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Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer's disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer's disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits. [ABSTRACT FROM AUTHOR]

Objective(s): Preeclampsia (PE) is a complication of pregnancy that might increase progeny risk of cardiovascular and metabolic problems, mainly in males. Renin angiotensin aldosterone system is known to be involved. (Pro) renin/renin receptor ((P)RR) has been shown to participate in cardiovascular pathology. The aim of this work was to evaluate (P)RR expression and function upon cardiovascular and renal tissues from PE dams' offspring. Materials and Methods: We used offspring from normal pregnant and preeclamptic rats, evaluating body, heart, aorta and kidney weight, length, and blood pressure along 3 months after birth. Subsets of animals received handle region peptide (HRP) (0.2 mg/Kg, sc). Another group received vehicle. Animals were sacrificed at first, second, and third months of age, tissues were extracted and processed for immunoblot to detect (P)RR, PLZF, β-catenin, DVL-1, and PKCα. (P)RR and PLZF were also measured by RT-PCR. Results: We found that offspring developed hypertension. Male descendants remained hypertensive throughout the whole experiment. Female animals tended to recover at second month and returned to normal blood pressure at third month. HRP treatment diminished hypertension in both male and female animals. Morphological evaluations showed changes in heart, aorta, and kidney weight, and HRP reverted this effect. Finally, we found that (P)RR, PLZF, and canonical WNT transduction pathway molecules were stimulated by PE, and HRP treatment abolished this increase. Conclusion: These findings suggest that PE can induce hypertension in offspring, and (P)RR seems to play an important role through the canonical WNT pathway and that gender seems to influence this response. [ABSTRACT FROM AUTHOR]

In this review, we will cover (i) the proteolytic cascade of the RAAS, (ii) its regulation by multiple feedback-controlled parameters, and (iii) the major effects of the RAAS. For the effects of the RAAS, we focus on the role of the RAAS in the regulation of volume homeostasis and vascular tone, as major determinants of arterial blood pressure. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a serious complication of diabetes, and its progression is influenced by factors like oxidative stress, inflammation, cell death, and fibrosis. Compared to drug treatment, exercise offers a cost-effective and low-risk approach to slowing down DN progression. Through multiple ways and mechanisms, exercise helps to control blood sugar and blood pressure and reduce serum creatinine and albuminuria, thereby alleviating kidney damage. This review explores the beneficial effects of exercise on DN improvement and highlights its potential mechanisms for ameliorating DN. In-depth understanding of the role and mechanism of exercise in improving DN would pave the way for formulating safe and effective exercise programs for the treatment and prevention of DN. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a disorder involving de novo development of hypertension plus end organ damage after 20 weeks of gestation. PE is considered to be a heterogeneous disease. There are 2 main types of PE: early-onset (<34 weeks of gestation), which is considered to be a placental disorder and is associated with vasoconstriction, low cardiac output, and placental hypoperfusion and organ damage due to decreased microcirculation to maternal organs; and late-onset PE, which is primarily a disorder of pregnant women with obesity, diabetes, and/or cardiovascular abnormalities. In late-onset PE, there is avid sodium reabsorption by the maternal kidneys, causing hypervolemia and increased cardiac output, along with vasodilatation causing venous congestion of organs. Although PE has been a well-known disease for a long time, it is interesting to note that there is no specific sodium (salt) intake recommendation for these patients. This may be due to the fact that studies since as far back as the 1900s have shown conflicting results, and the reasons for the inconsistent findings have not been fully explained; furthermore, the type of PE in these studies was not specifically defined. Some studies suggest that sodium restriction may be detrimental in early-onset PE, but may be feasible in late-onset PE. To explore this paradox, the current review explains the hemodynamic factors involved in these 2 types of PE, summarizes the findings of the current studies, and highlights the knowledge gaps and the research needed to determine whether increase or restriction of salt or sodium intake is beneficial in different types of PE. [ABSTRACT FROM AUTHOR]

Guo, Xinqi, Hongyu Ma, Ziye Cui, Qiyue Zhao, Ying Zhang, Lu Jia, Liping Zhang, Hui Guo, Xiangjian Zhang, Yi Zhang, Yue Guan, and Huijie Ma. Chronic intermittent hypobaric hypoxia reduces hypothalamic N-Methyl-d-Aspartate Receptor activity and sympathetic outflow in spontaneously hypertensive rats. High Alt Med Biol. 25:77–88, 2024. Objective: This study aims to determine the role of hypothalamic renin-angiotensin system (RAS) in the antihypertensive effect of chronic intermittent hypobaric hypoxia (CIHH). Methods: Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) received 35 days of hypobaric hypoxia simulating an altitude of 4,000 m, 5 h/day. The levels of RAS, blood pressure, and N-methyl-d-aspartate receptor (NMDAR) activities of hypothalamic paraventricular nucleus (PVN) presympathetic neurons from each group of rats were determined. Results: The systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure (MAP) of SHRs significantly decreased from the third week of CIHH treatment. This blood pressure reduction effect could be maintained for at least 2 weeks after stopping the CIHH treatment. CIHH treatment also attenuated the decrease in MAP and renal sympathetic nerve activity induced by hexamethonium administration in SHRs, but not in WKY rats. Furthermore, CIHH reversed the increase in serum angiotensin (Ang)II concentration and the expression of PVN angiotensin-converting enzyme (ACE) and AngII type 1 (AT1) receptors, as well as the decrease in serum Ang1–7 concentration and the expression of PVN ACE2 and Mas receptors in SHRs. In addition, the administration of CIHH resulted in a reduction in the frequency of miniature excitatory postsynaptic currents and amplitude of NMDAR current in PVN presympathetic neurons of SHRs, which means that CIHH decreased the pre- and postsynaptic NMDAR activity of PVN presympathetic neurons in SHRs. However, pretreatment with A779 (a Mas receptor blocker) or AngII abrogated the above effects. Meanwhile, Ang1–7 pretreatment mimicked the CIHH effect on pre- and postsynaptic NMDAR activity of presympathetic neurons in SHRs. Conclusions: Our data indicate that CIHH reduces pre- and postsynaptic NMDAR activity of PVN presympathetic neurons, sympathetic outflow, and blood pressure by decreasing the activity of the ACE/AngII/AT1 axis and increasing the activity of ACE2/Ang1–7/Mas axis in the hypothalamus in hypertension. [ABSTRACT FROM AUTHOR]

Background: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin‐angiotensin‐aldosterone system (RAAS) in cats is incompletely characterized. Hypothesis/Objectives: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. Animals: Twenty healthy client‐owned cats. Methods: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4‐week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time‐weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank‐sum testing. Results: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%‐86%; P =.009), angiotensin I (59% increase; IQR 27‐101%; P =.006), angiotensin II (56% increase; IQR 5‐70%; P =.023), angiotensin IV (42% increase; −19% to 89%; P =.013); and angiotensin 1‐7 (38% increase; IQR 9‐118%; P =.015). Conclusions and Clinical Importance: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) medication may reduce blood pressure (BP). Low BP is associated with worse outcomes but how this association is modified by HF medication has not been studied. We evaluated the association between BP and outcomes according to HF medication dose in HF with reduced ejection fraction (HFrEF). Methods and results: We studied HFrEF patients from the Swedish HF registry (2000–2018). Associations between systolic BP (SBP) and cardiovascular death (CVD) and/or HF hospitalization (HFH) were analysed according to doses of renin–angiotensin system (RAS) inhibitors, beta‐blockers and mineralocorticoid receptor antagonists (MRA). Among 42 040 patients (median age 74.0), lower baseline SBP was associated with higher risk of CVD/HFH (adjusted hazard ratio [HR] per 10 mmHg higher SBP: 0.92, 95% confidence interval [CI] 0.92–0.93), which was less high risk under optimized RAS inhibitor and beta‐blocker doses (10% decrease in event rates per 10 mmHg SBP increase in untreated patients vs. 7% decrease in patients at maximum dose, both adjusted p < 0.02). Among the 13 761 patients with repeated measurements, 9.9% reported a SBP decrease >10 mmHg when HF medication doses were increased, whereas 24.6% reported a SBP decrease >10 mmHg with stable/decreasing doses. Decreasing SBP was associated with higher risk of CVD/HFH in patients with stable (HR 1.10, 95% CI 1.04–1.17) or decreasing (HR 1.29, 95% CI 1.18–1.42) HF medication dose but not in patients with an increase in doses (HR 0.94, 95% CI 0.86–1.02). Conclusions: The association of lower SBP with higher risk of CVD/HFH is attenuated in patients with optimized HF medication. These results suggest that low or declining SBP should not limit HF medication optimization. [ABSTRACT FROM AUTHOR]

