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Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome. [ABSTRACT FROM AUTHOR]

Over 2 years have passed since the start of the COVID-19 pandemic, which has claimed millions of lives. Unlike the early days of the pandemic, when management decisions were based on extrapolations from in vitro data, case reports and case series, clinicians are now equipped with an armamentarium of therapies based on high-quality evidence. These treatments are spread across seven main therapeutic categories: anti-inflammatory agents, antivirals, antithrombotics, therapies for acute hypoxaemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin–angiotensin–aldosterone system and vitamins. For each of these treatments, the patient population characteristics and clinical settings in which they were studied are important considerations. Although few direct comparisons have been performed, the evidence base and magnitude of benefit for anti-inflammatory and antiviral agents clearly outweigh those of other therapeutic approaches such as vitamins. The emergence of novel variants has further complicated the interpretation of much of the available evidence, particularly for antibody therapies. Importantly, patients with acute and chronic kidney disease were under-represented in many of the COVID-19 clinical trials, and outcomes in this population might differ from those reported in the general population. Here, we examine the clinical evidence for these therapies through a kidney medicine lens. The COVID-19 pandemic was met with large-scale efforts to assess novel and repurposed therapeutic interventions that could reduce patient morbidity and mortality. Here, the authors discuss the different types of therapies available to treat COVID-19, including their relevance to patients with kidney failure and kidney transplant recipients. Key points: Multiple effective and safe therapeutics for COVID-19 have been developed since the start of the pandemic in early 2020, with several agents now approved for use across the spectrum of disease severity. COVID-19 therapeutics investigated to date include anti-inflammatory agents, antivirals, antithrombotics, therapies for acute hypoxaemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin–angiotensin–aldosterone system and vitamins. Patients with underlying kidney disease represent a vulnerable population at high risk of adverse outcomes from COVID-19, yet they were excluded or under-represented in many COVID-19 clinical trials. Additional data on the efficacy and safety of COVID-19 therapeutics in patients with chronic kidney disease are needed, as well as data on therapeutics for the prevention and treatment of COVID-19-associated acute kidney injury. [ABSTRACT FROM AUTHOR]

With chronic kidney disease (CKD) being a global arising health problem, strategies for delaying kidney disease progression and reducing the high cardiovascular risk inherent to CKD, are the main objectives of the actual management of patients with kidney diseases. In these patients, the control of arterial hypertension is essential, as high blood pressure (BP) is a strong determinant of worst cardiovascular and renal outcomes. Achieving target blood pressures recommended by international guidelines is mandatory and often demands a multiple levels management, including several pharmacological and lifestyle measures. Even in the presence of adequate BP control, the residual cardiovascular risk remains high. In this respect, the recent demonstration that novel agents such as sodium glucose transporter 2 (SGLT2) inhibitors or the new non-steroidal mineralocorticoid antagonist finerenone can retard the progression of kidney diseases and reduce cardiovascular mortality on top of standard of care treatment with renin-angiotensin system inhibitors represent enormous progresses. These studies also demonstrate that cardiovascular and renal protection can be obtained beyond blood pressure control. Other promising novelties are still to come such as renal denervation and endothelin receptor antagonists in the setting of diabetic and non-diabetic kidney diseases. In the present review, we shall discuss the classic and the new aspects for the management of hypertension in CKD, integrating the new data from recent clinical studies. [ABSTRACT FROM AUTHOR]

Background: Renin–angiotensin–aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is the cornerstone of antihypertensive treatment in patients with chronic kidney disease (CKD) and diabetes mellitus. Mineralocorticoid receptor antagonists (MRA) on top of conventional RAAS blockade confer cardio- and renoprotective effects. Yet, the detailed effects of this therapeutic approach on key RAAS effectors have not been elucidated to date. Methods: In this exploratory placebo-controlled study, 15 patients with CKD stages 2–3 and albuminuria due to diabetic kidney disease (DKD) were randomized to receive the MRA eplerenone or placebo in addition to ACEi therapy. Employing mass-spectrometry, we quantified plasma angiotensin levels [Ang I, Ang II, Ang-(1–7), Ang-(1–5), Ang III, Ang IV], renin and aldosterone in patients before and after 8 weeks of MRA treatment. Results: While blood pressure and kidney function were similar in the placebo and eplerenone treatment group during the study period, distinct differences in RAAS regulation occurred: eplerenone treatment resulted in an increase in plasma renin activity, Ang I and aldosterone concentrations, indicating global RAAS activation. In addition, eplerenone on top of ACEi profoundly upregulated the alternative RAAS effector Ang-(1–7). Conclusions: Combined eplerenone and ACEi therapy increases Ang-(1–7) levels in patients with CKD indicating a unique nephroprotective RAAS pattern with considerable therapeutic implications. [ABSTRACT FROM AUTHOR]

Purpose: The present paper will review the impact of different therapeutic interventions on the autonomic dysfunction characterizing chronic renal failure. Methods: We reviewed the results of the studies carried out in the last few years examining the effects of standard pharmacologic treatment, hemodialysis, kidney transplantation, renal nerve ablation and carotid baroreceptor stimulation on parasympathetic and sympathetic control of the cardiovascular system in patients with renal failure. Results: Drugs acting on the renin–angiotensin system as well as central sympatholytic agents have been documented to improve autonomic cardiovascular control. This has also been shown for hemodialysis, although with more heterogeneous results related to the type of dialytic procedure adopted. Kidney transplantation, in contrast, particularly when performed together with the surgical removal of the native diseased kidneys, has been shown to cause profound sympathoinhibitory effects. Finally, a small amount of promising data are available on the potential favorable autonomic effects (particularly the sympathetic ones) of renal nerve ablation and carotid baroreceptor stimulation in chronic kidney disease. Conclusions: Further studies are needed to clarify several aspects of the autonomic responses to therapeutic interventions in chronic renal disease. These include (1) the potential to normalize sympathetic activity in uremic patients by the various therapeutic approaches and (2) the definition of the degree of sympathetic deactivation to be achieved during treatment. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains a worldwide public health concern despite decades of research and the availability of numerous targeted therapies. While the intrinsic physiological mechanisms regulating cardiovascular function are similar between males and females, marked sex differences have been established in terms of CVD onset, pathophysiology, manifestation, susceptibility, prevalence, treatment responses and outcomes in animal models and clinical populations. Premenopausal females are generally protected from CVD in comparison to men of similar age, with females tending to develop cardiovascular complications later in life following menopause. Emerging evidence suggests this cardioprotection in females is, in part, attributed to sex differences in hormonal regulators, such as the renin–angiotensin system (RAS). To date, research has largely focused on canonical RAS pathways and shown that premenopausal females are protected from cardiovascular derangements produced by activation of angiotensin II pathways. More recently, a vasodilatory arm of the RAS has emerged that is characterized by angiotensin-(1-7) [(Ang-(1-7)], angiotensin-converting enzyme 2 and Mas receptors. Emerging studies provide evidence for a shift towards these cardioprotective Ang-(1-7) pathways in females, with effects modulated by interactions with estrogen. Despite well-established sex differences, female comparison studies on cardiovascular outcomes are lacking at both the preclinical and clinical levels. Furthermore, there are no specific guidelines in place for the treatment of cardiovascular disease in men versus women, including therapies targeting the RAS. This review summarizes current knowledge on sex differences in the cardiovascular actions of the RAS, focusing on interactions with gonadal hormones, emerging data for protective Ang-(1-7) pathways and potential clinical implications for established and novel therapies. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in a host of renal and cardiovascular functions. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), drugs that disrupt RAAS function, are effective in treating hypertension and offer other renoprotective effects independent of blood pressure (BP) reduction. As our understanding of RAAS physiology and the feedback mechanisms of ACE inhibition and angiotensin receptor blockade have improved, questions have been raised as to whether combination ACEI/ARB therapy is warranted in certain patients with incomplete angiotensin blockade on one agent. In this review, we discuss the rationale for combination ACEI/ARB therapy and summarize the results of key adult studies and the limited pediatric literature that have investigated this therapeutic approach. We additionally review novel therapies that have been developed over the past decade as alternative approaches to combination ACEI/ARB therapy, or that may be potentially used in combination with ACEIs or ARBs, in which further adult and pediatric studies are needed. [ABSTRACT FROM AUTHOR]

