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1.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360587

RESUMO

In the present study, we analyzed the activity of several aminopeptidases (angiotensinases) involved in the metabolism of various angiotensin peptides, in pituitary and adrenal glands of untreated Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) or treated with the antihypertensive drugs captopril and propranolol or with the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). Intra- and inter-gland correlations between angiotensinase activities were also calculated. Membrane-bound alanyl-, cystinyl-, and glutamyl-aminopeptidase activities were determined fluorometrically using aminoacyl-ß-naphthylamide as substrates. Depending on the type of angiotensinase analyzed, the results reflect a complex picture showing substantial differences between glands, strains, and treatments. Alanyl-aminopeptidase responsible for the metabolism of Ang III to Ang IV appears to be the most active angiotensinase in both pituitary and adrenals of WKY and particularly in SHR. Independently of treatment, most positive correlations are observed in the pituitary gland of WKY whereas such positive correlations are predominant in adrenals of SHR. Negative inter-gland correlations were observed in control SHR and L-NAME treated WKY. Positive inter-gland correlations were observed in captopril-treated SHR and propranolol-treated WKY. These results may reflect additional mechanisms for increasing or decreasing systolic blood pressure in WKY or SHR.


Assuntos
Glândulas Suprarrenais/metabolismo , Anti-Hipertensivos/farmacologia , Endopeptidases/metabolismo , Hipertensão/metabolismo , Hipotensão/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Hipófise/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Captopril/farmacologia , Endopeptidases/genética , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Hipotensão/tratamento farmacológico , Hipotensão/patologia , Masculino , Hipófise/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
2.
Zool Res ; 42(5): 633-636, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34423606

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1ß up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.


Assuntos
Anti-Hipertensivos/uso terapêutico , COVID-19/complicações , Captopril/uso terapêutico , Hipertensão/complicações , Pneumopatias/tratamento farmacológico , SARS-CoV-2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pneumopatias/etiologia , Pneumopatias/virologia , Camundongos , Replicação Viral/efeitos dos fármacos
3.
Biomed Pharmacother ; 139: 111670, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33945910

RESUMO

Cisplatin (Cis) is an effective cancer therapy commonly employed in many therapeutic regimens. However, treatment regimens that contain either a high dose or cumulative doses of Cis could trigger liver damage. A unique study demonstrated that captopril (Cap) protects against Cis-induced liver toxicity, but only some liver function enzymes and some antioxidant enzymes were investigated in that study. Our study aims to elucidate the protective mechanism of Cap against Cis liver toxicity. Acute liver toxicity was induced in rats by injecting a single Cis dose (7.5 mg/kg) in three groups (n = 6). Two groups were pre-treated with low (50 mg/kg) and high (100 mg/kg) Cap doses for one week before Cis injection, and the third group was injected with Cis only. The high Cap dose significantly improved liver function markers (ALT, AST, and ALP) and hepatic tissue pathology. The low Cap dose significantly improved ALP and, to a lesser extent, hepatic tissue pathology. Both Cap doses significantly decreased liver contents of MDA, IL-1ß, and cleaved caspase-3; and liver protein expression of TNF-α, Bax, and caspase-3. The high Cap dose significantly increased liver contents of GSH, GPx, CAT, and SOD, and the liver protein expression of Bcl2. Moreover, only the high Cap dose significantly decreased liver IL-6 content and cytochrome C protein expression. Cap did not inhibit the antitumor impact of Cis against HCT116 cancer cells. Therefore, Cap restricts Cis-induced liver toxicity by reducing inflammation and apoptosis and augmenting the antioxidant system.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Captopril/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos , Antioxidantes/farmacologia , Caspase 3/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino , Citocromos c , Regulação para Baixo/efeitos dos fármacos , Humanos , Testes de Função Hepática , Masculino , Ratos , Ratos Wistar , Proteína X Associada a bcl-2
4.
Biomacromolecules ; 22(5): 1910-1920, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33844512

