Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.703
Filtrar
2.
Artigo em Inglês | MEDLINE | ID: mdl-32371329

RESUMO

High-performance liquid chromatography (HPLC) and solid phase micro membrane tip extraction (SPMMTE) methods are developed for the simultaneous analysis of eleven cardiovascular drugs in human plasma. Iron nanoparticles were obtained by the green method, characterized by XRD, FT-IR, TEM, and EDS and utilized in SPMMTE for sample preparation. The mobile phase used was ammonium acetate buffer-methanol-acetonitrile (65:18:17) with a 1.0 mL/min flow rate at 260 nm detection. Column used was Sunshell C18 150 × 4.6 mm, 2.6 µm. The values of k, α, and Rs were ranged from 040 to109.22, 1.20 to 2.67 and 1.0 to 26.18. SPMMTE and HPLC methods were fast, reproducible, precise, robust, economic and rugged for analysis of methyldopa, hydrochlorothiazide, prazosin hydrochloride, furosemide, labetalol, propranolol, valsartan, losartan potassium, diltiazem, irbesartan and spironolactone in human plasma. The recoveries (%) of methyldopa, hydrochlorothiazide, prazosin hydrochloride, furosemide, labetalol, propranolol, valsartan, losartan potassium, diltiazem, irbesartan, and spironolactone were 91.0, 85.2, 92.3, 90.4, 90.1, 85.6, 86.6, 86.2, 85.1, 86.6, and 85.7, respectively. These results showed that SPMMTE and HPLC methods can be applied to test the described drugs in several matrices.


Assuntos
Anti-Hipertensivos/sangue , Nanopartículas Metálicas/química , Nanocompostos/química , Adsorção , Cromatografia Líquida de Alta Pressão , Diltiazem/sangue , Furosemida/sangue , Humanos , Hidroclorotiazida/sangue , Irbesartana/sangue , Ferro/química , Labetalol/sangue , Limite de Detecção , Losartan/sangue , Metildopa/sangue , Álcool de Polivinil/química , Prazosina/sangue , Propranolol/sangue , Reprodutibilidade dos Testes , Microextração em Fase Sólida , Espironolactona/sangue , Valsartana/sangue
3.
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
5.
Am J Physiol Renal Physiol ; 318(5): F1295-F1305, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249614

RESUMO

Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ETAR) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ETAR antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ETAR antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Atrasentana/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/farmacologia , Losartan/farmacologia , Podócitos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Camundongos , Fosforilação , Podócitos/metabolismo , Podócitos/patologia , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/prevenção & controle , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo
6.
Drug Discov Ther ; 14(2): 105-106, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32213760

RESUMO

Based on some publications that associate SARS-CoV-2 infection with the use of anti-hypertensive drug groups such as angiotensin-converting-enzyme inhibitors (e.g. enalapril) or angiotensin II receptor blockers (e.g. losartan), many patients from South America, Central America or Spain, have stopped or intend to interrupt their treatments with these drugs. Hence, it may exist ominous consequences due to this drop out. For this reason, it is necessary to quickly warn about this situation and the risks associated with it.


Assuntos
Anti-Hipertensivos/efeitos adversos , Infecções por Coronavirus/complicações , Hipertensão/complicações , Pneumonia Viral/complicações , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Betacoronavirus/fisiologia , Enalapril/efeitos adversos , Humanos , Hipertensão/tratamento farmacológico , Losartan/efeitos adversos , Pandemias , Peptidil Dipeptidase A , Internalização do Vírus
7.
Life Sci ; 250: 117549, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32179073

RESUMO

AIM: To evaluate physical fitness and cardiovascular effects in rats with renovascular hypertension, two kidneys, one clip (2K1C) submitted to voluntary exercise (ExV). MAIN METHODS: 24 h after surgery (SHAM and 2K1C) rats were submitted to ExV for one week (adaptation). ExV adherent rats were separated into exercise (2K1C-EX and SHAM-EX) or sedentary (2K1C-SED and SHAM-SED) groups. After 4 weeks, exhaustion test, plasma lactate, cardiovascular parameters were evaluated and gastrocnemius muscle was removed for evaluation of gene expression of muscle metabolism markers (PGC1α; AMPK, SIRT-1, UCP-3; MCP-1; LDH) and of the redox process. KEY FINDINGS: ExV decreased blood lactate concentration and increased SOD and CAT activity and a SIRT-1 and UCP-3 gene expression in the gastrocnemius muscle of 2K1C-ExV rats compared to 2K1C-SED rats. Gene expressions of PGC1α, UCP-3, MCT-1, AMPK were higher in 2K1C-ExV rats compared to SHAM-SED rats. Blood pressure in 2K1C-ExV was lower compared to 2K1C-SED and higher in SHAM-SED rats. Reflex bradycardia in 2K1C-EX rats increased compared to 2K1C-SED and was similar to SHAM-SED. The variation in mean blood pressure induced by ganglion blocker hexamethonium and Ang II AT1 receptor antagonist, losartan in the 2K1C-ExV rats was smaller compared to the 2K1C-SED rats and it was similar to the SHAM-SED rats. SIGNIFICANCE: O ExV induced adaptive responses in 2K1C-ExV rats by decreasing sympathetic and Ang II activities and stimulating intracellular signaling that favors redox balance and reduced blood lactate concentration. These adaptive responses, then, contribute to reduced arterial pressure, improved baroreflex sensitivity and physical fitness of 2K1C rats.


