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1.
PLoS One ; 15(3): e0230655, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208439

RESUMO

BACKGROUND: T-wave area dispersion (TW-Ad) is a novel electrocardiographic (ECG) repolarization marker associated with sudden cardiac death. However, limited data is available on the clinical correlates of TW-Ad. In addition, there are no previous studies on cardiovascular drug effects on TW-Ad. In this study, we examined the relation between TW-Ad and left ventricular mass. We also studied the effects of four commonly used antihypertensive drugs on TW-Ad. METHODS: A total of 242 moderately hypertensive males (age, 51±6 years; office systolic/diastolic blood pressure during placebo, 153±14/100±8 mmHg), participating in the GENRES study, were included. Left ventricular mass index was determined by transthoracic echocardiography. Antihypertensive four-week monotherapies (a diuretic, a beta-blocker, a calcium channel blocker, and an angiotensin receptor antagonist) were administered in a randomized rotational fashion. Four-week placebo periods preceded all monotherapies. The average value of measurements (over 1700 ECGs in total) from all available placebo periods served as a reference to which measurements during each drug period were compared. RESULTS: Lower, i.e. risk-associated TW-Ad values correlated with a higher left ventricular mass index (r = -0.14, p = 0.03). Bisoprolol, a beta-blocker, elicited a positive change in TW-Ad (p = 1.9×10-5), but the three other drugs had no significant effect on TW-Ad. CONCLUSIONS: Our results show that TW-Ad is correlated with left ventricular mass and can be modified favorably by the use of bisoprolol, although demonstration of any effects on clinical endpoints requires long-term prospective studies. Altogether, our results suggest that TW-Ad is an ECG repolarization measure of left ventricular arrhythmogenic substrate.


Assuntos
Anti-Hipertensivos/uso terapêutico , Ventrículos do Coração/fisiopatologia , Hipertensão/tratamento farmacológico , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Bisoprolol/farmacologia , Bisoprolol/uso terapêutico , Pressão Sanguínea , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Morte Súbita Cardíaca/prevenção & controle , Diuréticos/farmacologia , Diuréticos/uso terapêutico , Método Duplo-Cego , Ecocardiografia , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Função Ventricular/efeitos dos fármacos
2.
PLoS One ; 15(2): e0228274, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053637

RESUMO

OBJECTIVE: Fluid overload is common among critically ill patients and is associated with worse outcomes. We aimed to assess the effect of diuretics on urine output, vasopressor dose, acute kidney injury (AKI) incidence, and need for renal replacement therapies (RRT) among patients who receive vasopressors. PATIENTS AND METHODS: This is a single-center retrospective study of all adult patients admitted to the intensive care unit between January 2006 and December 2016 and received >6 hours of vasopressor therapy and at least one concomitant dose of diuretic. We excluded patients from cardiac care units. Hourly urine output and vasopressor dose for 6 hours before and after the first dose of diuretic therapy was compared. Rates of AKI development and RRT initiation were assessed with a propensity-matched cohort of patients who received vasopressors but did not receive diuretics. RESULTS: There was an increasing trend of prescribing diuretics in patients receiving vasopressors over the course of the study. We included 939 patients with median (IQR) age of 68(57, 78) years old and 400 (43%) female. The average hourly urine output during the first six hours following time zero in comparison with average hourly urine output during the six hours prior to time zero was significantly higher in diuretic group in comparison with patients who did not receive diuretics [81 (95% CI 73-89) ml/h vs. 42 (95% CI 39-45) ml/h, respectively; p<0.001]. After propensity matching, the rate of AKI within 7 days of exposure and the need for RRT were similar between the study and matched control patients (66 (15.6%) vs. 83 (19.6%), p = 0.11, and 34 (8.0%) vs. 37 (8.7%), p = 0.69, respectively). Mortality, however, was higher in the group that received diuretics. Ninety-day mortality was 191 (45.2%) in the exposed group VS 156 (36.9%) p = .009. CONCLUSIONS: While the use of diuretic therapy in critically ill patients receiving vasopressor infusions augmented urine output, it was not associated with higher vasopressor requirements, AKI incidence, and need for renal replacement therapy.


Assuntos
Diuréticos/farmacologia , Choque/tratamento farmacológico , Vasoconstritores/farmacologia , Lesão Renal Aguda/complicações , Idoso , Estudos de Coortes , Estado Terminal , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Substituição Renal , Estudos Retrospectivos , Choque/complicações , Choque/fisiopatologia , Choque/urina , Resultado do Tratamento , Vasoconstritores/uso terapêutico
3.
Am J Physiol Renal Physiol ; 318(2): F285-F297, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760770

RESUMO

Juxtaglomerular (JG) cells, major sources of renin, differentiate from metanephric mesenchymal cells that give rise to JG cells or a subset of smooth muscle cells of the renal afferent arteriole. During periods of dehydration and salt deprivation, renal mesenchymal stromal cells (MSCs) differentiate from JG cells. JG cells undergo expansion and smooth muscle cells redifferentiate to express renin along the afferent arteriole. Gene expression profiling comparing resident renal MSCs with JG cells indicates that the transcription factor Sox6 is highly expressed in JG cells in the adult kidney. In vitro, loss of Sox6 expression reduces differentiation of renal MSCs to renin-producing cells. In vivo, Sox6 expression is upregulated after a low-Na+ diet and furosemide. Importantly, knockout of Sox6 in Ren1d+ cells halts the increase in renin-expressing cells normally seen during a low-Na+ diet and furosemide as well as the typical increase in renin. Furthermore, Sox6 ablation in renin-expressing cells halts the recruitment of smooth muscle cells along the afferent arteriole, which normally express renin under these conditions. These results support a previously undefined role for Sox6 in renin expression.