RESUMO

Misfolding proteins could form oligomers or amyloid fibers, which can cause a variety of amyloid-associated diseases. Thus, the inhibition of protein misfolding and fibrillation is a promising way to prevent and treat these diseases. Captopril (CAP) is an angiotensin-converting enzyme inhibitor (ACEI) that is widely used to treat diseases such as hypertension and heart failure. In this study, we found that CAP inhibits human lysozyme (HL) fibrillation through the combination techniques of biophysics and biochemistry. The data obtained by thioflavin-T (ThT) and Congo red (CR) assays showed that CAP hindered the aggregation of HL amyloid fibrils by reducing the ß-sheet structure of HL amyloid, with an IC50 value of 34.75 ± 1.23 µM. Meanwhile, the particle size of HL amyloid decreased sharply in a concentration-dependent approach after CAP treatment. According to the visualization of atomic force microscopy (AFM) and transmission electron microscopy (TEM), we verified that in the presence of CAP, the needle-like fibers of HL amyloid were significantly reduced. In addition, CAP incubation dramatically improved the cell survival rate exposed to HL fibers. Our studies also revealed that CAP could form hydrogen bonds with amino acid residues of Glu 35 and Ala 108 in the binding pocket of HL, which help in maintaining the α-helical structure of HL and then prevent the formation of amyloid fibrillation. It can be concluded that CAP has antiamyloidogenic activity and a protective effect on HL amyloid cytotoxicity.


Assuntos
Amiloide , Muramidase , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Humanos , Análise Espectral
5.
Clin Exp Hypertens ; 43(6): 536-549, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-33870805

RESUMO

Background: Left ventricular hypertrophy (LVH) is an endpoint of hypertensive cardiac alterations. Renin-angiotensin-aldosterone system (RAAS) blockers are among the most effective on LVH regression. Physical exercise combined to antihypertensive drug contributes to arterial pressure (AP) control and LVH prevention. We evaluated the effects of physical exercise combined to captopril or losartan during eight weeks for spontaneously hypertensive rats (SHR) on some cardiac parameters.Methods: SHR (n=5-6 per group) were sedentary or trained 5 days a week in treadmill during 8 weeks; and they were treated with daily oral captopril (12.5, 25, or 50mg/kg), losartan (2.5, 5, or 10mg/kg), or vehicle. At the end, it was obtained systolic AP (SAP), electrocardiogram (ECG), and hearts metalloproteinase 2 (MMP-2) activity and histology.Results: Captopril 25 and 50 mg/kg, and losartan 10 mg/kg lowered SAP of sedentary and trained SHR. Losartan 5 mg/kg combined with physical exercise also lowered SAP. Combined with exercise, captopril 50 mg/kg lowered 13.6% of QT interval, 14.2% of QTc interval, and 22.8% of Tpeak-Tend compared to sedentary SHR. Losartan 5 and 10mg/kg lowered QT interval of sedentary and trained SHR. Losartan 2.5, 5 and 10mg/kg combined with physical exercise lowered respectively 25.4%, 24.8%, and 31.8% of MMP-2 activity. Losartan (10mg/kg) combined with exercise reduced cardiomyocyte diameter.Conclusion: These data support the hypothesis of physical exercise combined with RAAS blockers could improve the benefits on hypertensive LVH treatment.


Assuntos
Hipertensão , Hipertrofia Ventricular Esquerda , Losartan , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/prevenção & controle , Losartan/farmacologia , Metaloproteinase 2 da Matriz/farmacologia , Ratos , Ratos Endogâmicos SHR
6.
Clin Sci (Lond) ; 135(8): 1009-1014, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33881142