Assuntos
Hipertensão Renovascular/metabolismo , Músculo Esquelético/metabolismo , Condicionamento Físico Animal , Transdução de Sinais , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Bradicardia , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Rim/efeitos dos fármacos , Losartan/farmacologia , Masculino , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Endogâmicos F344 , Sirtuína 1/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Proteína Desacopladora 3/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-32050158

RESUMO

Measuring in vivo changes in the drug metabolizing activity of cytochrome P450 (CYP) enzymes is critical to understanding and assessing drug-drug, drug-diet and drug-disease interactions. The sensitivity and specificity of ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) makes it an ideal tool for analyzing drugs and their metabolites in biological matrices, and has demonstrated utility in CYP phenotyping across varied applications. Published CYP phenotyping cocktail assays often require large plasma sample volumes (0.5-1 mL), have relatively low sensitivity and multi-step complex sample preparation and extraction procedures. Further, variability exists in the way that recovery and matrix effects are investigated and reported, and some studies fail to report these data altogether. Therefore, the aim of this study was to develop, validate and optimize a simplified assay for the probe drugs caffeine (metabolized by CYP1A2), omeprazole (CYP2C19), losartan (CYP2C9), dextromethorphan (CYP2D6), midazolam (CYP3A4) and their respective enzyme-specific metabolites in small volumes (100 µL) of human plasma, that addresses the issues noted. Analyte extraction involved protein precipitation with acetonitrile and solid-phase extraction (SPE). Samples were analyzed using an Agilent 1290 infinity LC system in tandem with 6460A triple quadrupole mass spectrometers. The assay met FDA guideline-recommended requirements for specificity, sensitivity (analyte LLOQs 0.78-23.4 ng/mL), accuracy (intra-day RE% nominal concentration 90.7-110.2%; inter-day RE% 87.0-110.5%) and precision (intra-day analyte RSD% 0.46-11.4%; inter-day RSD% 1.36-11.2%). Recovery and matrix effects were thoroughly investigated and excluded as potential interferers with assay performance. This assay has been used successfully to phenotype CYP activity in a human clinical trial participant. Importantly, the authors provide a contemporary commentary on commonly found issues in the CYP phenotyping cocktail assay literature, and make recommendations concerning best-practice approaches and the standardization of data reporting in this area.


Assuntos
Sistema Enzimático do Citocromo P-450/sangue , Sistema Enzimático do Citocromo P-450/classificação , Técnicas Biossensoriais/métodos , Cafeína/metabolismo , Cromatografia Líquida de Alta Pressão , Dextrometorfano/metabolismo , Interações Medicamentosas , Humanos , Limite de Detecção , Losartan/metabolismo , Midazolam/metabolismo , Omeprazol/metabolismo , Fenótipo , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
9.
Xenobiotica ; 50(7): 847-857, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32048541

RESUMO

The present study aimed to determine the effect of Hibiscus sabdariffa and Zingiber officinale on antihypertensive activity and pharmacokinetic of losartan in hypertensive rats.Hypertension was induced in rats by oral administration of L-NAME (40 mg/kg per day). Pharmacodynamics and pharmacokinetics of losartan were evaluated without and with herbal treatment in hypertensive rats.Treatment of hypertensive rats with investigated herbs substantially reduced systolic blood pressure (SBP), and diastolic blood pressure (DBP) of rats. Treatment of rats (n = 5) with L-NAME plus H. sabdariffa plus losartan and L-NAME plus Z. officinale plus losartan reduced SBP by 16.20% and 14.88% and DBP by 14.82% and 17.52% respectively after 12 h, as compared to L-NAME alone treated rats. In a pharmacokinetic study, the Cmax and AUC0-t of losartan in L-NAME plus H. sabdariffa plus losartan and L-NAME plus Z. officinale plus losartan treated rats was increased by 0.7, 1.99 and 1.51, 3.00 fold respectively in comparison to the Cmax and AUC0-t obtained for L-NAME plus losartan treated group. In conclusion, both the investigated herbs significantly increased the antihypertensive effect and plasma concentration of losartan in L-NAME induced hypertensive rats. The current study predicted that the herb-drug interaction between H. sabdariffa-losartan and Z. officinale-losartan could occur; hence these results in rats may warrant further studies in humans, either in humans or in in vitro human liver microsomes.