Assuntos
Arteríolas/metabolismo , Sistema Justaglomerular/irrigação sanguínea , Células-Tronco Mesenquimais/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Renina/metabolismo , Fatores de Transcrição SOXD/metabolismo , Animais , Arteríolas/efeitos dos fármacos , Pressão Sanguínea , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Dieta Hipossódica , Diuréticos/farmacologia , Furosemida/farmacologia , Regulação da Expressão Gênica , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Renina/genética , Fatores de Transcrição SOXD/deficiência , Fatores de Transcrição SOXD/genética , Transdução de Sinais
4.
Biomed Chromatogr ; 34(2): e4744, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31725908

RESUMO

We proposed a biochemometrics strategy for tracing diuretic components of herbs based on quantitative determination and pharmacological evaluation. First, a sensitive and robust liquid chromatography coupled with tandem mass spectrometry approach was established for simultaneous quantification of six major triterpenoids in crude and salt-processed Alisma orientale. The separation of triterpenoids was achieved on a BEH C18 column with a mobile phase consisting of acetonitrile and water spiked with 0.1% formic acid. Six major triterpenoids were detected by multiple reaction monitoring in the negative ion mode. Glycyrrhetinic acid was used as the internal standard. The approach showed good linearity. Intra- and inter-day precisions were all within 2.9%. The recovery rates of each triterpenoid ranged from 97.9% to 103.2%. The approach was then successfully employed for quantitative analysis of six triterpenoids in ten batches of crude and salt-processed A. orientale. Second, the diuretic effects of crude and salt-processed A. orientale were evaluated in mice. Third, principal component analysis and canonical correlation analysis were used to uncover the relationship between the contents of six major triterpenoids and the diuretic effect of different crude and salt-processed samples. Alisol B, alisol F, and alisol A have a close positive correlation with the diuretic effect.


Assuntos
Alisma/química , Diuréticos , Extratos Vegetais/química , Animais , Cromatografia Líquida , Diuréticos/química , Diuréticos/farmacologia , Diuréticos/urina , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/urina , Micção/efeitos dos fármacos
5.
J Vet Cardiol ; 26: 51-62, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31809955

RESUMO

INTRODUCTION/OBJECTIVES: We hypothesized that torsemide and furosemide, at approximately equipotent dosages (similar diuresis), would have comparable effects on the circulating renin-angiotensin-aldosterone system. ANIMALS, MATERIALS AND METHODS: Six, healthy, middle-aged, male Beagles were randomized to receive torsemide (0.1 mg/kg PO q 12 h), furosemide (2.0 mg/kg PO q 12 h), or placebo for 10 days during three separate periods, separated by a 10-day washout period, in a crossover design. Blood was collected on days 1, 5, and 9 and 24-h urine collection ended on days 2, 6, and 10. After repeated measures analysis and Bonferonni correction, variables with an adjusted p<0.05 were investigated further, using Tukey's method. RESULTS: Twenty-four-hour urine production differed significantly between the diuretics only on day 10, with torsemide causing a 38% greater diuresis than furosemide. There was, however, no significant difference in average 3-day diuresis. There were no significant differences between diuretics in the 24-h urinary excretion of sodium, chloride, or potassium, though furosemide caused less kaliuresis than torsemide. Serum renin, angiotensin II, and aldosterone and the urine aldosterone-to-creatinine ratio were significantly increased in the diuretic groups, as compared to placebo on days 5/6 and 9/10. There were no significant differences in these values between diuretics. Creatinine and blood urea nitrogen concentrations rose comparably in the diuretic groups, remaining within reference intervals in all dogs. CONCLUSIONS: At approximately equipotent dosages (20:1), torsemide and furosemide produced comparable renin-angiotensin-aldosterone system activation. Torsemide's similar potassium excretion profile to furosemide decreases support for a hypothesized mineralocorticoid-receptor blocking capability.