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is the leading player of the protective renin-angiotensin system (RAS) pathway but also the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAS inhibitors seemed to interfere with the ACE2 receptor, and their safety was addressed in COVID-19 patients. Pedrosa et al. (Clin. Sci. (Lond.) (2021), 135, 465-481) showed in rats that captopril and candesartan up-regulated ACE2 expression and the protective RAS pathway in lung tissue. In culture of pneumocytes, the captopril/candesartan-induced ACE2 up-regulation was associated with inhibition of ADAM17 activity, counterbalancing increased ACE2 expression, which was associated with reduced SARS-CoV-2 spike protein entry. If confirmed in humans, these results could become the pathophysiological background for justifying RAS inhibitors as cornerstone cardiovascular protectives even during COVID-19 pandemic.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , COVID-19 , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Benzimidazóis , Compostos de Bifenilo , Captopril/farmacologia , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Ratos , Sistema Renina-Angiotensina , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Tetrazóis
7.
Horm Behav ; 130: 104952, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33647281

RESUMO

Spontaneously hypertensive rats (SHRs) ingest more NaCl than normotensive strains. Here we investigated NaCl intake and taste reactivity in adult male SHRs and normotensive Holtzman rats treated or not with AT1 receptor antagonist centrally in euhydrated condition and after fluid depletion. Taste reactivity was measured by the number of orofacial expressions to intra-oral infusions of 0.3 M NaCl. In euhydrated condition, intra-oral infusions of 0.3 M NaCl produced greater number of hedonic responses in SHRs than in normotensive rats, without differences in the number of aversive responses. Compared to euhydrated condition, the treatment with the diuretic furosemide + low dose of captopril (angiotensin converting enzyme blocker) increased the number of hedonic and reduced the number of aversive responses to intra-oral NaCl in normotensive rats, without changing the number of hedonic or aversive responses in SHRs. Losartan (AT1 receptor antagonist, 100 ng/1 µl) injected intracerebroventricularly in SHRs abolished 0.3 M NaCl intake induced by water deprivation + partial rehydration, whereas only transiently (first 30 min of the 60 min test) reduced hedonic responses, without changes in aversive responses to intra-oral NaCl. Losartan intracerebroventricularly also only transiently (first 30 min) reduced the number of hedonic responses to intra-oral NaCl in euhydrated SHRs. The results suggest that NaCl palatability is increased and independent from body fluid balance in SHRs. The results also suggest that central AT1 receptors are part of the mechanisms activated to increase NaCl intake and palatability in SHRs. A partial dissociation between NaCl intake and palatability in SHRs is also suggested.


Assuntos
Captopril , Sódio , Animais , Captopril/farmacologia , Furosemida/farmacologia , Losartan/farmacologia , Masculino , Ratos , Ratos Endogâmicos SHR
8.
Nutrients ; 13(2)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672674

RESUMO

Wine lees (WL) are by-products generated in the winemaking process. The aim of this study was to investigate the angiotensin-converting enzyme inhibitory (ACEi) activity, and the blood pressure (BP) lowering effect of WL from individual grape varieties. The relationship among their activities and phenolic profiles was also studied. Three WL, from Cabernet, Mazuela, and Garnacha grape varieties, were firstly selected based on their ACEi properties. Their phenolic profiles were fully characterized by UHPLC-ESI-Q-TOF-MS. Then, their potential antihypertensive effects were evaluated in spontaneously hypertensive rats (SHR). BP was recorded before and after their oral administrations (2, 4, 6, 8, 24, and 48 h) at a dose of 5 mL/kg bw. Cabernet WL (CWL) exhibited a potent antihypertensive activity, similar to that obtained with the drug Captopril. This BP-lowering effect was related to the high amount of anthocyanins and flavanols present in these lees. In addition, a potential hypotensive effect of CWL was discarded in normotensive Wistar-Kyoto rats. Finally, the ACEi and antihypertensive activities of CWL coming from a different harvest were confirmed. Our results suggest the potential of CWL for controlling arterial BP, opening the door to commercial use within the wine industry.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Polifenóis/farmacologia , Vitis/química , Vinho , Animais , Captopril/farmacologia , Hipertensão/tratamento farmacológico , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
9.
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
10.
Clin Sci (Lond) ; 135(6): 793-810, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33625485

RESUMO

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II)-dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.