Background: The use of renin–angiotensin–aldosterone system inhibitors has increased over the past few years. There are conflicting data as to their relationship with acute kidney injury following surgery. Objectives: The objective of the article was to evaluate the risk of acute kidney injury in diabetic older patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and their medical outcomes following fragility hip fracture surgery. Methods: Consecutive diabetic patients presenting with fragility hip fractures to our primary trauma center between January 2012 and June 2016 were included. Demographic and clinical data, including co-morbidities, medication use, and laboratory results, were collected from the electronic medical records. The primary outcome was the incidence of acute kidney injury; the secondary outcome was 1-year mortality. Results: Two hundred and seventeen patients were included; 125 were receiving treatment with medications targeting the renin–angiotensin–aldosterone system. Demographic and clinical characteristics were similar between groups. No association was found between the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the risk of acute kidney injury, which occurred in 25% of the cohort. Univariate analysis revealed that diuretic use, particularly furosemide, increased the risk of acute kidney injury during hospitalization (p = 0.003). However, in a multivariate analysis, only age and estimated glomerular filtration rates were associated with an increased risk of acute kidney injury. Patients with acute kidney injury were found to have increased mortality during the first post-operative year (p < 0.001). Conclusions: Acute kidney injury is a frequent complication after hip fracture surgery in elderly diabetic patients and is associated with increased 1-year mortality; however, it was not found to be associated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker pre-fracture treatment. [ABSTRACT FROM AUTHOR]

The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) become activated, resulting in increased blood pressure, heart rate, and blood volume. Consequent activation of the natriuretic peptide system (NPS) typically balances these effects; however, the NPS is unable to sustain compensation for excessive neurohormonal activation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that target the RAAS and SNS, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction (HFrEF) and suggests changes to current management paradigms. From this assessment, the evidence supports favoring sacubitril/valsartan over ACEIs or ARBs, and this therapy should be used in conjunction with beta-blockers to further decrease morbidity and mortality in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Background: Hypertension is highly prevalent in older adults and represents a major public health issue since recognition, awareness, treatment and control are insufficient. Analyses of prescription patterns in conjunction with clinical parameters can provide novel insights into the current practice of hypertension management and help to identify barriers to sufficient hypertension control.Methods: A cross-sectional analysis was conducted. Prevalence of hypertension, patterns of antihypertensive therapy, and determinants of blood pressure (BP) control were examined in the Berlin Aging Study II cohort, including 1654 community-dwelling older adults (60-85 years of age).Results: Of the participants, 75.9% had hypertension; 40.6% of these were not prescribed BP medications. Lack of hypertension awareness, younger age, absence of comorbidities, not being on a statin, and not having visited a physician in the past 3 months were associated with lack of treatment. Forty-two percent of treated hypertensive individuals received monotherapy and 58.0% received combination therapy. Renin-angiotensin-aldosterone system (RAAS) inhibitors, and β-blockers were most commonly prescribed, while calcium channel blockers were least prescribed. Only 38.5% of treated hypertensive individuals had their BP controlled to < 140/90 mmHg. Number and choice of BP medications were not predictive of BP control; neither were age, glycated hemoglobin (HbA1c), kidney function, or number of healthcare visits. However, female sex, lower low-density lipoprotein cholesterol (LDL-C) levels and current smoking, amongst others, were positively associated with BP control. There was evidence of significant effect modification by statins in the association of LDL-C and BP.Conclusion: The majority of older adults do not reach BP goals. Antihypertensive prescription patterns do not conform to current guidelines. Using more BP medications was not associated with higher odds of BP control. Lowering LDL-C might be favorable in terms of BP control. [ABSTRACT FROM AUTHOR]

Primary care physicians play a significant role in managing heart failure (HF), with the goals of reducing mortality, avoiding hospitalization, and improving patients’ quality of life. Most HF-related hospitalizations and deaths occur in patients with New York Heart Association functional class II or III, many of whom are perceived to have stable disease, which often progresses without clinical symptoms due to underlying deleterious effects of neurohormonal imbalance and endothelial dysfunction. Management includes lifestyle changes and stepped pharmacological therapy directed at the four stages of HF, with aggressive uptitration of therapies, including beta-blockers and inhibitors of the renin-angiotensin-aldosterone system. Recently, two new HF treatments have become available in clinical practice. Ivabradine was approved to reduce the risk of hospitalization for HF in patients with stable, symptomatic HF. Additionally, the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, was found to be significantly superior to enalapril in reducing risks of cardiovascular death and HF-related hospitalization. The respective 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America clinical practice guideline updates recommend that patients taking angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy be switched to ARNI therapy to further reduce morbidity and mortality. For HF management to be maximally effective, physicians must be knowledgeable about the risks and benefits of treatments and stay engaged with patients to identify signs of disease progression. This article provides an overview of the progressive nature of HF in apparently stable patients and describes areas for treatment improvement that may help to optimize patient care. [ABSTRACT FROM AUTHOR]

Background: There is no detailed strain analysis of cardiac functions in treated hypertensive pediatric patients. The aim of this study was to evaluate the cardio-protective effects of different drug classes in treated pediatric hypertensive patients.Methods: Sixty non-obese-treated hypertensive patients with preserved left ventricular (LV) systolic function and 45 age-, sex-, and body mass index-matched healthy subjects underwent clinical evaluation, including 24-h ambulatory blood pressure monitoring, standard echocardiographic examination, tissue Doppler imaging, and two-dimensional Speckle Tracking Echocardiography. The patients were divided into two subgroups based on the effects of the drugs on the Renin Angiotensin Aldosterone System. The subgroup hypertension (HT) 1 received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and HT 2 subgroup received calcium channel blocker, β-blocker, or diuretics.Results: There was no difference between the two groups and subgroups with respect to clinical, demographic, ABPM, ventricular volumes, ejection fraction, and tissue Doppler imaging (TDI) parameters. For patients and controls, respectively, global longitudinal strain was − 18.70 ± 3.41 versus − 21.01 ± 3.82 (P < 0.001), and global radial strain was 40.6 ± 9.8 versus 54.8 ± 12.8 (P = 0.004). Peak LV twist and peak LV torsion were not significantly different. The patient subgroup analyses with each other revealed no difference in systolic and diastolic myocardial deformation properties.Conclusions: Strain parameters were reduced in all treated hypertensive children compared to normotensive children, and the various cardiac mechanic parameters were similarly abnormal no matter what type of antihypertensive agent was used. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II) is a powerful vasoconstrictor of the renin-angiotensin system (RAS) that plays an important role in cardiovascular regulation in adult and developing vertebrates. Knowledge of ANG II’s contribution to developmental cardiovascular function comes from studies in fetal mammals and embryonic chickens. This is the first study to examine the role of ANG II in cardiovascular control in an embryonic reptile, the American alligator (Alligator mississippiensis). Using chronic low (~ 5-mg kg embryo−1), or high doses (~ 450-mg kg embryo−1) of captopril, an angiotensin-converting enzyme (ACE) inhibitor, we disrupted the RAS and examined the influence of ANG II in cardiovascular function at 90% of embryonic development. Compared to embryos injected with saline, mean arterial pressure (MAP) was significantly reduced by 41 and 72% under low- and high-dose captopril treatments, respectively, a greater decrease in MAP than observed in other developing vertebrates following ACE inhibition. Acute exogenous ANG II injection produced a stronger hypertensive response in low-dose captopril-treated embryos compared to saline injection embryos. However, ACE inhibition with the low dose of captopril did not change adrenergic tone, and the ANG II response did not include an α-adrenergic component. Despite decreased MAP that caused a left shifted baroreflex curve for low-dose captopril embryos, ANG II did not influence baroreflex sensitivity. This study demonstrates that ANG II contributes to cardiovascular function in a developing reptile, and that the RAS contributes to arterial blood pressure maintenance during development across multiple vertebrate groups. [ABSTRACT FROM AUTHOR]

