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Background There is uncertainty about the associations of angiotensive enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) drugs with COVID-19 disease. We studied whether patients prescribed these drugs had altered risks of contracting severe COVID-19 disease and receiving associated intensive care unit (ICU) admission. Methods This was a prospective cohort study using routinely collected data from 1205 general practices in England with 8.28 million participants aged 20–99 years. We used Cox proportional hazards models to derive adjusted HRs for exposure to ACE inhibitor and ARB drugs adjusted for sociodemographic factors, concurrent medications and geographical region. The primary outcomes were: (a) COVID-19 RT-PCR diagnosed disease and (b) COVID-19 disease resulting in ICU care. Findings Of 19 486 patients who had COVID-19 disease, 1286 received ICU care. ACE inhibitors were associated with a significantly reduced risk of COVID-19 disease (adjusted HR 0.71, 95% CI 0.67 to 0.74) but no increased risk of ICU care (adjusted HR 0.89, 95% CI 0.75 to 1.06) after adjusting for a wide range of confounders. Adjusted HRs for ARBs were 0.63 (95% CI 0.59 to 0.67) for COVID-19 disease and 1.02 (95% CI 0.83 to 1.25) for ICU care. There were significant interactions between ethnicity and ACE inhibitors and ARBs for COVID-19 disease. The risk of COVID-19 disease associated with ACE inhibitors was higher in Caribbean (adjusted HR 1.05, 95% CI 0.87 to 1.28) and Black African (adjusted HR 1.31, 95% CI 1.08 to 1.59) groups than the white group (adjusted HR 0.66, 95% CI 0.63 to 0.70). A higher risk of COVID-19 with ARBs was seen for Black African (adjusted HR 1.24, 95% CI 0.99 to 1.58) than the white (adjusted HR 0.56, 95% CI 0.52 to 0.62) group. Interpretation ACE inhibitors and ARBs are associated with reduced risks of COVID-19 disease after adjusting for a wide range of variables. Neither ACE inhibitors nor ARBs are associated with significantly increased risks of receiving ICU care. Variations between different ethnic groups raise the possibility of ethnic-specific effects of ACE inhibitors/ARBs on COVID-19 disease susceptibility and severity which deserves further study.

A growing body of clinical evidence shows that vascular leakage leads to pulmonary edema in coronavirus disease 2019 (COVID-19) patients. Coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) use membrane ectopeptidases to invade cells, most notably dipeptidyl peptidase 4 (DPP4; https://www.uniprot.org/uniprot/P27487), aminopeptidase N (APN; https://www.uniprot.org/uniprot/P15144), and angiotensin-converting enzyme 2 (ACE2; https://www.uniprot.org/uniprot/Q9BYF1).[1] It is important to distinguish this latter protein from ACE, which is the main target for conventional blood pressure lowering drugs: ACE inhibitors do not inhibit ACE2.[2] As a result of virus entry, these membrane ectopeptidases are internalized and their activity becomes downregulated. The common denominator between these membrane ectopeptidases is their enzyme specificity: they degrade peptide hormones, for instance, angiotensin II. For SARS-CoV-2 (as well as SARS-CoV), ACE2 is the predominant target for cellular uptake in vivo.[3] It is present on lung alveolar epithelial cells, enterocytes of the small intestine, endothelial cells, and arterial smooth muscle cells.[4] In an acid aspiration lung injury mouse model, ACE2 knockout (KO) worsened the resulting edema.[5] This was accompanied by increased angiotensin II levels[6] and was prevented by angiotensin II receptor KO, leading to the conclusion that the lack of ACE2-mediated angiotensin II degradation was responsible for the observed increase pulmonary vascular permeability. The same observations were made when downregulating ACE2 with the spike protein of the SARS CoV prior to acid aspiration.[6] Yet, the authors did not measure renin in these studies. This is crucial since normally angiotensin II rises result in rapid renin suppression,[7] thereby normalizing its levels. Moreover, ACE2 is just one of many angiotensin-degrading enzymes (angiotensinases). In full accordance with this concept, Gurley et al did not find increased angiotensin II levels after ACE2 KO.[8] Hence, whether the ACE2 KO dependent permeability changes are entirely due to ACE2-mediated angiotensin II degradation remains uncertain. ACE2 has multiple other substrates. Among these are the kinins, which are also degraded by DPP4.[9] We and others believe that this deserves attention, as it offers an alternative view, and forms a basis on which novel therapeutic opportunities might be proposed.[10]

In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002–2003 epidemic. This new disease was named COVID‐19 and the causative virus SARS‐CoV‐2. The SARS‐CoV‐2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein‐ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro‐inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1–7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self‐powered cascade, leading eventually to ARDS. Recently, Gurwitz proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID‐19 patients prior to development of ARDS. In this commentary article, the authors make the case for the election of telmisartan as such alternative on the basis of its pharmacokinetic and pharmacodynamic properties and present an open‐label randomized phase II clinical trial for the evaluation of telmisartan in COVID‐19 patients (https://www.clinicaltrials.gov/ct2/show/NCT04355936).

