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Background: Small-interfering RNA (siRNA) targeting hepatic AGT (angiotensinogen) mRNA depletes AGT, lowering blood pressure for up to 6 months. However, certain situations may require a rapid angiotensin increase. The REVERSIR (RVR) - reverse siRNA silencing technology a potential approach to counteract siRNA effects., Methods: Spontaneously hypertensive rats received 10 mg/kg AGT siRNA, and 3 weeks later were given AGT-RVR (1, 10, or 20 mg/kg). One week after AGT-RVR dosing, a redose of AGT siRNA assessed its post-AGT-RVR effectiveness for 2 weeks. Additionally, the impact of AGT-RVR after an equihypotensive dose of valsartan (4 mg/kg per day) was examined., Results: Baseline mean arterial pressure (MAP) was 144±1 mm Hg. AGT siRNA reduced MAP by ≈16 mm Hg and AGT by >95%, while renin increased 25-fold. All AGT-RVR doses restored MAP to baseline within 4 to 7 days. Notably, 10 and 20 mg/kg restored AGT and renin to baseline, while 1 mg/kg allowed ≈50% AGT restoration, with renin remaining above baseline. A second AGT siRNA treatment, following 1 mg/kg AGT-RVR, reduced MAP to the same degree as the initial dose, while following 10 mg/kg AGT-RVR, it resulted in ≈50% of the first dose's MAP effect at 2 weeks. The valsartan-induced MAP reduction was unaffected by AGT-RVR., Conclusions: In spontaneously hypertensive rats, angiotensinogen-RVR dose-dependently reversed AGT siRNA-induced AGT reduction, normalizing MAP. MAP normalization persisted even with 50% recovered AGT levels, likely due to upregulated renin maintaining adequate angiotensin generation. Post-AGT-RVR dosing, a second AGT siRNA dose lowered MAP again., Competing Interests: Disclosures A. Kasper, K. Wassarman, H.-C. Tu, and I. Zlatev are employees of Alnylam Pharmaceuticals. A.H. Jan Danser received a grant from Alnylam Pharmaceuticals, which has partially supported this work. The other authors report no conflicts.

Introduction: The clinical benefits of renin-angiotensin system inhibitors (RASi) in patients undergoing hemodialysis remain obscure., Methods: This is a post hoc cohort analysis of the LANDMARK trial investigate whether RASi use was associated with cardiovascular events (CVEs) and all-cause mortality. A total of 2135 patients at risk for vascular calcification were analyzed using a Cox proportional hazards model with propensity-score matching., Results: The risk of CVEs was similar between participants with RASi use at baseline and those without RASi use at baseline and between participants with RASi use during the study period and those without RASi use during the study period. No clinical benefits of RASi use on all-cause mortality were observed. Serum phosphate levels were significantly associated with the effect of RASi on CVEs., Conclusions: RASi use was not significantly associated with a lower risk of CVEs or all-cause mortality in hemodialysis patients at risk of vascular calcification., (© 2023 International Society for Apheresis and Japanese Society for Apheresis.)

Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg office BP, despite life-style measures and optimal medical therapies, including at least three antihypertensive drug classes at maximum tolerated dose (one should be a diuretic). This condition is strongly related to hypertension-mediated organ damage and, mostly, high risk of hospitalization due to hypertension emergencies or acute cardiovascular events. Hypertension guidelines proposed a triple combination therapy based on renin angiotensin system blocking agent, a thiazide or thiazide-like diuretic, and a dihydropyridinic calcium-channel blocker, to almost all patients with RHT, who should also receive either a beta-blocker or a mineralocorticoid receptor antagonist, or both, depending on concomitant conditions and contraindications. Several other drugs may be attempted, when elevated BP levels persist in these RHT patients, although their added efficacy in lowering BP levels on top of optimal medical therapy is uncertain. Also, renal denervation has demonstrated to be a valid therapeutic alternative in RHT patients. More recently, novel drug classes and molecules have been tested in phase 2 randomised controlled clinical trials in patients with RHT on top of optimal medical therapy with at least 2-3 antihypertensive drugs. These novel drugs, which are orally administered and are able to antagonize different pathophysiological pathways, are represented by non-steroid mineralocorticorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin receptor antagonists, all of which have proven to reduce seated office and 24-h ambulatory systolic/diastolic BP levels. The main findings of randomized clinical trials performed with these drugs  as well as their potential indications for the clinical management of RHT patients are summarised in this systematic review article., (© 2024. The Author(s).)

Cardiovascular diseases (CVD) are the main causes of death in hemodialysis patients, representing a public health challenge. We investigated the effect of different antihypertensive treatments on circulating levels of renin-angiotensin system (RAS) components in end-stage renal disease (ESRD) patients on hemodialysis. ESRD patients were grouped following the prescribed antihypertensive drugs: ß-blocker, ß-blocker+ACEi and ß-blocker+AT 1 R blocker. ESDR patients under no antihypertensive drug treatment were used as controls. Blood samples were collected before hemodialysis sessions. Enzymatic activities of the angiotensin-converting enzymes ACE and ACE2 were measured through fluorescence assays and plasma concentrations of the peptides Angiotensin II (Ang II) and Angiotensin-(1-7) [Ang-(1-7)] were quantified using mass spectrometry (LC-MS/MS). ACE activity was decreased only in the ß-blocker+ACEi group compared to the ß-blocker+AT 1 R, while ACE2 activity did not change according to the antihypertensive treatment. Both Ang II and Ang-(1-7) levels also did not change according to the antihypertensive treatment. We concluded that the treatment of ESRD patients on hemodialysis with different antihypertensive drugs do not alter the circulating levels of RAS components., Competing Interests: Conflict of Interests All authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

The health-beneficial outcomes of doenjang, a Korean fermented food have been questioned due to its high salt content; moreover, the detailed underlying mechanisms of its health beneficial effects are not fully investigated. Thus, this study aimed to investigate doenjang's anti-obesity effects, anti-hypertensive effects, and its underlying mechanisms in high-fat diet -induced obesity. Sprague-Dawley rats fed with normal diet (ND), high-fat diet (HD), HD with 8% additive salt (HDS), or HD with doenjang containing 8% salt (HDJ) for 13 weeks. Compared to HD and HDS groups, the HDJ group had lower body and epididymal fat tissue weight gain and showed hypotrophy and hypoplasia. The RAS-related mRNA levels in the adipose tissue, including Renin and Ace were downregulated in the HDJ group compared to HD and HDS groups. Additionally, HDJ groups had significant improvements in systolic blood pressure, serum RAS-associated parameters (e.g., angiotensin II and aldosterone), renal mRNA levels related to RAS (e.g., angiotensin II receptor type 1 and 2), and aldosterone-associated mRNA expressions (e.g., mineralocorticoid receptor) in the kidney of HD-induced obese rats. Most importantly, HDS and HDJ groups showed distinct outcomes regarding adipogenesis and electrolytes metabolism, even though both diets contain a high level of salt. HDS group showed a higher epididymal fat tissue weight, mass, and adipocyte size than HDJ group. In addition, compared with HDJ group, HDS group significantly decreased the release of Na+ and K+ throughout the urine and feces. The present study addresses that doenjang has anti-obesity effects and anti-hypertensive effects by activating RAS in the adipose tissue and kidney, respectively. Additionally, this study also demonstrates that salt in doenjang and the additive salt differently influences adipogenesis and electrolytes metabolism, supporting doenjang has health advantageous effects regardless of its high salt contents., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 Woo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