Background: Acute pancreatitis (AP) is an inflammatory disease mediated by damage in acinar cells and pancreatic inflammation with infiltration of leukocytes. The pancreatic renin-angiotensin system may play an important role in the pathogenesis of AP.Aim: The present study aimed to investigate the possible protective role of captopril (CAP), an angiotensin-converting enzyme inhibitor, in attenuating L-arginine-induced AP rat model and to elucidate the underlying molecular mechanisms.Methods: Forty-eight adult male Wister rats were divided into four equal groups: control group (vehicle, orally for 10 days), AP group (3 g/kg L-arginine, single i.p.) on 10th day of the experiment, CAP group (50 mg/kg captopril, orally, once daily), and MP group (30 mg/kg methylprednisolone, orally, once daily). CAP and MP were administered for 10 days prior to L-arginine injection. Rats were sacrificed 24 h after arginine injection. Inflammatory biomarkers; tumor necrosis factor alpha (TNF-α) concentration, myeloperoxidase (MPO) activity, and inducible nitric oxide synthase (iNOS) gene expression were determined in pancreas. Oxidative stress biomarkers; pancreatic nitric oxide (NO) and reduced glutathione (GSH) concentrations were measured. Moreover, serum α-amylase and lipase activities were measured and histopathological studies of the pancreas were done.Results: CAP group showed a significant reduction in pancreatic TNF-α concentration, MPO activity, NO concentration, and downregulation of iNOS gene expression compared to AP group. CAP group also showed a significant increase in GSH concentration with amelioration of histological changes of AP as well as MP group.Conclusion: Captopril treatment showed a protective and comparable effect with MP treatment in AP rat model. [ABSTRACT FROM AUTHOR]

Background: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. It has been reported that reactive oxygen species (ROS) are important components of intrarenal RAS activation. Melatonin is recognized as a powerful antioxidant, and we recently reported that impaired nighttime melatonin secretion correlates negatively with urinary angiotensinogen excretion, the surrogate marker of intrarenal RAS activity in patients with CKD. However, whether melatonin supplementation ameliorates the augmentation of intrarenal RAS in CKD has remained unknown. We aimed to clarify whether exogenous melatonin ameliorates intrarenal RAS activation via the reduction of ROS production.Methods: 5/6 Nephrectomized (Nx) rats were used as a chronic progressive CKD model and compared with sham-operated control rats. The Nx rats were divided into untreated Nx rats and melatonin-treated Nx rats. The levels of intrarenal RAS, ROS components, and renal injury were evaluated after 4 weeks of treatment.Results: Compared with the control rats, the untreated Nx rats exhibited significant increases in intrarenal angiotensinogen, angiotensin II (AngII) type 1 receptors, and AngII, accompanied by elevated blood pressure, higher oxidative stress (8-hydroxy-2′-deoxyguanosine), lower antioxidant (superoxide dismutase) activity, and increased markers of interstitial fibrosis (α-smooth muscle actin, Snail, and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed these abnormalities.Conclusion: Antioxidant treatment with melatonin was shown to ameliorate intrarenal RAS activation and renal injury in a 5/6 Nx rat model. [ABSTRACT FROM AUTHOR]

Hypertension is a leading cause of cardiovascular complications in children on dialysis. Volume overload and activation of the renin-angiotensin-aldosterone system play a major role in the pathophysiology of hypertension. The first step in managing blood pressure (BP) is the careful assessment of ambulatory BP monitoring. Volume control is essential and should start with the accurate identification of dry weight, based on a comprehensive assessment, including bioimpedance analysis and intradialytic blood volume monitoring (BVM). Reduction of interdialytic weight gain (IDWG) is critical, as higher IDWG is associated with a worse left ventricular mass index and poorer BP control: it can be obtained by means of salt restriction, reduced fluid intake, and optimized sodium removal in dialysis. Optimization of peritoneal dialysis and intensified hemodialysis or hemodiafiltration have been shown to improve both fluid and sodium management, leading to better BP levels. Studies comparing different antihypertensive agents in children are lacking. The pharmacokinetic properties of each drug should be considered. At present, BP control remains suboptimal in many patients and efforts are needed to improve the long-term outcomes of children on dialysis. [ABSTRACT FROM AUTHOR]

Despite the high mortality rate, there is no therapy to improve survival in heart failure with preserved ejection fraction (HFpEF). Large randomized controlled trials (RCTs) did not show clear mortality benefit of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) in HFpEF. However, because of the strict enrollment criteria, the patients who participated in these trials might represent a selected group of patients that is poorly representative of patients treated in routine clinical practice. In contrast, clinical characteristics of real-world patients are similar to those of patients enrolled in observational cohort studies (OCSs). Although many OCSs have examined the prognostic effect of RAS inhibitors in HFpEF, the results are inconsistent due to limited power with small sample sizes and/or inadequate adjustment for known prognostic factors. We aimed to conduct a meta-analysis of OCSs with and those without propensity score (PS) analysis and RCTs on the effect of RAS inhibitors on mortality in HFpEF patients. The search of electronic databases identified 4 OCSs with PS analysis (10,164 patients), 8 OCSs without PS analysis (16,393 patients), and 3 RCTs (8001 patients). Use of RAS inhibitors was associated with reduced mortality in the pooled analysis of OCSs with PS analysis (RR [95% CI] = 0.90 [0.81-1.00]) and in that of OCSs without PS analysis (0.81 [0.68-0.96]) but not in that of RCTs (0.99 [0.87-1.12]). In conclusion, the present meta-analysis suggests the potential mortality benefit of RAS inhibitors in HFpEF, emphasizing the importance of conducting new well-designed RCTs. [ABSTRACT FROM AUTHOR]

A co-morbidity of inflammatory conditions is increased cardio-renal risks. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs) which are used to treat pain and inflammation are also associated with increase in such risks. We hypothesized that inflammation and NSAIDs impose the cardio-renal risk through the activation of the renin-angiotensin-system (RAS), a regulating pathway of the renal and cardiovascular homeostasis. We investigated the effect of adjuvant arthritis and NSAIDs on the RAS. Western blotting and ELISA were used to measure the RAS components. Inflammation caused significant imbalances in the cardiac and renal angiotensin converting enzymes, their biologically active angiotensin peptides (AngII and Ang1-7) and the target proteins involved in the peptide-receptor binding (AngII type 1 and type 2, and Ang1-7 receptor, Mas) toward cardio-renal toxicity. However, 7 days treatment of arthritic animals with NSAIDs (rofecoxib, meloxicam, celecoxib and flurbiprofen) restored the constitutive balances, perhaps due to their anti-inflammatory properties. Inflammation exerts its cardio-renal effects by causing imbalance in the RAS. NSAIDs through their anti-inflammatory effect restore this imbalance. Thus, mechanisms other than imbalances in the RAS may be involved in the NSAIDs cardiotoxicity. [ABSTRACT FROM AUTHOR]