We examined the effects of the angiotensin receptor-neprilysin inhibitor LCZ696 on overt proteinuria and renal injury in type 2 diabetic Otsuka-Long- Evans-Tokushima-Fatty (OLETF) rats. Aged OLETF rats were also treated with either valsartan or valsartan plus hydralazine for comparison. LCZ696 caused greater attenuation of the progression of proteinuria than either valsartan alone or valsartan combined with hydralazine. Reduced glomerular injury and tubulointerstitial fibrosis were also observed in LCZ696-treated rats. Moreover, LCZ696 prevented increases in blood urea nitrogen (BUN) and creatinine levels. These data suggest that LCZ696 elicits a reno-protective effect against type 2 diabetes with overt proteinuria. Keywords: LCZ696, Proteinuria, Diabetic kidney disease (DKD)

Azilsartan (AZL), the active metabolite of azilsartan medoxomil, is the newest angiotensin receptor blocker that has been approved for the treatment of hypertension in 2012 in Japan. The present study aimed to evaluate the safety and pharmacokinetic properties of AZL in healthy Chinese subjects. We performed 2 phase 1 studies to investigate the pharmacokinetics and safety of AZL in healthy Chinese adults after a single dose (20 mg or 40 mg) or multiple doses of AZL (40 mg/d for 7 days; Study I) and after a single 40-mg dose under the fasted and fed conditions (Study II). Noncompartmental analysis and nonlinear mixed-effects modeling were used to analyze the pharmacokinetic properties of AZL. Twenty-seven healthy volunteers (14 men and 13 women) aged 20-32 years were enrolled and completed the study. During single dosing of AZL, the pharmacokinetics of AZL exhibited a linear profile between dosage and area under the concentration-time curve. There is no AZL accumulation after multiple doses. Food had no effect on the pharmacokinetic characteristics of AZL. AZL concentrations were best fit with a 2-compartment model, and the typical value of clearance was 1.63 L/h. Body weight had an impact on both the apparent clearance and peripheral volume of distribution. The pharmacokinetic parameters were consistent with previous studies in non-Chinese subjects. Model-based simulations indicated that a 45-kg subject would have approximately double the AZL exposure of a 90-kg subject. Whether the exposure difference has clinical significance needs to be confirmed in further studies among patients.

The most recent guidelines for the treatment of arterial hypertension have set blood pressure targets of below 130/80 mm Hg in most patients, recommending a single-pill combination (SPC) consisting of two drugs for treatment initiation. In addition to its strong antihypertensive effect, the use of valsartan is associated with a reduction in metabolic risk and in the incidence of hypertension-mediated organ damage and cardiovascular events. Valsartan is the only angiotensin receptor blocker of choice both in patients with hypertension and concomitant coronary artery disease, and in patients with heart failure. The combination of valsartan with amlodipine or hydrochlorothiazide is associated with a proven stronger hypotensive effect due to the synergistic effect of both molecules on the one hand, and a reduction in the frequency of side effects (such as peripheral oedema with amlodipine monotherapy or hypokalemia with hydrochlorothiazide monotherapy) on the other.

Background/aims To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile. Methods Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of β1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers. Results Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of β1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased. Conclusion Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.

Angiotensin receptor blockers (ARBs) are with increasing frequency used in arterial hypertension treatment, this class of medications is especially important in treatment of patients with obesity, metabolic syndrome and diabetes mellitus. Although not all the ARBs are the therapy of first choice in these patients. The special requirements are imposed upon antihypertensive mediations for patients with arterial hypertension and metabolic disorders such as high antihypertensive activity, maximum duration of action, possibility of increase of peripheral tissues sensitivity to insulin and, subsequently, metabolic profile. Besides, these patients require the use of combined therapy already at the treatment start. There are very few ARBs combinations with thiazide diuretics that exhibit these properties. The present review discusses possibilities of new ARB azilsartan medoxomil (Edarbi®) and its combination with chlortalidone (Edarbi® Clo) in decrease of cardiovascular risk in patients with obesity, metabolic syndrome and diabetes mellitus.

We previously described a novel “chemogenetic” animal model of heart failure that recapitulates a characteristic feature commonly found in human heart failure: chronic oxidative stress. This heart failure model uses a chemogenetic approach to activate a recombinant yeast d-amino acid oxidase in rat hearts in vivo to generate oxidative stress, which then rapidly leads to the development of a dilated cardiomyopathy. Here we apply this new model to drug testing by studying its response to treatment with the angiotensin II (ANG II) receptor blocker valsartan, administered either alone or with the neprilysin inhibitor sacubitril. Echocardiographic and [18F]fluorodeoxyglucose positron emission tomographic imaging revealed that valsartan in the presence or absence of sacubitril reverses the anatomical and metabolic remodeling induced by chronic oxidative stress. Markers of oxidative stress, mitochondrial function, and apoptosis, as well as classical heart failure biomarkers, also normalized following drug treatments despite the persistence of cardiac fibrosis. These findings provide evidence that chemogenetic heart failure is rapidly reversible by drug treatment, setting the stage for the study of novel heart failure therapeutics in this model. The ability of ANG II blockade and neprilysin inhibition to reverse heart failure induced by chronic oxidative stress identifies a central role for cardiac myocyte angiotensin receptors in the pathobiology of cardiac dysfunction caused by oxidative stress. NEW & NOTEWORTHY The chemogenetic approach allows us to distinguish cardiac myocyte-specific pathology from the pleiotropic changes that are characteristic of other “interventional” animal models of heart failure. These features of the chemogenetic heart failure model facilitate the analysis of drug effects on the progression and regression of ventricular remodeling, fibrosis, and dysfunctional signal transduction. Chemogenetic approaches will be highly informative in the study of the roles of redox stress in heart failure providing an opportunity for the identification of novel therapeutic targets.

