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1.
Biomed Pharmacother ; 165: 115116, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37418980

RESUMO

The vasopressin system has emerged as a therapeutic focus for lowering portal hypertension and reducing splanchnic vasodilation in patients with refractory ascites. Clinically available vasopressin agonists are limited by preferential selectivity for V1 receptors that also have steep concentration-response curves with potential risks of excess vasoconstriction and/or complete antidiuretic effects. OCE-205 is a novel, selective, partial V1a receptor agonist with mixed agonist/antagonist activity and no V2 receptor activation at therapeutic doses. We carried out two studies assessing the in vivo effects of OCE-205 in different rat models of cirrhosis and ascites. In a carbon tetrachloride rat cirrhosis model, OCE-205 administration produced a marked reduction in portal hypertension and hyperaldosteronism, along with robust diuretic and natriuretic effects. These effects were accompanied by marked decreases in ascites volume, with three of five animals experiencing total mobilization of ascites. There was no evidence of fluid overload or sodium or water retention, confirming OCE-205's lack of V2 receptor activity. In a second, corroborative study using a bile duct ligation rat model of ascites, OCE-205 produced significant decreases in ascites volume and body weight and a significant increase in urine volume versus vehicle. Urine sodium excretion increased significantly after the first administration of OCE-205 relative to vehicle; however, repeat administration over 5 days did not lead to hyponatremia. Thus, in separate in vivo models, the mixed agonist/antagonist OCE-205 demonstrated relevant and expected endpoint findings consistent with its known mechanism of action and in vitro pharmacology without apparent unwanted effects or nonspecific toxicities.


Assuntos
Hiperaldosteronismo , Hipertensão Portal , Ratos , Animais , Diuréticos/uso terapêutico , Natriuréticos , Ascite/tratamento farmacológico , Ascite/metabolismo , Vasopressinas/metabolismo , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Sódio/metabolismo , Receptores de Vasopressinas , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/metabolismo , Hiperaldosteronismo/complicações
2.
Nutrients ; 15(7)2023 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37049519

RESUMO

Excess sodium intake and insufficient potassium intake are a prominent global issue because of their influence on high blood pressure. Supplementation of potassium induces kaliuresis and natriuresis, which partially explains its antihypertensive effect. Balancing of minerals takes place in the kidney and is controlled by the circadian clock; in fact, various renal functions exhibit circadian rhythms. In our previous research, higher intake of potassium at lunch time was negatively associated with blood pressure, suggesting the importance of timing for sodium and potassium intake. However, the effects of intake timing on urinary excretion remain unclear. In this study, we investigated the effect of 24 h urinary sodium and potassium excretion after acute sodium and potassium load with different timings in mice. Compared to other timings, the middle of the active phase resulted in higher urinary sodium and potassium excretion. In Clock mutant mice, in which the circadian clock is genetically disrupted, urinary excretion differences from intake timings were not observed. Restricted feeding during the inactive phase reversed the excretion timing difference, suggesting that a feeding-induced signal may cause this timing difference. Our results indicate that salt intake timing is important for urinary sodium and potassium excretion and provide new perspectives regarding hypertension prevention.


Assuntos
Hipertensão , Cloreto de Sódio na Dieta , Camundongos , Animais , Cloreto de Sódio na Dieta/farmacologia , Natriuréticos/farmacologia , Sódio/urina , Cloreto de Sódio/farmacologia , Potássio/urina , Pressão Sanguínea
3.
Biochem Pharmacol ; 204: 115238, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36055382