Background: Pediatric primary hypertension (HTN) is increasingly recognized, but the effect of patient characteristics such as obesity and race on treatment outcomes is not well described. The renin-angiotensin-aldosterone system (RAAS) may also contribute to HTN. We hypothesized patient parameters of these factors, including baseline RAAS, influence blood pressure (BP) response to pharmacological treatment in HTN. Methods: This was a retrospective cohort of 102 consecutive patients with HTN. Primary outcomes were changes per year in systolic and diastolic BP (SBP, DBP). Secondary outcome was change per year in left ventricular mass index (LVMI). We evaluated whether baseline plasma renin activity (PRA), aldosterone, renin-to-aldosterone ratio, overweight/obesity, race, initial drug choice, and multidrug therapy were associated with the outcomes using general linear regression models adjusted for confounding variables. Results: Racially diverse (43% Hispanic, 28% black, 25% white) and predominantly overweight/obese (75%) patients were studied. Median length of follow-up was 14.5 months. Higher baseline aldosterone was associated with decreased SBP (−1.03 mmHg/year), DBP (−0.95 mmHg/year), and DBP z score (−0.07/year) during the study period. Higher baseline PRA was associated with decreased SBP z score (−0.04/year) and LVMI (−2.89 g/m/year). Stratified analyses revealed the relationships between baseline aldosterone and PRA, and annual reductions in outcomes were strengthened in nonobese and white patients. Conclusions: Pretreatment aldosterone and PRA predicted short-term follow-up BP and LVMI, especially in nonobese and white patients. The RAAS profile could guide treatment of HTN and suggests consideration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers as first-line treatment options. [ABSTRACT FROM AUTHOR]

Background Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. Objective We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. Study Design We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. Methods Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. Results Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). [ABSTRACT FROM AUTHOR]

Background: Clinical care decisions to treat chronic kidney disease (CKD) in a growing child must often be made without the benefit of evidence from clinical trials. We used observational data from the Chronic Kidney Disease in Children cohort to estimate the effectiveness of renin-angiotensin II-aldosterone system blockade (RAAS) to delay renal replacement therapy (RRT) in children with CKD. Methods: A total of 851 participants (median age: 11 years, median glomerular filtration rate [GFR]: 52 ml/min/1.73 m, median urine protein to creatinine ratio: 0.35 mg/mg) were included. RAAS use was reported at annual study visits. Both Cox proportional hazards models with time-varying RAAS exposure and Cox marginal structural models (MSM) were used to evaluate the effect of RAAS use on time to RRT. Analyses were adjusted or weighted to control for age, male sex, glomerular diagnosis, GFR, nephrotic range proteinuria, anemia, elevated blood pressure, acidosis, elevated phosphate and elevated potassium. Results: There were 217 RRT events over a 4.1-year median follow-up. At baseline, 472 children (55 %) were prevalent RAAS users, who were more likely to be older, have a glomerular etiology, have higher urine protein, be anemic, have elevated serum phosphate and potassium, take more medications, but less likely to have elevated blood pressure, compared with non-users. RAAS use was found to reduce the risk of RRT by 21 % (hazard ratio: 0.79) to 37 % (hazard ratio: 0.63) from standard regression adjustment and MSM models, respectively. Conclusions: These results support inferences from adult studies of a substantial benefit of RAAS use in pediatric CKD patients. [ABSTRACT FROM AUTHOR]

Inhibitors of the renin-angiotensin system used to treat several diseases have also been shown to be effective on bone tissue, suggesting that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may reduce fracture risk. The present study investigated the effects of losartan on the physicochemical and biomechanical properties of diabetic rat bone. Losartan (5 mg/kg/day) was administered via oral gavage for 12 weeks. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Whole femurs were tested under tension to evaluate the biomechanical properties of bone. The physicochemical properties of bone were analyzed by Fourier transform infrared spectroscopy. Although losartan did not recover decreases in the BMD of diabetic bone, it recovered the physicochemical (mineral and collagen matrix) properties of diabetic rat bone. Furthermore, losartan also recovered ultimate tensile strength of diabetic rat femurs. Losartan, an angiotensin II type 1 receptor blocker, has a therapeutic effect on the physicochemical properties of diabetic bone resulting in improvement of bone strength at the material level. Therefore, specific inhibition of this pathway at the receptor level shows potential as a therapeutic target for diabetic patients suffering from bone diseases such as osteopenia. [ABSTRACT FROM AUTHOR]

Heart rate is an established prognostic marker for longevity and is an important contributor in the pathophysiology of various cardiovascular diseases, including ischemic heart disease and heart failure. Most ischemic episodes are triggered by an increase in heart rate, which causes an imbalance between myocardial oxygen delivery and consumption. In addition, increased heart rate is a modifiable risk factor for chronic heart failure. Ivabradine, an inhibitor of I ion channels, is an approved second-line anti-ischemic drug for the treatment of angina. Ivabradine has been shown to decrease the risk of hospitalization in patients with chronic heart failure who were previously treated with β-blockers, renin-angiotensin system blockers or mineralocorticoid receptor antagonists. This review describes the rationale for the pathophysiological and clinical use of ivabradine as an anti-ischemic agent in patients with stable coronary disease and highlights its benefits and drawbacks compared with other first- and second-line anti-anginal drugs. The review also highlights the role of ivabradine as a treatment for patients with high-risk coronary artery disease in whom first-line anti-anginal drugs are insufficient or inadequate and percutaneous coronary intervention is contraindicated or revascularization is incomplete or unsuitable. [ABSTRACT FROM AUTHOR]

Background and Objective: Blood pressure (BP) control in hypertensive patients remains poor worldwide, particularly in high-risk patients with hypertension and diabetes. Guidelines recommend that such patients receive prompt pharmacological therapy at maximal doses to rapidly control BP. We aimed to evaluate efficacy and safety of single-pill combination (SPC) perindopril/indapamide (PER/IND) at full dose (10/2.5 mg) in hypertensive patients, including diabetics, with BP uncontrolled by previous medication. Methods: Twelve-week prospective, observational study in patients with uncontrolled hypertension (≥160-200 mmHg systolic BP [SBP] and <110 mmHg diastolic BP [DBP]) on a previous SPC or free-dose combination of renin-angiotensin system blocker plus thiazide diuretic, substituted with PER/IND 10/2.5 mg. Office BP, quality of life, and blood parameters were evaluated in the whole cohort and patients with type 2 diabetes mellitus. Results: 2120 ambulatory hypertensive patients were enrolled, including 307 with type 2 diabetes. Two weeks after substitution, SBP significantly decreased from 171.0 ± 13.3 to 148.6 ± 13.4 mmHg, and DBP from 98.6 ± 8.3 to 88.8 ± 7.9 mmHg (both p < 0.00001). A similar rapid decrease was noted in the diabetes subgroup. After 12 weeks, BP had reduced by 42/19 mmHg in the whole cohort (diabetes subgroup: 41/18 mmHg). Most (84%; diabetes subgroup: 77%) patients reached BP target (<140/90 mmHg). Laboratory tests and quality of life improved in the whole cohort and the diabetic subgroup. Conclusions: Switching to PER/IND at full dose (10/2.5 mg) was well tolerated, leading to fast BP reduction and control in the majority of patients with uncontrolled hypertension, including difficult-to-treat patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensives. Recently, these drugs have been associated with a protective effect against pancreatic cancer, but data on this putative association remain limited. Thus, the objective of this study was to determine whether the use of ACEIs and/or ARBs is associated with a decreased risk of pancreatic cancer.Methods: We conducted a population-based cohort study, using a nested case-control analysis within the UK Clinical Practice Research Datalink population. The cohort consisted of all patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2009, with follow-up until 31 December 2010. Cases were patients with newly diagnosed pancreatic cancer, which were matched with up to 10 controls on age, sex, calendar year of cohort entry, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of pancreatic cancer incidence associated with ever use of ACEIs and ARBs. A secondary analysis was conducted to assess whether the incidence of pancreatic cancer varied with cumulative duration of use of these drugs.Results: A cohort of 547 566 was assembled. During 3 040 332 person-years of follow-up, a total of 866 patients were newly diagnosed with pancreatic cancer (rate: 3/10 000 per year) and matched to 8636 controls. Overall, when compared with other antihypertensive drugs, the use of ACEIs was not associated with a decreased risk of pancreatic cancer overall (OR: 1.01, 95% CI: 0.86-1.17) or according to cumulative duration of use. The use of ARBs was not associated with a decreased risk of pancreatic cancer overall (OR: 0.93, 95% CI: 0.75-1.15), whereas a cumulative duration of use of 1-3 years was associated with a 38% decrease (OR: 0.62, 95% CI: 0.41-0.94), which returned to the null after >3 years of use (OR: 1.04, 95% CI: 0.74-1.46).Conclusions: The use of ARBs and ACEIs was not associated with an overall decreased risk of pancreatic cancer when compared with patients using other antihypertensive drugs. Additional research is needed to determine whether ARBs may confer a short-term protective effect. [ABSTRACT FROM AUTHOR]