Summary Purpose To investigate the expression of components of the renin-angiotensin system (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) by the cancer stem cell (CSC) subpopulations in moderately differentiated head and neck cutaneous squamous cell carcinoma (MDHNCSCC). Methodology 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining for PRR, ACE, ATIIR1 and ATIIR2 was performed on formalin-fixed paraffin-embedded sections of ten MDHNCSCC tissue samples. Immunofluorescence (IF) IHC staining was used to localise components of the RAS. Western blotting (WB) and RT-qPCR were performed on snap-frozen MDHNCSCC tissue samples and MDHNCSCC-derived primary cell lines to investigate protein transcription expression of these proteins, respectively. Results DAB IHC staining demonstrated the presence of PRR, ACE, ATIIR1 and ATIIR2 in all ten MDHNCSCC tissue samples. IF IHC staining showed expression of PRR and ATIIR2 by the OCT4+ cells, and ACE and ATIIR1 by the SOX2+ cells, within the tumour nests (TNs) and the peritumoural stroma (PTS). PRR, ACE, ATIIR1 and ATIIR2 were expressed by the endothelium of the microvessels within the PTS. WB confirmed protein expression for PRR, ACE and ATIIR1 in MDHNCSCC tissue samples and MDHNCSCC-derived primary cell lines. RT-qPCR showed transcriptional activation of PRR, ACE, ATIIR1 and ATIIR2 in MDHNCSCC tissue samples; and PRR, ACE, ATIIR1 but not ATIIR2, in MDHNCSCC-derived primary cell lines. Conclusion PRR, ACE, ATIIR1 and ATIIR2 are expressed by the CSC subpopulations within the TNs, the PTS, and the endothelium of the microvessels within the PTS, in MDHNCSCC.

Sacubitril-valsartan (Entresto), a new dual drug therapy that includes an angiotensin receptor neprilysin (NEP)15 inhibitor (sacubitril), is directed at reducing the risk of cardiovascular death and hospitalization for heart failure (HF) in patients with chronic HF (New York Heart Association classes II–IV) and reduced ejection fraction (HFrEF). Since its approval for the treatment of HFrEF, a commonly raised question has been whether treatment with this drug can complicate the interpretation of B-type natriuretic peptide (BNP) testing results compared to those of the N-terminal proBNP assay because Entresto may interfere with BNP clearance. The clinical and analytical studies addressing this issue are limited. Furthermore, the diversity of both BNP and NT-proBNP assays used in clinical laboratory practice have not been adequately evaluated in clinical trials, and studies to provide an evidence-based conclusion regarding the appropriate assays to use when a patient is on Entresto are lacking. In this article, 5 experts from the US and Europe provide their views regarding this issue. Do you think the differences between BNP and NT-proBNP measurements in patients receiving Entresto are only an early phenomenon because they both seem to be reduced over time? James Januzzi: In the PARADIGM-HF trial, NT-proBNP fell acutely after initiation of Entresto and then continued to drop over time until the end of the trial. Both the enalapril and Entresto arms had a slow, gradual drop in NT-proBNP by the end of trial. This drop likely reflects one of 2 possibilities. First, it may be the subtraction of noncompleters by the end of trial led to a perceived further drop in NT-proBNP (sicker patients that withdrew or died who likely had higher NT-proBNP concentrations). Alternatively, longer treatment with either therapy (angiotensin-converting enzyme inhibitor or angiotensin receptor neprilysin inhibitors) led to further stability, resulting in less synthesis and release of …

Mohamed Ibrahim ElGhareeb,1 Mohamed Hamed Khater,1 Ahmed Fakhr,2 Hanaa Abd-Elftah Khedr3 1Dermatology and Venereology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 2Microbiology, Molecular Biology and Immunology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 3Dermatology Department, Al Ahrar Hospital, Zagazig, EgyptCorrespondence: Mohamed Ibrahim ElGhareebDermatology and Venereology Department, Faculty of Medicine, Zagazig University, Zagazig, EgyptTel +20 109 290 7455Email moh_elghareeb@yahoo.comBackground: Psoriasis vulgaris is a chronic inflammatory and proliferative skin disease, characterized by the formation of itchy, erythematous skin patches or plaques. Patients with psoriasis are at an increased risk of developing metabolic syndrome, including obesity, hypertension, diabetes, and atherosclerosis. Recently, angiotensin II (Ang II) has been reported to be associated with the development of psoriasis. Ang II not only increases the blood pressure but is also a potent proinflammatory modulator and functions through interaction with angiotensin II type 1 receptor (AT1R). Moreover, it is hypothesized that the AT1R gene expression could be correlated with the severity of psoriasis and/or metabolic syndrome.Aim: We examined the association of Ang II type 1 receptor (AT1R) A1166C gene polymorphisms and metabolic syndrome with the severity of psoriasis.Patients and methods: The present case-control study included 25 patients with psoriasis vulgaris and 25 healthy subjects in Egypt. The psoriasis lesions in the patient group were assessed using the psoriasis area and severity index (PASI) score. The AT1R polymorphism A1166C (rs5186) was studied using restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) amplification of the gene from the whole blood sample in both groups. Serum lipid profile and blood sugar levels were assessed post 12h and 8h fasting, respectively, in both groups. The severity of metabolic syndrome was evaluated using the severity score.Results: The results of the present study demonstrated that the AT1R A1166C gene polymorphisms increased the risk of developing psoriasis in the Egyptian population. We found that 70% of patients with AC genotype and 100% of patients CC genotype reported a PASI score >20 and were considered to be severe cases with a statistically significant difference as compared with patients with AA genotype (p=0.003). In addition, a high statistically significant difference (p=0.001) existed among AT1R genotypes with respect to the percentage of metabolic syndrome in psoriasis patients. Similarly, a statistically significant difference (p=0.004) among AT1R genotypes with respect to metabolic score was found, with the highest level of score and percentage observed in patients with CC genotype than in patients with AC genotype. The lowest level was present among those with AA genotype.Conclusion: Patients with psoriasis expressing the C allele of AT1R1166 are susceptible to developing metabolic syndrome and have higher PASI scores as compared with patients carrying the A allele.Keywords: psoriasis, metabolic syndrome, angiotensin receptor, gene polymorphism