Assuntos
Hipertensão/fisiopatologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Dieta Hiperlipídica/efeitos adversos , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio , Losartan/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade , Sistema Renina-Angiotensina/efeitos dos fármacos
11.
Sci Rep ; 11(1): 2215, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33500491

RESUMO

Brain radiation can occur from treatment of brain tumors or accidental exposures. Brain radiation has been rarely considered, though, as a possible tool to alter protein levels involved in neurodegenerative disorders. We analyzed possible molecular and neuropathology changes of phosphorylated-Tau (pTau), all-Tau forms, ß-tubulin, amyloid precursor protein (APP), glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (IBA-1), myelin basic protein (MBP), and GAP43 in Frontal Cortex (FC), Hippocampus (H) and Cerebellum (CRB) of swine brains following total-body low-dose radiation (1.79 Gy). Our data show that radiated-animals had lower levels of pTau in FC and H, APP in H and CRB, GAP43 in CRB, and higher level of GFAP in H versus sham-animals. These molecular changes were not accompanied by obvious neurohistological changes, except for astrogliosis in the H. These findings are novel, and might open new perspectives on brain radiation as a potential tool to interfere with the accumulation of specific proteins linked to the pathogenesis of various neurodegenerative disorders.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Mamíferos/metabolismo , Proteínas tau/metabolismo , Animais , Captopril/farmacologia , DNA Polimerase beta/metabolismo , Relação Dose-Resposta à Radiação , Proteína GAP-43/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Fosforilação/efeitos da radiação , Suínos , Tubulina (Proteína)/metabolismo , Irradiação Corporal Total
12.
Drug Discov Today ; 26(3): 631-636, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33385574

RESUMO

The Coronavirus 2019 (COVID-19) pandemic represents the greatest worldwide public health crisis of recent times. The lack of proven effective therapies means that COVID-19 rages relatively unchecked. Current anti-COVID-19 pharmacotherapies are drugs originally designed for other diseases, and administered orally or intravascularly. Thus, they can have various adverse effects. A specific anti-Coronavirus drug should not only target the virus per se, but also treat the related respiratory and cardiovascular symptoms. Here, we examine the advantages and disadvantages of current anti-COVID-19 pharmacotherapies, and analyze the reasons why in the era of big data we have not yet established specific coronavirus therapies and related technical bottlenecks. Finally, we present our design of a novel nebulized S-nitrosocaptopril that is under development for targeting both coronaviruses and their related symptoms.


Assuntos
Antivirais , COVID-19 , Captopril/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/classificação , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/fisiopatologia , COVID-19/virologia , Captopril/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Desenvolvimento de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Humanos , Nebulizadores e Vaporizadores , Preparações Farmacêuticas , Sistema Respiratório/diagnóstico por imagem , Sistema Respiratório/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Resultado do Tratamento
13.
Appetite ; 158: 105037, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33186624

RESUMO

The renin-angiotensin system (RAS) controls hypertonic NaCl intake driven by sodium appetite. Here we investigated whether the antagonism of RAS interferes with hedonic and aversive orofacial motor responses, or palatability, to intraoral infusion of 0.3 M NaCl (hNaCl). Adult rats were depleted of sodium by combined sc injection of furosemide and 24 h removal of ambient sodium. In experiment 1, losartan (AT1 angiotensin II receptor antagonist, intracerebroventricular, 200 µg/µl), produced a three-fold increase in aversive orofacial motor responses to hNaCl. Losartan also suppressed hNaCl intake recorded immediately thereafter. In experiment 2, each animal had repeated recordings of hNaCl intake and orofacial responses to hNaCl distributed for 180 min. Paired recordings of intake and orofacial responses occurred within five successive blocks after the recordings of only orofacial responses when the animals were still sodium deplete (block zero). Captopril (angiotensin converting enzyme blocker, intraperitoneal, 30 mg/kg) inhibited by 75% the hedonic orofacial responses to hNaCl in blocks zero and 1. The hedonic responses to captopril remained the same throughout blocks, but became similar to vehicle from blocks 2 to 5. There was no difference in aversive responses to 0.3 M NaCl between captopril and vehicle. Captopril produced a 70-100% inhibition of hNaCl intake in blocks 1 to 5. The results suggest that angiotensin II acts in the brain increasing the palatability of hypertonic sodium during the consummatory phase of sodium appetite.