Aliskiren, a direct renin inhibitor is expected to achieve sufficient suppression of renin-angiotensin system. We evaluated the effect of aliskiren on the electrical and structural remodeling in a canine atrial fibrillation (AF) model. Twenty-eight dogs were divided into three groups: (1) pacing control group ( n = 12), with continuous atrial rapid pacing for 3 or 6 weeks, (2) pacing + aliskiren group ( n = 12), with oral aliskiren (30 mg/kg/day), and (3) sham group ( n = 4), no pacing nor drug administration. Electrophysiological properties and AF inducibility were evaluated every week. After the protocol, the left atrial tissue was sampled for the further histological and mRNA analysis. The electrical remodeling, AF inducibility, the left atrial enlargement and interstitial fibrosis were observed in pacing control group and were more prominent in the 6-week protocol (vs. 3 week, p < 0.05). The mRNA expressions of matricellular proteins exhibited upregulation in 3-week pacing control, but these upregulations became insignificant in 6 weeks. In contrast, collagen type 3 exhibited significant upregulation in 6 week but not in 3-week protocol. These changes were suppressed in the pacing + aliskiren group. Aliskiren suppressed the atrial remodeling in a canine AF model. This effect was accompanied by the suppression of tissue fibrosis. [ABSTRACT FROM AUTHOR]

This contribution summarizes the pivotal role of the ovarian renin–angiotensin system (OVRAS) in ovarian physiology and disease, with particular emphasis on human clinical implications and established translational applications. The presence of a complete OVRAS in all studied species has been known for decades. The OVRAS has major effects on follicle development/atresia and ovulation and steroid hormone secretion, that is, it is necessary for normal reproduction. It is well established that OVRAS activity is regulated by gonadotropins and depends on activation of proteases in the area of growing follicles. Angiotensin and angiotensin receptors are widely distributed in the ovarian follicle, preovulatory theca and granulosa cells, and postovulatory mural granulosa-lutein cells and regulate steroidogenesis. Molecular blockade of the OVRAS inhibits oocyte maturation and ovulation. Pathologically abnormal OVRAS function has been associated with infertility, polycystic ovarian syndrome (PCOS), ovarian hyperstimulation syndrome (OHSS), and ovarian cancer. Both hyperandrogenism in PCOS and third space fluid accumulation in OHSS have been convincingly linked to overexpression of renin and angiotensin. Blockade of angiotensin receptors is under study for the treatment of gynecologic cancer, OHSS, and PCOS. However, a full understanding of the OVRAS and translational applications is lacking. In part, this is due to the discovery in recent years of previously unknown renin–angiotensin system (RAS) components and novel functions of “classical” RAS components that remain to be integrated into translational studies; newer, more specific agents to block RAS components are available only now for such research and treatment. The need for further studies is evident. [ABSTRACT FROM AUTHOR]

The development and progression of cardiovascular disease (CVD) and renal disorders are very closely related. In patients with chronic kidney disease (CKD), therapies proven to protect the cardiovascular and renal systems simultaneously are generally used only at low doses or not at all. In particular, patients with CKD who receive angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, or mineralocorticoid-receptor antagonists (MRAs) often do not experience complete blockade of the renin-angiotensin-aldosterone system, primarily owing to the risk of hyperkalaemia. In this Review, we provide an overview of the available treatments required for adequate cardiorenal protection in patients with CKD. Drugs such as β-blockers that interfere with renin secretion will be discussed, in addition to agents that can prevent hyperkalaemia, such as potassium binders and nonsteroidal MRAs. Furthermore, the current literature on the role of statins, in addition to new compounds and dosing recommendations for the treatment of patients with CKD will also be reviewed. Further studies with these new compounds and doses are needed to ascertain whether these approaches can improve the long-term cardiovascular and renal prognosis in patients with CKD. [ABSTRACT FROM AUTHOR]

Background: The impact of renin-angiotensin system blockade (RASB) on the incidence of end-stage renal disease (ESRD) remains unclear in IgA nephropathy (IgAN). Methods: This study assessed associations between RASB treatment and the incidence of ESRD in IgAN using propensity score approaches. We retrospectively analyzed 1273 patients with IgAN biopsied between 1979 and 2010. Propensity scores were calculated using logistic regression. Associations between RASB and ESRD were examined using a Cox regression model adjusted by inverse probability of treatment weighted, regression, stratification and matching. Results: During follow-up (median 5.1 years), 130 patients developed ESRD. With Cox regression adjusted by inverse probability of treatment weighted, RASB use was significantly associated with a lower risk of ESRD (hazard ratio 0.58; 95 % confidence interval 0.42-0.80). Significant associations were observed for other propensity score-based approaches. In stratified analysis, a beneficial association between RASB and ESRD was observed in patients ≥35 years, with hypertension, reduced estimated glomerular filtration rate (<60 mL/min/1.73 m), mesangial proliferation and segmental glomerulosclerosis ( P for interaction <0.05), and tended to be greater in patients with proteinuria (≥1.0 g/24 h), extracapillary proliferation and receiving methylprednisolone pulse therapy ( P for interaction <0.10). Conclusion: Treatment with RASB was associated with a lower incidence of ESRD in the real-world practice of IgAN. [ABSTRACT FROM AUTHOR]

The Renin-Angiotensin-Aldosterone System (RAAS) is profoundly involved in the pathogenesis of renal and cardiovascular organ damage, and has been the preferred therapeutic target for renal protection for over 30 years. Monotherapy with either an Angiotensin Converting Enzime Inhibitor (ACE-I) or an Angiotensin Receptor Blocker (ARB), together with optimal blood pressure control, remains the mainstay treatment for retarding the progression toward end-stage renal disease. Combining ACE-Is and ARBs, or either one with an Aldosterone Receptor Antagonist (ARA), has been shown to provide greater albuminuria reduction, and to possibly improve renal outcome, but at an increased risk of potentially severe side effects. Moreover, combination therapy has failed to provide additional cardiovascular protection, and large prospective trials on hard renal endpoints are lacking. Therefore this treatment should, at present, be limited to selected patients with residual proteinuria and high renal risk. Future studies with novel agents, which directly act on the RAAS at multiple levels or have a more favourable side effect profile, are greatly needed to further explore and define the potential for and the limitations of profound pharmacologic RAAS inhibition. [ABSTRACT FROM AUTHOR]