The most important result of the revision of the European and Russian guidelines for the management of arterial hypertension (AH) was a special focus on initializing antihypertensive treatment with single-pill combinations (SPCs) in majority patients with AH. Combination of the angiotensin II receptor blocker and thiazide diuretic is one of the possible first line SPCs in the absence of specific clinical conditions according to the new guidelines. In this regard, SPC of telmisartan and hydrochlorothiazide (HCT), worth special noticing in the classes of sartans and thiazide diuretics, since both drugs have a long clinical experience and large body of evidence of antihypertensive efficacy and safety, as well as telmisartan also has a number of superior target-organ protective and metabolic properties distinguishing it from other members of the class. In real clinical practice TANDEM study telmisartan and its SPC with HCT showed high antihypertensive efficacy and good tolerability in patients with all AH grades and with isolated systolic AH and allowed to achieve target blood pressure levels in the most of patients. Long-lasting effect is another essential characteristic of telmisartan, this feature allows to control blood pressure throughout the day, including the morning surge, which is the most “dangerous” in terms of cardiovascular risk. Telmisartan also provide powerful target-organ protection realized at the level of all AH target-organs. Finally, another unique pharmacological property of telmisartan and its combination with HCT is a favourable effect on the carbohydrate and lipid profile, which comprises of increasing tissue sensitivity to insulin, normalizing blood glucose levels, reducing blood total cholesterol, low-density lipoprotein cholesterol and triglycerides and thereby reducing risk of atherosclerosis development and progression. Telmisartan/HCT SPC should be recommended for wide use in hypertensive patients to control blood pressure, protect end-organs, improve prognosis and reduce cardiovascular risk due to its high antihypertensive efficacy, the ability to provide the large target-organ protection and a beneficial metabolic effect.

Aim To assess the impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on renal and mortality outcomes in people with Type 2 diabetes and proteinuria. Methods A literature search up to 6 June 2019 was performed. We included randomized trials of ≥100 participants with Type 2 diabetes and micro- or macroalbuminuria comparing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with placebo ± background anti-hypertensives or non-angiotensin-converting enzyme inhibitor or angiotensin receptor blocker-containing anti-hypertensives, which included follow-up of ≥12 months. Endpoints included doubling of serum creatinine, end-stage renal disease, all-cause and cardiovascular mortality and progression and regression of proteinuria. A Hartung-Knapp random-effects model (between-study variance calculated using the Paule-Mandel estimator) producing a risk ratio with 95% confidence interval was employed. Results The use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was not associated with a significant reduction in the risk of a doubling in serum creatinine (n = 7 trials, RR = 0.77, 95% CI = 0.50-1.21). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers reduced the risk of progressing to end-stage renal disease (n = 8, RR = 0.79, 95% CI = 0.75-0.83). No difference in all-cause (n = 11, RR = 0.98, 95% CI = 0.89-1.08) or cardiovascular mortality (n = 6 trials, RR = 1.08, 95% CI = 0.92-1.28), nor the composite outcome of doubling in serum creatinine, end-stage renal disease or mortality (n = 3 trials, RR = 0.87, 95% CI = 0.72-1.06), was observed. Progression of proteinuria was decreased with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use vs. control (n = 10, RR = 0.49, 95% CI = 0.33-0.74). Regression of proteinuria was not improved with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (n = 11, RR = 1.55, 95% CI = 0.93-2.58). Conclusion Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may reduce the risk of end-stage renal disease and slow the progression of nephropathy, but they do not appear to decrease all-cause or cardiovascular mortality in people with Type 2 diabetes and proteinuria.