Arterial hypertension is one of the most common and significant cardiovascular risk factors. There are many well-known and identified risk factors for its development. In recent times, there has been growing concern about the potential impact of COVID-19 on the cardiovascular system and its relation to arterial hypertension. Various theories have been developed that suggest a connection between COVID-19 and elevated blood pressure. However, the precise link between SARS-CoV-2 infection and the long-term risk of developing hypertension remains insufficiently explored. Therefore, the primary objective of our study was to investigate the influence of COVID-19 infection on blood pressure elevation and the subsequent risk of developing arterial hypertension over an extended period. To accomplish this, we conducted a thorough search review of relevant papers in the PubMed and SCOPUS databases up to 3 September 2023. Our analysis encompassed a total of 30 eligible articles. Out of the 30 papers we reviewed, 19 of them provided substantial evidence showing a heightened risk of developing arterial hypertension following COVID-19 infection. Eight of the studies showed that blood pressure values increased after the infection, while three of the qualified studies did not report any notable impact of COVID-19 on blood pressure levels. The precise mechanism behind the development of hypertension after COVID-19 remains unclear, but it is suggested that endothelial injury and dysfunction of the renin–angiotensin–aldosterone system may be contributory. Additionally, changes in blood pressure following COVID-19 infection could be linked to lifestyle alterations that often occur alongside the illness. Our findings emphasize the pressing requirement for thorough research into the relationship between COVID-19 and hypertension. These insights are essential for the development of effective prevention and management approaches for individuals who have experienced COVID-19 infection. [ABSTRACT FROM AUTHOR]

Aims: To determine differences in the management of diabetic kidney disease (DKD) relevant to patient sex, ethnicity and socio‐economic group in UK primary care. Methods: A cross‐sectional analysis as of January 1, 2019 was undertaken using the IQVIA Medical Research Data dataset, to determine the proportion of people with DKD managed in accordance with national guidelines, stratified by demographics. Robust Poisson regression models were used to calculate adjusted risk ratios (aRR) adjusting for age, sex, ethnicity and social deprivation. Results: Of the 2.3 million participants, 161,278 had type 1 or 2 diabetes, of which 32,905 had DKD. Of people with DKD, 60% had albumin creatinine ratio (ACR) measured, 64% achieved blood pressure (BP, <140/90 mmHg) target, 58% achieved glycosylated haemoglobin (HbA1c, <58 mmol/mol) target, 68% prescribed renin–angiotensin–aldosterone system (RAAS) inhibitor in the previous year. Compared to men, women were less likely to have creatinine: aRR 0.99 (95% CI 0.98–0.99), ACR: aRR 0.94 (0.92–0.96), BP: aRR 0.98 (0.97–0.99), HbA1c: aRR 0.99 (0.98–0.99) and serum cholesterol: aRR 0.97 (0.96–0.98) measured; achieve BP: aRR 0.95 (0.94–0.98) or total cholesterol (<5 mmol/L) targets: aRR 0.86 (0.84–0.87); or be prescribed RAAS inhibitors: aRR 0.92 (0.90–0.94) or statins: aRR 0.94 (0.92–0.95). Compared to the least deprived areas, people from the most deprived areas were less likely to have BP measurements: aRR 0.98 (0.96–0.99); achieve BP: aRR 0.91 (0.8–0.95) or HbA1c: aRR 0.88 (0.85–0.92) targets, or be prescribed RAAS inhibitors: aRR 0.91 (0.87–0.95). Compared to people of white ethnicity; those of black ethnicity were less likely to be prescribed statins aRR 0.91 (0.85–0.97). Conclusions: There are unmet needs and inequalities in the management of DKD in the UK. Addressing these could reduce the increasing human and societal cost of managing DKD. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism. [ABSTRACT FROM AUTHOR]

Background: Endoplasmic reticulum (ER) stress has been shown to play a critical role in the pathogenesis of hypertension. However, the underlying mechanisms for lowering blood pressure (BP) by suppressing ER stress remain unclear. Here, we hypothesized that inhibition of ER stress could restore the balance between RAS components and lower BP in spontaneously hypertensive rats (SHRs). Methods: Wistar-Kyoto (WKY) rats and SHRs received vehicle or 4-PBA, an ER stress inhibitor, in the drinking water for 4 weeks. BP was measured by tail-cuff plethysmography, and the expression of RAS components was examined by Western blot. Results: Compared with vehicle-treated WKY rats, vehicle-treated SHRs exhibited higher blood pressure and increased renal ER stress and oxidative stress, accompanied by impaired diuresis and natriuresis. Moreover, SHRs had higher ACE and AT1R and lower AT2R, ACE2, and MasR expressions in the kidney. Interestingly, 4-PBA treatment improved impaired diuresis and natriuresis and lowered blood pressure in SHRs, accompanied by reducing ACE and AT1R protein expression and increasing AT2R, ACE2, and MasR expression in the kidneys of SHRs. In addition, these changes were associated with the reduction of ER stress and oxidative stress. Conclusions: These results suggest that the imbalance of renal RAS components was associated with increased ER stress in SHRs. Inhibition of ER stress with 4-PBA reversed the imbalance of renal RAS components and restored the impaired diuresis and natriuresis, which, at least in part, explains the blood pressure-lowering effects of 4-PBA in hypertension. [ABSTRACT FROM AUTHOR]

Simple Summary: High blood pressure (hypertension) is a common medical issue in cats. Amlodipine is a medication used to treat hypertension, but it might activate hormone systems that can be harmful in the long term. This preliminary study evaluated a hormone system called the renin–angiotensin–aldosterone system (RAAS) in cats with high blood pressure being treated with amlodipine compared to healthy cats with normal blood pressure, and found that hypertensive cats treated with amlodipine were RAAS activated. Since RAAS activation can have harmful long-term effects, including cardiac fibrosis (scar formation in the heart) and salt and water retention, medications to suppress the RAAS might be helpful in cats with high blood pressure that are treated with amlodipine. Background: Chronic renin–angiotensin–aldosterone system (RAAS) activation is harmful. Amlodipine activates RAAS in humans and dogs, but contradictory data exist for systemically hypertensive (SHT) cats. Hypothesis: Cats with SHT and chronic kidney disease treated with amlodipine (SHT/CKD-A) are RAAS activated. Animals: Client-owned cats: unmedicated normotensive (NT) cats (n = 9); SHT/CKD-A cats (n = 5) with median systolic blood pressure of 170 mmHg (vs. 195 mmHg, pre-treatment), chronic kidney disease, and receiving no RAAS-suppressive therapy. Methods: Serum was frozen (−80 °C) until RAAS analysis via equilibrium analysis. The RAAS variables (reported as median (minimum–maximum)) were compared between groups, using Mann–Whitney U test. Results: Angiotensin 1, angiotensin 1,7, angiotensin III, and angiotensin 1,5, and angiotensin-converting enzyme (ACE)-2 activity were higher in SHT/CKD-A cats compared to NT cats, while ACE activity was lower in SHT/CKD-A cats compared to NT cats (p < 0.05 all). A marker for alternative RAAS influence (ALT-S) was significantly higher (69; 58–73 pmol/pmol) in SHT/CKD-A cats compared to NT cats (35; 14–63 pmol/pmol; p = 0.001). Aldosterone concentrations were significantly higher (393; 137–564 pmol/L) in SHT/CKD-A cats compared to NT cats (129; 28–206 pmol/L; p = 0.007). Conclusion and Clinical Importance: Circulating RAAS is activated in systemically hypertensive cats receiving amlodipine. Although this study did not parse out the individual contributions of SHT, chronic kidney disease, and amlodipine, the findings suggest that the use of concurrent RAAS-suppressant therapy, specifically aldosterone antagonism, in amlodipine-treated SHT cats with chronic kidney disease might be indicated. [ABSTRACT FROM AUTHOR]