BACKGROUND Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) block distinct components of the renin-angiotensin system. Whether this translates into differential effects on cardiovascular disease events remains unclear. METHODS AND RESULTS We used the ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) trial and the SPRINT (Systolic Blood Pressure Intervention Trial) to emulate target trials of new users of ARBs versus ACEIs on cardiovascular disease events (primary outcome) and death (secondary outcome). We estimated marginal cause-specific hazard ratios (HRs) and treatment-specific cumulative incidence functions with inverse probability of treatment weights. We identified 3298 new users of ARBs or ACEIs (ACCORD-BP: 374 ARB versus 884 ACEI; SPRINT: 727 ARB versus 1313 ACEI). For participants initiating ARBs versus ACEIs, the inverse probability of treatment weight rate of the primary outcome was 3.2 versus 3.5 per 100 person-years in ACCORD-BP (HR, 0.91 [95% CI, 0.63-1.31]) and 1.8 versus 2.2 per 100 person-years in SPRINT (HR, 0.81 [95% CI, 0.56-1.18]). There were no appreciable differences in pooled analyses, except that ARBs versus ACEIs were associated with a lower death rate (HR, 0.56 [95% CI, 0.37-0.85]). ARBs were associated with a lower rate of the primary outcome among subgroups of male versus female participants, non-Hispanic Black versus non-Hispanic White participants, and those randomly assigned to standard versus intensive blood pressure ( P interaction : <0.01, 0.05, and <0.01, respectively). CONCLUSIONS In this secondary analysis of ACCORD-BP and SPRINT, new users of ARB- versus ACEI-based antihypertensive medication regimens experienced similar cardiovascular disease events rates, with important subgroup differences and lower rates of death overall. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01206062, NCT00000620.

Background: Hypertensive emergency is a critical disease that causes multifaceted sequelae, including end-stage kidney disease and cardiovascular disease. Although the renin-angiotensin-aldosterone (RAA) system is enormously activated in this disease, there are few reports that attempt to characterize the effect of early use of RAA inhibitors (RASi) on the temporal course of kidney function., Methods: This retrospective cohort study was conducted to clarify whether the early use of RASi during hospitalization offered more favorable benefits on short-term renal function and long-term renal outcomes in patients with hypertensive emergencies. We enrolled a total of 49 patients who visited our medical center with acute severe hypertension and multiple organ dysfunction between April 2012 and August 2020. Upon admission, the patients were treated with intravenous followed by oral antihypertensive drugs, including RASi and Ca channel blockers (CCB). Kidney function as well as other laboratory and clinical parameters were compared between RASi-treated and CCB- treated group over 2 years., Results: Antihypertensive treatment effectively reduced blood pressure from 222 ± 28/142 ± 21 to 141 ± 18/87 ± 14 mmHg at 2 weeks and eGFR was gradually restored from 33.2 ± 23.3 to 40.4 ± 22.5 mL/min/1.73m 2 at 1 year. The renal effect of antihypertensive drugs was particularly conspicuous when RASi was started in combination with other conventional antihypertensive drugs at the early period of hospitalization (2nd day [IQR: 1-5.5]) and even in patients with moderately to severely diminished eGFR (< 30 mL/min/1.73 m 2 ) on admission. In contrast, CCB modestly restored eGFR during the observation period. Furthermore, renal survival probabilities were progressively deteriorated in patients who had manifested reduced eGFR (< 15 mL/min/1.73 m 2 ) or massive proteinuria (urine protein/creatinine ≥ 3.5 g/gCr) on admission. Early use of RASi was associated with a favorable 2-year renal survival probability (0.90 [95%CI: 0.77-1.0] vs. 0.63 [95%CI: 0.34-0.92] for RASi ( +) and RASi (-), respectively, p = 0.036) whereas no apparent difference in renal survival was noted for CCB., Conclusions: Early use of RASi contributes to the renal functional recovery from acute reduction in eGFR among patients with hypertensive emergencies. Furthermore, RASi offers more favorable effect on 2-year renal survival, compared with CCB., (© 2023. The Author(s).)

Background: Describing the antihypertensive medication regimens used in the SPRINT (Systolic Blood Pressure Intervention Trial) would contextualize the standard and intensive systolic blood pressure (SBP) interventions and may inform future implementation efforts to achieve population-wide intensive SBP goals., Methods: We included SPRINT participants with complete medication data at the prerandomization and 12-month visits. Regimens were categorized by antihypertensive medication class. Analyses were stratified by treatment group (standard goal SBP <140 mm Hg versus intensive goal SBP <120 mm Hg)., Results: Among 7860 participants (83.7% of 9361 randomized), the median number of classes used at the prerandomization visit was 2.0 and 2.0 in the standard and intensive groups ( P =0.559). At 12-months, the median number of classes used was 3.0 and 2.0 in the intensive and standard groups ( P <0.001). Prerandomization, angiotensin-converting enzyme inhibitor (ACE), or angiotensin-II receptor blocker (ARB) monotherapy was the most common regimen in the intensive and standard groups (12.6% versus 12.2%). At 12-months, ACE/ARB monotherapy was still the most common regimen among standard group participants (14.7%) and was used by 5.3% of intensive group participants. Multidrug regimens used by the intensive and standard participants at 12 months were as follows: an ACE/ARB with thiazide (12.2% and 7.9%); an ACE/ARB with calcium channel blocker (6.2% and 6.8%); an ACE/ARB, thiazide, and calcium channel blocker (11.4% and 4.3%); and an ACE/ARB, thiazide, calcium channel blocker, and beta-blocker (6.5% and 1.2%)., Conclusions: SPRINT investigators favored combining ACEs or ARBs, thiazide diuretics, and calcium channel blockers to target SBP <120 mm Hg, compared to ACE/ARB monotherapy to target SBP <140 mm Hg., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01206062.

Hypertension is the third leading cause of the global disease burden, and while populations live longer, adopt more sedentary lifestyles, and become less economically concerned, the prevalence of hypertension is expected to increase. Pathologically elevated blood pressure (BP) is the strongest risk factor for cardiovascular disease (CVD) and related disability, thus making it imperative to treat this disease. Effective standard pharmacological treatments, i.e., diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blocker (ARBs), beta-adrenergic receptor blockers (BARBs), and calcium channel blockers (CCBs), are available. Vitamin D (vitD) is known best for its role in bone and mineral homeostasis. Studies with vitamin D receptor (VDR) knockout mice show an increased renin-angiotensin-aldosterone system (RAAS) activity and increased hypertension, suggesting a key role for vitD as a potential antihypertensive agent. Similar studies in humans displayed ambiguous and mixed results. No direct antihypertensive effect was shown, nor a significant impact on the human RAAS. Interestingly, human studies supplementing vitD with other antihypertensive agents reported more promising results. VitD is considered a safe supplement, proposing its great potential as antihypertensive supplement. The aim of this review is to examine the current knowledge about vitD and its role in the treatment of hypertension.