BACKGROUND Renal inflammation and immune cell infiltration are characteristic of several forms of hypertension. Our laboratory has previously demonstrated that renal-inflammation-associated lymphangiogenesis occurs in salt-sensitive and nitric-oxide-inhibition-induced hypertension. Moreover, enhancing renal lymphatic density prevented the development of these two forms of hypertension. Here, we investigated the effects of angiotensin II-induced hypertension on renal lymphatic vessel density in male and female mice. METHODS Wild-type and genetically engineered male and female mice were infused with angiotensin II for 2 or 3 weeks. Isolated splenocytes and peritoneal macrophages from mice, and commercially available mouse lymphatic endothelial cells were used for in vitro studies. RESULTS Compared to vehicle controls, angiotensin II-infused male and female mice had significantly increased renal lymphatic vessel density in association with pro-inflammatory immune cells in the kidneys of these mice. Direct treatment of lymphatic endothelial cells with angiotensin II had no effect as they lack angiotensin II receptors; however, angiotensin II treatment of splenocytes and peritoneal macrophages induced secretion of the lymphangiogenic growth factor VEGF-C in vitro. Utilizing our genetic mouse model of inducible renal lymphangiogenesis, we demonstrated that greatly augmenting renal lymphatic density prior to angiotensin II infusion prevented the development of hypertension in male and female mice and this was associated with a reduction in renal CD11c+F4/80- monocytes. CONCLUSION Renal lymphatics play a significant role in renal immune cell trafficking and blood pressure regulation, and represent a novel avenue of therapy for hypertension.

Background Diabetic nephropathy is the leading cause of kidney failure worldwide. NADPH oxidase 4 (NOX4) is an obvious cause for reactive oxygen species production in the kidney mainly via renin-angiotensin system. High reactive oxygen species results in kidney damage through direct effect or through activation of other pathways such as the extracellular regulated kinase (ERK) signaling pathway. Aim The present study was constructed to investigate the effect of angiotensin II receptor blocker, valsartan, on NOX4, ERK1/2expression, and malondialdehyde level as well as their effects on the progression of diabetic nephropathy in type 1 diabetic rat model. Methods The experimental rats were divided into three groups: group I control healthy untreated rats, group II streptozotocin-induced diabetic rats, and group III valsartan treated streptozotocin-induced diabetic rats. Results Valsartan showed significantly decreased NOX4 and ERK1/2 mRNA, NOX4 and pERK1/2 protein concentration, and oxidative stress as evidenced by low malondialdehyde concentration in treated diabetic rats. Valsartan attenuates albuminuria, improve overall kidney function parameters, and pathological changes compared to diabetic non-treated rats. Conclusion Valsartan treatment impedes renal damage and improve kidney function in treated diabetic nephropathy rats. The beneficial effect of valsartan was mediated through decrease oxidative stress via downregulation of NOX4 and ERK1/2 and decreased reactive oxygen species production.

Introduction Previous in vitro studies demonstrated that aldosterone nongenomically induces transglutaminase (TG) and reactive oxygen species (ROS), which enhanced angiotensin II receptor (ATR) dimerization. There are no in vivo data in the kidney. Material and methods Male Wistar rats were intraperitoneally injected with normal saline solution, or aldosterone (Aldo: 150 μg/kg BW); or received pretreatment with eplerenone (mineralocorticoid receptor (MR) blocker, Ep. + Aldo), or with apocynin (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, Apo. + Aldo) 30 min before aldosterone. Thirty minutes after aldosterone injection, protein abundances of dimeric and monomeric forms of AT1R and AT2R, and protein abundances and localizations of TG2 and p47phox, a cytosolic subunit of NADPH oxidase, were determined by Western blot analysis and immunohistochemistry, respectively. Results Protein abundances of dimeric forms of AT1R and AT2R were enhanced by 170% and 70%, respectively. Apocynin could block dimeric forms of both receptors while eplerenone inhibited only AT2R. Monomeric protein levels of both receptors were maintained. Aldosterone significantly enhanced TG2 and p47phox protein abundances, which were blunted by eplerenone or apocynin. Aldosterone stimulated p47phox protein expression in both the cortex and the medulla while TG2 was induced mostly in the medulla. Eplerenone or apocynin normalized the immunoreactivity of both TG2 and p47phox. Conclusions This is the first in vivo study demonstrating that aldosterone nongenomically increases renal TG2 and p47phox protein expression and then activates AT1R and AT2R dimerizations. Aldosterone-stimulated AT1R and AT2R dimerizations are mediated through activation of NADPH oxidase. Aldosterone-induced AT1R dimer formation is an MR-independent pathway, whereas the formation of AT2R dimer is modulated in an MR-dependent manner.

We investigated expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 by the embryonic stem cell-like population on the endothelium of the microvessels and perivascular cells within keloid-associated lymphoid tissues.Immunohistochemical staining for prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 was performed on 11 formalin-fixed, paraffin-embedded sections of keloid tissue samples. Immunofluorescence staining was performed on three keloid tissue samples by co-staining with OCT4, CD34, ERG, and tryptase. Real-time quantitative polymerase chain reaction was performed on five keloid tissue samples and four keloid-derived primary cell lines. Western blotting was performed on the four keloid-derived primary cell lines for mRNA and protein expression of these proteins, respectively.Immunohistochemical and immunofluorescence staining showed expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 in all 11 keloid tissue samples. Prorenin receptor and angiotensin II receptor 1 were expressed on the endothelium and the pericyte layer of the microvessels and perivascular cells, angiotensin II receptor 2 was localized to the endothelium of the microvessels and the tryptase-positive perivascular cells, and angiotensin-converting enzyme was localized to the endothelium of the microvessel, within the keloid-associated lymphoid tissues. Real-time quantitative polymerase chain reaction showed transcripts of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid tissue samples and keloid-derived primary cell lines, whereas angiotensin II receptor 2 was detected in keloid tissue samples only. Western blotting confirmed the presence of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid-derived primary cell lines.Prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 were expressed by the embryonic stem cell-like population within the keloid-associated lymphoid tissues, suggesting that this primitive population may be a potential therapeutic target by modulation of the renin-angiotensin system.