Assuntos
Sistema Renina-Angiotensina , Sódio , Animais , Apetite , Captopril/farmacologia , Losartan/farmacologia , Ratos , Cloreto de Sódio
14.
Kardiologiia ; 60(8): 130-140, 2020 Sep 17.
Artigo em Russo | MEDLINE | ID: mdl-33164724

RESUMO

The article discusses results of secondary analysis of the data obtained in the SPRINT study and published in recent years. Unresolved issues in the tactics of managing patients with arterial hypertension are discussed. One of such issues is choosing an optimum level of blood pressure (BP) for a subgroup of patients with certain characteristics, including elderly and senile patients, patients with chronic kidney disease, and patients with arterial hypertension who continue smoking. The article discusses calculation of a threshold of risk for complications of cardiovascular diseases, at which a maximum advantage of intensified regimens of antihypertensive therapy could be achieved. In addition, the article addresses approaches to selection of antihypertensive drugs in the current conditions. The authors discussed the role of candesartan in the treatment of arterial hypertension, a sartan most studied in a broad range of patients. The issue of a rapid increase in BP without a damage to target organs is addressed; evidence for the role of captopril in such clinical situation is provided.


Assuntos
Doenças Cardiovasculares , Hipertensão , Idoso , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Captopril/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico
15.
Toxicol Appl Pharmacol ; 408: 115255, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007385

RESUMO

Silicosis is a major public health concern with various contributing factors. The renin-angiotensin system (RAS)is a critical regulator in the pathogenesis of this disease. We focused on two key RAS enzymes, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2), to elucidate the activation of the ACE-angiotensin II (Ang II)-angiotensin II receptor 1 (AT1) axis and the inhibition of the ACE2-angiotensin-(1-7) [Ang-(1-7)]-Mas receptor axis in C57BL/6mice following SiO2 treatment. Silica exposure caused nodule formation, pulmonary interstitial fibrosis, epithelial-mesenchymal transition (EMT), abnormal deposition of extracellular matrix, and impaired lung function in mice. These effects were attenuated by the inhibition of ACE (captopril), blockade of the AT1(losartan), or systemic knockdown of the Ace gene. These effects were exacerbated by the inhibition of ACE2 (MLN-4760), blockade of the Mas (A779), or knockdown of the Ace2 gene. N-Acetyl-Seryl-Asparyl-Lysyl-Proline (Ac-SDKP), an anti-fibrotic peptide, ameliorated the silica-exposure-induced pathological changes by targeting the RAS system by activating the protective ACE2-Ang-(1-7)-Mas axis and inhibiting the deleterious ACE-Ang II-AT1 axis, thereby exerting a protective effect. This was confirmed in mouse lung type II epithelial cells (MLE-12) pretreated with Ang II and/or gene silencing separately targeting Ace and Ace2.The effects of Ac-SDKP were similar to those produced by Ace gene silencing and were partly attenuated by Ace2 deficiency. These findings suggested that RAS plays critical roles in the pathomechanism of silicosis fibrosis and that Ac-SDKP regulates lung RAS to inhibit EMT in silicotic mice and MLE-12 cells.


Assuntos
Transição Epitelial-Mesenquimal , Pulmão/metabolismo , Oligopeptídeos , Sistema Renina-Angiotensina , Silicose/metabolismo , Angiotensina I/antagonistas & inibidores , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/genética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Captopril/farmacologia , Linhagem Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Losartan/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/antagonistas & inibidores , Peptidil Dipeptidase A , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicose/patologia , Silicose/fisiopatologia
16.
Phytother Res ; 34(12): 3379-3387, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32725873

