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Does aldosterone upregulate the brain renin-angiotensin system in rats with heart failure?

ABSTRACT: The brain renin-angiotensin system (RAS) contributes to increased sympathetic drive in heart failure (HF). The factors upregulating the brain RAS in HF remain unknown. We hypothesized that aldosterone (ALDO), a downstream product of the systemic RAS that crosses the blood-brain barrier, signals the brain to increase RAS activity in HF. We examined the relationship between circulating and brain ALDO in normal intact rats, in adrenalectomized rats receiving subcutaneous infusions of ALDO, and in rats with ischemia-induced HF and sham-operated controls. Brain ALDO levels were proportional to plasma ALDO levels across the spectrum of rats studied. Compared with sham-operated controls rats, HF rats had higher plasma and hypothalamic tissue levels of ALDO. HF rats also had higher expression of mRNA and protein for angiotensin-converting enzyme and angiotensin type 1 receptors in the hypothalamus, increased reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and superoxide generation in the paraventricular nucleus of the hypothalamus, increased excitation of paraventricular nucleus neurons, and increased plasma norepinephrine. HF rats treated for 4 weeks with intracerebroventricular RU28318 (1 microg/h), a selective mineralocorticoid receptor antagonist, had less hypothalamic angiotensin-converting enzyme and angiotensin type 1 receptor mRNA and protein, less reduced nicotinamide-adenine dinucleotide phosphate-induced superoxide in the paraventricular nucleus, fewer excited paraventricular nucleus neurons, and lower plasma norepinephrine. RU28318 had no effect on plasma ALDO or on angiotensin-converting enzyme or angiotensin type 1 receptor expression in brain cortex. The data demonstrate that ALDO of adrenal origin enters the hypothalamus in direct proportion to plasma levels and suggest that ALDO contributes to the upregulation of hypothalamic RAS activity and sympathetic drive in heart failure.

SUBMITTER: Yu Y

PROVIDER: S-EPMC2790402 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Does aldosterone upregulate the brain renin-angiotensin system in rats with heart failure?

Yu Yang Y Wei Shun-Guang SG Zhang Zhi-Hua ZH Gomez-Sanchez Elise E Weiss Robert M RM Felder Robert B RB

Hypertension (Dallas, Tex. : 1979) 20080128 3

The brain renin-angiotensin system (RAS) contributes to increased sympathetic drive in heart failure (HF). The factors upregulating the brain RAS in HF remain unknown. We hypothesized that aldosterone (ALDO), a downstream product of the systemic RAS that crosses the blood-brain barrier, signals the brain to increase RAS activity in HF. We examined the relationship between circulating and brain ALDO in normal intact rats, in adrenalectomized rats receiving subcutaneous infusions of ALDO, and in r ...[more]

PMID: 18227408

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Project description:The purpose of this study was to assess the relationship between biomarkers of renin-angiotensin-aldosterone system (RAAS) activation and decongestion strategies, worsening renal function, and clinical outcomes.High-dose diuretic therapy in patients with acute heart failure (AHF) is thought to activate the RAAS; and alternative decongestion strategies, such as ultrafiltration (UF), have been proposed to mitigate this RAAS activation.This study analyzed 427 AHF patients enrolled in the DOSE-AHF (Diuretic Optimization Strategies in Acute Heart Failure) and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trials. We assessed the relationship between 2 markers of RAAS activation (plasma renin activity [PRA] and aldosterone) from baseline to 72 h and 96 h and decongestion strategy: high- versus low-dose and continuous infusion versus bolus furosemide for DOSE-AHF and UF versus stepped pharmacologic care for CARRESS-HF. We determined the relationships between RAAS biomarkers and 60-day outcomes.Patients with greater RAAS activation at baseline had lower blood pressures, lower serum sodium levels, and higher blood urea nitrogen (BUN) concentration. Continuous infusion furosemide and UF were associated with greater PRA increases (median: +1.66 vs. +0.66 ng/ml/h with continuous vs. bolus infusion, respectively, p = 0.021; +4.05 vs. +0.56 ng/ml/h with UF vs. stepped care, respectively, p = 0.014). There were no significant differences in RAAS biomarker changes with high- versus low-dose diuretic therapy (both: p > 0.5). Neither baseline log PRA nor log aldosterone was associated with increased death or HF hospitalization (hazard ratio [HR] for a doubling of 1.05; 95% confidence interval [CI]: 0.98 to 1.13; p = 0.18; and HR: 1.13; 95% CI: 0.99 to 1.28; p = 0.069, respectively). The change in RAAS biomarkers from baseline to 72 and 96 h was not associated with outcomes (both: p > 0.5).High-dose loop diuretic therapy did not result in RAAS activation greater than that with low-dose diuretic therapy. UF resulted in greater PRA increase than stepped pharmacologic care. Neither PRA nor aldosterone was significantly associated with short-term outcomes in this cohort. (Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure [DOSE-AHF]; NCT00577135; Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome [CARRESS]; NCT00608491).