African Americans (AAs) are susceptible to hypertension (HTN) and its associated organ damage leading to adverse cardiovascular (CV) outcomes. Psychological stress is proposed to contribute to the development of HTN; however, the potential role of the renin-angiotensin system (RAS) in stress-related HTN in AAs is largely unknown. In this study, we tested the hypothesis that activation of RAS is a potential contributing factor for altered CV responses to stress, and suppression of angiotensin II (Ang II) activity will improve hemodynamic responses to a prolonged mental stressor in healthy young AAs. Utilizing a double-blind, randomized, crossover study design, 132 normotensive AAs (25 ± 7 years) were treated with either a placebo (PLC) or 150 mg/d irbesartan (an Ang II type 1 receptor blocker; ARB) for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before, during and after a 45 minute-mental stress. The magnitude of stress-induced increase in blood pressure with ARB was blunted and delayed compared to PLC. Systolic blood pressure at the end of recovery on ARB was significantly lower compared to either PLC (110 ± 13 vs 117 ± 12 mm Hg respectively; P < 0.001) or the prestress level on ARB (P = 0.02). ARB treatment reduced overall vasoconstriction and improved poststress UNaV. ARB attenuated blood pressure responses to mental stress and improved the poststress BP recovery process which were partly linked to reduced overall vasoconstriction and improved stress-induced UNaV in young adult AAs prior to the development of disease conditions. These results suggest that treatment approaches that inhibit RAS action could have significant relevance to potentially lower susceptibility to stress responses and eventually the premature development of HTN in AAs.

Aims The aim of this study was to evaluate the effect of discontinuation of losartan in response to synthetic erythropoietin therapy on hemoglobin level in patients on maintenance hemodialysis. Methods & Materials This study was a pre-and post-interventional clinical trial. The population of the study was hemodialysis patients with chronic renal failure. In the beginning of the study, and three months after removal of losartan, the patients’ hemoglobin changes were compared. Findings Hemoglobin was significantly increased at the end of the study in all patients (from 10.90±1.66 at the beginning of the study to 11.37±1.42g/dl at the end of 3 months, P=0.046). No significant changes were seen in the hemoglobin level before and after intervention between patients according age, sex, and duration of the disease. Conclusion There was a significant increase in hemoglobin level at the end of study after losartan discontinuation. But this increase did not have a significant relationship with patient’s age, sex as well as the duration of the disease.

Hypertension is one of the major public health problems worldwide due to its strong impact on cardiovascular morbidity and mortality. It can cause damage in target organs such as arteries. Previous studies have shown that the blockade of angiotensin II type 1 receptor (AT1) with an angiotensin II receptor blocker (ARB) may reverse vascular pathology independent of blood pressure lowering. Antihypertensive agents such as ARBs have demonstrated some vascular and cardiac benefits. Studies on the distribution of elemental constituents in tissues have a great importance in the study of diseases since chemical imbalance can alter biological functions. The efficiency of ARBs in protecting organs at an elemental level has not been demonstrated in the literature. The aim of this work was to evaluate, at an elemental level, the effects of two ARBs (losartan and olmesartan) in the aortic arch of hypertensive rats. Low-energy X-ray fluorescence technique was used to analyze elemental and morphological differences in aortic samples. In view of the amount of O, Na, Mg and Zn in the aorta of the rats treated with losartan were comparable to the health rats, it can be conclude that losartan is more efficient in protect, at an elemental level, the aortic arch of hypertensive rats.

BACKGROUND : the study of molecular genetic markers and pathogenetic mechanisms of neurohormonal activation, as well as their importance in the formation of heart failure in obesity, is an urgent problem of modern medicine, the solution of which will allow effective prevention of cardiovascular complications, optimize treatment and improve the prognosis of obese patients. AIMS : search for genetic markers presumably involved in the pathogenesis of secondary diastolic heart failure in patients with obesity. MATERIALS AND METHODS : PCR-diagnostics of whole blood of 104 patients with obesity was carried out, which were divided into 2 groups, depending on the presence of diastolic heart failure. The following candidate genes were analyzed: angiotensinogen AGT gene (C521T and T704C), angiotensin II receptor gene of the first type AGTR1 (A1166C), angiotensin II receptor gene of the second type AGTR2 (G1675A), aldosterone synthase gene CYP11B2 (C (-344) T). RESULTS : It is shown that the development of secondary diastolic heart failure in obese individuals of both sexes is associated with the mutation of the aldosterone synthase gene CYP11B2 , namely, with the replacement of the C allele at the -344 position by the T allele and the presence of the T / T genotype. The relative risk of developing the disease with the T / T genotype was 5.93 times higher in men (p = 0.008) and 4.57 times in women (p = 0.014). For men, the mutation of the angiotensinogen AGT gene, namely the replacement of the allele C at position 521 by the T allele, is important. At the same time, the relative risk of development of SDS in the T / T genotype is increased by 4.26 times (p = 0.039). Mutations of the genes of the angiotensin II receptor of the first type AGTR1 (A1166C) and the angiotensin II receptor of the second type AGTR2 (G1675A) are not associated with the development of diastolic heart failure in obese patients. CONCLUSIONS : The data presented can be used to stratify the risk of secondary heart failure in obese individuals.