With more than 6,000 new pediatric patients with treatment-resistant nephrotic syndrome in the US each year alone, the unmet need for novel, podocyte-specific therapies is substantial. Recently, the established therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) was used as a starting point to gain insight into the pathomechanism of primary podocytopathies. A calcium (Ca)-mediated pathway has been identified that connects the angiotensin type 1 receptor (AT1R) to podocyte cytoskeletal dynamics, essential for a functioning glomerular filtration barrier. This discovery provided an important missing piece in our understanding of the pathomechanism of filter barrier damage, revealing Ca signaling as critical for podocyte health and disease. The identification of the two Ca permeant channels TRPC5 and TRPC6 as mediators of this pathway not only bolstered the importance of podocyte cytoskeleton dynamics but also revealed promising drug targets for treatment-resistant nephrotic syndrome. This review will focus on this novel signaling pathway in primary podocytopathies and its implications for next-generation therapies for glomerular disease. [ABSTRACT FROM AUTHOR]

Unlabelled: No large cohort study has yet determined the incidence of acute kidney injury (AKI) in children with heart failure treated with renin-angiotensin system (RAS) inhibitors. We thus retrospectively analyzed the incidence and risk factors for severe AKI (stages 2-3 according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines) at our institutions from 2008 to 2011. Among 312 children (162 boys; median age, 7.3 months), 59 cases of AKI occurred in 45 children. The incidence of AKI was 14.3 cases per 100 person-years overall (follow-up 413.6 person-years), or 27.3, 16.8, and 4.5 cases per 100 person-years in children aged <1, 1-3, and ≥4 years, respectively. Among them, 23 (39.0 %) children had metabolic acidosis and 14 (23.7 %) had hyperkalemia. Younger age, myocardial disease, cyanotic congenital heart disease, use of spironolactone, and cardiac surgery were independent risk factors for AKI. Furthermore, 37.3 % of children suffered dehydration during AKI.Conclusion: AKI incidence is relatively high in children, particularly younger children, with heart failure treated using RAS inhibitors. Careful monitoring of renal function and serum electrolytes is essential. Proper management of fluid balance after infection and cardiac surgery may reduce the risk of AKI. Temporary discontinuation in RAS inhibitors should be considered during dehydration or surgery.What Is Known: • Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are the two main classes of renin-angiotensin system (RAS) inhibitors used to treat hypertension, heart failure, and chronic kidney disease. Acute kidney injury (AKI) and hyperkalemia are potentially life-threatening complications associated with the use of ACEIs and ARBs. Some reports have suggested that dehydration and cardiac surgery are risk factors for AKI in children. However, no large-scale cohort studies have determined the incidence of AKI, its risk factors, and its outcomes in children with heart failure treated with ACEIs and/or ARBs. What is new: • In this retrospective cohort study, we determined the incidence, severity, and risk factors for severe AKI in children with heart failure treated with ACEIs and/or ARBs. The incidence of AKI in these children was relatively high (14.3 episodes per 100 person-years). In addition, younger age, myocardial disease, cyanotic congenital heart disease, concomitant use of spironolactone, and cardiac surgery were risk factors for AKI. Furthermore, 37.3 % of children had dehydration during AKI episodes. • Our results suggested that appropriate fluid balance after infection and cardiac surgery might reduce the risk of AKI and its complications. Temporary discontinuation or reductions in the levels of ACEIs and/or ARBs during dehydration or before surgery may also be warranted in these patients. [ABSTRACT FROM AUTHOR]

Introduction: Bradykinin-mediated angioedema (AE) is a rare side effect of some medications, including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). In France, side-effects to treatments are reported to the national pharmacovigilance database. Methods: The national MedDRA database was searched using the term 'angioedema'. Patients were included if they met the clinical criteria corresponding to bradykinin-mediated AE, if their C1-inhibitor levels were normal, and if they were treated with an ACEi or an ARB. Results: 7998 cases of AE were reported between 1994 and 2013. Among these, 112 met the criteria for bradykinin-mediated AE with normal C1-inhibitor levels. On the 112 drug-AE, patients were treated with an ARB in 21 % of cases (24 patients), or an ACEi in 77 % of cases (88 patients), in combination with another treatment in 17 cases (mTORi for 3 patients, iDPP-4 for 1 patient, hormonal treatment for 7 patients). ENT involvement was reported in 90 % of cases (tongue: 48.2 %, larynx: 23.2 %). The median duration of treatment before the first attack was 720 days, and the mean duration of attacks was 36.6 h. Forty-one percent (19/46) of patients relapsed after discontinuing treatment. Conclusion: Angioedema triggered by medication blocking the renin/angiotensin system is rare but potentially severe, with a high risk of recurrence despite cessation of the causative drug. [ABSTRACT FROM AUTHOR]

Background: Several studies have demonstrated that spironolactone has an anti-albuminuric property in diabetic nephropathy. As an adverse event, spironolactone often induces the elevation of creatinine levels with hypotension and hyperkalemia. Therefore, we aimed to evaluate the efficacy and safety of spironolactone in Japanese patients with type 2 diabetes treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Methods: Fifty-two Japanese patients with diabetic nephropathy and albuminuria (100 mg/gCr-2000 mg/gCr) treated with renin-angiotensin system (RAS) blockade were enrolled in a prospective, randomized, open-label study. The patients were subjected to add-on treatment with spironolactone 25 mg once daily and compared with matched controls for 8 weeks. The primary outcome was a reduction in the rate of albuminuria at 8 weeks compared with the baseline value. This study was registered with UMIN Clinical Trials Registry (000008016). Results: Albuminuria was reduced by 33 % (95 % confidence interval: 22-54; P = 0.0002) at 8 weeks with spironolactone. In the spironolactone group, blood pressure tended to lower and the estimated glomerular filtration rate (eGFR) was significantly decreased compared to those in the control group. When adjusted by systolic blood pressure and eGFR, spironolactone treatment still showed a significant effect on albuminuria reduction in a linear mixed model (coefficient ± standard error; 514.4 ± 137.6 mg/gCr, P < 0.0005). No patient was excluded from the study because of hyperkalemia. Conclusions: Spironolactone reduced albuminuria along with conventional RAS inhibitors in patients with diabetic nephropathy. Our study suggests that spironolactone exerts anti-albuminuric effects independent of systemic hemodynamic alterations. [ABSTRACT FROM AUTHOR]

The burden of cardiovascular disease (CVD) is continuously and progressively raising worldwide. Essential hypertension is a major driver of cardiovascular events, including coronary artery disease, myocardial infarction, ischemic stroke and congestive heart failure. This latter may represent the final common pathway of different cardiovascular diseases, and it is often mediated by progressive uncontrolled hypertension. Despite solid advantages derived from effective and sustained blood pressure control, and the widespread availability of effective antihypertensive medications, the vast majority of the more than 1 billion hypertensive patients worldwide continue to have uncontrolled hypertension. Among various factors that may be involved, the abnormal activation of neurohormonal systems is one consistent feature throughout the continuum of cardiovascular diseases. These systems may initiate biologically meaningful 'injury responses'. However, their sustained chronic overactivity often may induce and maintain the progression from hypertension towards congestive heart failure. The renin-angiotensin-aldosteron system, the sympathetic nervous system and the endothelin system are major neurohormonal stressor systems that are not only able to elevate blood pressure levels by retaining water and sodium, but also to play a role in the pathophysiology of cardiovascular diseases. More recently, the angiotensin receptor neprilysin inhibitor (ARNI) represents a favourable approach to inhibit neutral endopeptidase (NEP) and suppress the RAAS via blockade of the AT1 receptors, without the increased risk of angioedema. LCZ696, the first-in-class ARNI, has already demonstrated BP lowering efficacy in patients with hypertension, in particular with respect to systolic blood pressure levels, improved cardiac biomarkers, cardiac remodelling and prognosis in patients with heart failure. This manuscript will briefly overview the main pathophysiological and therapeutic aspects of ARNI in the clinical management of hypertension and heart failure. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this research was to provide a comprehensive description of the effect of benazepril on the dynamics of the renin-angiotensin aldosterone system (RAAS) in dogs. Methods: Blood specimens for renin activity (RA), angiotensin II (AII), and aldosterone (ALD) quantitation in plasma were drawn from 12 healthy adult beagle dogs randomly allocated to 2 treatment groups: (i) benazepril 5 mg PO, q24 h (n: 6) and (ii) placebo (n: 6), in a cross-over design. A mechanism-based pharmacokinetic/pharmacodynamic model, which includes the periodic nature of RA, AII, and ALD during placebo treatment and the subsequent changes in dynamics following repeated dosing with benazepril, was developed. Results: The disposition kinetics of benazepril active metabolite, benazeprilat, was characterized using a saturable binding model to the angiotensin converting enzyme. The modulatory effect of benazeprilat on the RAAS was described using a combination of immediate response models. Our data show that benazepril noticeably influences the dynamics of the renin cascade, resulting in a substantial decrease in AII and ALD, while increasing RA throughout the observation span. Conclusions: The model provides a quantitative framework for better understanding the effect of ACE inhibition on the dynamics of the systemic RAAS in dogs. [ABSTRACT FROM AUTHOR]