The development of essential hypertension involves several factors. Vascular dysfunction, characterized by endothelial dysfunction, low-grade inflammation and structural remodeling, plays an important role in the initiation and maintenance of essential hypertension. Although the mechanistic pathways by which essential hypertension develops are poorly understood, several pharmacological classes available on the clinical settings improve blood pressure by interfering in the cardiac output and/or vascular function. This review is divided in two major sections. The first section depicts the major molecular pathways as renin angiotensin aldosterone system (RAAS), endothelin, nitric oxide signalling pathway and oxidative stress in the development of vascular dysfunction. The second section describes the role of some pharmacological classes such as i) RAAS inhibitors, ii) dual angiotensin receptor-neprilysin inhibitors, iii) endothelin-1 receptor antagonists, iv) soluble guanylate cyclase modulators, v) phosphodiesterase type 5 inhibitors and vi) sodium-glucose cotransporter 2 inhibitors in the context of hypertension. Some classes are already approved in the treatment of hypertension, but others are not yet approved. However, due to their potential benefits these classes were included., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Global incidence and prevalence of hypertension continues to increase and remains a significant challenge. The ever-increasing number of cases are due to comorbid conditions such as obesity and diabetes, as well as lifestyle indiscretions such as excessive salt intake. Hypertension, congestive heart failure, and kidney disease are all conditions resulting from abnormal Renin-Angiotensin-Aldosterone activation and adverse remodeling. Firibastat, a novel Brain Aminopeptidase inhibitor, may be able to help achieve blood pressure control in those with resistant hypertension. In this review article, we will discuss the biochemical pathway of firibastat and various trials assessing drug efficacy in animals and humans. This drug has the potential to curb the risk of uncontrolled hypertension and help improve long term cardiovascular morbidity and mortality., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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Background: Concerns have been raised on a potential interaction between renin-angiotensin system inhibitors (RASI) and the susceptibility to coronavirus disease 2019 (COVID-19). No data have been so far reported on the prognostic impact of RASI in patients suffering from ST-elevation myocardial infarction (STEMI) during COVID-19 pandemic, which was the aim of the present study., Methods: STEMI patients treated with primary percutaneous coronary intervention (PPCI) and enrolled in the ISACS-STEMI COVID-19 registry were included in the present sub-analysis and divided according to RASI therapy at admission., Results: Our population is represented by 6095 patients, of whom 3654 admitted in 2019 and 2441 in 2020. No difference in the prevalence of SARSCoV2 infection was observed according to RASI therapy at admission (2.5% vs 2.1%, p = 0.5), which was associated with a significantly lower mortality (adjusted OR [95% CI]=0.68 [0.51-0.90], P = 0.006), confirmed in the analysis restricted to 2020 (adjusted OR [95% CI]=0.5[0.33-0.74], P = 0.001). Among the 5388 patients in whom data on in-hospital medication were available, in-hospital RASI therapy was associated with a significantly lower mortality (2.1% vs 16.7%, OR [95% CI]=0.11 [0.084-0.14], p < 0.0001), confirmed after adjustment in both periods. Among the 62 SARSCoV-2 positive patients, RASI therapy, both at admission or in-hospital, showed no prognostic effect., Conclusions: This is the first study to investigate the impact of RASI therapy on the prognosis and SARSCoV2 infection of STEMI patients undergoing PPCI during the COVID-19 pandemic. Both pre-admission and in-hospital RASI were associated with lower mortality. Among SARSCoV2-positive patients, both chronic and in-hospital RASI therapy showed no impact on survival., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Renin-angiotensin system (RAS) inhibitors have been postulated to influence susceptibility to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This study investigated whether there is an association between their prescription and the incidence of COVID-19 and all-cause mortality., Methods: We conducted a propensity-score matched cohort study comparing the incidence of COVID-19 among patients with hypertension prescribed angiotensin-converting enzyme I (ACE) inhibitors or angiotensin II type-1 receptor blockers (ARBs) to those treated with calcium channel blockers (CCBs) in a large UK-based primary care database (The Health Improvement Network). We estimated crude incidence rates for confirmed/suspected COVID-19 in each drug exposure group. We used Cox proportional hazards models to produce adjusted hazard ratios for COVID-19. We assessed all-cause mortality as a secondary outcome., Results: The incidence rate of COVID-19 among users of ACE inhibitors and CCBs was 9.3 per 1000 person-years (83 of 18,895 users [0.44%]) and 9.5 per 1000 person-years (85 of 18,895 [0.45%]), respectively. The adjusted hazard ratio was 0.92 (95% CI 0.68 to 1.26). The incidence rate among users of ARBs was 15.8 per 1000 person-years (79 out of 10,623 users [0.74%]). The adjusted hazard ratio was 1.38 (95% CI 0.98 to 1.95). There were no significant associations between use of RAS inhibitors and all-cause mortality., Conclusion: Use of ACE inhibitors was not associated with the risk of COVID-19 whereas use of ARBs was associated with a statistically non-significant increase compared to the use of CCBs. However, no significant associations were observed between prescription of either ACE inhibitors or ARBs and all-cause mortality.

Background/aims: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, there have been concerns about the association between exposure to renin-angiotensin-aldosterone system (RAAS) inhibitors and the risk and severity of COVID-19., Methods: We performed a case-control study that utilized up-to-date data on the South Korean population provided by the Korean National Health Insurance System. Of the 62,909 patients with hypertension or heart failure tested for COVID-19, there were 1,644 (2.6%) confirmed cases. After case-control matching, multivariable-adjusted conditional logistic regression analysis was performed., Results: Comparison between patients exposed to RAAS inhibitors and those not exposed to RAAS inhibitors revealed that the adjusted odds ratio (OR) and 95% confidence interval (CI) for COVID-19 infection and death were 0.981 (95% CI, 0.849 to 1.135) and 0.875 (95% CI, 0.548 to 1.396), respectively. Subgroup analysis for the major confounders, age and region of diagnosis, resulted in OR of 0.912 (95% CI, 0.751 to 1.108) and 0.942 (95% CI, 0.791 to 1.121), respectively., Conclusion: The present study demonstrated no evidence of association between RAAS inhibitor exposure and risk and severity of COVID-19.

Importance: The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes., Objective: To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19., Data Sources: PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020., Study Selection: The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs., Data Extraction and Synthesis: Three authors independently extracted data on mortality and severe AEs associated with COVID-19. Severe AEs were defined as intensive care unit admission or the need for assisted ventilation. For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs., Main Outcomes and Measures: Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19., Results: A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation. Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101 949 total patients, of whom 26 545 (26.0%) were receiving ACEIs or ARBs. When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P < .001) and severe AEs (aOR, 0.68; 95% CI, 0.53-0.88; P < .001) were found. Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 0.66 [95% CI, 0.49-0.91]; P = .01; aOR, 0.51 [95% CI, 0.32-0.84]; P = .008) and severe AEs (unadjusted OR, 0.70 [95% CI, 0.54-0.91]; P = .007; aOR, 0.55 [95% CI, 0.36-0.85]; P = .007)., Conclusions and Relevance: In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to establish causality.