Assuntos
Anti-Hipertensivos/farmacologia , Losartan/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Hipertensivos/farmacocinética , Gengibre , Interações Ervas-Drogas , Hibiscus , Losartan/farmacocinética , Masculino , Extratos Vegetais/farmacocinética , Ratos
10.
J Environ Manage ; 261: 110170, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31999612

RESUMO

Population growth and deteriorating health issues have led to an increase in the consumption of angiotensin receptor blockers (ARBs), such as losartan (LOR), for treating high blood pressure and, as a result, to the frequent detection of these drugs in water and wastewater. The present study focuses on the oxidation of LOR by UV photolysis, UV(/Fe2+)-activated persulfate (PS) and hydrogen peroxide (H2O2) systems. The effects of operating parameters including pH value, reaction time, concentration of oxidant and activator on the efficacy of treatment were studied. The target compound degradation by direct UV photolysis, UV/PS and UV/H2O2 systems proved to be efficient and followed a pseudo-first-order kinetic model. The application of UV/oxidant systems even at lower PS or H2O2 concentrations resulted in more than 95% of LOR degradation in 10 min. In addition, the use of UV/Fe2+-activated oxidant systems led to a further increase in the kobs by improving the LOR oxidation in aqueous solution. The effectiveness of LOR mineralization based on total organic carbon (TOC) removal was also considered. The optimized results of the studied systems obtained in ultrapure water were used in groundwater to assess the effectiveness of LOR decomposition in more complex environmental matrix. Moreover, the acute toxicity of LOR solutions before and after the UV/Fe2+-activated PS and H2O2 oxidation to luminous bacteria (Vibrio fischeri) was investigated.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Anti-Hipertensivos , Peróxido de Hidrogênio , Losartan , Oxirredução , Fotólise , Raios Ultravioleta , Águas Residuárias , Água
12.
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
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
15.
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
16.
Biol Sex Differ ; 10(1): 58, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829239

RESUMO

BACKGROUND: Placental ischemia and hypertension, characteristic features of preeclampsia, are associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. However, the factors that contribute to these cerebral abnormalities are not clear. Several lines of evidence suggest that angiotensin II can impact cerebrovascular function; however, the role of the renin angiotensin system in cerebrovascular function during placental ischemia has not been examined. We tested whether the angiotensin type 1 (AT1) receptor contributes to impaired CBF autoregulation in pregnant rats with placental ischemia caused by surgically reducing uterine perfusion pressure. METHODS: Placental ischemic or sham operated rats were treated with vehicle or losartan from gestational day (GD) 14 to 19 in the drinking water. On GD 19, we assessed CBF autoregulation in anesthetized rats using laser Doppler flowmetry. RESULTS: Placental ischemic rats had impaired CBF autoregulation that was attenuated by treatment with losartan. In addition, we examined whether an agonistic autoantibody to the AT1 receptor (AT1-AA), reported to be present in preeclamptic women, contributes to impaired CBF autoregulation. Purified rat AT1-AA or vehicle was infused into pregnant rats from GD 12 to 19 via mini-osmotic pumps after which CBF autoregulation was assessed. AT1-AA infusion impaired CBF autoregulation but did not affect brain water content. CONCLUSIONS: These results suggest that the impaired CBF autoregulation associated with placental ischemia is due, at least in part, to activation of the AT1 receptor and that the RAS may interact with other placental factors to promote cerebrovascular changes common to preeclampsia.


Assuntos
Circulação Cerebrovascular , Homeostase , Isquemia/fisiopatologia , Placenta/irrigação sanguínea , Receptor Tipo 1 de Angiotensina/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Feminino , Losartan/farmacologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Ratos Sprague-Dawley
18.
Mikrochim Acta ; 186(12): 801, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31741056

RESUMO

A surface-enhanced Raman scattering (SERS) method is described for the determination of prazosin (PRH) and losartan (LOS). Silver nanoparticles modified with ß-cyclodextrin (CD-S-Ag NPs) were prepared and serve as a sensitive SERS substrate. ß-CD is both a reductant for silver ions and a host molecule that binds the analytes which leads to strong SERS enhancement. The method has distinct features: (a) The linear response extends from 0.1 to 60 µM for PRH, and from 1.0 to 100 µM for LOS; (b) the respective limits of detection are as low as 15 nM and 0.92 µM; and (c) the specific SERS bands of PRH and LOS are located at 703 and 1298 cm-1 respectively. The method was successfully applied to the determination of PRH and LOS illegally added to healthcare products. The recovery of PRH and LOS from spiked samples ranges between 91.3 and 109.3%, and from 87.4 to 105.2%, respectively, both with relative standard deviation of <5%. Graphical abstractSchematic representation of a SERS method involving ß-CD-S-Ag nanoparticles for determination of prazosin and losartan via formation of an inclusion complex.