We encountered a case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) caused by duloxetine, serotonin and norepinephrine reuptake inhibitor (SNRI). A 74-year-old woman complaining of severe lethargy was transferred to our emergency department. Her serum sodium level was 109 mEq/L. Plasma hypo-osmolality with urine normo-osmolality was observed, indicating SIADH. Her essential hypertension had long been treated with telmisartan, and she had just started duloxetine 20 mg/day for chronic musculoskeletal pain 4 days prior to admission. On prescribing duloxetine in the primary care setting, clinicians should be aware of the possibility of duloxetine-induced hyponatremia, particularly in combination with telmisartan.

Glomerular arteriolar vasoconstriction and tubulointerstitial injury are observed before glomerular damage occurs in models of hypertension. High interstitial ATP concentrations, caused by the increase in arterial pressure, alter renal mechanisms involved in the long-term control of blood pressure, autoregulation of glomerular filtration rate and blood flow, tubuloglomerular feedback (TGF) responses, and sodium excretion. Elevated ATP concentrations and augmented expression of P2X receptors have been demonstrated under a genetic background or induction of hypertension with vasoconstrictor peptides. In addition to the alterations of the microcirculation in the hypertensive kidney, the vascular actions of elevated intrarenal angiotensin II levels may be mitigated by the administration of broad purinergic P2 antagonists or specific P2Y12, P2X1, and P2X7 receptor antagonists. Furthermore, the prevention of tubulointerstitial infiltration with immunosuppressor compounds reduces the development of salt-sensitive hypertension, indicating that tubulointerstitial inflammation is essential for the development and maintenance of hypertension. Inflammatory cells also express abundant purinergic receptors, and their activation by ATP induces cytokine and growth factor release that in turn contributes to augment tubulointerstitial inflammation. Collectively, the evidence suggests a pathophysiological activation of purinergic P2 receptors in angiotensin-dependent hypertension. Coexistent increases in intrarenal angiotensin II and activates Ang II AT1 receptors, which interacts with over-activated purinergic receptors in a complex manner, suggesting convergence of their post-receptor signaling processes.

Targeting the renin‐angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open‐label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low‐ vs standard‐dose (LOW vs STD) prolonged‐release tacrolimus and to angiotensin‐converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell–mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin‐angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231., The prevalence and progression of interstitial fibrosis and tubular atrophy over 24 months is reduced in adult de novo kidney transplant recipients who receive low‐dose prolonged release tacrolimus combined with renin‐angiotensin system (RAS) blockers compared to patients who receive low‐dose tacrolimus without RAS blockade or patients who receive standard dose tacrolimus with or without RAS blockade.

Ethnopharmacology relevance Pimpinella anisum is used in traditional medicine because of its pharmacological properties which include cardiovascular action. However, no scientific information supports this use. Aim of the study This study investigated the effects of Pimpinella on arterial blood pressure (BP) and its pharmacological mechanism of action. Material and methods Pimpinella seeds were extracted with water, concentrated and freeze-dried yielding the aqueous extract (AE). A non-invasive BP assessment method was used (via the caudal artery) on Wistar, Wistar Kyoto, SHRs and rats that were submitted to high intake of dietary salt. Direct BP and heart rate were evaluated in Wistar rats in the absence or presence of atropine, L-NAME and angiotensin II. Spontaneous diuresis and the effect of AE on depolarized portal vein of Wistar rats was also examined. Results The data revealed that AE reduced BP in all groups evaluated and its effects were not due to diuretic, sympatholytic or parasympathomimetic actions. Additionally, it was shown that AE does not act as an angiotensin receptor blocker and does not induce hypotension by reducing vascular resistance induced by oxide nitric. In the depolarized portal vein, AE inhibited calcium influx, which indicates that AE acts as calcium channel blocker. Conclusion This study validates the cardiovascular actions of Pimpinella and characterizes the hypotensive effects of Pimpinella that are related to the blockade of calcium channels.

Inflammatory monocytes have been shown to play key roles in cancer metastasis through promotion of tumor cell extravasation, growth, and angiogenesis. Monocyte recruitment to metastases is mediated primarily via the CCL2–CCR2 chemotactic axis. Thus, disruption of this axis represents an attractive therapeutic target for the treatment of metastatic disease. Losartan, a type I angiotensin II receptor (AT1R) antagonist, has been previously shown to have immunomodulatory actions involving monocyte and macrophage activity. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, we investigated the effects of losartan and its primary metabolite on CCL2-mediated monocyte recruitment and CCR2 receptor function using mouse tumor models and in vitro human monocyte cultures. We show, in this study, that losartan and its metabolite potently inhibit monocyte recruitment through the noncompetitive inhibition of CCL2-induced ERK1/2 activation, independent of AT1R activity. Studies in experimental metastasis models demonstrated that losartan treatment significantly reduced the metastatic burden in mice, an effect associated with a significant decrease in CD11b+/Ly6C+-recruited monocytes in the lungs. Collectively, these results indicate that losartan can exert antimetastatic activity by inhibiting CCR2 signaling and suppressing monocyte recruitment and therefore suggest that losartan (and potentially other AT1R blocker drugs) could be repurposed for use in cancer immunotherapy.