Assuntos
Furosemida/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Torasemida/farmacologia , Animais , Estudos Cross-Over , Diuréticos/farmacologia , Cães , Furosemida/administração & dosagem , Masculino , Torasemida/administração & dosagem
6.
Biomed Res Int ; 2019: 6927374, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886241

RESUMO

Lagopsis supina is a well-known traditional Chinese medicine and used as an agent for diuresis in China for centuries. This is the first time to evaluate the diuretic activity of the ethanol extract of L. supina (LS) and its four fractions (LSA, LSB, LSC, and LSD) in normal rats. After the administration of LS-H, LS-M, LSB-H, and LSC-L, the urine output of the rats was significantly increased, while the urine excretion was significantly reduced after treatment with LSB-L. The urine Na+ excretion was remarkably increased with LS-H, LS-M, LSA-H, LSA-L, LSB-H, LSC-L, and LSD-L, and the urine K+ excretion was significantly increased after administration of LS-H and LSB-H. Moreover, the urine Na+ and K+ excretion was significantly reduced after treatment with LSC-H and LSD-H. However, the urine pH values and urine and serum Na+-K+-ATPase levels did not show remarkable change after administration of LS or its four fractions in comparison with the control group. On the contrary, LS and its four fractions can suppress the renin-angiotensin-aldosterone system (RAAS), including ADH arrest by LSB-H, LSB-L, LSC-L, LSD-L, and LSD-H and ALD arrest by LSD-L, as well as promote ANP release by LS-M, LSB-H, LSC-H, and LSD-H, while furosemide can suppress only arrest of ADH within 24 h compared with the control group. In addition, LS and its four fractions did not change the urine and serum TNF-α and IL-6 levels in normal rats within 24 h. This study will provide a quantitative basis for explaining the natural medicinal use of LS as a diuretic agent for edema and promoting the diuretic process.


Assuntos
Antidiuréticos , Diuréticos , Lamiaceae/química , Extratos Vegetais , Animais , Antidiuréticos/química , Antidiuréticos/farmacologia , Diuréticos/química , Diuréticos/farmacologia , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Sódio/urina , Urinálise , Micção/efeitos dos fármacos
7.
Crit Care Resusc ; 21(4): 258-64, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31778632

RESUMO

OBJECTIVE: To compare the physiological and biochemical effects of a single intravenous dose of furosemide or acetazolamide in critically ill patients. DESIGN: Single centre, pilot randomised controlled trial. SETTING: Large tertiary adult intensive care unit (ICU). PARTICIPANTS: Twenty-six adult ICU patients deemed to require diuretic therapy. INTERVENTION: Single dose of intravenous 40 mg furosemide or 500 mg acetazolamide. MAIN OUTCOME MEASURES: Data were collected on urine output, cumulative fluid balance, and serum and urine biochemistry for 6 hours before and 6 hours after diuretic administration. RESULTS: Study patients had a median age of 55 years (IQR, 50-66) and median APACHE III score of 44 (IQR, 37-52). Furosemide caused a much greater increase in-urine output and much greater median mass chloride excretion (121.7 mmol [IQR, 81.1-144.6] v 23.3 mmol [IQR, 20.4-57.3]; P < 0.01) than acetazolamide. Furosemide also resulted in a progressively more negative fluid balance while acetazolamide resulted in greater alkalinisation of the urine (change in median urinary pH, +2 [IQR, 1.75-2.12] v 0 [IQR, 0-0.5]; P = 0.02). In keeping with this effect, furosemide alkalinised and acetazolamide acidified plasma (change in median serum pH, +0.03 [IQR, 0.01-0.04] v -0.01 [IQR, -0.04 to 0]; P = 0.01; change in median serum HCO3-, +1.5 mmol/L [IQR, 0.75-2] v -2 mmol/L [IQR, -3 to 0]; P < 0.01). CONCLUSIONS: Furosemide is a more potent diuretic and chloriuretic agent than acetazolamide in critically ill patients, and achieves a threefold greater negative fluid balance. Compared with acetazolamide, furosemide acidifies urine and alkalinises plasma. Our findings imply that combination therapy might be a more physiological approach to diuresis in critically ill patients.


Assuntos
Acetazolamida/farmacologia , Acetazolamida/farmacocinética , Estado Terminal/terapia , Diuréticos/farmacologia , Diuréticos/farmacocinética , Furosemida/farmacologia , Furosemida/farmacocinética , Acetazolamida/administração & dosagem , Adulto , Idoso , Diuréticos/administração & dosagem , Eletrólitos/sangue , Furosemida/administração & dosagem , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento , Urodinâmica/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos
8.
Pflugers Arch ; 471(11-12): 1383-1396, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31654198