Background: Many fishes have been known for their good nutritional effects especially in the cardiovascular aspect. Some specific fish peptides have anti-hypertensive effects., Objective: In the present study, we hypothesized that the hexapeptide (MEVFVP) from flounder fish muscle can be a potent antihypertensive peptide, therefore, decided to perform this experiment., Methods: The peptide MEVFVP from flounder fish muscle (40 mg/kg) and vehicle were administered per os to spontaneously hypertensive rats (SHRs) (SHR-M and SHR-C, respectively). Additionally, plasma MEVFVP was measured serially before and after its oral administration to Sprague Dawley rats., Results: Blood pressures (BPs), especially systolic BP, in SHR rats were decreased around 3-6 hours after MEVFVP administration. Compared with SHR-C rats, endothelin-1 (ET-1) mRNA expression in multiple tissues, and plasma levels of ET-1, angiotensin II, and aldosterone were lower in SHR-M rats, whereas the phosphorylation of AMP-activated protein kinase (AMPK) was increased in the kidney of SHR-M rats. The administered peptide was not detected in rat plasma, while ex vivo incubation of the peptide in rat plasma caused its rapid degradation within minutes., Conclusion: Our results show that the MEVFVP has an antihypertensive effect by regulating renin- angiotensin-aldosterone system, ET-1 and AMPK despite its limited bioavailability., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: There is an ongoing controversy about harms and benefits of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in hypertensive patients with coronavirus disease 2019 (COVID-19). Given the unresolved debate, we investigated the association of ARBs with in-hospital outcomes of these patients., Methods: In this retrospective observational study, we studied patients with COVID-19 who referred to Sina Hospital in Tehran, Iran, from 20 February to 29 May 2020. Patients with either positive real-time reverse-transcriptase polymerase-chain-reaction test of swab specimens, or high clinical suspicion according to the World Health Organization's interim guidance were included. We followed-up patients for incurring death, severe COVID-19, and in-hospital complications., Results: We evaluated 681 patients with COVID-19 of whom 37 patients were excluded due to incomplete medical records and 8 patients who used ACEIs which left 636 patients in the analysis. In this cohort, 108 (17.0%) patients expired and 407 (64.0%) patients incurred severe COVID-19. Of 254 (39.9%) patients with hypertension, 122 (48.0%) patients were receiving an ARB. After adjustment for possible confounders, we found no independent association between taking ARBs and in-hospital outcomes except for acute kidney injury (AKI), in patients with confirmed or clinically suspected COVID-19, either hypertensive or not-hypertensive. We found that discontinuation of ARBs during hospitalization was associated with a greater risk of mortality, invasive ventilation, and AKI (all P ˂ 0.002)., Conclusions: We found that taking ARBs by patients with hypertension and confirmed or clinically suspected COVID-19 is not associated with poorer in-hospital outcomes after adjustment for possible confounders., (© American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported., Methods and Results: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis., Conclusion: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aim: Angiotensin converting enzyme (ACE) type 2 is the receptor of SARSCoV-2 for cell entry into lung cells. Because ACE-2 may be modulated by ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), there are concern that patients treated with ACEIs and ARBs are at higher risk for COVID-19 infection or severity. This study sought to analyse the association of severe forms of COVID-19 and mortality with hypertension and a previous treatment with ACEI and ARB., Methods: Prospective follow-up of 433 consecutive patients hospitalised for COVID-19 pneumonia confirmed by PCR or highly probable on clinical, biological, and radiological findings, and included in the COVHYP study. Mortality and severe COVID-19 (criteria: death, intensive care unit, or hospitalisation >30 days) were compared in patients receiving or not ACEIs and ARBs. Follow-up was 100% at hospital discharge, and 96.5% at >1month., Results: Age was 63.6±18.7 years, and 40%) were female. At follow-up (mean 78±50 days), 136 (31%) patients had severity criteria (death, 64 ; intensive care unit, 73; hospital stay >30 days, 49). Hypertension (55.1% vs 36.7%, P<0.001) and antihypertensive treatment were associated with severe COVID-19 and mortality. The association between ACEI/ARB treatment and COVID-19 severity criteria found in univariate analysis (Odds Ratio 1.74, 95%CI [1.14-2.64], P=0.01) was not confirmed when adjusted on age, gender, and hypertension (adjusted OR1.13 [0.59-2.15], P=0.72). Diabetes and hypothyroidism were associated with severe COVID-19, whereas history of asthma was not., Conclusion: This study suggests that previous treatment with ACEI and ARB is not associated with hospital mortality, 1- and 2-month mortality, and severity criteria in patients hospitalised for COVID-19. No protective effect of ACEIs and ARBs on severe pneumonia related to COVID-19 was demonstrated., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Hypertension is a common clinical problem in patients with cancer. This is explained by its high prevalence in the general population, by the improvement in life expectancy in oncology patients thanks to the progress of anti-cancer therapies, but also by cancer therapy, which is sometimes burdened with cardiovascular toxicity. Early detection of hypertension and proper management are crucial to ensure the continuation of oncology treatment and to protect patients from the consequences of hypertension. Renin-angiotensin system blockers and calcium channel blockers are the first-line treatments., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Angiotensin (Ang)-(1-7) is a beneficial renin-angiotensin system (RAS) hormone that elicits protective cardiometabolic effects in young animal models of hypertension, obesity, and metabolic syndrome. The impact of Ang-(1-7) on cardiovascular and metabolic outcomes during aging, however, remains unexplored. This study tested the hypothesis that Ang-(1-7) attenuates age-related elevations in blood pressure and insulin resistance in mice. Young adult (two-month-old) and aged (16-month-old) male C57BL/6J mice received Ang-(1-7) (400 ng/kg/min) or saline for six-weeks via a subcutaneous osmotic mini-pump. Arterial blood pressure and metabolic function indices (body composition, insulin sensitivity, and glucose tolerance) were measured at the end of treatment. Adipose and cardiac tissue masses and cardiac RAS, sympathetic and inflammatory marker gene expression were also measured. We found that chronic Ang-(1-7) treatment decreased systolic and mean blood pressure, with a similar trend for diastolic blood pressure. Ang-(1-7) also improved insulin sensitivity in aged mice to levels in young mice, without effects on glucose tolerance or body composition. The blood pressure-lowering effects of Ang-(1-7) in aged mice were associated with reduced sympathetic outflow to the heart. These findings suggest Ang-(1-7) may provide a novel pharmacological target to improve age-related cardiometabolic risk.

: In patients with aortic stenosis, the presence of hypertension negatively affects the hemodynamic severity of the stenosis, and worsens adverse left ventricular remodeling. It accelerates the progression of the stenosis and is associated with worse prognosis. Proper management of hypertension is thus crucial but there are concerns about the safety and efficacy of antihypertensive medications as well as uncertainty about optimal blood pressure (BP) targets and their impact on left ventricular mass regression and survival benefits. In the present review, we discuss these issues based on the evidence available in the current literature. Focus is first directed on the consequences of a persistently elevated BP before and after surgical aortic valve replacement or transcatheter valve implantation, and the clinical significance of an abnormal BP response during exercise in patients with significant aortic stenosis. Available data on use of antihypertensive drugs are then critically addressed, the conclusion being that calcium channel blockers may be associated with lower survival, and that diuretics may have disadvantages in patients with left ventricular hypertrophy and smaller left ventricular cavity dimensions, β-blockers may be well tolerated and a better choice for patients with concomitant coronary artery disease and arrhythmias. Renin--angiotensin system blockers improve survival given either before or after valve intervention. Emphasis is placed on the fact that evidence is not derived from randomized trials but only from observational studies. Finally, we discuss the optimal SBP level to reach in patients with aortic stenosis. Again, randomized trials are not available but observational evidence suggests that values between 130 and 139 mmHg systolic and 70-90 mmHg diastolic might represent the best option, and lower BP targets should probably be avoided.