Hypertension is frequent in children with chronic kidney disease (CKD). Its prevalence varies according to CKD stage and cause. It is relatively uncommon in children with congenital kidney disease, while acquired kidney disease is associated with a higher prevalence of hypertension. Studies in children with CKD utilizing ambulatory blood pressure monitoring also showed a high prevalence of masked hypertension. Uncontrolled and longstanding hypertension in children is associated with progression of CKD. Aggressive treatment of high blood pressure should be an essential part of care to delay CKD progression in children. [ABSTRACT FROM AUTHOR]

We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet-fed parents were fed N (NN) or high-fat (H) diets (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diets (HH). Adult male and female offspring were implanted with BP telemetry probes and intracerebroventricular cannulas to infuse MC4R antagonist or vehicle. Infusion of the MC4R antagonist SHU-9119 (1 nmol/h) for 7 days caused larger increases in calorie intake and body weight in obese compared with lean offspring. In male offspring, HH and HN groups exhibited higher baseline BP compared with NN and NH, and HH showed a greater reduction in BP during SHU-9119 infusion. In female offspring, HH also showed higher baseline BP and greater reduction in BP during MC4R blockade. SHU-9119 reduced heart rate in all groups, but reductions were more pronounced in offspring from lean parents. Combined α and β-adrenergic blockade reduced BP more in male HH offspring compared with NN controls. Losartan reduced BP more in male NH, HN, and HH offspring compared with NN controls. Losartan and α- and β-adrenergic blockade reduced BP similarly in all female groups. These results suggest that endogenous MC4R activity contributes to elevated BP in obese offspring from obese parents. Our findings also indicate important sex differences in the mechanisms of BP control in male and female offspring of obese parents. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the impact of UI TEAM RX, a pharmacy-based enhanced services and care model, on adherence in patients with hypertension and prescribed a renin-angiotensin system antagonist (RASA). Methods A single-center, retrospective, observational cohort study was conducted in an academic health system, University of Illinois Hospital & Health Sciences System (UI Health). The cohort consisted of patients who utilized UI Health's outpatient pharmacies between May 2016 and December 2018 to fill RASA prescriptions. Patients who were not part of the UI TEAM RX care model served as the control group, while patients enrolled in UI TEAM RX formed the intervention group. The control and intervention groups were matched based on index date, age, gender, and race. The primary outcome was mean change in a rolling 6-month calculation of proportion of days covered (PDC). The secondary outcome was the percentage of patients who had reached their blood pressure goal at follow-up at 12 months. Results Patients receiving UI TEAM RX intervention showed significant improvement in mean PDC at 6-month follow-up compared to control patients (P < 0.01). The proportion of patients with a PDC above 0.8 was higher in the intervention group, but this difference was not statistically significant. There was also a 16.4% increase in the proportion of patients who reached their blood pressure goal in the intervention group, although this increase was not statistically significant. Conclusion The UI TEAM RX program had a statistically significant impact on patients' mean PDCs. An increase in the number of patients reaching their blood pressure goal was also seen. [ABSTRACT FROM AUTHOR]

Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin–angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRRRVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRRRVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRRRVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract Graphical Abstract [ABSTRACT FROM AUTHOR]

A solitary functioning kidney (SFK) from birth predisposes to hypertension and kidney dysfunction, and this may be associated with impaired fluid and sodium homeostasis. Brief and early angiotensin-converting enzyme inhibition (ACEi) in a sheep model of SFK delays onset of kidney dysfunction. We hypothesized that modulation of the renin–angiotensin system via brief postnatal ACEi in SFK would reprogram renal sodium and water handling. Here, blood pressure (BP), kidney haemodynamics and kidney excretory function were examined in response to an isotonic saline load (0.13 ml/kg/min, 180 min) at 20 months of age in SFK (fetal unilateral nephrectomy at 100 days gestation; term 150 days), sham and SFK+ACEi sheep (ACEi in SFK 4–8 weeks of age). Basal BP was higher in SFK than sham (∼13 mmHg), and similar between SFK and SFK+ACEi groups. Saline loading caused a small increase in BP (∼3–4 mmHg) the first 2 h in SFK and sham sheep but not SFK+ACEi sheep. Glomerular filtration rate did not change in response to saline loading. Total sodium excretion was similar between groups. Total urine excretion was similar between SFK and sham animals but was ∼40% less in SFK+ACEi animals compared with SFK animals. In conclusion, the present study indicates that water homeostasis in response to a physiological challenge is attenuated at 20 months of age by brief early life ACEi in SFK. Further studies are required to determine if ACEi in early life in children with SFK could compromise fluid homeostasis later in life. [ABSTRACT FROM AUTHOR]

Background: The prevalence of hypertension in Qatar is 33 percent of the adult population. It is postulated that the salivary microbiome can regulate blood pressure (BP). However, limited investigations exist to prove this hypothesis. Therefore, we examined the difference in the salivary microbiome composition between hypertensive and normotensive Qatari subjects. Methods: A total of 1190 Qatar Genome Project (QGP) participants (Mean age = 43 years) were included in this study. BP for all participants was classified into Normal (n = 357), Stage1 (n = 336), and Stage2: (n = 161) according to the American Heart Association guidelines. 16S-rRNA libraries were sequenced and analyzed using QIIME-pipeline, and PICRUST was used to predict functional metabolic routes. Machine Learning (ML) strategies were applied to identify salivary microbiome-based predictors of hypertension. Results: Differential abundant analysis (DAA) revealed that Bacteroides and Atopobium were the significant members of the hypertensive groups. Alpha and beta diversity indices indicated dysbiosis between the normotensive and hypertensive groups. ML-based prediction models revealed that these markers could predict hypertension with an AUC (Area under the curve) of 0.89. Functional predictive analysis disclosed that Cysteine and Methionine metabolism and the sulphur metabolic pathways involving the renin-angiotensin system were significantly higher in the normotensive group. Therefore, members of Bacteroides and Atopobium can serve as predictors of hypertension. Likewise, Prevotella, Neisseria, and Haemophilus can be the protectors that regulate BP via nitric acid synthesis and regulation of the renin-angiotensin system. Conclusion: It is one of the first studies to assess salivary microbiome and hypertension as disease models in a large cohort of the Qatari population. Further research is needed to confirm these findings and validate the mechanisms involved. [ABSTRACT FROM AUTHOR]