RESUMO

The rapid fall in blood pressure following unclipping of the stenotic renal artery in the Goldblatt two-kidney one-clip (2K1C) model of renovascular hypertension is proposed to be due to release of renomedullary vasodepressor lipids, but the mechanism has remained unclear. In this study, we hypothesized that the hypotensive response to unclipping is mediated by exosomes released from the renal medulla. In male C57BL6/J mice made hypertensive by the 2K1C surgery, unclipping of the renal artery after 10 days decreased mean arterial pressure (MAP) by 23 mmHg one hr after unclipping. This effect was accompanied by a 556% increase in the concentration of exosomes in plasma as observed by nanoparticle tracking analysis. Immunohistochemical analysis of exosome markers, CD63 and AnnexinII, showed increased staining in interstitial cells of the inner medulla of stenotic but not contralateral control kidney of clipped 2K1C mice. Treatment with rapamycin, an inducer of exosome release, blunted the hypertensive response to clipping, whereas GW-4869, an exosome biosynthesis inhibitor, prevented both the clipping-induced increase in inner medullary exosome marker staining and the unclipping-induced fall in MAP. Plasma exosomes isolated from unclipped 2K1C mice showed elevated neutral lipid content compared to sham mouse exosomes by flow cytometric analysis after Nile red staining. Exosomes from 2K1C but not sham control mice exerted potent MAP-lowering and diuretic-natriuretic effects in both 2K1C and angiotensin II-infused hypertensive mice. These results are consistent with increased renomedullary synthesis and release of exosomes with elevated antihypertensive neutral lipids in response to increased renal perfusion pressure.


Assuntos
Anti-Hipertensivos , Exossomos , Hipertensão , Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Diuréticos/farmacologia , Hipertensão/terapia , Rim , Lipídeos , Masculino , Camundongos , Natriuréticos/farmacologia , Sirolimo/farmacologia
4.
Int Heart J ; 63(1): 8-14, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35095081

RESUMO

Acute pulmonary embolism (PE) remains a significant cause of cardiovascular morbidity and mortality worldwide. Brain natriuretic peptide (BNP) combined with catheter-directed therapy (CDT) may improve right ventricular (RV) dysfunction and stabilize hemodynamics in acute PE.We retrospectively studied 159 patients with confirmed acute PE who were treated with CDT and admitted to the intensive care unit of our department between September 2016 and May 2020. The patients were divided into the control group and the rhBNP group based on whether to receive recombinant human BNP treatment (rhBNP) or not. The basic characteristics of the patients between the control group and the rhBNP group was systematically compared during admission and follow-up. Risk factors for all-cause mortality within 30 days were determined using multivariate logistic regression analysis.Respiratory rate was found to be significantly lower in the rhBNP group than in the control group. Patients in the rhBNP group had significantly lower levels of white blood cell, C-reactive protein (CRP), D-dimers, troponin I, creatinine, and N-terminal (NT) -proBNP compared with those in the control group. Levels of tricuspid annular plane systolic excursion were significantly higher in the rhBNP group than in the control group. The percentage of patients with rehospitalization readmission due to PE differed significantly between the control group and the rhBNP group. On the basis of the multivariate regression analysis, CRP, creatinine, troponin I, and NT-proBNP were independent factors of all-cause mortality in 30 days.rhBNP is effective in the treatment of patients with RV dysfunction caused by acute PE who underwent CDT, which may be an alternative treatment option for improving clinical prognosis.


Assuntos
Cateterismo de Swan-Ganz , Natriuréticos/uso terapêutico , Peptídeo Natriurético Encefálico/uso terapêutico , Embolia Pulmonar/terapia , Disfunção Ventricular Direita/tratamento farmacológico , Doença Aguda , Idoso , Feminino , Humanos , Masculino , Trombólise Mecânica , Pessoa de Meia-Idade , Embolia Pulmonar/complicações , Embolia Pulmonar/diagnóstico , Proteínas Recombinantes , Estudos Retrospectivos , Terapia Trombolítica , Resultado do Tratamento , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/etiologia
5.
J Am Heart Assoc ; 10(21): e022542, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34713714