COVID-19, caused by infection with SARS-CoV-2, is a disease characterised by cough, fever and fatigue, which progresses to life-threatening lung injury in approximately 5% of patients. The SARS-CoV-2 virus enters the cell via ACE2. ACE2 is a component of the renin-angiotensin system (RAS) which has an important counterregulatory effect on the classical ACE-dependent pathway. Several antihypertensives increase ACE2 expression or activity, leading to concern that this may facilitate SARS-CoV-2 entry and worsen COVID-19 disease. However, ACE2 is protective against lung injury while ANG II (which is catabolised by ACE2) is associated with lung injury both in mice and humans. We propose that medications which inhibit the RAS ACE-dependent pathway may be beneficial in treating COVID-19 and should be explored in animal models and clinical trials. Here we give an overview of the RAS pathway with respect to COVID-19 and argue that strategies which manipulate this pathway might reduce the destructive lung manifestations of COVID-19 and improve patient outcomes., (© Royal College of Physicians 2020. All rights reserved.)

Background: Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19., Methods: In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437., Findings: We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62-2·41) and risk factors (1·46, 1·23-1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77-1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64-1·00) or angiotensin-receptor blockers (1·10, 0·88-1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34-0·80). The adjusted ORs were similar across severity degrees of COVID-19., Interpretation: RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19., Funding: Instituto de Salud Carlos III., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The development of risk factors associated with cardiovascular disorders present a major public health challenge in both developed countries and countries with emerging economies. Hypertension and associated complications including stroke and myocardial infarction have reached pandemic levels. Current management strategies of hypertension predominantly include the utilization of pharmaceutical drugs which are often associated with undesirable side effects. Moreover, the drugs are often too expensive for populations from resource-limited Southern African rural, and some urban, communities. As a result, most patients rely on ethno-medicinal plants for the treatment of a variety of diseases including cardiovascular and metabolic disorders. The effectiveness of these plants in managing several cardiovascular diseases has been attributed to the presence of bioactive phytochemical constituents. In this review, the treatment options that target the renin-angiotensin system (RAS) in the management of hypertension were summarized, with special emphasis on ethno-medicinal plants and their influence on the ACE1 RAS pathway. The dearth of knowledge regarding the effect of ethno-medicinal plants on the ACE2 pathway was also highlighted.

BACKGROUND This study evaluated the impact of clinical features and concomitant conditions on the clinical selection of different renin-angiotensin system (RAS) inhibitors in patients with hypertension, and built a renin-angiotensin inhibitors selection model (RAISM) to provide a reference for clinical decision making. MATERIAL AND METHODS We included 213 hypertensive patients in the study cohort; patients were divided into two groups: the angiotensin-converting enzyme inhibitor (ACEI) combined with calcium channel blocker (CCB) group (ACEI+CCB group) and the angiotensin receptor antagonist (ARB) combined with CCB group (ARB+CCB group). Basic demographic characteristics and concomitant conditions of the patients were compared. Single-factor and multi-factor analysis was performed by adopting logistic regression model. The RAISM was established by utilizing the nomograph technology. C-index and calibration curve were used to evaluate the model's efficacy. RESULTS In the study, 34.27% of the patients used ACEI+CCB and 65.73% of patients used ARB+CCB. The difference in age, body mass index (BMI), elderly patient, diabetes, renal dysfunction, and hyperlipidemia between the 2 groups determined medication selection. To be specific, compared to the group using ARB+CCB, the odds ratios and 95% confidence interval (CI) of the aforementioned factors for the ACEI+CCB group were 0.476 (0.319-0.711), 1.274 (1.001-1.622), 0.365 (0.180-0.743), 0.471 (0.203-1.092), 0.542 (0.268-1.094), and 0.270 (0.100-0.728), respectively; The C-index of RAISM acquired from the model construction parameters was 0.699, and the correction curve demonstrated that the model has good discriminative ability. CONCLUSIONS The outcome of our study suggests that independent discriminating factors that influence the clinical selection of different RAS inhibitors were elderly patient, renal insufficiency, and hyperlipidemia; and the RAISM constructed in this study has good predictability and clinical benefit.

The aim of this work was to analyse the hypotensive effect of amaranth protein/peptides on spontaneously hypertensive rats (SHR). The mechanism of action of these peptides was studied in vivo and ex vivo. We also tested the effect of protection against gastrointestinal digestion (GID) exerted by an O:W emulsion on the integrity of the antihypertensive peptides. All samples tested produced a decrease in blood pressure (SBP). The animals treated with emulsion (G E ) and emulsion + peptide (G E+VIKP ) showed the most significant reduction in the SBP (42 ± 2 mmHg and 35 ± 2 mmHg, respectively). The results presented suggest that after GID, a variety of peptides with biological activities were released or were resistant to this process. These peptides play a role in the regulation of the SBP by acting on plasma ACE, plasma renin and the vascular system. These results support the use of amaranth protein/peptides in the elaboration of functional foods for hypertensive individuals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Objectives: We conducted a pilot, pragmatic, cluster-randomized trial to evaluate feasibility and preliminary effectiveness of screening for CKD using a triple-marker approach (creatinine, cystatin C, and albumin/creatinine ratio), followed by education and guidance, to improve care of hypertensive veterans in primary care. We used the electronic health record for identification, enrollment, intervention delivery, and outcome ascertainment., Design, Setting, Participants, & Measurements: We randomized 1819 veterans without diabetes but with hypertension (41 clusters) into three arms: ( 1 ) CKD screening followed by patient and provider education; ( 2 ) screening, education, plus pharmacist comanagement; or ( 3 ) usual care. The primary clinical outcome was BP change over 1 year. Implementation and process measures included proportion screened; CKD detection rate; and total and new use of renin-angiotensin system inhibitors, nonsteroidal anti-inflammatory drugs, and diuretics., Results: Median age was 68 years, 55% were white, 1658 (91%) had a prior creatinine measure, but only 172 (9%) had prior urine albumin/creatinine ratio, and 83 (5%) had a prior cystatin C measure. Among those in the intervention, 527 of 1215 (43%) were identified with upcoming appointments to have CKD screening. Of these, 367 (69%) completed testing. Among those tested, 77 (21%) persons had newly diagnosed CKD. After 1 year, change in systolic BP was -1 mm Hg (interquartile range, -11 to 11) in usual care, -2 mm Hg (-11 to 11) in the screen-educate arm, and -2 mm Hg (-13 to 10) in the screen-educate plus pharmacist arm; P =0.49. There were no significant differences in secondary outcomes in intention-to-treat analyses. In as-treated analyses, higher proportions of participants in the intervention arms initiated a renin-angiotensin system inhibitor (15% and 12% versus 7% in usual care, P =0.01) or diuretic (9% and 12% versus 4%, P =0.03)., Conclusions: The pragmatic design made identification, enrollment, and intervention delivery highly efficient. The limited ability to identify appointments resulted in inadequate between-arm differences in CKD testing rates to determine whether screening improves clinical outcomes., (Copyright © 2020 by the American Society of Nephrology.)

Maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular diseases in adult offspring. Our previous study demonstrated that maternal HFD enhances pressor responses to ANG II or a proinflammatory cytokine (PIC), which is associated with increased expression of brain renin-angiotensin system (RAS) components and PICs in adult offspring. The present study further investigated whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor-α (TNF-α) blocks sensitization of ANG II hypertension in offspring of HFD dams. All offspring were bred from dams with normal fat diet (NFD) or HFD starting two weeks before mating and maintained until weaning of the offspring. Then the weaned offspring were treated with an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water through the end of testing with a slow-pressor dose of ANG II. RT-PCR analyses of the lamina terminalis and paraventricular nucleus revealed upregulation of mRNA expression of several RAS components and PICs in male offspring of HFD dams when compared with age-matched offspring of NFD dams. The enhanced gene expression was attenuated by blockade of either RAS or PICs. Likewise, ANG II administration produced an augmented pressor response in offspring of HFD dams. This was abolished by either ACE or TNF-α inhibitor. Taken together, this study provides mechanistic evidence and a therapeutic strategy that systemic inhibition of the RAS and PICs can block maternal HFD-induced sensitization of ANG II hypertension, which is associated with attenuation of brain RAS and PIC expression in offspring.

Background: Hypertension is a major cause of death and morbidity worldwide and is increasing in prevalence. The Renin-angiotensin system (RAS) is the most common mechanism involved in the pathophysiology of hypertension. Understanding the mechanism of the pathophysiologic processes will help direct potential therapeutic strategies to treat hypertension and improve cardiac function. Recently, a novel drug LCZ696 containing both an angiotensin receptor blocker valsartan and a neprilysin inhibitor (AHU377) has shown a promising effect on the treatment of hypertension. However, the effects of LCZ696 on the expression of main components of RAS, namely, angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin II type 1 receptor (AT1 R), angiotensin II type 2 receptor (AT2 R), and angiotensin (1-7) receptor/Mas receptor (MasR) remain unclear. The aim of the present study was to evaluate the effects of LCZ696 on the protective arms of RAS in the cardiac tissue when compared with valsartan under the equal inhibition of AT1 R. We hypothesized that the superior effects of LCZ696 may contribute to its greater effect on the RAS than valsartan., Materials and Methods: Sixteen-week-old female spontaneously hypertensive rats (SHRs) were used in this study. Wistar-Kyoto (WKY) rats were used as controls. All rats were randomly divided into LCZ696 (n = 10), valsartan (n = 10), SHR (n = 10), and WKY (n = 10) groups under a 12-hour dark and 12-hour light cycle and provided with regular chow diet and water. The tail-cuff method was performed to measure blood pressure. Cardiac function was assessed by echocardiography., Results: The blood pressure value was lower in LCZ696 than valsartan in SHR after 12 weeks of treatment. Further, LCZ696 inhibits the ACE and AT1 R protein expression in the cardiac of SHR and significantly upregulate the protective axis of RAS components, including ACE2, MasR, and AT2 R. Left ventricular AT2 R messenger RNA (mRNA) expression was higher in the LCZ696+SHR group compared with valsartan. In addition, real-time polymerase chain reaction analysis revealed that LCZ696 enhanced the mRNA expression of antihypertensive components AT2 R, ACE2, and MasR and decreased the expression of AT1 R. However, only AT2 R and ACE2 mRNA expressions have a statistical difference between the LCZ696 and valsartan groups. No difference was observed in the mRNA expression of ACE and MasR. The stronger positive signal of transforming growth factor β in the left ventricle was inhibited in each administrated group compared with SHR groups., Conclusions: LCZ696 ameliorates the vasoconstrictor axis of the RAS AT1 R and stimulate the protective arm effectors, ACE2 and AT2 R, as well as reverses the compensatory upregulation of neuronal nitric oxide synthase and endothelial nitric oxide synthase in SHR. These findings suggest the mechanistic insight of the cardiac-protective and greater hypotensive effects of LCZ696.

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin-angiotensin system (RAS) and transforming growth factor β (TGFβ) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3 -/- mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3 -/- mice by olmesartan treatment. Upregulation of TGFβ and activation of its downstream in Col4a3 -/- mice were attenuated by olmesartan in Col4a3 -/- mice. Intriguingly, TGFβ expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3 -/- mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3 -/- mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFβ-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFβ feedback loop to counterbalance intrarenal RAS activation., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Alamandine is a new member of the angiotensin family. Here, we studied the mRNA and protein expression of cardiac angiotensin-converting enzyme 2 (ACE2) in the chronic phase of a rat model of 2-kidney, 1-clip hypertension (2K1C), and the effects of 2-week alamandine infusion on blood pressure, cardiac indices, and ACE2 mRNA and protein expression in the hearts. The rats were subjected to to sham-operation or placement of plexiglass clips around the left renal artery. Alamandine, at a dose of 600 µg/kg/d, was administered for 2 weeks via an osmotic mini-pump. At 18 weeks, after induction of hypertension, blood pressure and cardiac indices of contractility were measured using a Powerlab Physiograph system. The ACE2 mRNA and protein levels were determined using real time-PCR and Western blotting, respectively. In the hypertensive rats, alamandine caused a significant decrease in systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), left ventricular end-diastolic pressure (p < 0.001) and, left ventricular systolic pressure (p < 0.001) and increase in the maximum rate of pressure change in the left ventricle (dP/dt(max)) (p < 0.05). Also, the ACE2 mRNA expression in the heart increased in the hypertensive rats compared to the normotensive rats (p < 0.05), and alamandine restored this to normal values, although these changes were only seen at the mRNA and not the protein level. Histological analysis of cardiac tissue confirmed that alamandine decreased cardiac fibrosis and hypertrophy in 2K1C hypertensive rats. Our results indicate that alamandine, which acts as a depressor arm of the renin-angiotensin system, could be developed for treating hypertension.

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg -1 ·wk -1 ), or 3) SNT (40 mg·kg -1 ·day -1 ) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

Deletion of the prorenin receptor (PRR) in adipose tissue elevates systolic blood pressure (SBP) and the circulating soluble form of PRR (sPRR) in male mice fed a high-fat (HF) diet. However, sex differences in the contribution of adipose-PRR and sPRR to the regulation of the renin-angiotensin system (RAS) in key organs for blood pressure control are undefined. Therefore, we assessed blood pressure and the systemic and intrarenal RAS status in adipose-PRR knockout (KO) female mice. Blockade of RAS with losartan blunted SBP elevation in HF diet-fed adipose-PRR KO mice. ANG II levels were significantly increased in the renal cortex of HF diet-fed adipose-PRR KO female mice, but not systemically. HF diet-fed adipose-PRR KO mice exhibited higher vasopressin levels, water retention, and lower urine output than wild-type (WT) mice. The results also showed that deletion of adipose-PRR increased circulating sPRR and total hepatic sPRR contents, suggesting the liver as a major source of elevated plasma sPRR in adipose-PRR KO mice. To mimic the elevation of circulating sPRR and define the direct contribution of systemic sPRR to the regulation of the RAS and vasopressin, C57BL/6 female mice fed a standard diet were infused with recombinant sPRR. sPRR infusion increased plasma renin levels, renal and hepatic angiotensinogen expression, and vasopressin. Together, these results demonstrate that the deletion of adipose-PRR induced an elevation of SBP likely mediated by an intrarenal ANG II-dependent mechanism and that sPRR participates in RAS regulation and body fluid homeostasis via its capacity to activate the RAS and increase vasopressin levels. NEW & NOTEWORTHY The elevation of systolic blood pressure appears to be primarily mediated by cortical ANG II in high-fat diet-fed adipose-prorenin receptor knockout female mice. In addition, our data support a role for soluble prorenin receptor in renin-angiotensin system activation and vasopressin regulation.