RESUMO

Hypertension is a public health concern that needs immediate attention upon diagnosis. The demand for natural alternatives is on the rise; Hibiscus sabdariffa and Olea europaea are traditionally used for hypertension management in Egypt. In this study, we aimed to investigate the antihypertensive efficacy and safety of two doses of an herbal product of Hibiscus sabdariffa calyxes and Olea europaea leaves (NW Roselle) in Egyptian patients with grade 1 essential hypertension. We equally randomized 134 patients to receive captopril 25 mg, low-dose NW Roselle, or high-dose NW Roselle BID for 8 weeks. No significant decrease was found in systolic blood pressure or diastolic blood pressure when we compared low-dose NW Roselle and high-dose NW Roselle to captopril (p > .05). In all groups, mean reduction in BP at 8 weeks was significant; 16.4/9.9 mmHg (p < .0001), 15.4/9.6 mmHg (p < .0001), and 14.9/9.4 mmHg (p < .0001) with captopril, low-dose NW Roselle, and high-dose NW Roselle respectively. In addition, low-dose NW Roselle induced a significant reduction in the mean level of triglycerides (17.56 mg/dL; p = .038). In conclusion, NW Roselle had comparable antihypertensive efficacy and safety to captopril in Egyptian patients with grade 1 essential hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Captopril/uso terapêutico , Hibiscus/química , Hipertensão/tratamento farmacológico , Olea/química , Extratos Vegetais/uso terapêutico , Plantas Medicinais/química , Adulto , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/farmacologia
17.
Mol Pharmacol ; 98(4): 454-461, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32606204

RESUMO

Endogenous opioid peptides in the amygdala regulate many of our behaviors and emotional responses. In particular, the endogenous opioid enkephalin plays a significant role in regulating amygdala activity, but its action is strongly limited by peptidases, which degrade enkephalin into inactive fragments. Inhibiting peptidases may be an attractive method to enhance endogenous opioid signaling; however, we do not know which specific peptidase(s) to target. Using inhibition of glutamate release onto the intercalated cells of the amygdala as an assay for enkephalin activity, we applied specific peptidase inhibitors to determine which peptidase(s) regulate enkephalin signaling in this region. Thiorphan (10 µM), captopril (1 µM), or bestatin (10 µM) were used to inhibit the activity of neprilysin, angiotensin-converting enzyme, or aminopeptidase N, respectively. In rat brain slices containing the intercalated cells, we found that inhibition of glutamate release by a submaximal concentration of enkephalin was doubled by application of all three peptidase inhibitors combined. Then, we tested inhibitors individually and found that inhibition of neprilysin alone could enhance enkephalin responses to the same extent as inhibitors of all three peptidases combined. This indicates neprilysin is the predominant peptidase responsible for degrading enkephalins in the intercalated cells of the amygdala. This differs from the striatum, locus coeruleus, and spinal cord, where multiple peptidases metabolize enkephalin. These data highlight the importance of knowing which specific peptidase(s) control opioid actions in the relevant neural circuit and how they change in disease states to allow rational choices of drugs targeting the specific peptidase of interest. SIGNIFICANCE STATEMENT: Endogenous opioids modulate many of our emotional and behavioral responses. In the amygdala, they modulate our pain, fear, and addictive behaviors. Their actions are terminated when they are catabolized into inactive fragments by at least three different peptidases. In this study, we found that neprilysin selectively controls endogenous opioid concentrations at synapses in the intercalated cells of the amygdala. This peptidase may be a target for regulation of endogenous opioid modulation of amygdala-mediated emotional and behavioral responses.


Assuntos
Tonsila do Cerebelo/metabolismo , Encefalinas/metabolismo , Neprilisina/metabolismo , Inibidores de Proteases/farmacologia , Animais , Captopril/farmacologia , Sinapses Elétricas/efeitos dos fármacos , Sinapses Elétricas/metabolismo , Ácido Glutâmico/metabolismo , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Neprilisina/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tiorfano/farmacologia
18.
Cancer Cell ; 37(6): 800-817.e7, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32516590

RESUMO

Tumors are influenced by the mechanical properties of their microenvironment. Using patient samples and atomic force microscopy, we found that tissue stiffness is higher in liver metastases than in primary colorectal tumors. Highly activated metastasis-associated fibroblasts increase tissue stiffness, which enhances angiogenesis and anti-angiogenic therapy resistance. Drugs targeting the renin-angiotensin system, normally prescribed to treat hypertension, inhibit fibroblast contraction and extracellular matrix deposition, thereby reducing liver metastases stiffening and increasing the anti-angiogenic effects of bevacizumab. Patients treated with bevacizumab showed prolonged survival when concomitantly treated with renin-angiotensin inhibitors, highlighting the importance of modulating the mechanical microenvironment for therapeutic regimens.