The antagonists of the renin-angiotensin system (RAS) have gained increasing popularity in the last two decades due to their indisputable efficacy in a number of cardiovascular disorders, coupled with an unsurpassed tolerability. However some years ago a partial and non-predefined meta-analysis raised the possibility that angiotensin receptor antagonists in particular may increase the incidence of cancer. This observation, although not confirmed by subsequent, larger analyses, caused a remarkable and understandable concern even outside the medical community. Herein we will summarize the available evidence pro and con the hypothesis of a carcinogenetic activity of RAS antagonists coming to the conclusion that these drugs may actually exert an anticancer action. [ABSTRACT FROM AUTHOR]

Most patients hospitalized for acutely decompensated heart failure (ADHF) present with symptoms and signs of volume overload, which are also associated with high rates of death and re-hospitalization. Several studies have investigated the possible use of extracorporeal ultrafiltration in the management of ADHF, evaluating potential clinical benefits in terms of hospitalization and survival rates versus those of conventional diuretic therapy. Though ultrafiltration remains an extremely appealing therapeutic option for patients with AHDF, some of the most recent studies have reported conflicting results. Differences in the selection of study population, heterogeneity of the indications for the use of ultrafiltration, disparity in the ultrafiltration protocols, and high variability in the pharmacologic therapies used for the control group could explain some of these contradictory findings. The purpose of the present review is to provide an overview and an update on the mechanisms and clinical effects of ultrafiltration and on currently available evidence supporting its use in ADHF. [ABSTRACT FROM AUTHOR]

Nearly one-third of the world's population has hypertension. The human and societal impact of hypertension is enormous. Primary hypertension accounts for 95 % of cases of hypertension in adults. The pathogenesis of primary hypertension is complex. The kidney and the sympathetic nervous system play important roles in the development and maintenance of hypertension. This review discusses their respective roles, the interaction between the two, implications of sympathetic overactivity in kidney disease and therapeutic interventions that have been developed on the basis of this knowledge, especially modulation of the sympathetic nervous system. [ABSTRACT FROM AUTHOR]

Obesity-related hypertension is associated with increased activity of the renin-angiotensin-aldosterone system (RAAS), increasing arterial stiffness. Aerobic exercise decreases pulse wave velocity (PWV), therefore a treatment option for hypertension and obesity. Assess RAAS activity and PWV before and after 4 weeks of aerobic training in unmedicated, pre-to-stage-1 hypertensives. Ten obese subjects (52±3.2 years, body mass index=33.5±1.4) performed 30 min of aerobic exercise on a treadmill 3 days per week at 65% of peak oxygen consumption (VO2peak). Descriptive characteristics, systolic and diastolic blood pressure (SBP and DBP), PWV, and a blood draw was performed at baseline, following the 4-week control and training interventions. No differences in descriptive characteristics during the control period were observed, however, a significant decrease in plasma aldosterone (ALDO) (255.4±75 to 215.8±66 pg ml−1, P=0.001), SBP (140±12 to 136±10.4 mm Hg; P=0.02), DBP (89±4.2 to 85±6.3 mm Hg; P=0.03) and central PWV (11.2±0.6 to 9.8±0.8 m s−1; P=0.04) was shown pre-to-post exercise training. Four weeks of moderate-intensity aerobic training in obese, hypertensives decreases plasma ALDO independently of body weight and is significantly correlated to decreases in PWV reductions. [ABSTRACT FROM AUTHOR]

Proportions of elderly aged ≥65 and ≥75 within Japan will increase to 30 and 20 %, respectively, in 2025, when 'Baby-Boom Generations' will reach the age of 75 years. Okabayashi and colleagues report that even in elderly patients with IgA nephropathy (IgAN), immunosuppressive treatment can reduce proteinuria, with no adverse events. Their findings remind us of recent finding from STOP-IgAN study; additional immunosuppressive therapy to intensive supportive care [specifically renin-angiotensin system (RAS) inhibitors (RASi)] did not improve the outcome. If STOP-IgAN makes doctors believe that immunosuppression is not necessary, many patients could lose opportunity to eliminate their kidney disease. Indeed, we have experienced patients with IgAN, who despite hematuria, could not undergo renal biopsy or immunosuppressive treatment at another facility because of low proteinuria, and exhibited advanced lesions in their renal biopsy at our institution. The discrepancy between Okabayashi's and STOP-IgAN study was derived not only from differences in population age (≥60 years vs. 18-70 years). STOP-IgAN excluded the crescentic IgAN, whereas Okabayashi et al. found active manifestations (hematuria, mesangial proliferation, and cellular/fibrocellular crescent). Therefore, immunosuppressive therapy is required even in elderly patients. In STOP-IgAN, RASi were used first, and then immunosuppressive agent was additionally used. RASi has important implications to reduce glomerular capillary pressure and to suppress the intrarenal RAS activity. However, immunosuppressant should be administered initially to cure hematuria. In fact, microscopic-hematuria was resolved in only 16 and 42 % of two-assigned groups in STOP-IgAN, respectively. Okabayashi et al. provided a timely message regarding the significance of immunosuppressive treatment of IgAN. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system (RAAS) has a key role in the regulation of blood pressure, sodium and water balance, and cardiovascular and renal homeostasis. In diabetic nephropathy, excessive activation of the RAAS results in progressive renal damage. RAAS blockade using angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers is the cornerstone of treatment of diabetic renal disease. Alternative RAAS-blockade strategies include renin inhibition and aldosterone blockade. Data from small initial studies of these agents are promising. However, single-agent interventions do not fully block the RAAS and patients treated with these therapies remain at high residual renal risk. Approaches to optimize drug responses include dietary changes and increasing dosages. The theoretically attractive option of combining different RAAS interventions has also been tested in clinical trials but long-term outcomes were disappointing. However, dual RAAS blockade might represent a good therapeutic option for specific patients. A better knowledge of the pathophysiology of the RAAS is crucial to fully understand the mechanisms of action of RAAS blockers and to exploit their renoprotective effects. Moreover, lifestyle interventions or diagnostic tools might be used to optimize RAAS blockade and identify those patients who are most likely to benefit from the therapy. [ABSTRACT FROM AUTHOR]

Treatment with a number of antihypertensive agents is usually necessary to achieve blood pressure control in patients with obesity-related hypertension. Diuretics, renin-angiotensin system inhibitors and dihydropyridine calcium channel blockers are commonly used first, with subsequent additions of aldosterone antagonists and/or dual α- and β-blocking agents as necessary. Treatment should be based on an understanding of the underlying mechanisms of obesity-related hypertension, and individualized according to patient characteristics and co-morbidities. [ABSTRACT FROM AUTHOR]