Purpose of Review: To present the available data on the risks and benefits for ACEi/ARB usage in patients with advanced CKD., Recent Findings: It has been well established that ACEi/ARB use is beneficial in patients with mild-to-moderate CKD, especially in patients with proteinuria. The majority of available data includes patients with diabetes mellitus. However, data in individuals with advanced CKD are limited. Additionally, data available for this subset of patients is conflicting and the definition of advanced CKD varies across clinical trials., Summary: On the basis of our literature review, evidence suggests continuing ACEi/ARB therapy in patients with advanced CKD (eGFR less than 15 ml/min/1.73 m) unless hyperkalemia ensues unresponsive to therapy, hypotension develops or have unusually rapid worsening of eGFR (not usual progressive decline). These patients should be monitored closely. There is not enough data to support starting ACEi/ARBs de novo in patients with advanced CKD (eGFR less than 15 ml/min/1.73 m). If RAS blockade is started de novo in this subgroup, we recommend close monitoring.

Background: Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) activity are involved in the pathogenesis of hypertension (HT) accompanied by chronic kidney disease (CKD). Oxidative stress in the hypothalamus increases SNA in HT. Administration of an angiotensin ΙΙ receptor blocker (olmesartan; OLM) or renal denervation (RDN) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combination therapy with OLM and RDN reduces both SNA by decreasing oxidative stress in the hypothalamus and RAAS activity in hypertensive mice with CKD., Methods and Results: In 5/6-nephrectomized ICR-mice (Nx-mice) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by increased SNA and albuminuria compared with control-mice. Nx-mice were orally administered OLM, vehicle, or underwent RDN during OLM administration, and divided into Nx-OLM, Nx-VEH, and Nx-OLM/RDN groups, respectively. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH at 8-weeks after treatment, SBP was significantly decreased and both SNA and oxidative stress levels in the hypothalamus were significantly suppressed, without worsened creatinine clearance. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH, albuminuria was also suppressed, and the heart per body weight was decreased. In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration was significantly decreased compared with Nx-VEH., Conclusion: These findings suggest that combination therapy with OLM/RDN has antihypertensive effects in association with suppressing SNA by reducing oxidative stress in the hypothalamus and the plasma aldosterone concentration in hypertensive mice with CKD.

Non-communicable diseases including cardiovascular diseases (CVDs) and associated metabolic disorders are responsible for nearly 40 million deaths globally per year. Hypertension or high blood pressure (BP) is one of the primary reasons for the development of CVDs. A healthy nutritional strategy complementing with physical activity can substantially reduce high BP and prevent the occurrence of CVD-associated morbidity and mortality. Bioactive peptides currently are the next wave of the promising bench to clinic options for potential targeting chronic and acute health issues including hypertension. Peptides demonstrating anti-inflammatory, anti-oxidant, and angiotensin-converting enzyme-I inhibitory activity are widely studied for the amelioration of hypertension and associated CVDs. Isolating these potent bioactive peptides from different food sources is a promising endeavor toward nutraceutical based dietary management and prevention of hypertension. Understanding the pathophysiology of hypertension and the action mechanisms of the bioactive peptides would complement in designing and characterizing more potent peptides and suitable comprehensive dietary plans for the prevention of hypertension and associated CVDs., (© 2019 Elsevier Inc. All rights reserved.)

While it has been known since the 1940s that men have greater increases in blood pressure (BP) compared with women, there have been intense efforts more recently to increase awareness that women are also at risk for developing hypertension and that cardiovascular diseases (CVDs) are the leading causes of death among both men and women in the United States. With the release of the 2017 Hypertension Clinical Guidelines, 46% of adults in the United States are now classified as hypertensive, and hypertension is the primary modifiable risk factor for the development of CVD. This increase in the prevalence of hypertension is reflected in an increase in prevalence among both men and women across all demographics, although there were greater increases in the prevalence of hypertension among men compared with women. As a result, the well-established gender difference in the prevalence of hypertension is even more pronounced and now extends into the sixth decade of life. The goals of this review are to (i) review the historical clinical trial data and hypertension guidelines from the perspective of both genders and then (ii) review the role of the renin-angiotensin system and T-cell activation in contributing to sex differences in BP control.

We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450 (CYP450)-dependent ω-hydroxylase, potentiate prohypertensive actions of angiotensin II (ANG II) in Cyp1a1-Ren-2 transgenic rats, a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of 20-HETE receptor antagonist (AAA) in this model. Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. Treatment with AAA was started either simultaneously with induction of hypertension or 10 days later, during established hypertension. Systolic blood pressure (SBP) was monitored by radiotelemetry, indices of renal and cardiac injury, and kidney ANG II levels were determined. In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161 ± 3 compared with 199 ± 3 mmHg in untreated I3C-induced rats), reduced albuminuria, glomerulosclerosis index, and cardiac hypertrophy ( P <0.05 in all cases). Untreated I3C-induced rats showed augmented kidney ANG II (405 ± 14 compared with 52 ± 3 fmol/g in non-induced rats, P <0.05) which was markedly lowered by AAA treatment (72 ± 6 fmol/g). Remarkably, in TGR with established hypertension, AAA also decreased SBP (from 187 ± 4 to 158 ± 4 mmHg, P <0.05) and exhibited organoprotective effects in addition to marked suppression of kidney ANG II levels. In conclusion, 20-HETE antagonist attenuated the development and largely reversed the established ANG II-dependent malignant hypertension, likely via suppression of intrarenal ANG II levels. This suggests that intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this hypertension form., (© 2018 The Author(s).)

Purpose: Oxaliplatin-induced peripheral neuropathy has remained an unresolved issue in clinical practice. Our previous study hypothesized that inhibition of the renin-angiotensin system (RAS) may produce a preventive effect on oxaliplatin-induced neuropathy. The aim of this study was to clarify whether RAS inhibitors prevent oxaliplatin-induced peripheral neuropathy., Methods: This study retrospectively analyzed data from cancer patients who had received chemotherapy including oxaliplatin and were treated with or without RAS inhibitors. This retrospective observational study was conducted at Ehime University Hospital using electronic medical records from May 2009 to December 2016. The primary end point was the incidence of severe peripheral neuropathy during or after oxaliplatin treatment, according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate Cox proportional hazards model analysis was used to identify risk factors., Findings: A total of 150 patients were included in the study. The estimated incidence of peripheral neuropathy was 36.9% and 91.7% in the RAS inhibitor group and the non-RAS inhibitor group, respectively. The multivariate analysis using a Cox proportional hazards model showed that the RAS inhibitor group was slightly associated with a decreased risk of neurotoxicity (adjusted hazard ratio, 0.42 [95% CI, 0.18-0.99]; P = 0.048)., Implications: The present findings suggest that RAS inhibitors have the ability to prevent oxaliplatin-induced peripheral neuropathy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