Assuntos
Bevacizumab/farmacologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Sinergismo Farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fibroblastos Associados a Câncer/patologia , Captopril/farmacologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Losartan/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Microambiente Tumoral/efeitos dos fármacos
19.
PLoS One ; 15(5): e0233788, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470081

RESUMO

In pre-hypertension, moderate control of blood pressure (BP) can be obtained by a nutritional approach. The effects of a diet enriched with defatted larvae of the mealworm Tenebrio molitor (Coleoptera: Tenebrionidae) (TM) endowed with ACE inhibitory activity was studied in both spontaneously hypertensive rats (SHR) and in the age-matched normotensive Wistar Kyoto strain. These were fed for 4 weeks with standard laboratory rodent chow supplemented with or without TM or captopril. In SHR, the TM diet caused a significant reduction in BP, heart rate and coronary perfusion pressure, as well as an increase in red blood cell glutathione/glutathione disulphide ratio. Rat brain slices of SHR were more resistant to oxidative stress and contained lower levels of inflammatory cytokines, while vascular and liver enzyme-activities were not affected. These results suggest that TM can be considered a new functional food that can lower BP in vivo and thus control cardiovascular-associated risk factors such as hypertension.


Assuntos
Pressão Sanguínea , Suplementos Nutricionais , Frequência Cardíaca , Hipertensão/dietoterapia , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Hipertensão/tratamento farmacológico , Larva , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Tenebrio
20.
J Immunother Cancer ; 8(1)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32448803

RESUMO

BACKGROUND: It is now recognized that many anticancer treatments positively modulate the antitumor immune response. Clinical and experimental studies have shown that inhibitors of the classical renin-angiotensin system (RAS) reduce tumor progression and are associated with better outcomes in patients with colorectal cancer. RAS components are expressed by most immune cells and adult hematopoietic cells, thus are potential targets for modulating tumor-infiltrating immune cells and can provide a mechanism of tumor control by the renin-angiotensin system inhibitors (RASi). AIM: To investigate the effects of the RASi captopril on tumor T lymphocyte distribution in a mouse model of colorectal liver metastases. METHODS: Liver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi (captopril 750 mg/kg) or carrier (saline) was administered to the mice daily via intraperitoneal injection, from day 1 post-tumor induction to endpoint (day 15 or 21 post-tumor induction). At the endpoint, tumor growth was determined, and lymphocyte infiltration and composition in the tumor and liver tissues were analyzed by flow cytometry and immunohistochemistry (IHC). RESULTS: Captopril significantly decreased tumor viability and impaired metastatic growth. Analysis of infiltrating T cells into liver parenchyma and tumor tissues by IHC and flow cytometry showed that captopril significantly increased the infiltration of CD3+ T cells into both tissues at day 15 following tumor induction. Phenotypical analysis of CD45+ CD3+ T cells indicated that the major contributing phenotype to this influx is a CD4 and CD8 double-negative T cell (DNT) subtype, while CD4+ T cells decreased and CD8+ T cells remained unchanged. Captopril treatment also increased the expression of checkpoint receptor PD-1 on CD8+and DNT subsets . CONCLUSION: Captopril treatment modulates the immune response by increasing the infiltration and altering the phenotypical composition of T lymphocytes and may be a contributing mechanism for tumor control.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Captopril/farmacologia , Captopril/uso terapêutico , Carcinoma/imunologia , Carcinoma/secundário , Linhagem Celular Tumoral/transplante , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/imunologia , Linfócitos T/imunologia
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