RESUMO

Background The gut-derived hormone GLP-1 (glucagon-like peptide-1) exerts beneficial effects against established risk factors for chronic kidney disease. GLP-1 influences renal function by stimulating diuresis and natriuresis and thus lowering arterial blood pressure. The role of the sympathetic nervous system has been implicated as an important link between obesity with elevated arterial pressure and chronic kidney disease. The primary aim of this study was to determine the contribution of renal sympathetic nerves on intrapelvic GLP-1-mediated diuresis and natriuresis in high-fat diet (HFD)-induced obese rats. Methods and Results Obesity was induced in rats by HFD for 12 weeks, followed by either surgical bilateral renal denervation or chronic subcutaneous endopeptidase neprilysin inhibition by sacubitril for a week. Diuretic and natriuretic responses to intrapelvic administration of the GLP-1R (GLP-1 receptor) agonist exendin-4 were monitored in anesthetized control and HFD rats. Renal GLP-1R expression and neprilysin expression and activity were measured. The effects of norepinephrine on the expression of GLP-1R and neprilysin in kidney epithelial LLC-PK1 cells were also examined. We found that diuretic and natriuretic responses to exendin-4 were significantly reduced in the HFD obese rats compared with the control rats (cumulative urine flow at 40 minutes, 387±32 versus 650±65 µL/gkw; cumulative sodium excretion at 40 minutes, 42±5 versus 75±10 µEq/gkw, P<0.05). These responses in the HFD rats were restored after ablation of renal nerves (cumulative urine flow at 40 minutes, 625±62 versus 387±32 µL/gkw; cumulative sodium excretion at 40 minutes, 70±9 versus 42±5 µEq/gkw, P<0.05). Renal denervation induced significant reductions in arterial pressure and heart rate responses to intrapelvic GLP-1 in the HFD rats. Renal denervation also significantly increased the GLP-1R expression and reduced neprilysin expression and activity in renal tissues from the HFD rats. Chronic subcutaneous neprilysin inhibition by sacubitril increased GLP-1-induced diuretic and natriuretic effects in the HFD rats. Finally, exposure of the renal epithelial cells to norepinephrine in vitro led to downregulation of GLP-1R expression but upregulation of neprilysin expression and activity. Conclusions These results suggest that renal sympathetic nerve activation contributes to the blunted diuretic and natriuretic effects of GLP-1 in HFD obese rats. This study provides significant novel insight into the potential renal nerve-neprilysin-GLP-1 pathway involved in renal dysfunction during obesity that leads to hypertension.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Natriurese , Insuficiência Renal Crônica , Aminobutiratos , Animais , Compostos de Bifenilo , Dieta Hiperlipídica , Diurese , Diuréticos , Exenatida/farmacologia , Rim/fisiologia , Natriuréticos , Neprilisina , Norepinefrina , Obesidade , Ratos , Sódio , Sistema Nervoso Simpático
6.
J Med Chem ; 64(11): 7691-7701, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34038119

RESUMO

A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.


Assuntos
Natriuréticos/química , Bloqueadores dos Canais de Potássio/química , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Animais , Benzofuranos/química , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/química , Diuréticos/metabolismo , Diuréticos/farmacologia , Cães , Meia-Vida , Haplorrinos , Humanos , Masculino , Natriuréticos/metabolismo , Natriuréticos/farmacologia , Piperazinas/química , Potássio/urina , Bloqueadores dos Canais de Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos , Ratos Endogâmicos SHR
7.
Circ Heart Fail ; 14(4): e007871, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33775110

RESUMO

BACKGROUND: Hospitalization for heart failure (HF) is associated with increased risk of death among patients with chronic HF. The degree to which hospitalization for HF is a distinct biologic entity with independent prognostic value versus a marker of higher risk chronic HF patients is unclear. METHODS: After excluding patients with new-onset HF, the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) included 4205 patients hospitalized for worsening chronic HF with reduced or preserved ejection fraction. The present analysis compared patients by presence or absence of prior HF hospitalization within 12 months and by timing of prior HF hospitalization relative to index hospitalization. Associations with 180-day all-cause mortality were assessed, including adjustment for 27 prespecified clinical factors. RESULTS: Overall, 2241 (53.3%) patients had a HF hospitalization within the prior 12 months and 1964 (46.7%) did not. Mortality rates at 180 days were 15.5% and 11.9%, respectively. In unadjusted analyses, prior HF hospitalization was associated with increased risk of 180-day mortality (HR, 1.35 [95% CI, 1.14-1.59]; P<0.01). After adjustment, the point estimate was attenuated and the association not statistically significant (HR, 1.18 [95% CI, 0.99-1.40]; P=0.064). Similarly, after adjustment, compared with patients without prior hospitalization, prior HF hospitalization was not associated with mortality, irrespective of timing (0-4 months: HR, 1.10 [95% CI, 0.87-1.39], P=0.41; 4-8 months: HR, 0.95 [95% CI, 0.70-1.27]; P=0.72; 8-12 months: HR, 1.06 [95% CI, 0.74-1.51], P=0.77; >12 months: HR, 0.81 [95% CI, 0.63-1.06], P=0.12). CONCLUSIONS: In this cohort of patients hospitalized for worsening HF, prior HF hospitalization was not associated with 180-day mortality after comprehensively accounting for patient characteristics measured during the index patient visit. Clinical confounders measured at the point-of-care may explain previously observed associations between prior HF hospitalization and mortality, and these clinical factors may be a more direct means of predicting patient survival. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00475852.


Assuntos
Insuficiência Cardíaca/mortalidade , Hospitalização/estatística & dados numéricos , Volume Sistólico , Idoso , Doença Crônica , Progressão da Doença , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Natriuréticos/uso terapêutico , Peptídeo Natriurético Encefálico/uso terapêutico , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida
8.
Adv Med Sci ; 66(1): 206-214, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33735829

RESUMO

PURPOSE: Several studies have demonstrated that C-type natriuretic peptide (CNP) stimulates osteoblastic proliferation seemly via antagonizing the expression of fibroblast growth factor (FGF)-23 in vitro. The main aim of the present study is to probe whether the post-receptor pathways of FGF-23 participate in osteogenesis caused by CNP. METHODS: Osteoblasts were cultured in the absence or presence of CNP: 0, 10, and 100 â€‹pmol/L, for 24 â€‹h, 48 â€‹h and 72 â€‹h, respectively. RESULTS: The findings of the present study indicated that osteoblastic proliferation was directly promoted by exogenous CNP in a dose-dependent manner; osteoblastic FGF-23 was significantly down-regulated by CNP at 24 â€‹h post-treatment; RAF-1, extracellular signal-regulated kinases (ERK), and P38 were substantially suppressed by CNP in a dose- and time-dependent manner; and signal transducer and activator of transcription (STAT)-1 was not changed on the premise of the down-regulated FGF-23 in osteoblasts treated with CNP. CONCLUSION: CNP may promote osteogenesis via inhibiting ERK and P38, rather than STAT-1, in the downstream of FGF-23/RAF-1 pathway.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Natriuréticos/farmacologia , Peptídeo Natriurético Tipo C/farmacologia , Osteoblastos/citologia , Osteogênese , Proteínas Proto-Oncogênicas c-raf/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/genética , Masculino , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Proteínas Proto-Oncogênicas c-raf/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
9.
Am J Med Sci ; 361(2): 261-268, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33526214

RESUMO

BACKGROUND: The most vexing problem in hyponatremic conditions is to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C-RSW). Both have identical clinical parameters but diametrically opposite therapeutic goals of water- restricting water-logged patients with SIADH or administering salt and water to dehydrated patients with C-RSW. While C-RSW is considered a rare condition, the report of a high prevalence of C-RSW in the general hospital wards creates an urgency to differentiate one syndrome from the other on first encounter. We decided to identify the natriuretic factor (NF) we previously demonstrated in plasma of neurosurgical and Alzheimer diseases (AD) who had findings consistent with C-RSW. METHODS: We performed the same rat renal clearance studies to determine natriuretic activity (NA) in serum from a patient with a subarachnoid hemorrhage (SAH) and another with AD and demonstrated NA in their sera. The sera were subjected to proteomic and SWATH (Sequential Windowed Acquisition of All) analyses which identified increased levels of haptoglobin related protein (Hpr) without signal peptide (Hpr-WSP). RESULTS: Recombinant Hpr with His tag at the N terminus had no NA. Hpr-WSP had a robust NA in a dose-dependent manner when injected into rats. Serum after recovery from C-RSW in the SAH patient had no NA. CONCLUSIONS: Hpr-WSP may be the NF in C-RSW which should be developed as a biomarker to differentiate C-RSW from SIADH on first encounter, introduces a new syndrome of C-RSW in AD and can serve as a proximal diuretic to treat congestive heart failure.


Assuntos
Doença de Alzheimer/sangue , Antígenos de Neoplasias/sangue , Natriuréticos/sangue , Hemorragia Subaracnóidea/sangue , Desequilíbrio Hidroeletrolítico/sangue , Idoso , Animais , Biomarcadores/sangue , Encéfalo/metabolismo , Feminino , Haptoglobinas , Humanos , Rim/metabolismo , Masculino , Ratos , Síndrome
11.
J Card Fail ; 27(6): 670-676, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33497809

RESUMO

BACKGROUND: The inflammatory cytokine IL-6 has been previously implicated in the pathophysiology of acute decompensated heart failure (HF). Prior observations in acute HF patients have suggested that IL-6 may be associated with outcomes and modulated by nesiritide. We aimed to evaluate the associations between serial IL-6 measurements, mortality and rehospitalization in acute HF. METHODS AND RESULTS: We analyzed the associations between IL-6 in acute HF, readmission, and mortality (30 and 180 days) using a cohort of 883 hospitalized patients from the ASCEND-HF trial (nesiritide vs placebo). Plasma IL-6 was measured at randomization (baseline), 48-72 hours, and 30 days. The median IL-6 was highest at baseline (14.1 pg/mL) and decreased at subsequent time points (7.6 pg/mL at 30 days). In a univariable Cox regression analysis, the baseline IL-6 was associated with 30- and 180-day mortality (hazard ratio per log 1.74, 95% confidence interval 1.09-2.78, P = .021; hazard ratio 3.23, confidence interval 1.18-8.86, P = .022, respectively). However, there was no association after multivariable adjustment. IL-6 at 48-72 hours was found to be independently associated with 30-day mortality (hazard ratio 8.2, confidence interval 1.2-57.5, P= .03), but not 180-day mortality in multivariable analysis that included the ASCEND-HF risk model and amino terminal pro-B-type natriuretic peptide as covariates. In comparison with placebo, nesiritide therapy was not associated with differences in serial IL-6 levels. CONCLUSIONS: Although elevated IL-6 levels were associated with higher all-cause mortality in acute HF, no independent association with this outcome was identified at baseline or 30-day measurements. In contrast with prior reports, we did not observe any impact of nesiritide over placebo on serial IL-6 levels.


Assuntos
Insuficiência Cardíaca , Interleucina-6 , Doença Aguda , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Natriuréticos/uso terapêutico , Peptídeo Natriurético Encefálico , Modelos de Riscos Proporcionais
12.
Anim Reprod Sci ; 225: 106685, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33388612

RESUMO

The present study was conducted to evaluate the effects in vitro on oocyte mitochondrial function of C-type natriuretic peptide (CNP) when treatments were imposed before in vitro maturation (IVM). Immature oocytes were either directly matured in vitro for 24 h (Control, no pre-IVM), or cultured in basic medium not supplemented or supplemented with CNP (100 nM) (Control pre-IVM and CNP pre-IVM, respectively) for 6 h, followed by IVM for 24 h. The results indicated treatment with CNP before IVM affected patterns of distribution of mitochondria, increased the mitochondrial content, membrane potential, and decreased the ROS content in cattle oocytes before and after IVM. Furthermore, treatment of immature cattle oocytes with CNP before IVM induced marked increases in the relative abundance of mRNA transcripts and proteins related to mitochondria development and antioxidative defense mechanisms. Treatment with CNP before oocyte IVM also resulted in an enhanced relative abundance of sirtuin-1 (SIRT1) mRNA transcript in cattle oocytes. Taken together, these results provide evidence that treatment of cattle oocytes with CNP before IVM improved mitochondrial function and antioxidant defense mechanisms in cattle oocytes. Findings in the present study provide insights into the potential mechanisms by which CNP has positive effects on oocyte cytoplasmic organelles, specifically mitochondria.


Assuntos
Bovinos , Técnicas de Maturação in Vitro de Oócitos/veterinária , Mitocôndrias/metabolismo , Peptídeo Natriurético Tipo C/farmacologia , Oócitos/efeitos dos fármacos , Animais , Células do Cúmulo/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Natriuréticos/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo
13.
Diabetes Care ; 44(2): 440-447, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33318125

RESUMO

OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for heart failure hospitalization potentially by inducing sodium excretion, osmotic diuresis, and plasma volume contraction. Few studies have investigated this hypothesis, but none have assessed cumulative sodium excretion with SGLT2 inhibition during standardized sodium intake in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The DAPASALT trial was a mechanistic, nonrandomized, open-label study in patients with type 2 diabetes with preserved kidney function on a controlled standardized sodium diet (150 mmol/day). It evaluated the effects of dapagliflozin on sodium excretion, 24-h blood pressure, and extracellular, intracellular, and plasma volumes at the start of treatment (ST) (days 2-4), end of treatment (ET) (days 12-14), and follow-up (FU) (days 15-18). RESULTS: Fourteen patients were included in the efficacy analysis. Mean (SD) baseline sodium excretion (150 [32] mmol/24-h) did not significantly change during treatment (change at ST: -7.0 mmol/24-h [95% CI -22.4, 8.4]; change at ET: 2.1 mmol/24-h [-28.8, 33.0]). Mean baseline 24-h systolic blood pressure was 128 (10) mmHg and significantly reduced at ST (-6.1 mmHg [-9.1, -3.1]; P < 0.001) and ET (-7.2 mmHg [-10.0, -4.3]; P < 0.001). Dapagliflozin did not significantly alter plasma volume or intracellular volume, while extracellular volume changed at ST (-0.7 L [-1.3, -0.1]; P = 0.02). As expected, 24-h urinary glucose excretion significantly increased during dapagliflozin treatment and reversed during FU. CONCLUSIONS: During standardized sodium intake, dapagliflozin reduced blood pressure without clear changes in urinary sodium excretion, suggesting that factors other than natriuresis and volume changes may contribute to the blood pressure-lowering effects.


Assuntos
Diabetes Mellitus Tipo 2 , Sódio na Dieta , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos/uso terapêutico , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos , Humanos , Rim , Natriuréticos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
14.
Heart ; 107(5): 396-402, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747497

RESUMO

OBJECTIVE: B-type natriuretic peptide (BNP) has favourable effects on left ventricular remodelling, including antifibrotic and antiapoptotic properties. We tested the hypothesis that infusion of BNP after an acute myocardial infarction would reduce left ventricular systolic and diastolic volumes and improve left ventricular ejection fraction compared with placebo. METHODS: A total of 58 patients who underwent successful revascularisation for an acute ST elevation anterior myocardial infarction were randomised to receive 72-hour infusion of BNP at 0.006 µg/kg/min or placebo. Left ventricular end diastolic and systolic volumes and left ventricular ejection fraction were measured at baseline and at 30 days by multigated acquisition scan. Left ventricular infarction size was measured by cardiac MRI. RESULTS: BNP infusion led to significantly higher BNP levels and plasma cyclic guanosine monophosphate at 72 hours. No significant difference in change of left ventricular volumes or ejection fraction from baseline to 30 days was observed between groups. Although left ventricular infarction size measured by cardiac MRI was not significantly different between BNP infusion versus placebo (p=0.39), there was a trend towards reduced infarction size in patients with a baseline ejection fraction of <40% (p=0.14). CONCLUSIONS: Infusion of BNP in patients with an anterior myocardial infarction did not affect parameters of left ventricular remodelling. Patients treated with BNP who had a baseline left ventricular ejection fraction of <40% had a trend towards reduced left ventricular infarction size compared with placebo. These results do not support the use of intravenous BNP in patients after recent myocardial infarction. TRIAL REGISTRATION NUMBER: NCT00573144.