New Findings: What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by angiotensin II and xanthine oxidase within the chemoreflex arc and vasculature. We tested whether chemoreflex control of sympathetic outflow, hypoxic vasodilatation and blood pressure are altered by angiotensin blockade (losartan) and/or xanthine oxidase inhibition (allopurinol). What is the main finding and its importance? Both drugs lowered blood pressure without altering sympathetic outflow, reducing chemoreflex sensitivity or enhancing hypoxic vasodilatation. Losartan and allopurinol are effective therapies for achieving blood pressure control in sleep apnoea., Abstract: Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensin II type 1 receptor (AT 1 R) blockade. Both AT 1 R blockade and xanthine oxidase inhibition ameliorate chronic intermittent hypoxia-induced endothelial dysfunction. We hypothesized that treatment with losartan and allopurinol would reduce chemoreflex sensitivity and improve hypoxic vasodilatation in patients with obstructive sleep apnoea. Eighty-six hypertensive patients with apnoea-hypopnoea index ≥25 events h -1 and no other cardiovascular, pulmonary, renal or metabolic disease were randomly assigned to receive allopurinol, losartan or placebo for 6 weeks. Treatment with other medications and/or continuous positive airway pressure remained unchanged. Tests of chemoreflex sensitivity and hypoxic vasodilatation were performed during wakefulness before and after treatment. Ventilation (pneumotachography), muscle sympathetic nerve activity (microneurography), heart rate (electrocardiography), arterial oxygen saturation (pulse oximetry), blood pressure (sphygmomanometry), forearm blood flow (venous occlusion plethysmography) and cerebral flow velocity (transcranial Doppler ultrasound) were measured during eupnoeic breathing and graded reductions in inspired O 2 tension. Losartan and allopurinol lowered arterial pressure measured during eupnoeic breathing and exposure to acute hypoxia. Neither drug altered the slopes of ventilatory, sympathetic or cardiovascular responses to acute hypoxia. We conclude that losartan and allopurinol are viable pharmacotherapeutic adjuncts for achieving blood pressure control in hypertensive obstructive sleep apnoea patients, even those who are adequately treated with continuous positive airway pressure., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Aim: To study the effects of angiotensin receptor blockers (ARBs) on insulin secretion in hypertensive patients with type 2 diabetes., Materials and Methods: A total of 41 patients were enrolled in this open-label, active comparator-controlled, crossover study. After a 2-week run-in period with amlodipine, the participants were assigned to receive either fimasartan (60-120 mg daily) or amlodipine (5-10 mg daily) for 16 weeks. Thereafter, they were treated with the other drug for another 16 weeks. Physical examinations and laboratory tests were performed before and after each treatment., Results: Blood pressure, glycated haemoglobin and oral glucose tolerance test (OGTT) values were similar with each treatment. Fimasartan treatment significantly increased median (range) homeostatic assessment of β-cell function values (49.9 [22.5-174.4] vs 46.9 [15.6-148.0]), area under the curve of insulin during OGTT (27 284 [9501-94 525] vs 26 818 [8112-76 704] pmol/L × min), insulinogenic index at 60 minutes (19.7 [3.0-131.2] vs 15.0 [2.4-103.8] pmol/mmol) and at 120 minutes (19.1 [1.9-85.5] vs 12.6 [-4.3-178.8] pmol/mmol) compared with those with amlodipine (all P < .05); however, acute insulin response and insulin resistance indices were similar for both agents., Conclusions: Compared with amlodipine, fimasartan increased late-phase glucose-stimulated insulin secretion in patients with type 2 diabetes and hypertension. This finding suggests that ARBs would be more beneficial in such patients compared with other classes of anti-hypertensives., (© 2018 John Wiley & Sons Ltd.)

Purpose: Possible factors that could influence changes in patterns of prescribing antihypertensives could be identified by monitoring national trends in hypertension treatment. The choice of pharmacologic treatment in people with hypertension has important therapeutic and financial implications, due to the fact that the financial costs associated with hypertension continue to increase. The aims of our study were to identify and analyze changes in the usage of antihypertensive drugs in Croatia from 2000 to 2016 and to identify the changes in prescribing patterns as well as mean prices per defined daily dose (DDD)., Methods: Data on consumption in Croatia were obtained from the International Medical Statistics database. According to the World Health Organization's Collaborating Center for Drugs Statistics Methodology, per-annum volumes of drugs are presented in DDD per 1000 population per day (DDD/1000), while data on financial expenditure are presented in euros., Findings: The consumption of drugs for cardiovascular disease in Croatia during the period from 2000 to 2016 increased 150.81%, while financial expenditure in the same period increased 47.32%. The most frequently prescribed subgroup was agents acting on the renin-angiotensin system (RAS). Their share among antihypertensives increased from 39.13% (2000) to 53.39% (2016). The share of diuretics in the same period decreased from 20.16% in 2000 to 12.73% in 2016., Implications: The prescribing patterns of antihypertensive drugs in Croatia have changed, which could be a result of a combination of different factors, such as changes in laws, pharmaceutical marketing, and guidelines on hypertension therapy. The most prescribed subgroup in all of the investigated years was agents acting on the RAS, mainly because of the increased prescribing of combinations of RAS agents plus diuretics. The financial implications of legal changes and the introduction of new generic drugs led to decreased cost per DDD of antihypertensives during the investigated period, but the total expenditure on antihypertensives in Croatia increased due to increased consumption., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background/aims: In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade., Methods: Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities., Results: Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15)., Conclusions: Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: Inhibition of the renin-angiotensin system may have effects on vascular structure and function beyond the effects on blood pressure (BP) reduction. We studied the ability of a single arm cuff oscillometric method (Arteriograph, TensioMed, Hungary) to assess effects of antihypertensive treatment on BP and arterial stiffness. Furthermore, this technique was compared to pulse wave analysis and applanation tonometry (SphygmoCor, AtCor Medical, Australia)., Materials and Methods: Brachial and aortic BP, augmentation index (AIx), and carotid-femoral pulse wave velocity (PWV) was simultaneously assessed by both techniques in 71 untreated hypertensive patients. Thereafter, 58 completed double-blind randomized treatment for 12 weeks with ramipril or doxazosin., Results: Treatment (assessed by the Arteriograph) reduced aortic more than brachial systolic BP (-13.2 vs. -11.2 mm Hg; p = .002) and improved all indices of arterial stiffness. This greater reduction in aortic to brachial systolic BP was more marked by ramipril than by doxazosin (-20.9 and -17.1 vs. -4.3 and -4.2 mm Hg; p = .006), with a similar trend for AIx (-6.2 vs. -2.2%; p = .058). Both devices showed correlations for aortic and brachial systolic and diastolic BP and AIx (r = 0.75-0.86, all p < .001), while agreement for PWV was weaker (r = 0.28; p = .043). The Arteriograph generally recorded higher values for aortic BP and AIx than the SphygmoCor., Conclusions: Antihypertensive treatment reduced aortic systolic BP more than brachial BP and improved arterial stiffness. Blocking the renin-angiotensin system may have additional effects beyond BP reduction. We demonstrate the feasibility of the Arteriograph to monitor changes in BP and arterial stiffness by treatment.