RESUMO

The epithelial Na+ channel (ENaC) is essential for Na+/K+ homeostasis and blood pressure control. Its activity is regulated by proteases in rodents. To gain more information on proteolytic ENaC regulation in humans, we tested the hypotheses that (1) human kidney α- and γ-ENaC subunits are furin-cleaved, glycosylated, and altered by medication that change plasma aldosterone; (2) prostasin-cleaved γ-ENaC is increased in proteinuria, and (3) cleaved ENaC moieties prevail at the membranes and in urinary extracellular vesicles (uEVs). We developed three monoclonal antibodies (mAbs) targeting (1) the neo-epitope generated after furin cleavage in γ-ENaC (mAb-furin); (2) the intact prostasin cleavage-site in γ-ENaC (mAb-intactRKRK), and (3) the α-ENaC subunit (mAb-alpha). Nephrectomy tissue and uEVs were used for immunoblotting and -histochemistry. In human kidney tissue, mAb-furin detected a ≈ 65-70 kDa protein, compatible with furin-cleaved γ-ENaC; mAb-intactRKRK detected full-length (≈ 90-100 kDa) and furin-cleaved (≈ 70-75 kDa) γ-ENaC. mAb-alpha detected a ≈ 50 kDa protein compatible with furin-cleaved α-subunit. Furin-cleaved γ-ENaC was detected predominantly within membrane fractions and deglycosylation shifted full-length γ-ENaC migration ~ 20 kDa. While γ-ENaC uEV levels were below the detection limit, α-ENaC migrated as intact (≈ 75 kDa) and furin-cleaved (≈ 50 kDa) in uEVs. Kidney levels of α- and γ-ENaC in diuretic- (n = 3) and ACE-inhibitor-treated (n = 4) patients were not different from controls (n = 4). Proteinuric patients (n = 6) displayed similar level of furin-cleaved γ-ENaC as controls (n = 4). Cleaved α-ENaC abundance was significantly lower in the kidneys from proteinuria patients. In conclusion, the study demonstrates ENaC cleavage as an event in human kidney that could contribute to physiological regulation and pathophysiological activation of ENaC.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Epitélio/metabolismo , Furina/metabolismo , Rim/metabolismo , Subunidades Proteicas/metabolismo , Canais de Sódio/metabolismo , Aldosterona/metabolismo , Animais , Diuréticos/farmacologia , Epitélio/efeitos dos fármacos , Glicosilação , Humanos , Rim/efeitos dos fármacos , Camundongos , Proteinúria/metabolismo , Serina Endopeptidases/metabolismo , Sódio/metabolismo
9.
S Afr Med J ; 109(9): 632-634, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31635585

RESUMO

Amiloride is an antagonist of the renal tubular epithelial sodium channel (ENaC). As such, it is a diuretic that is both potassium and magnesium sparing. It is used for the treatment of potassium depletion and hypertension, and is the specific therapy for hypertension due to overactivity of the ENaC (Liddle syndrome and several additional genetic causes of the Liddle phenotype - low renin and low aldosterone). It is listed as a World Health Organization essential drug, but has never been registered in South Africa (SA) and can therefore only be prescribed under a Section 21 application to the SA Health Products Regulatory Authority (SAHPRA) on a case-by-case basis. In SA, >50% of patients treated for hypertension are not controlled. In the USA, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study reported that African Americans are more likely to be diagnosed with hypertension, more likely to be treated, more likely to be treated intensively, and less likely to achieve blood pressure (BP) control. Although the reasons are complex, studies show that 10 - 20% of blacks may carry the Liddle phenotype. Observational data and a controlled clinical trial done in three African countries have shown that these patients respond to amiloride and not to conventional guideline-based antihypertensive treatment. The former is likely to result in a significant reduction in cardiovascular, stroke and kidney morbidity and mortality, because of improved BP control. Amiloride is very unlikely to ever be registered in SA, as it was first developed >50 years ago, and SAHPRA regulations prevent widespread prescription of this essential drug. This is a classic Gordian knot that requires a novel approach from authorities to sever the knot and improve the health of many South Africans.


Assuntos
Amilorida/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Hipertensão/tratamento farmacológico , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Amilorida/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/farmacologia , Diuréticos/uso terapêutico , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Bloqueadores do Canal de Sódio Epitelial/uso terapêutico , Disparidades nos Níveis de Saúde , Humanos , Hipertensão/fisiopatologia , África do Sul
10.
J Pharm Pharmacol ; 71(12): 1832-1838, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31588559

RESUMO

OBJECTIVES: This study aimed to investigate the diuretic efficacy of myricetin-3-O-α-rhamnoside (myricitrin), a common naturally occurring plant-derived flavonoid, obtained from Marlierea eugeniopsoides (D.Legrand & Kausel) D.Legrand leaves in rats. METHODS: For that, female Wistar rats were treated by oral route with the different treatments and kept in metaboloic cages for 8-h or 24-h experiment. The volume and urinary parameters were measured at the end of the period and compared between groups. KEY FINDINGS: When orally given to rats and compared to the vehicle-treated group, myricitrin (0.3 and 1 mg/kg) was able to stimulate rat diuresis, natriuresis and kaliuresis. The combination myricitrin plus hydrochlorothiazide, but not plus furosemide or amiloride, potentiated the urinary volume when compared to the effects of drugs alone. Besides, the 8-h renal effects of myricitrin were prevented in the presence of a cyclooxygenase inhibitor and a muscarinic receptor antagonist. However, all groups treated with myricitrin showed a significant reduction in Cl- excretion. In addition, a reduction in the urinary excretion of Cl- and HCO 3 - was detected on 24-h analysis, a result that showed to be associated with an increase of these anions in the blood samples from the myricitrin-treated group. Despite these alterations, no changes in urinary or blood pH were detected. CONCLUSIONS: Taking together, although the results of this study point to the diuretic potential of myricitrin, the reduction in urinary Cl- and HCO 3 - excretion should be considered in future approaches, as well as for therapeutic applicability.


Assuntos
Diuréticos/farmacologia , Flavonoides/farmacologia , Myrtaceae/química , Animais , Diurese/efeitos dos fármacos , Diuréticos/administração & dosagem , Diuréticos/isolamento & purificação , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Flavonoides/administração & dosagem , Flavonoides/isolamento & purificação , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/farmacologia , Natriurese/efeitos dos fármacos , Ratos , Ratos Wistar
11.
Am J Physiol Heart Circ Physiol ; 317(5): H958-H968, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31490733

RESUMO

Previously we have shown that increased expression of renal epithelial sodium channels (ENaC) may contribute to the renal sodium and water retention observed during chronic heart failure (CHF). The goal of this study was to examine whether renal denervation (RDN) changed the expressions of renal sodium transporters ENaC, sodium-hydrogen exchanger-3 proteins (NHE3), and water channel aquaporin 2 (AQP2) in rats with CHF. CHF was produced by left coronary artery ligation in rats. Four weeks after ligation surgery, surgical bilateral RDN was performed. The expression of ENaC, NHE3, and AQP2 in both renal cortex and medulla were measured. As a functional test for ENaC activation, diuretic and natriuretic responses to ENaC inhibitor benzamil were monitored in four groups of rats (Sham, Sham+RDN, CHF, CHF+RDN). Western blot analysis indicated that RDN (1 wk later) significantly reduced protein levels of α-ENaC, ß-ENaC, γ-ENaC, and AQP2 in the renal cortex of CHF rats. RDN had no significant effects on the protein expression of kidney NHE3 in both Sham and CHF rats. Immunofluorescence studies of kidney sections confirmed the reduced signaling of ENaC and AQP2 in the CHF+RDN rats compared with the CHF rats. There were increases in diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. RDN reduced the diuretic and natriuretic responses to benzamil in CHF rats. These findings suggest a critical role for renal nerves in the enhanced expression of ENaC and AQP2 and subsequent pathophysiology of renal sodium and water retention associated with CHF.NEW & NOTEWORTHY This is the first study to show in a comprehensive way that renal denervation initiated after a period of chronic heart failure reduces the expression of epithelial sodium channels and aquaporin 2 leading to reduced epithelial sodium channel function and sodium retention.


Assuntos
Aquaporina 2/metabolismo , Denervação Autônoma , Canais Epiteliais de Sódio/metabolismo , Insuficiência Cardíaca/metabolismo , Rim/inervação , Rim/metabolismo , Natriurese , Eliminação Renal , Sódio/urina , Amilorida/análogos & derivados , Amilorida/farmacologia , Animais , Aquaporina 2/genética , Doença Crônica , Modelos Animais de Doenças , Diuréticos/farmacologia , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/efeitos dos fármacos , Canais Epiteliais de Sódio/genética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/urina , Rim/efeitos dos fármacos , Masculino , Natriurese/efeitos dos fármacos , Ratos Sprague-Dawley , Eliminação Renal/efeitos dos fármacos
12.
DNA Cell Biol ; 38(10): 1134-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433203

RESUMO

Diabetes mellitus is a complicated metabolic disease characterized by hyperglycemia. Diabetic nephropathy (DN) is a progressive kidney disease, which results in mortality in diabetic patients. The present study was designed to investigate the effect of applying spironolactone (S), captopril (C), and their combination (S+C) on some renal performance indices and microRNAs' (miRNAs) expression. A total of 35 two-month-old male Wistar rats were provided for the study. Intraperitoneal injection of freshly dissolved streptozotocin (60 mg/kg) in cold citrate buffer was used to induce diabetes. Blood samples were examined through calorimetry to assess serum concentrations of glucose, blood urea nitrogen (BUN), and creatinine. To measure the microalbuminuria and transforming growth factor-ß (TGF-ß) levels and to evaluate the miRNAs expression levels of the kidney tissue, the ELISA method and the real-time PCR were used. The obtained results serve as in vivo evidence for the positive relationship between miR-192 and TGF-ß levels in the DN rats. A significant increase and decrease were found for miR-29a/b/c and the miR-192 expression of DN after treatment with S, C, and S+C. TGF-ß levels and microalbuminuria of diabetic rats also increased. The results obtained from this research study suggest that S, C, and S + C can improve DN by targeting miR-192 and miR-29 family and changing their expression. These findings suggest that miR-192 and miRs-29a/b/c can be potential targets for DN remediation.


Assuntos
Captopril/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Espironolactona/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Diuréticos/farmacologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
13.
Kidney Blood Press Res ; 44(5): 915-927, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437845

RESUMO

BACKGROUND: Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital admissions and health care costs. Indeed, loop diuretics are the first-line therapy to overcome fluid overload in heart failure patients. The pathophysiological mechanisms of fluid and sodium retention are complex and depend on several neuro-hormonal signals mainly acting on sodium reabsorption along the renal tubule. Consequently, doses and administration modalities of diuretics must be carefully tailored to patients in order to overcome under- or overtreatment. The frequent and tricky development of diuretic resistance depends in part on post-diuretic sodium retention, reduced tubular secretion of the drug, and reduced sodium/chloride sensing. Sodium and chloride depletions have been recently shown to be major factors mediating these processes. Aquaretics and high-saline infusions have been recently suggested in cases of hyponatremic conditions. This review discusses the limitations and strengths of these approaches. SUMMARY: Long-term diuretic use may lead to diuretic resistance in cardio-renal syndromes. To overcome this complication intravenous administration of loop diuretics and a combination of different diuretic classes have been proposed. In the presence of hyponatremia, high-saline solutions in addition to loop diuretics might be beneficial, whereas aquaretics require caution to avoid overcorrection. Key Messages: Diuretic resistance is a central theme for cardio-renal syndromes. Hyponatremia and hypochloremia may be part of the mechanisms for diuretic resistance. Aquaretics and high-saline solutions have been proposed as possible new therapeutic solutions.


Assuntos
Síndrome Cardiorrenal/terapia , Diuréticos/uso terapêutico , Insuficiência Cardíaca/terapia , Rim/patologia , Nefrologia/métodos , Diuréticos/farmacologia , Humanos
14.
J Vet Intern Med ; 33(5): 2319-2326, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31397944

RESUMO

BACKGROUND: Public pressure exists in the United States to eliminate race-day furosemide administration despite its efficacy in decreasing the severity of equine exercise pulmonary hemorrhage (EIPH). No effective alternative prophylaxis strategies have been identified. OBJECTIVE: To investigate alternative protocols to race-day furosemide that might mitigate EIPH. ANIMALS: Seven fit Thoroughbreds with recent EIPH. METHODS: Double-blinded placebo-controlled Latin square crossover using a treadmill followed by a blinded placebo-controlled crossover study at a racetrack. First, horses exercised supramaximally to fatigue 24 hours after initiating 5 EIPH prophylaxis protocols: 0.5 and 1.0 mg/kg furosemide IV 24 hours pre-exercise with and without controlled access to water, and 24 hour controlled access to water. Effects were compared to those measured after giving a placebo 24 hours pre-exercise, and 0.5 mg/kg furosemide IV 4 hours pre-exercise. Bronchoalveolar lavage (BAL) erythrocyte count was determined 45-60 minutes postexercise after endoscopy to assign an EIPH score. Data were analyzed using linear mixed effects models. The most promising protocol from the treadmill study was further evaluated in 6 horses using endoscopy and BAL after 1100 m simulated races. RESULTS: Intravenous furosemide (0.5 mg/kg) administered 24 hours pre-exercise combined with controlled access to water decreased the severity of EIPH on the treadmill and at the racetrack. CONCLUSION AND CLINICAL IMPORTANCE: Administering 0.5 mg/kg furosemide 24 hours pre-racing combined with controlling water intake may be a strategy to replace race-day furosemide administration for the management of EIPH. A larger study is indicated to further evaluate whether this protocol significantly mitigates EIPH severity.


Assuntos
Furosemida/farmacologia , Hemorragia/veterinária , Doenças dos Cavalos/prevenção & controle , Animais , Líquido da Lavagem Broncoalveolar/citologia , Estudos Cross-Over , Diuréticos/administração & dosagem , Diuréticos/farmacologia , Contagem de Eritrócitos , Feminino , Furosemida/administração & dosagem , Hemorragia/prevenção & controle , Cavalos , Pneumopatias/prevenção & controle , Pneumopatias/veterinária , Masculino
15.
Am J Physiol Renal Physiol ; 317(4): F967-F977, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390232

RESUMO

We studied sex differences in response to high K+ (HK) intake on thiazide-sensitive cation (Na+ and K+) excretion in wild-type (WT) and ANG II receptor subtype 1a (AT1aR) knockout (KO) mice. Renal clearance experiments were performed to examine Na+-Cl- cotransporter (NCC) activity on mice fed with control and HK (5% KCl, 7 days) diets. Hydrochlorothiazide (HCTZ)-induced changes in urine volume, glomerular filtration rate, absolute Na+ and K+ excretion, and fractional excretion were compared. HK-induced changes in NCC, Na+/H+ exchanger isoform 3 (NHE3), and ENaC expression were examined by Western blot analysis. In WT animals under the control diet, HCTZ-induced cation excretion was greater in female animals, reflecting larger increases in Na+ excretion, since there was little sex difference in HCTZ-induced K+ excretion. Under the HK diet, the sex difference in HCTZ-induced cation excretion was reduced because of larger increments in K+ excretion in male animals. The fraction of K+ excretion was 57 ± 5% in male WT animals and 36 ± 4% in female WT animals (P < 0.05), but this difference was absent in AT1aR KO mice. NCC abundance was higher in female animals than in male animals but decreased by similar fractions on HK diet. NHE3 abundance decreased, whereas cleaved forms of γ-ENaC increased, with HK in all groups; these changes were similar in male and female animals and were not significantly affected by AT1aR ablation. These results indicate that, with the HK diet, male animals display greater distal Na+ delivery and greater activation of K+ secretion mechanisms, all suggesting a more powerful male adaptation to HK intake.


Assuntos
Cátions/urina , Diuréticos/farmacologia , Complexo II de Transporte de Elétrons/metabolismo , Hidroclorotiazida/farmacologia , Rim/metabolismo , Potássio/farmacologia , Animais , Feminino , Taxa de Filtração Glomerular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Potássio/urina , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Caracteres Sexuais , Trocador 3 de Sódio-Hidrogênio/metabolismo , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Urodinâmica
16.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1889-1894, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342718

RESUMO

To search for the active diuretic fractions of Clematidis Armandii Caulis( CAC) and determine its main active chemical components by using liquid chromatography-mass spectrometry( LC-MS) and diuretic activity evaluation. CAC 75% ethanol extracts and extracts from different polar solvents were orally administered to saline-loaded rats at different doses. 6 h urinary volume,p H and contents of electrolyte Na+,K+and Cl-were measured. The chemical components of the active fractions were separated and identified by ultra performance liquid chromatography-electrospray ionization-quadrupole time of flight-mass spectrometry( UPLC-ESI-Q-TOF-MS/MS) method. As compared with the control group,the urine volume was increased by 44%( P< 0. 01) and 34%( P < 0. 05) in CAC75% ethanol extract 57. 74 and 28. 8 mg·kg-1 groups respectively; the Na+excretion was increased by 52%( P< 0. 01) and 45%( P<0. 05),respectively; while the Cl-excretion was increased by 101%( P<0. 01) and 85%( P<0. 05),respectively. The urine volume,Na+excretion and Cl-excretion were increased by 50%( P< 0. 01),58%( P< 0. 05),and 65%( P< 0. 05) respectively in petroleum ether extract 70. 98 mg·kg-1 group as compared with the control group. While for the n-butanol extract 194. 18 mg·kg-1 group,the urine volume,Na+and Cl-excretion were increased by 42%( P<0. 01),41%( P<0. 05) and 97%( P<0. 01),respectively. The diuretic activity of other fractions was not obvious. There was no statistical difference in K+excretion in all groups. The results of LC-MS analysis showed that six compounds,including two sterols,one chromogen and three fatty acids,were identified from petroleum ether extract.Fourteen compounds,including six triterpenoid saponins,six lignin glycosides,one sterol glycoside and one phenolic glycoside,were identified from the n-butanol extract. All the results suggested that the ethanol extract of CAC had remarkable diuretic activity and its main effective components included sterol,triterpenoid saponin and lignin glycosides.


Assuntos
Ascomicetos/química , Diuréticos/farmacologia , Materia Medica/farmacologia , Animais , Ratos , Solventes , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
17.
Drug Dev Res ; 80(6): 800-806, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31243798

RESUMO

Gymnosperma glutinosum (Spreng) Less (Asteraceae) is a shrub used in traditional medicine for the treatment of inflammatory and renal diseases. The ent-dihydrotucumanoic acid (DTA) is a diterpene obtained from G. glutinosum. This study evaluated the antioxidant, genotoxic, and diuretic properties of DTA, as well as its in vitro and in vivo anti-inflammatory actions. The antioxidant actions of DTA were assessed with the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), ferric reducing antioxidant power (FRAP), and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) assays, the genotoxic action was assessed with the comet assay, and the diuretic effects of DTA were assessed using metabolic cages. The anti-inflammatory actions were evaluated using primary murine peritoneal macrophages stimulated with LPS and the λ-carrageenan-induced hind paw edema test. DTA lacked antioxidant (IC50 > 25,000 µg/mL) activity in the ABTS, FRAP, and DPPH assays. DTA at 500-1,000 µg/mL showed moderate genotoxicity. In LPS-stimulated macrophages, DTA showed IC50 values of 74.85 µg/mL (TNF-α) and 58.12 µg/mL (NO), whereas the maximum inhibition of IL-6 (24%) and IL-1ß (36%) was recorded at 200 µg/mL. DTA induced in vivo anti-inflammatory effects with ED50 = 124.3 mg/kg. The in vitro anti-inflammatory activity of DTA seems to be associated with the decrease in the release of TNF-α and NO. DTA promoted the excretion of urine (ED50 = 86.9 mg/kg), Na+ (ED50 = 66.7 mg/kg), and K+ (ED50 = 8.6 mg/kg). The coadministration of DTA with L-NAME decreased the urinary excretion shown by DTA alone. Therefore, the diuretic activity is probably associated with the participation of nitric oxide synthase. In conclusion, DTA exerted anti-inflammatory and diuretic effects, but lacked antioxidant effects.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Diuréticos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Antioxidantes/química , Antioxidantes/uso terapêutico , Antioxidantes/toxicidade , Asteraceae , Benzotiazóis/química , Compostos de Bifenilo/química , Carragenina , Ensaio Cometa , Citocinas/metabolismo , Diuréticos/química , Diuréticos/uso terapêutico , Diuréticos/toxicidade , Edema/induzido quimicamente , Edema/tratamento farmacológico , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Picratos/química , Ácidos Sulfônicos/química
18.
PLoS One ; 14(6): e0218734, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238335