Assuntos
Natriuréticos/uso terapêutico , Peptídeo Natriurético Encefálico/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Volume Sistólico/efeitos dos fármacos , Remodelação Ventricular , Método Duplo-Cego , Guanosina Monofosfato/sangue , Ventrículos do Coração/diagnóstico por imagem , Humanos , Infusões Intravenosas , Imagem Cinética por Ressonância Magnética , Revascularização Miocárdica , Peptídeo Natriurético Encefálico/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem
15.
JCI Insight ; 5(22)2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33055420

RESUMO

Heart failure is often accompanied by titin-dependent myocardial stiffness. Phosphorylation of titin by cGMP-dependent protein kinase I (PKGI) increases cardiomyocyte distensibility. The upstream pathways stimulating PKGI-mediated titin phosphorylation are unclear. We studied whether C-type natriuretic peptide (CNP), via its guanylyl cyclase-B (GC-B) receptor and cGMP/PKGI signaling, modulates titin-based ventricular compliance. To dissect GC-B-mediated effects of endogenous CNP in cardiomyocytes, we generated mice with cardiomyocyte-restricted GC-B deletion (CM GC-B-KO mice). The impact on heart morphology and function, myocyte passive tension, and titin isoform expression and phosphorylation was studied at baseline and after increased afterload induced by transverse aortic constriction (TAC). Pressure overload increased left ventricular endothelial CNP expression, with an early peak after 3 days. Concomitantly, titin phosphorylation at Ser4080, the site phosphorylated by PKGI, was augmented. Notably, in CM GC-B-KO mice this titin response was abolished. TAC-induced hypertrophy and fibrosis were not different between genotypes. However, the KO mice presented mild systolic and diastolic dysfunction together with myocyte stiffness, which were not observed in control littermates. In vitro, recombinant PKGI rescued reduced titin-Ser4080 phosphorylation and reverted passive stiffness of GC-B-deficient cardiomyocytes. CNP-induced activation of GC-B/cGMP/PKGI signaling in cardiomyocytes provides a protecting regulatory circuit preventing titin-based myocyte stiffening during early phases of pressure overload.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Peptídeo Natriurético Tipo C/farmacologia , Proteínas Quinases/metabolismo , Receptores do Fator Natriurético Atrial/fisiologia , Animais , GMP Cíclico/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Natriuréticos/farmacologia , Fosforilação , Proteínas Quinases/genética
16.
Sci Rep ; 10(1): 18213, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106527

RESUMO

The present study aimed to evaluate the effects of C-type natriuretic peptide (CNP) on meiotic arrest and developmental competence of bovine oocyte derived from follicles of different sizes. Collected immature cumulus-oocyte complexes from small follicles (< 3 mm) and medium follicles (3-8 mm) were cultured for 6 h in basal medium supplementated without or with 200 nM CNP. We observed that CNP effectively sustained meiotic arrest at germinal vesicle stage in in vitro cultured bovine oocytes from follicles of different sizes. Moreover, CNP treatment significantly improved the levels of cGMP in both cumulus cells and oocytes, as well as the levels of cAMP in oocytes regardless of follicle size. Based on the above results, we tested the effect of a novel in vitro maturation (IVM) system based on CNP-pretreatment, including a pre-IVM phase for 6 h using 200 nM CNP, followed by a extended IVM phase for 28 h, on developmental competence of bovine oocyte derived from small follicles (< 3 mm) and medium follicles (3-8 mm) compared to standard IVM system. The results showed that athough the novel IVM system based on CNP-pretreatment enhanced the developmental potencial of oocytes obtained from large follicles, but had no effect on the developmental comptence of oocytes obtained from small follicles.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Técnicas de Maturação in Vitro de Oócitos/métodos , Meiose/efeitos dos fármacos , Peptídeo Natriurético Tipo C/farmacologia , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Animais , Bovinos , Células Cultivadas , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Feminino , Natriuréticos/farmacologia , Oócitos/crescimento & desenvolvimento , Folículo Ovariano/crescimento & desenvolvimento
17.
A A Pract ; 14(9): e01295, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32909725

RESUMO

We report for the first time therapy-resistant hypernatremia (plasma sodium concentration ≥150 mmol per liter) developing in 6 of 12 critically ill coronavirus disease 2019 (COVID-19) patients age 57-84 years requiring mechanical ventilation. There was no correlation between plasma sodium concentrations and sodium input. Plasma concentrations of chloride were elevated, those of potassium decreased. These findings are consistent with abnormally increased renal sodium reabsorption, possibly caused by increased angiotensin II activity secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced downregulation of angiotensin-converting enzyme 2 (ACE2) receptors. As hypernatremia was associated with increased length of intensive care unit stay, special attention should be paid to the electrolyte status of COVID-19 patients.