Assuntos
Anti-Hipertensivos/análise , Losartan/análise , Nanopartículas Metálicas/química , Prazosina/análise , Prata/química , beta-Ciclodextrinas/química , Tamanho da Partícula , Análise Espectral Raman , Propriedades de Superfície
19.
J Diabetes Res ; 2019: 4957879, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737685

RESUMO

Patients with diabetes mellitus (DM) type 1 and 2 are at a higher risk of cognitive decline and dementia; however, the underlying pathology is poorly understood. Kynurenic acid (KYNA), endogenous kynurenine metabolite, displays pleiotropic effects, including a blockade of glutamatergic and cholinergic receptors. Apart from well-known glial origin, kynurenic acid is robustly synthesized in the endothelium and its serum levels correlate with homocysteine, a risk factor for cognitive decline. Studies in an experimental DM model suggest that a selective, hippocampal increase of the kynurenic acid level may be an important factor contributing to diabetes-related cognitive impairment. The aim of this study was to assess the effects of chronic, four-week administration of losartan, angiotensin receptor blocker (ARB), on the brain KYNA in diabetic rats. Chromatographic and rt-PCR techniques were used to measure the level of KYNA and the expression of genes encoding kynurenine aminotransferases, KYNA biosynthetic enzymes, in the hippocampi of rats with streptozotocin-induced DM, treated with losartan. The effect of losartan on KYNA synthesis de novo was also evaluated in vitro, in brain cortical slices. The hippocampal increase of KYNA content occurred in diabetic rats treated and nontreated with insulin. Losartan did not affect KYNA levels when administered per se to naïve or diabetic animals but normalized KYNA content in diabetic rats receiving concomitantly insulin. The expression of CCBL1 (kat 1), AADAT (kat 2), and KAT3 (kat 3) genes did not differ between analyzed groups. Low concentrations of losartan did not affect KYNA production in vitro. The neuroprotective effect of ARBs in diabetic individuals may be, at least partially, linked to modulation of KYNA metabolism. The ability of ARB to modulate synthesis of KYNA in diabetic brain does not seem to result from changed expression of genes encoding KATs. We propose possible involvement of angiotensin AT4 receptors in the observed action of losartan.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Diabetes Mellitus Experimental/metabolismo , Hipocampo/efeitos dos fármacos , Ácido Cinurênico/metabolismo , Losartan/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Diabetes Mellitus Tipo 1/metabolismo , Hipocampo/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Ratos , Ratos Wistar
20.
Turk J Med Sci ; 49(5): 1582-1589, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652041

RESUMO

Background/aim: Losartan, an antihypertensive drug, is highly preferred in patients with diabetes mellitus (DM) and hypertension because of its retarding effect on diabetic nephropathy. In this study, we investigated the potential therapeutic effect of different doses of losartan on hepatic damage in a streptozotocin (STZ, 50 mg/kg)-induced DM model in rats. Materials and methods: In this study, five different groups were formed: control, DM, low-dose losartan (5 mg/kg), mid-dose losartan (20 mg/kg), and high-dose losartan (80 mg/kg). Liver tissues of experimental groups were evaluated immunohistochemically for TUNEL, iNOS, eNOS, VEGF, and NF-κB pathways. In addition to immunohistochemical analysis, analyses of SOD and MDA, which are oxidative stress markers, were also performed and the results were evaluated together. Results: When biochemical and immunohistochemical findings were evaluated together, it was found that the results obtained from the mid-dose losartan group were closer to those of the control than the other groups. Conclusion: This study indicated that mid-dose losartan administration may have a therapeutic effect by inhibiting apoptosis and regulating iNOS, eNOS, VEGF, and NF-κB protein expressions in DM-induced hepatic damage.


Assuntos
Anti-Hipertensivos/administração & dosagem , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Experimental/metabolismo , Hepatopatias/prevenção & controle , Losartan/administração & dosagem , NF-kappa B/biossíntese , NF-kappa B/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/biossíntese , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Wistar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA