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1.
Exp Physiol ; 109(8): 1305-1316, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38890799

RESUMO

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose-dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR-C in regulating plasma concentrations of NPs and associated cGMP-mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.


Assuntos
GMP Cíclico , Hemodinâmica , Rim , Animais , Ovinos , Rim/metabolismo , GMP Cíclico/metabolismo , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Fator Natriurético Atrial/metabolismo , Fator Natriurético Atrial/sangue , Feminino , Peptídeo Natriurético Encefálico/metabolismo , Renina/metabolismo , Renina/sangue , AMP Cíclico/metabolismo , Peptídeo Natriurético Tipo C/metabolismo , Aldosterona/sangue , Aldosterona/metabolismo , Pressão Sanguínea/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Peptídeos Natriuréticos/metabolismo , Natriurese
2.
Heart Fail Rev ; 29(5): 945-948, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38926215

RESUMO

The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) study, published in August of 2023, was the first randomized clinical trial to compare natriuresis-guided decongestion (based on spot urinary sodium measurement) to standard of care in patients with acute heart failure with congestion receiving loop diuretic therapy. Based on results from their trial, the authors concluded that natriuresis-guided loop diuretic treatment was safe and improved natriuresis and diuresis without impacting long-term clinical outcomes. The original PUSH-AHF trial included limited information about renal outcomes and left clinicians with important questions about how natriuresis-guided decongestion might affect their patients' renal function. On May 12, 2024, however, at the 2024 Annual Congress of the HFA-ESC, Dr. Kevin Damman provided an in-depth exploration of renal outcomes from the trial when he presented a pre-specified, secondary analysis, renal function in the PUSH-AHF trial. This review puts the sub-study findings into context by considering the history of the original trial from which they came from and explaining the need for a close study of its renal outcomes particularly. It highlights the potential impact of renal function in PUSH-AHF on clinical practice and future directions that should be considered by the cardiology research community.


Assuntos
Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Congressos como Assunto , Rim/fisiopatologia , Sociedades Médicas , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Natriurese/efeitos dos fármacos , Natriurese/fisiologia , Doença Aguda
3.
Br J Pharmacol ; 181(18): 3401-3419, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38773354

RESUMO

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.


Assuntos
Rim , Natriurese , Canal de Liberação de Cálcio do Receptor de Rianodina , Animais , Masculino , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Cães , Humanos , Ratos , Natriurese/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Ratos Sprague-Dawley , Adulto , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Tiazepinas/farmacologia , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Pessoa de Meia-Idade , Cardiotônicos/farmacologia , Cardiotônicos/administração & dosagem , Feminino
4.
Am J Physiol Renal Physiol ; 327(3): F435-F449, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38779754

RESUMO

We have previously observed that prolonged administration of rapamycin, an inhibitor targeting the mammalian target of rapamycin complex (mTORC)1, partially reduced hypertension and alleviated kidney inflammation in Dahl salt-sensitive (SS) rats. In contrast, treatment with PP242, an inhibitor affecting both mTORC1/mTORC2, not only completely prevented hypertension but also provided substantial protection against kidney injury. Notably, PP242 exhibited potent natriuretic effects that were not evident with rapamycin. The primary objective of this study was to pinpoint the specific tubular sites responsible for the natriuretic effect of PP242 in SS rats subjected to either 0.4% NaCl (normal salt) or 4.0% NaCl (high salt) diet. Acute effects of PP242 on natriuretic, diuretic, and kaliuretic responses were determined in unanesthetized SS rats utilizing benzamil, furosemide, or hydrochlorothiazide [inhibitors of epithelial Na+ channel (ENaC), Na-K-2Cl cotransporter (NKCC2), or Na-Cl cotransporter (NCC), respectively] either administered alone or in combination. The findings indicate that the natriuretic effects of PP242 in SS rats stem predominantly from the inhibition of NCC and a reduction of ENaC open probability. Molecular analysis revealed that mTORC2 regulates NCC activity through protein phosphorylation and ENaC activity through proteolytic cleavage in vivo. Evidence also indicated that PP242 also prevents the loss of K+ associated with the inhibition of NCC. These findings suggest that PP242 may represent an improved therapeutic approach for antihypertensive intervention, potentially controlling blood pressure and mitigating kidney injury in salt-sensitive human subjects.NEW & NOTEWORTHY This study explored mechanisms underlying the natriuretic effects of mammalian target of rapamycin protein complex 2 inhibition using PP242 and revealed both epithelial Na+ channel and Na-Cl cotransporter in the distal tubular segments were potentially inhibited. These observations, with prior lab evidence, indicate that PP242 prevents hypertension via its potent inhibitory effects on these specific sodium transporters and by reducing renal immune responses. This dual action, coupled with potassium sparing effects, suggests an improved approach for managing hypertension and associated kidney damage.


Assuntos
Canais Epiteliais de Sódio , Alvo Mecanístico do Complexo 2 de Rapamicina , Natriurese , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta , Membro 3 da Família 12 de Carreador de Soluto , Animais , Canais Epiteliais de Sódio/metabolismo , Natriurese/efeitos dos fármacos , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Masculino , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Hipertensão/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/metabolismo , Modelos Animais de Doenças , Ratos , Amilorida/farmacologia , Amilorida/análogos & derivados , Pressão Sanguínea/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Indóis , Purinas
5.
Eur J Heart Fail ; 26(6): 1347-1357, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734982

RESUMO

AIM: In a randomized controlled trial, we recently showed that a natriuresis-guided diuretic approach improved natriuresis and diuresis in patients with acute heart failure (HF). In this pre-specified analysis, we investigated the association between (worsening) renal function, outcomes and the effect of intensive natriuresis-guided loop diuretic therapy as compared with standard of care. METHODS AND RESULTS: The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) trial randomized patients to natriuresis-guided diuretic therapy or standard of care. Serum creatinine and estimated glomerular filtration rate (eGFR) were assessed at fixed timepoints, and worsening renal function (WRF) was assessed at 72 h. The primary outcome was the interaction between randomized treatment allocation, baseline eGFR and the dual primary outcome of PUSH-AHF: total natriuresis at 24 h and time to all-cause mortality or HF rehospitalization at 180 days. In 309 patients, median baseline eGFR was 53 (35-73) ml/min/1.73 m2, and 58% had eGFR <60 ml/min/1.73 m2. Baseline eGFR did not significantly modify the treatment effect of natriuresis-guided diuretic therapy on natriuresis at 24 h (p for interaction = 0.730). However, baseline eGFR significantly modified the effect on all-cause mortality and HF rehospitalization (p for interaction = 0.017): the risk of this second primary outcome was lower in patients with lower eGFR who were randomized to the natriuresis-guided group. In the natriuresis-guided arm, eGFR decreased more (-11.0 vs. -6.91 ml/min/1.73 m2; p = 0.002) during the first 3 days, but this effect was attenuated at discharge (-10.3 vs. -8.69 ml/min/1.73 m2; p = 0.38). WRF was more frequently observed in patients randomized to natriuresis-guided treatment, but was not associated with worse clinical outcomes. CONCLUSIONS: Natriuresis-guided diuretic treatment improved diuresis and natriuresis irrespective of baseline eGFR and occurrence of WRF, was effective even in patients with low eGFR, and the observed effect on eGFR was transient and not associated with worse clinical outcomes.


Assuntos
Taxa de Filtração Glomerular , Insuficiência Cardíaca , Natriurese , Humanos , Feminino , Masculino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Idoso , Natriurese/efeitos dos fármacos , Pessoa de Meia-Idade , Diuréticos/uso terapêutico , Diuréticos/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Resultado do Tratamento , Doença Aguda , Creatinina/sangue
9.
J Hypertens ; 42(6): 1086-1093, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38690907

RESUMO

BACKGROUND: Early-life programming due to prematurity and very low birth weight (VLBW, <1500 g) is believed to contribute to development of hypertension, but the mechanisms remain unclear. Experimental data suggest that altered pressure natriuresis (increased renal perfusion pressure promoting sodium excretion) may be a contributing mechanism. We hypothesize that young adults born preterm will have a blunted pressure natriuresis response to mental stress compared with those born term. METHODS: In this prospective cohort study of 190 individuals aged 18-23 years, 156 born preterm with VLBW and 34 controls born term with birth weight at least 2500 g, we measured urine sodium/creatinine before and after a mental stress test and continuous blood pressure before and during the stress test. Participants were stratified into groups by the trajectory at which mean arterial pressure (MAP) increased following the test. The group with the lowest MAP trajectory was the reference group. We used generalized linear models to assess poststress urine sodium/creatinine relative to the change in MAP trajectory and assessed the difference between groups by preterm birth status. RESULTS: Participants' mean age was 19.8 years and 57% were women. Change in urine sodium/creatinine per unit increase in MAP when comparing middle trajectory group against the reference group was greater in those born preterm [ß 5.4%, 95% confidence interval (95% CI) -11.4 to 5.3] than those born term (ß 38.5%, 95% CI -0.04 to 92.0), interaction term P = 0.002. CONCLUSION: We observed that, as blood pressure increased following mental stress, young adults born preterm exhibited decreased sodium excretion relative to term-born individuals.


Assuntos
Nascimento Prematuro , Sódio , Estresse Psicológico , Humanos , Feminino , Masculino , Adulto Jovem , Estresse Psicológico/fisiopatologia , Estresse Psicológico/urina , Adolescente , Sódio/urina , Estudos Prospectivos , Nascimento Prematuro/fisiopatologia , Pressão Sanguínea/fisiologia , Recém-Nascido , Creatinina/urina , Adulto , Natriurese
10.
Physiol Rep ; 12(9): e16033, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38740564

RESUMO

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.


Assuntos
Furosemida , Insuficiência Cardíaca , Rim , Peptídeo Natriurético Encefálico , Sódio , Volume Sistólico , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/metabolismo , Masculino , Feminino , Idoso , Projetos Piloto , Furosemida/farmacologia , Furosemida/administração & dosagem , Sódio/metabolismo , Sódio/urina , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/metabolismo , Rim/metabolismo , Rim/fisiopatologia , Rim/efeitos dos fármacos , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Diuréticos/farmacologia , Diuréticos/administração & dosagem , GMP Cíclico/metabolismo , GMP Cíclico/urina , Idoso de 80 Anos ou mais
12.
Curr Probl Cardiol ; 49(8): 102688, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38821235

RESUMO

Acute heart failure (AHF) is characterized by the emergence or intensification of symptoms and signs indicative of congestion or systemic hypoperfusion, stemming from an underlying structural or functional cardiac disorder. Intravenous loop diuretics play a pivotal role in achieving effective decongestion and ensuring clinical stability; the efficacy of these medications is crucial for determining the patient's hospital course and early outpatient progression. Individuals who exhibit a suboptimal response to diuretics or develop diuretic resistance (DR) are at an elevated risk for cardiovascular mortality and readmission due to AHF. However, there is a lack of standardized definition and diagnostic criteria for DR. Early identification of patients with DR is critical, as they may benefit from more aggressive decongestion strategies to mitigate this resistance. Natriuresis, the excretion of sodium in urine, serves as a direct measure of a diuretic's effectiveness. Low levels of natriuresis have been linked to poorer outcomes. Several studies have underscored the prognostic significance of natriuresis across various heart failure scenarios. However, the relationship between natriuresis and in-hospital DR has not been extensively studied. Observational research has indicated that inadequate natriuresis following the administration of loop diuretics correlates with a diminished diuretic response and an increased likelihood of mortality and heart failure rehospitalization. Further investigation is warranted to assess the predictive value of basal natriuresis concerning DR, in-hospital outcomes, and early outpatient cardiovascular events. This would help in identifying patients who are likely to respond poorly to diuretic therapy and may require alternative or more intensive treatment approaches.


Assuntos
Resistência a Medicamentos , Insuficiência Cardíaca , Natriurese , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/diagnóstico , Natriurese/efeitos dos fármacos , Natriurese/fisiologia , Doença Aguda , Diuréticos/uso terapêutico , Prognóstico , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia
13.
Eur J Heart Fail ; 26(7): 1507-1517, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38721803

RESUMO

AIMS: The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown. METHODS AND RESULTS: We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0-3 h), the load phase (3-6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6-9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (-0.50 [-12.7, 7.4] kg at 2 months, and -0.75 [-15.9, 7.5] kg at 3 months; both p < 0.0001). CONCLUSIONS: The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors.