Nephropathy remains a major cause of morbidity and a key determinant of mortality in patients with type 1 or type 2 diabetes mellitus. Research is ongoing to identify biomarkers that in addition to albuminuria and glomerular filtration rate assist in the prediction and monitoring of renal disease in diabetes mellitus. Current strategies to treat this condition focus on intensification of glycaemic control and excellent control of blood pressure using regimens based on blockade of the reninangiotensin system. Other approaches to control blood pressure and afford renoprotection are under active clinical investigation, including renal denervation and endothelin receptor antagonism. With increasing understanding of the underlying pathophysiological processes implicated in diabetic nephropathy, new specific renoprotective treatment strategies are anticipated to become available over the next few years. [ABSTRACT FROM AUTHOR]

Background Our retrospective study and phase I trial of gemcitabine and candesartan combination therapy suggested the inhibition of renin-angiotensin system potentially has a role in the treatment of advanced pancreatic cancer. The aim of this multicenter phase II trial was to assess the efficacy and toxicity of gemcitabine and candesartan combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naive patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m over 30 min on days 1, 8, and 15 and oral candesartan at a dose of 16 mg in normotensive patients, and 8 mg initially in hypertensive patients, with dose escalation to 16 mg allowed, from days 1 to 28, repeated every 4 weeks. Results A total of 35 patients with advanced pancreatic cancer were enrolled. Overall response rate and disease control rate were 11.4 % and 62.9 %. The median PFS and OS were 4.3 and 9.1 months with 1-year survival rate of 34.2 %. The median PFS was significantly longer in patients receiving 16 mg compared with 8 mg of candesartan (4.6 vs. 3.5 months, p = 0.031). Major severe toxicities were neutropenia (23 %), leukopenia (17 %) and thrombocytopenia (11 %). Grade 2 hypotension was observed in 3 patients (9 %) and candesartan was discontinued in 2 patients due to hypotension. Conclusions In this multicenter phase 2 trial, gemcitabine and candesartan combination therapy was tolerable but failed to demonstrate activity against advanced pancreatic cancer. (UMIN CTR: UMIN000005580) [ABSTRACT FROM AUTHOR]

Background and Objectives: Obesity exacerbates hypertension and stimulates the renin-angiotensin-aldosterone system (RAAS). Full-dose RAAS inhibition could be a therapeutic option in overweight or obese patients with hypertension. This study compared four RAAS inhibitors at full therapeutic doses to determine their effect on blood pressure (BP) and cardiovascular risk factors in these patients. Methods: We conducted a 24-week, single-blind, randomized, parallel-group study in 120 overweight or obese patients (body mass index ≥27 kg/m) with hypertension, aged 18-60 years. The primary endpoint was the change in mean 24-h systolic BP and diastolic BP from baseline to study end. Central BP, arterial stiffness, and metabolic and cardiac indices were also investigated. Patients were randomly allocated to perindopril 10 mg/day, enalapril 20 mg/day, losartan 100 mg/day or telmisartan 80 mg/day. Nonpharmacological interventions were also recommended. Results: Reductions in mean 24-h systolic BP (and diastolic BP) were all significant ( p < 0.05 versus baseline) for perindopril, enalapril, losartan and telmisartan: systolic BP −22, −11, −12 and −15 mmHg, respectively; (and diastolic BP −13, −6, −13 and −12 mmHg, respectively). Aortic elasticity improved with perindopril and telmisartan. Perindopril was associated with the greatest reductions in central aortic BP and leptin levels [30 % versus 2 %, 7 % and 14 % with enalapril, losartan and telmisartan, respectively (all p < 0.05 versus perindopril)]. Reductions in other BP, echocardiographic, metabolic and anthropometric parameters occurred with all treatments. Conclusion: Full-dose RAAS inhibition, particularly with perindopril, effectively reduces BP, improves arterial structure and regulates cardiovascular risk factors in overweight or obese patients with hypertension. [ABSTRACT FROM AUTHOR]

Alport Syndrome (AS) is an inherited progressive disease that is caused by mutations of the genes encoding the key collagen chains, α3, α4, and α5, which are necessary for the composition of collagen type IV to form a robust glomerular basement membrane (GBM), capable of withstanding the significant biomechanical strain to which the glomerulus is subjected. Progressive loss of the filtration barrier allows excessive proteinuria, which ultimately leads to end-stage kidney disease (ESKD). The evidence for a beneficial renoprotective effect of renin-angiotensin-aldosterone system (RAAS) blockade by angiotensin-converting enzyme (ACE) inhibition and/or angiotensin receptor blockers (ARBs) is well established in AS and recent evidence has shown that it can significantly delay the time to onset of renal replacement therapy and ESKD. Future potential treatments of AS disease progression are evaluated in this review. [ABSTRACT FROM AUTHOR]

Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin-angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models. Aims: We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the β-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model. Methods: Sixty-five Abcb4 mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting. Results: Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p = 0.008), fibrosis score (TP 3 months and TP 8 months, p = 0.043 and p = 0.008, respectively; TP delayed 8 months, p < 0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p < 0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein. Conclusions: Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4 mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC. [ABSTRACT FROM AUTHOR]

We aimed to assess the efficacy and safety of low-dose propranolol for treatment of infantile hemangiomas (IHs) in China. Our prospective study included data from 89 patients with IH, aged 1-12 months. Plasma renin activity, angiotensin II, and aldosterone were measured before initiation of propranolol therapy. Patients were administered propranolol (0.75-1 mg/kg/day) under close observation. The volume, texture, and color of lesions were used to evaluate efficacy. Safety endpoints included heart rate, systolic and diastolic blood pressures, alanine transaminase, aspartate transaminase, thyroid function tests, and fasting blood glucose. Adverse effects were recorded. Mean plasma angiotensin II concentration in patients with IH was higher than that in age-matched healthy children, whereas mean plasma renin activity was lower. Mean aldosterone level was higher at 1-3 months but lower at 4-12 months, than values reported previously. After propranolol therapy for 6 months, IH regression was classed as grade IV in 44 patients (49.4 %), grade III in 21 patients (23.6 %), and grade II in 24 patients (27.0 %); none were grade I. Mild adverse effects, including diarrhea, restless sleep, nausea, cold extremities, and hypoglycemia, occurred in 12 patients (13.5 %). Slight decreases in heart rate and blood pressure occurred in all patients ( p < 0.05). The IHs of four patients (4.5 %) relapsed after treatment cessation at 4-5 months. Conclusion: Low-dose propranolol is effective and safe for Chinese children with IH, and larger-scale studies are merited. Mechanisms underlying IH pathogenesis, and possible involvement of the renin-angiotensin-aldosterone system, deserve study. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II)-induced inflammatory and oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether renin-angiotensin system (RAS) activation in the hypothalamic paraventricular nucleus (PVN) contributes to the ANG II-induced hypertensive response via interaction with neurotransmitters in the PVN. Rats underwent subcutaneous infusion of ANG II or saline for 4 weeks. These rats were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS), an angiotensin II type 1 receptor (AT1-R) antagonist, via osmotic minipump. ANG II infusion resulted in higher levels of glutamate, norepinephrine (NE), AT1-R and pro-inflammatory cytokines (PIC), and lower level of gamma-aminobutyric acid (GABA) in the PVN. Rats receiving ANG II also had higher levels of mean arterial pressure, plasma PIC, NE and aldosterone than control animals. PVN treatment with LOS attenuated these ANG II-induced hypertensive responses. In conclusion, these findings suggest that the RAS activation in the PVN contributes to the ANG II-induced hypertensive response via interaction with PIC and neurotransmitters (glutamate, NE and GABA) in the PVN. [ABSTRACT FROM AUTHOR]