RESUMO

Ceterach officinarum Willd is a plant widespread throughout Europe and used in southern Italy as a diuretic. Beliefs in the benefits of C. officinarum aqueous extract in the treatment of calcium oxalate kidney stones are widely held. Little is known, however, about the actual mechanism of its antilithiatic action. Our results in this in vitro study corroborate C. officinarum aqueous extract as a good source of antioxidants with a high antioxidant effects. Our results also demonstrate a major impact of C. officinarum aqueous extract on in vitro induced calcium oxalate crystallization kinetics and crystal morphology, showing its critical role in kidney stone formation and/or elimination. We show that progressively increasing doses of C. officinarum aqueous extract cause a sequence of effects. A powerful inhibitory action on calcium oxalate monohydrate (COM) growth and aggregation is first observed. C. officinarum aqueous extract also appears highly effective in stimulating nucleation increasing the number and reducing the size of COM crystals, which become progressively thinner, rounded and concave in a dose-dependent manner. These shape-modified COM crystals are known to be less adherent to renal tubular cells and more easily excreted through the urinary tract preventing kidney stone formation. Further, C. officinarum aqueous extract promotes the formation of calcium oxalate dihydrate (COD) rather than the monohydrate so that, at the highest concentrations used, only COD crystals are observed, in significant greater numbers with a clear reduction in their size, in a dose-dependent manner. Furthermore, AFM analyses allowed us to reveal the presence of C. officinarum component(s) on the surfaces of COD and modified COM crystals. The crystal surface adsorbed component(s) are shown to be similarly active as the total aqueous extract, suggesting a trigger factor which may direct crystal modification towards COD forms. In urolithiasis pathogenesis COD crystals are less dangerous than the COM forms due to their lower affinity for renal tubular cells. Our results are important in understanding the mechanisms which guide the modification induced by C. officinarum on the crystallization process. Based on these data, together with no adverse toxic effect being observed on the in vitro model of human intestinal enterocytes, C. officinarum aqueous extract could represent an attractive natural therapy for the treatment of urolithiasis.


Assuntos
Oxalato de Cálcio/química , Gleiquênias , Cálculos Renais/química , Cálculos Renais/tratamento farmacológico , Plantas Medicinais , Antioxidantes/farmacologia , Células CACO-2 , Cristalização , Diuréticos/farmacologia , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Gleiquênias/química , Humanos , Técnicas In Vitro , Itália , Cinética , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Modelos Químicos , Extratos Vegetais/farmacologia , Plantas Medicinais/química
19.
Am J Physiol Regul Integr Comp Physiol ; 317(2): R319-R327, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31166691

RESUMO

Catheter-based renal denervation (RDN) was introduced as a treatment for resistant hypertension. There remain critical questions regarding the physiological mechanisms underlying the hypotensive effects of catheter-based RDN. Previous studies indicate that surgical denervation reduces renin and the natriuretic response to saline loading; however, the effects on these variables of catheter-based RDN, which does not yield complete denervation, are largely unknown. The aim of this study was to investigate the effects of catheter-based RDN on glomerular-associated renin and regulation of fluid and sodium homeostasis in response to physiological challenges. First, immunohistochemical staining for renin was performed in normotensive sheep (n = 6) and sheep at 1 wk (n = 6), 5.5 mo (n = 5), and 11 mo (n = 5) after unilateral RDN using the same catheter used in patients (Symplicity). Following catheter-based RDN (1 wk), renin-positive glomeruli were significantly reduced compared with sham animals (P < 0.005). This was sustained until 5.5 mo postdenervation. To determine whether the reduction in renin after 1 wk had physiological effects, in a separate cohort, Merino ewes were administered high and low saline loads before and 1 wk after bilateral RDN (n = 9) or sham procedure (n = 8). After RDN (1 wk), the diuretic response to a low saline load was significantly reduced (P < 0.05), and both the diuretic and natriuretic responses to a high saline load were significantly attenuated (P < 0.05). In conclusion, these findings indicate that catheter-based RDN acutely alters the ability of the kidney to regulate fluid and electrolyte balance. Further studies are required to determine the long-term effects of catheter-based RDN on renal sodium and water homeostasis.


Assuntos
Cateteres , Diuréticos/farmacologia , Rim/metabolismo , Sódio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Cateteres/efeitos adversos , Denervação/métodos , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Artéria Renal/fisiopatologia , Renina/metabolismo , Ovinos
20.
Rev Alerg Mex ; 66(2): 254-256, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31200423

RESUMO

BACKGROUND: Furosemide is the most commonly prescribed loop diuretic worldwide. Although, its extended use, furosemide rarely induces allergic reactions. Until 2013, only 49 cases of furosemide allergy had been described. CLINICAL CASE: We have reported on a patient who developed a delayed, erythematous and pruritic skin eruption after the ingestion of furosemide. The implication of furosemide in the reaction was established by a positive lymphocyte transformation test (LTT). CONCLUSION: This is the first reported case of hypersensitivity to furosemide in which this drug was confirmed as the trigger by a positive LTT. LTT could become a decent diagnostic alternative for patients who experience delayed reactions to furosemide.


Assuntos
Diuréticos/efeitos adversos , Erupção por Droga/etiologia , Furosemida/efeitos adversos , Hipersensibilidade Tardia/etiologia , Ativação Linfocitária/efeitos dos fármacos , Idoso , Diuréticos/farmacologia , Feminino , Furosemida/farmacologia , Humanos
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