensin receptor blockers could attenuate DOX­induced cardiomyopathy. The present study tested the hypothesis that simultaneous administration of valsartan (Val) with DOX could prevent DOX­induced myocardial injury by modulating myocardial NAD(P)H oxidase (NOX) expression in rats. Eight­week­old male Sprague­Dawley rats were randomly divided into control (CON), DOX, and DOX+Val groups. After 10 weeks, surviving rats underwent echocardiography examination, myocardial mRNA and protein expression detection of NOX1, NOX2 and NOX4. H9C2 cells were used to perform in vitro experiments, reactive oxygen species (ROS) production and apoptosis were observed under the conditions of down­ or upregulation of NOX2 and NOX4 in DOX­ and DOX+Val­treated H9C2 cells. Cardiac function was significantly improved, pathological lesion and collagen volume fraction were significantly reduced in the DOX+Val group compared with the DOX group (all P<0.05). Myocardial protein and mRNA expression of NOX2 and NOX4 was significantly downregulated in DOX+Val group compared with in the DOX group (all P<0.05). In vitro, ROS production and apoptosis in DOX­treated H9C2 cells was significantly reduced by NOX2­small interfering (si)RNA and NOX4­siRNA, and significantly increased by overexpressing NOX2 and NOX4. To conclude, Val applied simultaneously with DOX could prevent DOX­induced myocardial injury and reduce oxidative stress by downregulating the myocardial expression of NOX2 and NOX4 in rats.


Assuntos
Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Valsartana/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Testes de Função Cardíaca/efeitos dos fármacos , Masculino , NADPH Oxidase 2/genética , NADPH Oxidase 4/genética , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Valsartana/farmacologia
20.
Exp Biol Med (Maywood) ; 245(11): 983-993, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32408765

RESUMO

IMPACT STATEMENT: Our study provided new insight into the mechanism underlying the preservation of the peritoneum by valsartan. The results demonstrated that the mice receiving chronic high glucose (HG) peritoneal dialysis solution infusion showed a typical feature of peritoneal fibrosis (PF), as well as higher expression of α-smooth muscle actin (α-SMA) and collagen I. In vitro, HG increased the protein expression of α-SMA and collagen I in a dose-dependent manner, while valsartan significantly ameliorated these pathological changes. Interestingly, there was a parallel decrease in the activity of mammalian target of rapamycin complex 1 (mTORC1) and the protein expression levels of α-SMA and collagen I upon treatment with valsartan in vivo and in vitro. Moreover, the mTOR agonist MHY1485 reversed the downregulation of α-SMA and collagen I in vitro, even in the presence of valsartan. Altogether, our findings reported for the first time that valsartan exerts a protective effect against HG-induced PF by inhibiting the activity of the mTORC1 pathway.


Assuntos
Soluções para Diálise/toxicidade , Glucose/toxicidade , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/prevenção & controle , Valsartana/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Soluções para Diálise/química , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Diálise Peritoneal/métodos , Fibrose Peritoneal/metabolismo , Peritônio/efeitos dos fármacos , Peritônio/patologia , Transdução de Sinais/efeitos dos fármacos
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