Assuntos
Aminobutiratos , Antagonistas de Receptores de Angiotensina , Compostos de Bifenilo , Combinação de Medicamentos , Insuficiência Cardíaca , Natriurese , Volume Sistólico , Tetrazóis , Valsartana , Humanos , Valsartana/uso terapêutico , Aminobutiratos/uso terapêutico , Aminobutiratos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Masculino , Feminino , Idoso , Tetrazóis/uso terapêutico , Tetrazóis/administração & dosagem , Volume Sistólico/fisiologia , Volume Sistólico/efeitos dos fármacos , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/administração & dosagem , Resultado do Tratamento , Sódio , Diurese/efeitos dos fármacos , Diuréticos/uso terapêutico , Diuréticos/administração & dosagem , Estudos Prospectivos
14.
J Hypertens ; 42(9): 1632-1640, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38780161

RESUMO

OBJECTIVES: Potassium supplementation reduces blood pressure and the occurrence of cardiovascular diseases, with K + -induced natriuresis playing a potential key role in this process. However, whether these beneficial effects occur in diabetes remains unknown. METHODS: In this study, we examined the impact of high-K + intake on renal Na + /K + transport by determining the expression of major apical Na + transporters, diuretics responses (as a proxy for specific Na + transporter function), urinary Na + /K + excretion, and plasma Na + /K + concentrations in db/db mice, a model of type 2 diabetes mellitus. RESULTS: Although db/m mice exhibited increased fractional excretion of sodium (FE Na ) and fractional excretion of potassium (FE K ) under high-K + intake, these responses were largely blunted in db/db mice, suggesting impaired K + -induced natriuresis and kaliuresis in diabetes. Consequently, high-K + intake increased plasma K + levels in db/db mice, which could be attributed to the abnormal activity of sodium-hydrogen exchanger 3 (NHE3), sodium-chloride cotransporter (NCC), and epithelial Na + channel (ENaC), as high-K + intake could not effectively decrease NHE3 and NCC and increase ENaC expression and activity in the diabetic group. Inhibition of NCC by hydrochlorothiazide could correct the hyperkalemia in db/db mice fed a high-K + diet, indicating a key role for NCC in K + -loaded diabetic mice. Treatment with metformin enhanced urinary Na + /K + excretion and normalized plasma K + levels in db/db mice with a high-K + diet, at least partially, by suppressing NCC activity. CONCLUSION: Collectively, the impaired K + -induced natriuresis in diabetic mice under high-K + intake may be primarily attributed to impaired NCC-mediated renal K + excretion, despite the role of NHE3.


Assuntos
Hiperpotassemia , Natriurese , Potássio , Trocador 3 de Sódio-Hidrogênio , Animais , Natriurese/efeitos dos fármacos , Camundongos , Potássio/urina , Potássio/sangue , Potássio/metabolismo , Trocador 3 de Sódio-Hidrogênio/metabolismo , Masculino , Diabetes Mellitus Tipo 2/complicações , Suplementos Nutricionais
15.
Curr Probl Cardiol ; 49(8): 102674, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38795800