Hypertension is one of the major health problems leading to the development of cardiovascular diseases. Despite a rapid expansion in global hypertension prevalence, molecular mechanisms leading to hypertension are not fully understood largely due to the complexity of pathogenesis involving several factors. Salt intake is recognized as a leading determinant of blood pressure, since reduced dietary salt intake is related to lower morbidity and mortality, and hypertension in relation to cardiovascular events. Compared with salt-resistant populations, salt-sensitive individuals exhibit high sensitivity in blood pressure responses according to changes in salt intake. In this setting, the kidney plays a major role in the maintenance of blood pressure under the hormonal control of the renin–angiotensin–aldosterone system. In the present review, we summarize the current overview on the molecular mechanisms for modulation of blood pressure associated with renal ion channels/transporters including sodium–hydrogen exchanger isoform 3 (NHE3), Na+-K+-2Cl– cotransporter (NKCC2), sodium–chloride cotransporter (NCC), epithelial sodium channel (ENaC) and pendrin expressed in different nephron segments. In particular, recent studies on experimental animal models with deletion of renal ion channels led to the identification of several crucial physiological mechanisms and molecules involved in hypertension. These findings could further provide a potential for novel therapeutic approaches applicable on human patients with hypertension. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is an important fluid regulation system in the body, and excessive activation of the circulatory or local RAS can increase blood pressure (BP). Excess fluoride can increase BP, although the underlying mechanism related to activation of the RAS remains unclear. Thus, the aim of this study was to elucidate the role of the RAS in fluoride-induced hypertension. Markers of the circulating and local RASs related to pathological changes to the kidneys, myocardium, and aorta were measured. Fluoride reduced serum levels of renin, angiotensin II (Ang II), and angiotensin (1−7) [Ang (1−7)], and dysregulated plasma levels of aldosterone and potassium levels. Excess fluoride can damage the kidneys, myocardium, and aorta, overactivate the renal angiotensin converting enzyme (ACE)-Ang II-angiotensin type 1 receptor axis, and inhibit activation of the ACE2-Ang (1−7)-Mas axis, leading to dysregulation of alpha epithelial sodium channels and significantly increased expression of Ang II in the myocardium and aorta. Hence, excess fluoride can cause low-renin hypertension via an imbalance between the circulatory and local RASs. • Excess fluoride can lead to low-renin hypertension (LRH). • Fluoride influences aldosterone secretion. • Excess fluoride can inhibit the circulating renin-angiotensin system (RAS). • Excess fluoride can activate the renal and cardiovascular RASs. • The mechanism of LRH involves an imbalance between the circulatory and local RASs. [ABSTRACT FROM AUTHOR]

The pathophysiology of heart failure with reduced ejection fraction (HFrEF) is a complex process in which a number of neurohormonal systems are involved. Targeting only some of these systems, but not all, translates into a partial benefit of HF treatment. The nitric oxide-soluble guanylate cyclase (sGC)-cGMP pathway is impaired in HF, leading to cardiac, vascular and renal disturbances. Vericiguat is a once-daily oral stimulator of sGC that restores this system. No other disease-modifying HF drugs act on this system. Despite guidelines recommendations, a substantial proportion of patients are not taking all recommended drugs or when taking them, they do so at low doses, limiting their potential benefits. In this context, treatment should be optimized considering different parameters, such as blood pressure, heart rate, renal function, or potassium, as they may interfere with their implementation at the recommended doses. The VICTORIA trial showed that adding vericiguat to standard therapy in patients with HFrEF significantly reduced the risk of cardiovascular death or HF hospitalization by 10% (NNT 24). Furthermore, vericiguat does not interfere with heart rate, renal function or potassium, making it particularly useful for improving the prognosis of patients with HFrEF in specific settings and clinical profiles. [ABSTRACT FROM AUTHOR]

Introduction: High-fructose diet (HFr) causes metabolic syndrome, and HFr-induced hypertension and renal damage are exaggerated in Dahl salt-sensitive (DS) rats. Exercise training (Ex) has antihypertensive and renal protective effects in rats fed HFr; however, there has been little discussion about the DS rats, which exhibit metabolic disturbances. This study thus examined the effects of Ex on DS rats fed HFr. Methods: Male DS rats were divided into three groups. The control group was fed a control diet, and both the HFr group and the HFr–Ex group were fed an HFr (60% fructose). The HFr–Ex group also underwent treadmill running (20 m·min−1, 60 min·d−1, 5 d·wk−1). After 12 wk, renal function, histology, and renin–angiotensin system were examined. Results: HFr increased blood pressure, urinary albumin, and creatinine clearance, and Ex inhibited these increases. HFr induced glomerular sclerosis, podocyte injury, afferent arteriole thickening, and renal interstitial fibrosis, and Ex ameliorated them. HFr reduced plasma renin activity, and Ex further reduced the activity. HFr also increased the expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor, and Ex restored the ACE expression to the control levels. HFr decreased the expression of ACE2, angiotensin II type 2 receptor, and Mas receptor, and Ex restored the ACE2 and Mas receptor expressions to the control levels and further decreased the angiotensin II type 2 receptor expression. HFr increased the ACE activity and decreased the ACE2 activity, and Ex restored these activities to the control levels. Conclusions: Ex prevents HFr-induced hypertension and renal damages in DS rats. The changes in renal renin–angiotensin system may be involved in the mechanism of the antihypertensive and renal protective effects of Ex. [ABSTRACT FROM AUTHOR]

Angiotensinogen is the proximal precursor of the angiotensin peptide hormones of the renin-angiotensin-aldosterone system (RAAS). Clinical trials are ongoing targeting angiotensinogen for the treatment of hypertension and heart failure. The epidemiology of angiotensinogen is not well defined, particularly its relationship to ethnicity, sex, and blood pressure (BP)/hypertension. The authors sought to determine the relationship of circulating angiotensinogen levels to ethnicity, sex, BP, incident hypertension, and prevalent hypertension in a modern sex-balanced ethnically diverse cohort. Plasma angiotensinogen levels were measured in 5,786 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). Linear, logistic, and Cox proportional hazards models were utilized to examine the associations of angiotensinogen with BP, prevalent hypertension, and incident hypertension, respectively. Angiotensinogen levels were significantly higher in females than males and differed across self-reported ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. Higher levels were associated with higher BP and odds of prevalent hypertension, after adjusting for other risk factors. Equivalent relative differences in angiotensinogen were associated with greater differences in BP in males vs females. In males not taking RAAS-blocking medications, a standard deviation increment in log-angiotensinogen was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49-3.80), while in females the same increment in angiotensinogen was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30-1.65). Significant differences in angiotensinogen levels are present between sexes and ethnicities. A positive association is present between levels and prevalent hypertension and BP, which differs between sexes. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: Human physiology and epidemiology studies have demonstrated complex interactions between the renin–angiotensin–aldosterone system, parathyroid hormone and calcium homeostasis. Several of these studies have suggested that aldosterone inhibition may lower parathyroid hormone (PTH) levels. The objective of this study was to assess the effect of 4 weeks of maximally tolerated mineralocorticoid receptor antagonist therapy with eplerenone on PTH levels in patients with primary hyperparathyroidism (P‐HPT) when compared to amiloride and placebo. We also investigated the synergistic effect of these interventions when combined with cinacalcet for an additional 2 weeks. Design: Randomized, double‐blinded, three parallel‐group, placebo‐controlled trial. Patients: Patients with P‐HPT. Results: Most patients were women (83%) and White (76%). Maximally tolerated doses of eplerenone and amiloride induced significant reductions in blood pressure and increases in renin and aldosterone production; however, despite these physiologic changes, neither intervention induced significant changes in PTH or calcium levels when compared to the placebo. Both eplerenone and amiloride therapy induced significant reductions in procollagen type 1 N‐terminal propeptide levels when compared to placebo. When cinacalcet therapy was added, PTH and calcium levels were markedly reduced in all groups; however, there was no significant difference in PTH or serum calcium reductions between groups. Conclusions: Although maximally tolerated therapy with eplerenone and amiloride induced expected changes in renin, aldosterone and blood pressure, there were no meaningful changes in PTH or serum calcium levels in P‐HPT patients. These results suggest that inhibition of aldosterone action does not have a clinically meaningful role in medical therapy for P‐HPT. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 infection promotes the failure of the counter-regulatory RAS axis. • The failure of RAS is mediated by the binding of the spike protein of the virus with ACE2 (causing malfunction of these receptors). • The consequent accumulation of Ang II can directly contribute to development of high BP in the acute phase of infection. • Accrued data suggest that acute rise in BP is an independent predictor of bad outcome in COVID-19 patients. • A similar mechanism has been postulated to explain the rise in BP following COVID-19 vaccination ("Spike Effect"). Among the various comorbidities potentially worsening the clinical outcome in patients hospitalized for the acute respiratory syndrome coronavirus-2 (SARS-CoV-2), hypertension is one of the most prevalent. However, the basic mechanisms underlying the development of severe forms of coronavirus disease 2019 (COVID-19) among hypertensive patients remain undefined and the direct association of hypertension with outcome in COVID-19 is still a field of debate. Experimental and clinical data suggest that SARS-CoV-2 infection promotes a rise in blood pressure (BP) during the acute phase of infection. Acute increase in BP and high in-hospital BP variability may be tied with acute organ damage and a worse outcome in patients hospitalized for COVID-19. In this context, the failure of the counter-regulatory renin-angiotensin-system (RAS) axis is a potentially relevant mechanism involved in the raise in BP. It is well recognized that the efficient binding of the Spike (S) protein to angiotensin converting enzyme 2 (ACE2) receptors mediates the virus entry into cells. Internalization of ACE2, downregulation and malfunction predominantly due to viral occupation, dysregulates the protective RAS axis with increased generation and activity of angiotensin (Ang) II and reduced formation of Ang 1,7. Thus, the imbalance between Ang II and Ang 1–7 can directly contribute to excessively rise BP in the acute phase of SARS-CoV-2 infection. A similar mechanism has been postulated to explain the raise in BP following COVID-19 vaccination ("Spike Effect" similar to that observed during the infection of SARS-CoV-2). S proteins produced upon vaccination have the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure and free-floating S proteins released by the destroyed cells previously targeted by vaccines may interact with ACE2 of other cells, thereby promoting ACE2 internalization and degradation, and loss of ACE2 activities. [Display omitted] [ABSTRACT FROM AUTHOR]

Resistant hypertension (RH) is defined as the failure to achieve blood pressure control despite using triple combination therapy with a renin-angiotensin system inhibitor (RAS-i), a calcium antagonist, and a diuretic. The endothelin (ET) system is implicated in the regulation of vascular tone, primarily through vasoconstriction, intervenes in cardiac contractility with inotropic effects, and contributes to water and sodium renal reabsorption. ET inhibitors, currently approved for the treatment of pulmonary hypertension, seem to be also useful for essential hypertension and RH as well. Studies into the development of new dual ET inhibitors, which inhibit both type A and B ET (ETA and ETB) receptors, present initial results of managing RH. Aprocitentan (ACT-132577) is a novel, orally active and well tolerated dual ET receptor antagonist, which has been examined in several experimental studies and clinical trials with promising results for RH control. The recent publication of the large PRECISION study in The Lancet journal provides further reassurance regarding the efficacy and safety of aprocitentan for RH, with the aim of overcoming unmet needs in the management of this difficult group of patients. [ABSTRACT FROM AUTHOR]

The prognosis of hypertension leads to organ damage by causing nephropathy, stroke, retinopathy, and cardiomegaly. Retinopathy and blood pressure have been extensively discussed in relation to catecholamines of the autonomic nervous system (ANS) and angiotensin II of the renin–angiotensin aldosterone system (RAAS) but very little research has been conducted on the role of the ECS in the regulation of retinopathy and blood pressure. The endocannabinoid system (ECS) is a unique system in the body that can be considered as a master regulator of body functions. It encompasses the endogenous production of its cannabinoids, its degrading enzymes, and functional receptors which innervate and perform various functions in different organs of the body. Hypertensive retinopathy pathologies arise normally due to oxidative stress, ischemia, endothelium dysfunction, inflammation, and an activated renin–angiotensin system (RAS) and catecholamine which are vasoconstrictors in their biological nature. The question arises of which system or agent counterbalances the vasoconstrictors effect of noradrenaline and angiotensin II (Ang II) in normal individuals? In this review article, we discuss the role of the ECS and its contribution to the pathogenesis of hypertensive retinopathy. This review article will also examine the involvement of the RAS and the ANS in the pathogenesis of hypertensive retinopathy and the crosstalk between these three systems in hypertensive retinopathy. This review will also explain that the ECS, which is a vasodilator in its action, either independently counteracts the effect produced with the vasoconstriction of the ANS and Ang II or blocks some of the common pathways shared by the ECS, ANS, and Ang II in the regulation of eye functions and blood pressure. This article concludes that persistent control of blood pressure and normal functions of the eye are maintained either by decreasing systemic catecholamine, ang II, or by upregulation of the ECS which results in the regression of retinopathy induced by hypertension. [ABSTRACT FROM AUTHOR]

Renin-angiotensin system (RAS) inhibitors and calcium channel blockers (CCB) are often used together in chronic kidney disease (CKD). The PubMed, EMBASE, and Cochrane Library databases were searched to identify randomized controlled trials (RCTs) in order to explore better subtypes of CCB for the treatment of CKD. This meta-analysis of 12 RCTs with 967 CKD patients who were treated with RAS inhibitors demonstrated that, when compared with L-type CCB, N-/T-type CCB was superior in reducing urine albumin/protein excretion (SMD, −0.41; 95% CI, −0.64 to −0.18; p < 0.001) and aldosterone, without influencing serum creatinine (WMD, −3.64; 95% CI, −11.63 to 4.35; p = 0.37), glomerular filtration rate (SMD, 0.06; 95% CI, −0.13 to 0.25; p = 0.53), and adverse effects (RR, 0.95; 95% CI, 0.35 to 2.58; p = 0.93). In addition, N-/T-type CCB did not decrease the systolic blood pressure (BP) (WMD, 0.17; 95% CI, −1.05 to 1.39; p = 0.79) or diastolic BP (WMD, 0.64; 95% CI, −0.55 to 1.83; p = 0.29) when compared with L-type CCB. In CKD patients treated with RAS inhibitors, N-/T-type CCB is more effective than L-type CCB in reducing urine albumin/protein excretion without increased serum creatinine, decreased glomerular filtration rate, and increased adverse effects. The additional benefit is independent of BP and may be associated with decreased aldosterone (PROSPERO, CRD42020197560). [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme inhibitors (ACEI) such as benazepril are commonly prescribed in both humans and dogs with heart disease to mitigate the renin–angiotensin–aldosterone system (RAAS); however, the dose-dependent effects of benazepril on comprehensive RAAS components remain unknown. In this study, nine purpose-bred healthy dogs received three different dosages of oral benazepril (0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg) in a randomized crossover design following induction of RAAS activation by consuming a low-sodium diet. Blood samples were collected at serial time intervals after benazepril dosing to measure plasma benazeprilat (active metabolite of benazepril) and serum RAAS biomarkers. Blood pressure and echocardiogram were performed at baseline and after each benazepril administration. Time-weighted averages for RAAS biomarkers for 12 h post-dose and hemodynamic variables were compared between dosing groups using Wilcoxon rank-sum testing. Compared to the lowest dosage of benazepril (0.125 mg/kg), the highest dosage (0.5 mg/kg) resulted in lower time-weighted average values of angiotensin (Ang) II (− 38%, P = 0.004), Ang1-5 (− 53%, P = 0.001), ACE-S (surrogate for ACE activity; − 59%, P = 0.0002), and ALT-S (surrogate for alternative RAAS activity; − 22%, P = 0.004), and higher values of AngI (+ 78%, P = 0.014) and PRA-S (surrogate for plasma renin activity; + 58%, P = 0.040). There were no relevant differences between dosing groups for blood pressure or echocardiographic variables. Knowledge of dose-dependent alterations in biomarkers of the classical and alternative RAAS pathways could help inform clinical trials for dosage optimization in both dogs and humans. [ABSTRACT FROM AUTHOR]

This review includes the latest guidelines that have significantly changed the diagnosis as well as the management of hypertension in patients and special populations with chronic kidney disease. Moreover, previous reviews on this topic do not cover any guidelines on management. Because the majority of these patients are being managed in the community hospitals by internists, this review is likely to add to their knowledge in improving outcomes in this population subgroup. Hypertension (HTN) and chronic kidney disease (CKD) are pathophysiologic states that are intimately related, such that long-term HTN can lead to poor kidney function, and renal function decline can lead to worsening blood pressure (BP) control. HTN in CKD is caused by an interplay of factors, including salt and water retention, with extracellular volume expansion, sympathetic nervous system overactivity, renin-angiotensin-aldosterone system activation, and endothelial dysfunction. BP variability in the CKD population is significant, however, and thus requires close monitoring for appropriate management. With accumulating evidence, the diagnosis as well as management of HTN in CKD has been evolving in the last decade. In this comprehensive review based on current evidence and recommendations, we summarize the basics of pathophysiology, BP variability, diagnosis, and management of HTN in CKD with an emphasis on special populations with CKD. [ABSTRACT FROM AUTHOR]

Summary: Obstructive sleep apnea is a chronic, sleep‐related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin–angiotensin–aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin–angiotensin–aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04–0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05–60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11–7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42–10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86–5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57–6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub‐group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between‐study variance in elevation of the renin–angiotensin–aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension. [ABSTRACT FROM AUTHOR]

Obesity, along with type 2 diabetes mellitus (T2DM), is a major contributor to hypertension. The renin-angiotensin-aldosterone system is involved in the occurrence of diabetes and hypertension. However, the mechanism by which obesity is related to T2DM induced hypertension is unclear. In this study, we observed that blood pressure and serum renin content were increased in patients with diabetes and hypertension. Hydrogen sulfide (H2S), as an endogenous bioactive molecule, has been shown to be a vasodilator. Db/db mice, characterized by obesity and T2DM, and juxtaglomerular (JG) cells, which line the afferent arterioles at the entrance of the glomeruli to produce renin, treated with glucose, palmitic acid (PA) and oleic acid (OA), were used as animal and cellular models. NaHS, the H2S donor, was administered to db/db mice through intraperitoneal injection. NaHS significantly alleviated blood pressure in db/db mice, decreased the renin content in the serum of db/db mice and reduced renin secretion from JG cells. NaHS modulated renin release via cAMP and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), including synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2), which mediate renin exocytosis. Furthermore, NaHS increased the levels of autophagy-related proteins and colocalization with EGFP-LC3 puncta with renin-containing granules and VAMP2 to consume excessive renin to maintain intracellular homeostasis. Therefore, exogenous H2S attenuates renin release and promotes renin-vesicular autophagy to relieve diabetes-induced hypertension. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the safety and effectiveness of sacubitril/valsartan (sac/val) for elderly patients with hypertension and heart failure in the real-world setting. Patients with established hypertension complicated with structural or functional impairment of ventricular fillings [New York Heart Association (NYHA) functional class II–IV)] were enrolled. The effectiveness of sac/val in terms of BP reduction and improvement in frailty and echocardiographic evaluation of cardiac function were examined from baseline to 6-month administration. Overall, 241 patients were treated with sac/val and 227 with renin angiotensin aldosterone system inhibitor (RAASi) for hypertension control. There were significant difference in the degree of systolic blood pressure reduction between two groups. Echocardiography showed that sac/val significantly improved left ventricular ejection fraction [4.0% (95% CI: 2.0–7.5) vs −1.0 (95% CI: −4.0–2.0), P = 0.001] during the follow-up visits. Significant improvements in NYHA function class and FRAIL scores post sac/val were observed after 3 and 6 month treatment. The rate of primary cardiovascular composite outcome was higher in patients in the RAASi group (26.9%; 95% CI: 19.6–34.0) than in the sac/val group (22.0%; 95% CI: 16.7–27.3). Sac/val may be useful not only for reducing BP, but also for improving the structural and functional parameters of echocardiography, eventually resulting in a significant improvement of the overall symptomatic status, a significant reduction in NYHA class, and functional improvement. • Sac/val could significantly reduced BP and serum NT-proBNP levels, as well as contribute to higher EF and lower LV mass by its impact on cardiovascular hemodynamics. • Participants receiving sac/val exhibited a significant improvement of overall symptomatic status with a significant reduction in NYHA-class and functional improvement evaluated by questionnaire-based measures of patientlevel activity in real-world settings. • Sac/val reduced the risks of composite cardiovascular events occurrence and of hospitalization of heart failure, as compared with RAASi. • The safety profile of sac/val was favorable in the balance of serum potassium. [ABSTRACT FROM AUTHOR]

Introduction: While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. Methods: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. Results: Klotho protein supplementation decreased albuminuria (−43%), systolic blood pressure (−16%), fibroblast growth factor (FGF) 23 (−51%) and serum phosphate levels (−19%), renal angiotensin II concentration (−43%), fibrosis index (−70%), renal expressions of collagen I (−55%), and transforming growth factor β (−59%) (p < 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+45%), glomerular filtration rate (+76%), renal expressions of klotho (+148%), superoxide dismutase (+124%), and bone morphogenetic protein (BMP) 7 (+174%) (p < 0.05 for all). Conclusion: Our data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney. [ABSTRACT FROM AUTHOR]

Patients with heart failure (HF) presenting with low blood pressure (BP) have been underrepresented in large-scale clinical trials. We investigated the characteristics and implementation of conventional guideline-directed medical therapy (GDMT; renin-angiotensin system inhibitors and β-blockers) in patients with low BP hospitalized for HF with systolic dysfunction. Conventional GDMT was evaluated by discharge BP among 2043 consecutive patients with HF and left ventricular ejection fraction (LVEF) < 50% in the WET-HF registry. Among the 708 (34.7%) patients with lower discharge BP (≤ 100 mmHg; the lower tertiles), exploratory subgroups included patients with previous HF hospitalization, inotrope use, New York Heart Association (NYHA) III–IV class, and lower estimated glomerular filtration rate (eGFR) and LVEF (lower than median value). We evaluated the risk-adjusted association between GDMT implementation and 2-year adverse events (all-cause mortality or HF rehospitalization). Among the 2043 patients (age 74 [63–82] years), the median systolic BP was 108 (98–120) mmHg. Among patients with lower BP, GDMT prescription rate was 62.7%, and GDMT use was associated with decreased adverse events (HR:0.74, 95%CI:0.58–0.94). GDMT prescription rates were lower among higher-NYHA class and lower-eGFR subgroups compared with their reference subgroups, and directionally similar outcomes were noted in all subgroups (favoring GDMT use); however, this association was somewhat attenuated in the lower-eGFR group (HR:0.87, 95%CI:0.64–1.17). Conventional GDMT use was associated with decreased adverse outcomes in most patients with HF compounded by systolic dysfunction and low BP, albeit caution is warranted in patients with renal dysfunction. • ≈60% of HF patients with systolic dysfunction and low BP received conventional GDMT. • Low BP was associated with worse long-term clinical outcomes. • Conventional GDMT use was associated with better clinical outcomes in low BP group. • The favorable prognostic effect of GDMT was consistent across all high-risk subgroups. • This association was somewhat attenuated in the lower-eGFR subgroup. [ABSTRACT FROM AUTHOR]

The roles of angiotensin II (Ang II) AT1 (AT1a) receptors and its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of two-kidney, 1-clip (2K1C) Goldblatt hypertension have not been investigated previously. The present study tested the hypothesis that deletion of the AT1a receptor or NHE3 selectively in the proximal tubules of the kidney attenuates the development of 2K1C hypertension using novel mouse models with proximal tubule-specific deletion of AT1a receptors or NHE3. 2K1C Goldblatt hypertension was induced by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks in adult male wild-type (WT), global Agtr1a−/−, proximal tubule (PT)-specific PT-Agtr1a−/− or PT-Nhe3−/− mice, respectively. As expected, telemetry blood pressure increased in a time-dependent manner in WT mice, reaching a maximal response by Week 3 (p < 0.01). 2K1C hypertension in WT mice was associated with increases in renin expression in the clipped kidney and decreases in the nonclipped kidney (p < 0.05). Plasma and kidney Ang II were significantly increased in WT mice with 2K1C hypertension (p < 0.05). Tubulointerstitial fibrotic responses were significantly increased in the clipped kidney (p < 0.01). Whole-body deletion of AT1a receptors completely blocked the development of 2K1C hypertension in Agtr1a−/− mice (p < 0.01 vs. WT). Likewise, proximal tubule-specific deletion of Agtr1a in PT-Agtr1a−/− mice or NHE3 in PT-Nhe3−/− mice also blocked the development of 2K1C hypertension (p < 0.01 vs. WT). Taken together, the present study provides new evidence for a critical role of proximal tubule Ang II/AT1 (AT1a)/NHE3 axis in the development of 2K1C Goldblatt hypertension. [ABSTRACT FROM AUTHOR]

Background: The synthesis and secretion of renin in juxtaglomerular (JG) cells are closely regulated by the blood pressure. To date, however, the molecular identity through which JG cells respond to the blood pressure remains unclear. Results: Here we discovered that Piezo1, a mechanosensitive ion channel, was colocalized with renin in mouse kidney as well as As4.1 cells, a commonly used JG cell line. Activation of Piezo1 by its agonist Yoda1 induced an intracellular calcium increase and downregulated the expression of renin in these cells, while knockout of Piezo1 in JG cells abolished the effect of Yoda1. Meanwhile, mechanical stress using microfluidics also induced an intracellular calcium increase in wildtype but not Piezo1 knockout JG cells. Mechanistically, we demonstrated that activation of Piezo1 upregulated the Ptgs2 expression via the calcineurin-NFAT pathway and increased the production of Ptgs2 downstream molecule PGE2 in JG cells. Surprisingly, we discovered that increased PGE2 could decreased the renin expression through the PGE2 receptor EP1 and EP3, which inhibited the cAMP production in JG cells. In mice, we found that activation of Piezo1 significantly downregulated the renin expression and blood pressure in wildtype but not adeno-associated virus (AAV)-mediated kidney specific Piezo1 knockdown mice. Conclusions: In summary, these results revealed that activation of Piezo1 could downregulate the renin expression in JG cells and mice, subsequently a reduction of blood pressure, highlighting its therapeutic potential as a drug target of the renin-angiotensin system. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is one of the most dangerous complications of pregnancy, characterized by hypertension, proteinuria, and symptoms of multiple organ failure, which are detected de novo after 20 weeks of pregnancy. The renin–angiotensin–aldosterone system (RAAS) is one of the first to recognize pregnancy and is an important regulator of blood pressure. The placenta has its own RAAS, the role of which in the development of PE is not fully understood. In this work, for the first time, we characterized the expression of RAAS components and miRNAs controlling it in the placenta at various times of PE manifestation. The data obtained will allow the development of a new strategy in the future for the search for therapeutic agents for patients suffering from PE and cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The inhibition of renin angiotensin system pathway has been largely documented to be effective in the control of cardiovascular events. The present study investigated the effect of angiotensin converting enzyme (ACE) inhibitor on fasting blood glucose level in hypertension induced by the inhibition of nitric oxide synthase (NOS) in male Wistar rats. Hypertension was induced by the inhibition of NOS using a non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). The blockade of NOS resulted in an increase in blood pressure, ACE, angiotensin II and endothelin-1 levels, and a decrease in fasting blood glucose and nitric oxide (NO) levels. The hypertensive rats treated with ACE inhibitor (ramipril) recorded a decrease in blood pressure, ACE, angiotensin II, endothelin-1, NO and fasting blood glucose levels, and an increase in prostacyclin level. In conclusion, ACE inhibitor potentiated the hypoglycaemic effect of NOS inhibitor and this effect is independent of NO and pancreatic insulin release. [ABSTRACT FROM AUTHOR]

The activity of the epithelial Na+ channel (ENaC) in principal cells of the distal nephron fine-tunes renal Na+ excretion. The renin-angiotensin-aldosterone system modulates ENaC activity to control blood pressure, in part, by influencing Na+ excretion. NADPH oxidase activator 1-dependent NADPH oxidase 1 (NOXA1/NOX1) signaling may play a key role in angiotensin II (ANG II)- dependent activation of ENaC. The present study aimed to explore the role of NOXA1/NOX1 signaling in ANG II-dependent activation of ENaC in renal principal cells. Patch-clamp electrophysiology and principal cell-specific Noxa1 knockout (PC-Noxa1 KO) mice were used to determine the role of NOXA1/NOX1 signaling in ANG II-dependent activation of ENaC. The activity of ENaC in the luminal plasma membrane of principal cells was quantified in freshly isolated split-opened tubules using voltage-clamp electrophysiology. ANG II significantly increased ENaC activity. This effect was robust and observed in response to both acute (40 min) and more chronic (48–72 h) ANG II treatment of isolated tubules and mice, respectively. Inhibition of ANG II type 1 receptors with losartan abolished ANG II-dependent stimulation of ENaC. Similarly, treatment with ML171, a specific inhibitor of NOX1, abolished stimulation of ENaC by ANG II. Treatment with ANG II failed to increase ENaC activity in principal cells in tubules isolated from the PC-Noxa1 KO mouse. Tubules from wild-type littermate controls, though, retained their ability to respond to ANG II with an increase in ENaC activity. These results indicate that NOXA1/NOX1 signaling mediates ANG II stimulation of ENaC in renal principal cells. As such, NOXA1/NOX1 signaling in the distal nephron plays a central role in Na+ homeostasis and control of blood pressure, particularly as it relates to regulation by the renin-ANG II axis. NEW & NOTEWORTHY Activity of the epithelial Na+ channel (ENaC) in the distal nephron fine-tunes renal Na+ excretion. Angiotensin II (ANG II) has been reported to enhance ENaC activity. Emerging evidence suggests that NADPH oxidase (NOX) signaling plays an important role in the stimulation of ENaC by ANG II in principal cells. The present findings indicate that NOX activator 1/NOX1 signaling mediates ANG II stimulation of ENaC in renal principal cells. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 is caused by SARS-CoV-2 and is more severe in the elderly, racial minorities, and those with comorbidities such as hypertension and diabetes. These pathologies are often controlled with medications involving the renin–angiotensin–aldosterone system (RAAS). RAAS is an endocrine system involved in maintaining blood pressure and blood volume through components of the system. SARS-CoV-2 enters the cells through ACE2, a membrane-bound protein related to RAAS. Therefore, the use of RAAS inhibitors could worsen the severity of COVID-19's symptoms, especially amongst those with pre-existing comorbidities. Although a vaccine is currently available to prevent and reduce the symptom severity of COVID-19, other options, such as nitric oxide and hydrogen sulfide, may also have utility to prevent and treat this virus. [ABSTRACT FROM AUTHOR]

We investigated the effect of dietary inclusions of Moringa seed (5% and 10%) on blood pressure, angiotensin-1 converting enzyme (ACE) activity, and gene expression, as well as redox status in hypertensive rats. Wistar strain albino rats were fed moringa seed-based diets for two weeks prior L-NAME (40 mg/kg/day, p.o.) administration for another ten days. Subsequently, the blood pressure was monitored. Furthermore, the kidney homogenates were assayed for ACE activity and gene expression, as well as oxidative stress markers. The increased (systolic = 297 ± 59.30 mmHg; diastolic= 242 ± 51.96 mmHg) blood pressure, arginase activity, and reduced nitric oxide level were significantly ameliorated in hypertensive rats treated with the seed. However, the elevated ACE activity was significantly reduced but not the upregulated ACE1 gene. Also, the reduced antioxidant enzyme activities were ameliorated with a significant downregulation in their regulator-Nrf2. Rutin (4.07 ± 0.02 mg/g) and quercitrin (4.06 ± 0.01 mg/g), among others, were found in the seed. This study suggests that moringa seed offers its antihypertensive properties by acting as an ACE inhibitor but not its gene modulator, and also modulates the antioxidant system through interaction with Nrf2. Moringa seed could act as an ACE inhibitor and not its gene modulator. [ABSTRACT FROM AUTHOR]

Natriuretic peptides (NPs) induce vasodilation, natriuresis, and diuresis, counteract the renin–angiotensin–aldosterone system and autonomic nervous system, and are key regulators of cardiovascular volume and pressure homeostasis. Baroreflex afferent pathway is an important reflex loop in the neuroregulation of blood pressure (BP), including nodose ganglion (NG) and nucleus tractus solitarius (NTS). Dysfunction of baroreflex would lead to various hypertensions. Here, we carried out functional experiments to explore the effects of NPs on baroreflex afferent function. Under physiological and hypertensive condition (high-fructose drinking-induced hypertension, HFD), BP was reduced by NPs through NG microinjection and baroreflex sensitivity (BRS) was enhanced via acute intravenous NPs injection. These anti-hypertensive effects were more obvious in female rats with the higher expression of NPs and its receptor A/B (NPRA/NPRB) and lower expression of its receptor C (NPRC). However, these effects were not as obvious as those in HFD rats compared with the same gender control group, which is likely to be explained by the abnormal expression of NPs and NPRs in the hypertensive condition. Our data provide additional evidence showing that NPs play a crucial role in neurocontrol of BP regulation via baroreflex afferent function and may be potential targets for clinical management of metabolic-related hypertension. [ABSTRACT FROM AUTHOR]

Aims: To compare the efficacy of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid receptor antagonists (MRAs), selective aldosterone antagonists and nonselective aldosterone antagonists, on top of renin‐angiotensin‐aldosterone system (RAAS) blockade, in reducing kidney‐specific composite events, cardiovascular outcomes, and other events of special interest in participants with type 2 diabetes (T2D) and chronic kidney disease (CKD). Methods: PubMed, EMBASE and CENTRAL were searched for studies published up to January 20, 2022. Randomized clinical trials enrolling participants with T2D and CKD were included, in which SGLT2 inhibitors, nonsteroidal MRAs, selective aldosterone antagonists and nonselective aldosterone antagonists were compared with either each other, or with placebo or no treatment. A network meta‐analysis using a Bayesian approach was performed. The primary outcome was a kidney‐specific composite event. Secondary outcomes included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, and all‐cause mortality. We also examined blood pressure and safety outcomes of interest, including acute kidney injury, hyperkalaemia, hyponatraemia, and volume reduction events. All research was conducted according to a protocol registered in the PROSPERO database (CRD42022307113). Results: This meta‐analysis of 17 trials randomizing 22 981 participants found SGLT2 inhibitors (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52 to 0.73) and nonsteroidal MRAs (OR 0.76, 95% CI 0.66 to 0.88) were associated with significantly lower kidney‐specific composite events than the control groups. Nonsteroidal MRAs (OR 0.78, 95% CI 0.66 to 0.92) and SGLT2 inhibitors (OR 0.57, 95% CI 0.45 to 0.72) were associated with greater reductions in hospitalization for heart failure than the control groups. SGLT2 inhibitors were associated with a lower risk of hospitalization for heart failure events compared with nonsteroidal MRAs (OR 0.73, 95% CI 0.55‐0.97). SGLT2 inhibitors were associated with a reduction in cardiovascular death (OR 0.80, 95% CI 0.65 to 0.98) and all‐cause mortality (OR 0.79, 95% CI 0.66 to 0.93) compared with the control groups. When compared to the control groups, both nonsteroidal MRAs (weighted mean difference [WMD] −10.96, 95% CI −20.49 to −1.46) and SGLT2 inhibitors (WMD −3.50, 95% CI −6.01 to −1.013) were linked with lower systolic blood pressure, nonsteroidal MRAs (OR 2.27, 95% CI 2.02 to 2.56) and nonselective aldosterone antagonists (OR 3.22, 95% CI 1.43 to 7.66) were associated with an increased risk of hyperkalaemia, nonsteroidal MRAs were linked with an increased risk of hyponatraemia (OR 16.56, 95% CI 2.78 to 455.19), and SGLT2 inhibitors were associated with an increased risk of volume reduction events (OR 1.28, 95% CI 1.06 to 1.56). SGLT2 inhibitors were ranked the best for our primary and secondary outcomes. Confidence in the evidence was often high or moderate. Conclusions: In this network meta‐analysis, the use of SGLT2 inhibitors or nonsteroidal MRAs, combined with RAAS blockade, was associated with a reduction in kidney‐specific composite events and hospitalization for heart failure events in patients with T2D and CKD compared to placebo or no treatment. SGLT2 inhibitors were associated with a lower risk of hospitalization for heart failure events compared with nonsteroidal MRAs. Use of SGLT2 inhibitors was associated with lower mortality than placebo or no treatment. [ABSTRACT FROM AUTHOR]

Childhood trauma is an important risk factor for the onset and course of psychiatric disorders and particularly major depression. Recently, the renin-angiotensin-aldosterone system, one of the core stress hormone systems, has been demonstrated to be modified by childhood trauma. Childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ) in a community-dwelling sample (N = 2038). Plasma concentrations of renin and aldosterone were measured in subjects with childhood trauma (CT; N = 385) vs. subjects without this experience (NoCT; N = 1653). Multivariable linear regression models were calculated to assess the associations between CTQ, systolic and diastolic blood pressure, renin and aldosterone concentrations, and the ratio of aldosterone and systolic blood pressure (A/SBP). CT subjects demonstrated higher plasma aldosterone (A) concentrations, a lower systolic and diastolic blood pressure, and a higher A/SBP. In addition, both aldosterone concentrations, as well as A/SBP, correlated with the severity of childhood trauma. These findings could not be attributed to differences in concomitant medication. In conclusion, childhood trauma was associated with neurobiological markers, which may impact the risk for psychiatric disorders, primarily major depression. The altered A/SBP ratio points to a desensitisation of peripheral mineralocorticoid receptor function, which may be a target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is the primary pathway for regulating blood pressure in the body, and angiotensin-converting enzymes (ACEs) play a crucial role in it. Hirudo nipponia is an invertebrate that contains a variety of active peptides; however, there are no studies on the ACE inhibitory activity of hirudo. In the present study, our aim was to identify the active peptides in hirudo based on active peptide database analysis, unexpectedly filling the gap in hirudo ACE inhibitory activity research. Prep-HPLC was used to separate the part below 3 kD from hirudo. The peptide composition of the isolates was obtained based on Orbitrap LC-MS. The activity of each group of peptides was predicted by the database and the activity was determined by bioassay. Peptides with validation activity were screened through the database. In total, 337 peptides and 18 peptides matching the NCBI leech protein database were identified. All four fractions showed ACE inhibitory activity, and the IC50 was 0.8266, 0.2708, 0.4432, and 0.1764 mg/mL, respectively. Six screened peptides showed good affinity for ACE. This work reveals for the first time that low-molecular-weight peptides from H. nipponia have ACE inhibitory activity, which can provide a new explanation for leech treatment of hypertension. [ABSTRACT FROM AUTHOR]

Background: In people and dogs, torasemide has higher bioavailability, longer half‐life, and longer duration of action than equivalent doses of furosemide but data regarding pharmacological properties of torasemide in cats are limited. Objective: To assess pharmacokinetic and pharmacodynamic parameters of torasemide in healthy cats, and to investigate the effects of a single administration of torasemide on indicators of diuresis, plasma creatinine concentration, blood pressure, electrolyte concentrations and markers of the renin‐angiotensin‐aldosterone system (RAAS). Animals: Six clinically healthy adult European shorthair cats. Methods: Randomized 4‐period crossover design with 3 groups and 4 treatments. Pharmacokinetic parameters were obtained using a noncompartmental analysis, and the clinically effective dose was assessed using a Hill model. Results: Mean absolute bioavailability was estimated at 88.1%. Mean total body clearance was 3.64 mL/h/kg and mean terminal half‐life was 12.9 hours. Urine output significantly increased after torasemide administration (P <.001). The urine sodium : potassium ratio (uNa : uK) paralleled and was statistically correlated to urine output (P <.001). Administration of a single torasemide dose led to a significant dose‐dependent increase in urine aldosterone : creatinine ratio (uAldo : C; P <.001) and a transient decrease in plasma potassium concentration (P <.001) but did not affect blood pressure or plasma creatinine concentration. Conclusions and Clinical Importance: A single torasemide dose leads to a significant increase in diuresis and renin‐angiotensin‐aldosterone system (RAAS) activation in healthy cats, with high absolute bioavailability, and without clinically relevant adverse effects. Pharmacokinetic parameters indicate that once daily dosing of 0.27 mg/kg may be appropriate in a clinical setting. [ABSTRACT FROM AUTHOR]