Project description:Background Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, received US Food and Drug Administration approval in 2015 for heart failure with reduced ejection fraction (HFrEF). Our objective was to describe the sacubitril/valsartan initiation rate, associated characteristics, and 6-month follow-up dosing among veterans with HFrEF who are renin-angiotensin-aldosterone system inhibitor (RAASi) naïve. Methods and Results Retrospective cohort study of veterans with HFrEF who are RAASi naïve defined as left ventricular ejection fraction (LVEF) ≤40%; ≥1 in/outpatient heart failure visit, first RAASi (sacubitril/valsartan, angiotensin-converting enzyme inhibitor [ACEI]), or angiotensin-II receptor blocker [ARB]) fill from July 2015 to June 2019. Characteristics associated with sacubitril/valsartan initiation were identified using Poisson regression models. From July 2015 to June 2019, we identified 3458 sacubitril/valsartan and 29 367 ACEI or ARB initiators among veterans with HFrEF who are RAASi naïve. Sacubitril/valsartan initiation increased from 0% to 26.5%. Sacubitril/valsartan (versus ACEI or ARB) initiators were less likely to have histories of stroke, myocardial infarction, or hypertension and more likely to be older and have diabetes mellitus and lower LVEF. At 6-month follow-up, the prevalence of ≥50% target daily dose for sacubitril/valsartan, ACEI, and ARB initiators was 23.5%, 43.2%, and 47.1%, respectively. Conclusions Sacubitril/valsartan initiation for HFrEF in the Veterans Administration increased in the 4 years immediately following Food and Drug Administration approval. Sacubitril/valsartan (versus ACEI or ARB) initiators had fewer baseline cardiovascular comorbidities and the lowest proportion on ≥50% target daily dose at 6-month follow-up. Identifying the reasons for lower follow-up dosing of sacubitril/valsartan could support guideline recommendations and quality improvement strategies for patients with HFrEF.

Project description:AimsRecently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1-7) [Ang (1-7)]. Ang (1-7) is part of the angiotensin-converting enzyme-Ang (1-7)-Mas pathway which is considered to antagonize the renin-angiotensin-aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.Methods and resultsDipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3-LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin [78.3 (interquartile range, IQR 26.3-227.7) vs. 120.7 IU/mL (IQR 34.74-338.9), P < 0.001, for Q1-3 vs. Q4] and aldosterone [88 (IQR 44-179) vs. 116 IU/mL (IQR 46-241), P < 0.001, for Q1-3 vs. Q4] concentrations. The strongest independent predictors for higher concentration of DPP3 were log-alanine aminotransferase, log-total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor-23 and N-terminal pro-B-type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant.ConclusionsIn patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.

Dataset Information

Does aldosterone upregulate the brain renin-angiotensin system in rats with heart failure?

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Does aldosterone upregulate the brain renin-angiotensin system in rats with heart failure?

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