RESUMO

BACKGROUND: Some clinical guidelines recommend serial measurement of natriuresis to detect diuretic resistance (DR) in acute heart failure (AHF) patients, but it adds complexity to the management. OBJECTIVES: To correlate a single measurement of basal natriuresis (BN) on admission with the development of DR and clinical evolution in AHF hospitalized patients. METHODS: Prospective and multicenter study included AHF hospitalized patients, without shock or creatinine >2.5mg%. Patients received 40mg of intravenous furosemide on admission, then BN was measured, and diuretic treatment was guided by protocol. BN was considered low if <70 meq/L. DR was defined as the need of furosemide >240mg/day, tubular blockade (TB), hypertonic saline solution (HSS) or renal replacement therapy (RRT). In-hospital cardiovascular (CV) mortality, CV mortality and AHF readmissions at 60-day post-discharge were evaluated. RESULTS: 157 patients were included. BN was low in 22%. DR was development in 19% (12.7% furosemide >240mg/day, 8% TB, 4% RRT). Low NB was associated with DR (44% vs 12%; p 0.0001), persistence of congestion (26.5% vs 11.4%; p 0.05), furosemide >240 mg/day (29% vs 8%; p 0.003), higher cumulative furosemide dose at 72 hours (220 vs 160mg; p 0.0001), TB (20.6 vs 4.9%; p 0.008), RRT (11.8 vs 1.6%; p 0.02), worsening of AHF (27% vs 9%; p 0.01), inotropes use (21% vs 7%; p 0.48), respiratory assistance (12% vs 2%; p 0.02) and a higher in-hospital CV mortality (12% vs 4%; p 0.1). No association was demonstrated with post-discharge endpoints. CONCLUSIONS: In AHF patients, low BN was associated with DR, persistent congestion, need for aggressive decongestion strategies, and worse in-hospital evolution.


Assuntos
Diuréticos , Resistência a Medicamentos , Furosemida , Insuficiência Cardíaca , Natriurese , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Feminino , Masculino , Estudos Prospectivos , Idoso , Natriurese/efeitos dos fármacos , Natriurese/fisiologia , Doença Aguda , Diuréticos/uso terapêutico , Furosemida/uso terapêutico , Furosemida/administração & dosagem , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Mortalidade Hospitalar/tendências
16.
Cardiorenal Med ; 14(1): 270-280, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38565080

RESUMO

BACKGROUND: Increased renal sodium avidity is a hallmark feature of the heart failure syndrome. SUMMARY: Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure. KEY MESSAGES: Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration.


Assuntos
Insuficiência Cardíaca , Rim , Sódio , Humanos , Insuficiência Cardíaca/fisiopatologia , Sódio/metabolismo , Rim/fisiopatologia , Rim/metabolismo , Natriurese/fisiologia , Diuréticos/uso terapêutico , Síndrome Cardiorrenal/fisiopatologia , Síndrome Cardiorrenal/metabolismo
17.
Clin Exp Nephrol ; 28(8): 728-739, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38581621

RESUMO

BACKGROUND: Hypertension is one of the major etiologies that cause chronic kidney disease (CKD) and can exacerbate kidney dysfunction. Zinc is an essential trace element playing a role in blood pressure regulation, and zinc deficiency, a common comorbidity in patients with CKD, can cause hypertension. However, the precise mechanism underlying zinc deficiency-induced hypertension is unknown. Sodium (Na+) retention due to inappropriate Na+ reabsorption in the renal tubule is the principal pathophysiology of hypertension. Therefore, this study aimed to investigate the association between zinc deficiency and salt sensitivity. METHODS: Adult mice were fed a zinc-adequate (ZnA) or zinc-deficient (ZnD) diet combined with/without high salt in drinking water (HS) for 4 weeks (n = 6 each). Changes in blood pressure, urinary sodium excretion, and the expressions of the proximal tubular Na+ transporter, Na+/H+ exchanger 3 (NHE3), which mostly contributes to filtered Na+ reabsorption and the downstream Na+-Cl- transporter (NCC) were analyzed. RESULTS: Urinary Na+ excretion significantly increased in ZnD mice, indicating that zinc deficiency causes natriuresis. NHE3 expressions were significantly suppressed, whereas NCC was upregulated in ZnD mice. Interestingly, the combination of high salt and ZnD diet (HS-ZnD) reversed the urinary Na+ loss. The NCC remained activated and NHE3 expressions paradoxically increased in HS-ZnD mice compared with those fed the combination of high salt and ZnA diet. In addition, blood pressure significantly increased only in HS-ZnD mice. CONCLUSION: The combination of zinc deficiency and high salt causes hypertension. Zinc is associated with salt-sensitivity, potentially through NHE3 and NCC regulation.


Assuntos
Pressão Sanguínea , Hipertensão , Cloreto de Sódio na Dieta , Trocador 3 de Sódio-Hidrogênio , Zinco , Animais , Zinco/deficiência , Zinco/metabolismo , Hipertensão/etiologia , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos , Trocador 3 de Sódio-Hidrogênio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/genética , Sódio/urina , Sódio/metabolismo , Natriurese
18.
Am J Physiol Renal Physiol ; 326(5): F737-F750, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38482554

RESUMO

Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule but higher Na+ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.