Assuntos
Infecções por Coronavirus/complicações , Hidratação/métodos , Hipernatremia/complicações , Natriuréticos/uso terapêutico , Pneumonia Viral/complicações , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Estudos de Casos e Controles , Cloretos/sangue , Estudos de Coortes , Infecções por Coronavirus/sangue , Feminino , Hidratação/estatística & dados numéricos , Mortalidade Hospitalar , Humanos , Hipernatremia/sangue , Hipernatremia/epidemiologia , Hipernatremia/terapia , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Diálise Renal , Respiração Artificial , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Estudos Retrospectivos , SARS-CoV-2
18.
Am J Physiol Renal Physiol ; 319(4): F712-F728, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32893663

RESUMO

Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this "potential bicarbonate." The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus/tratamento farmacológico , Glucosídeos/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Natriurese/efeitos dos fármacos , Natriuréticos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Trocador 3 de Sódio-Hidrogênio/metabolismo , Equilíbrio Ácido-Base/efeitos dos fármacos , Animais , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Modelos Animais de Doenças , Glicosúria/metabolismo , Glicosúria/fisiopatologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Trocador 3 de Sódio-Hidrogênio/deficiência , Trocador 3 de Sódio-Hidrogênio/genética
19.
Heart Vessels ; 35(9): 1218-1226, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32270357

RESUMO

The mechanisms of the diuretic effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor and its predictors in heart failure (HF) patients with coexisting type 2 diabetes mellitus (T2DM) remain under investigation. A total of 40 hospitalized HF patients with T2DM (68 ± 13 years old, male gender 63%) were prospectively enrolled and received ipragliflozin at a dose of 50 mg once daily after breakfast for at least 4 consecutive days. They underwent first-morning blood and urine tests, and 24-h urine tests before and after short-term ipragliflozin therapy. Daily urine volume significantly increased from 1365 ± 511 mL/day on day 0 to 1698 ± 595 mL/day on day 3 (P < 0.001), which resulted in significant decreases in body weight and plasma brain natriuretic peptide level. Changes in 24-h urine volume were strongly and independently correlated with changes in 24-h urine sodium excretion (r = 0.80, P < 0.001), but was not significantly correlated with those in 24-h urine sugar excretion (r = 0.29, P = 0.07). Lower concentration of first-morning urine sodium and higher loop diuretic dosage before ipragliflozin therapy were associated with urine volume increment with ipragliflozin therapy, and former retained its independent predictor (Odds ratio 0.96, 95% CI 0.93-0.99, P = 0.02). First-morning urine sodium ≤ 53 mEq/L and baseline loop diuretics ≥ 20 mg/day predicted increased urine volume on day 3 with high diagnostic accuracy. Ipragliflozin has acute natriuretic activity, and first-morning urine sodium and baseline dosage of loop diuretics strongly predicted the diuretic effects. Ipragliflozin therapy may restore responsiveness to loop diuretics in symptomatic HF patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Natriurese/efeitos dos fármacos , Natriuréticos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tiofenos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Glucosídeos/efeitos adversos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Natriuréticos/efeitos adversos , Estudos Prospectivos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Tiofenos/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
20.
Bull Exp Biol Med ; 168(5): 634-636, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32246367

RESUMO

In rats, intramuscular injection of oxytocin (0.25 nmol/100 g body weight) increased sodium excretion from 19±5 to 120±11 µmol/min. A significant correlation (p<0.001) was revealed between renal excretion of oxytocin and sodium ions. Under the action of oxytocin, natriuresis was characterized by diminished reabsorption of fluid in the proximal tubule of the nephron attested by elevated lithium clearance rate and from stimulation of V1a receptors in the cells of thick ascending loop of Henle. Pmp-Tyr(Me)-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2, a V1a receptors antagonist, prevented the natriuretic effect of oxytocin.


Assuntos
Natriurese/efeitos dos fármacos , Ocitocina/farmacologia , Animais , Feminino , Injeções Intramusculares , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Natriuréticos/administração & dosagem , Natriuréticos/farmacologia , Ocitocina/administração & dosagem , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sódio/metabolismo
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