Assuntos
Angiotensina II , Hipertensão , Natriurese , Trocador 3 de Sódio-Hidrogênio , Animais , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Feminino , Trocador 3 de Sódio-Hidrogênio/metabolismo , Natriurese/efeitos dos fármacos , Diuréticos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fatores Sexuais , Simulação por Computador , Sódio/metabolismo , Ratos , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Caracteres Sexuais , Modelos Animais de Doenças , Diurese/efeitos dos fármacos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Rim/metabolismo , Rim/efeitos dos fármacos , Rim/fisiopatologia
19.
Hypertens Res ; 47(4): 998-1016, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38302775

RESUMO

The aim was to evaluate the effects of renal denervation (RDN) on autoregulation of renal hemodynamics and the pressure-natriuresis relationship in Ren-2 transgenic rats (TGR) with aorto-caval fistula (ACF)-induced heart failure (HF). RDN was performed one week after creation of ACF or sham-operation. Animals were prepared for evaluation of autoregulatory capacity of renal blood flow (RBF) and glomerular filtration rate (GFR), and of the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. Their basal values of blood pressure and renal function were significantly lower than with innervated sham-operated TGR (p < 0.05 in all cases): mean arterial pressure (MAP) (115 ± 2 vs. 160 ± 3 mmHg), RBF (6.91 ± 0.33 vs. 10.87 ± 0.38 ml.min-1.g-1), urine flow (UF) (11.3 ± 1.79 vs. 43.17 ± 3.24 µl.min-1.g-1) and absolute sodium excretion (UNaV) (1.08 ± 0.27 vs, 6.38 ± 0.76 µmol.min-1.g-1). After denervation ACF TGR showed improved autoregulation of RBF: at lowest RAP level (80 mmHg) the value was higher than in innervated ACF TGR (6.92 ± 0.26 vs. 4.54 ± 0.22 ml.min-1.g-1, p < 0.05). Also, the pressure-natriuresis relationship was markedly improved after RDN: at the RAP of 80 mmHg UF equaled 4.31 ± 0.99 vs. 0.26 ± 0.09 µl.min-1.g-1 recorded in innervated ACF TGR, UNaV was 0.31 ± 0.05 vs. 0.04 ± 0.01 µmol min-1.g-1 (p < 0.05 in all cases). In conclusion, in our model of hypertensive rat with ACF-induced HF, RDN improved autoregulatory capacity of RBF and the pressure-natriuresis relationship when measured at the stage of HF decompensation.


Assuntos
Síndrome Cardiorrenal , Fístula , Insuficiência Cardíaca , Hipertensão , Ratos , Animais , Ratos Transgênicos , Pressão Sanguínea , Natriurese , Rim , Circulação Renal , Simpatectomia , Taxa de Filtração Glomerular
20.
Chem Biodivers ; 21(4): e202400175, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38345349

RESUMO

This research demonstrates the diuretic effect of naringenin, a flavanone aglycone found in citrus, on spontaneously hypertensive female and male rats (SHR). The data reinforces existing literature findings that male SHR exhibits higher systolic blood pressure than age-matched females. Urine volume assessed over 8 hours was lower when obtained from SHR males than females. When these animals were orally treated with different doses of naringenin (0.1-1 mg/kg), this increased urinary volume in both genders at the highest dose tested. In contrast, the lowest dose promoted a significant natriuretic effect. The other electrolytes analyzed in urine were not significantly altered, except potassium excretion, which was shown to be increased in the urine of SHR males. Furthermore, naringenin showed promise in reducing calcium oxalate (CaOx) crystal formation in an in vitro model, presenting potential advantages in lithiasis prevention.


Assuntos
Hipertensão , Urolitíase , Ratos , Feminino , Masculino , Animais , Ratos Endogâmicos SHR , Natriurese/fisiologia , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Diurese/fisiologia , Urolitíase/tratamento farmacológico , Urolitíase/prevenção & controle
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