OBJECTIVE: Angiotensin II (Ang II) exerts its effect through two G-protein coupled receptors: Angiotensin II type 1 receptors (AT1) and type 2 receptors (AT2). Both these receptor subtypes are poorly understood in asthma. In this study, we investigated effects of AT1 receptor antagonist losartan, novel AT2 receptor agonist novokinin and AT2 receptor antagonist PD123319 in a mouse model of asthma. METHODS: Mice were divided into control (CON) and allergen sensitized (SEN) groups. SEN was sensitized with ovalbumin (OVA) on day 1 and 6 (30μg; i.p.), followed by 5% OVA aerosol challenge (days 11–13). Treatments included a) losartan (SEN+LOS; 20 mg/kg i.p., day 14), b) Novokinin (SEN+NOV; 0.3 mg/kg i.p., day 14) c) PD123319 (SEN+PD; 5 mg/kg i.p., day 14). Experiments for airway responsiveness, bronchoalveolar lavage and tracheal ring reactivity using isolated organ bath were performed. RESULTS: Airway responsiveness to methacholine (48 mg/ml) was significantly higher in SEN (563.71±40% vs 294.3±123.84 in CON).). This response was potentiated in SEN+PD group (757±30%; p

BackgroundGuidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF) have medical therapy titrated to target doses derived from clinical trials, as tolerated. The degree to which titration occurs in contemporary U.S. practice is unknown.ObjectivesThis study sought to characterize longitudinal titration of HFrEF medical therapy in clinical practice and to identify associated factors and reasons for medication changes.MethodsAmong 2,588 U.S. outpatients with chronic HFrEF in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry with complete medication data and no contraindications to medical therapy, use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) were examined at baseline and at 12-month follow-up.ResultsAt baseline, 658 (25%), 525 (20%), 287 (11%), and 45 (2%) patients were receiving target doses of MRA, beta-blocker, ACEI/ARB, and ARNI therapy, respectively. At 12months, proportions of patients with medication initiation or dose increase were 6% for MRA, 10% for beta-blocker, 7% for ACEI/ARB, and 10% for ARNI; corresponding proportions with discontinuation or dose decrease were 4%, 7%, 11%, and 3%, respectively. Over 12months,&nbsp

Renin-angiotensin-aldosterone system (RAAS) inhibitors are a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan modulates the neurohormonal axis by inhibiting both angiotensin receptors and neprilysin, and improves neurohormonal balance more than blocking the RAAS alone.The PARADIGM-HF trial validated this new treatment option for patients with HFrEF. Sacubitril/valsartan was also more effective than enalapril in slowing disease progression by decreasing the risk of worsening heart failure requiring hospitalization or emergency admission and the need for intensified therapy, heart failure devices or cardiac transplantation. More than 70% of patients included in PARADIGM-HF were in NYHA class II, and overall, the results indicate that sacubitril/valsartan should be started in the earliest symptomatic stages of the disease.As PARADIGM-HF has excellent robustness for a cardiovascular trial, sacubitril/valsartan has been included as a new treatment option with a strong level of recommendation in the main international guidelines.This expert task force proposes a practical guide to the use of this new drug that has been endorsed by the Working Group on Heart Failure of the Portuguese Society of Cardiology. Resumo: Os inibidores do sistema renina-angiotensina-aldosterona são uma das pedras basilares no tratamento da insuficiência cardíaca com fração de ejeção reduzida. O sacubitril/valsartan promove a modulação neuro-hormonal, bloqueando os recetores da angiotensina e inibindo a neprilisina, e produz um maior equilíbrio neuro-hormonal, mais do que o bloqueio do sistema renina-angiotensina-aldosterona isoladamente. O estudo PARADIGM-HF validou essa nova opção para o tratamento de doentes com insuficiência cardíaca e fração de ejeção reduzida, em alternativa ao IECA/ARA.O sacubitril/valsartan demonstrou ser mais eficaz do que o enalapril em retardar a progressão da doença, diminuindo o risco de agravamento da insuficiência cardíaca através da diminuição da necessidade de hospitalização e da menor necessidade de intensificação terapêutica, dispositivos ou transplante cardíaco. Mais de 70% dos doentes incluídos no estudo PARADIGM-HF estavam em classe II da NYHA, suportando a utilização do sacubitril/valsartan precocemente após o início dos sintomas.Como o estudo PARADIGM-HF apresentou uma robustez sem precedentes para um estudo cardiovascular, o sacubitril/valsartan foi incluído como uma nova opção de tratamento nas Recomendações internacionais mais relevantes, com um elevado nível de evidência (I-B).Este grupo de peritos em Insuficiência Cardíaca vem propor uma orientação prática para a utilização deste novo fármaco, subscrita pelo Grupo de Estudos de Insuficiência Cardíaca da Sociedade Portuguesa de Cardiologia. Keywords: Sacubitril/valsartan, PARADIGM-HF, Practical guidance, Heart failure with reduced ejection fraction, Palavras-chave: Sacubitril/valsartan, PARADIGM-HF, Guia prático, Insuficiência cardíaca com fração de ejeção reduzida

Background. Epidemiologic findings on the effect of metabolic syndrome (MetS) and its treatment on colorectal cancer (CRC) survival have been inconsistent and have not been previously studied in an Arab population such as the Omani population.Patients and Methods. Data from the hospital records of 301 CRC patients treated in Sultan Qaboos University (SQUH), Oman, from 2006 to 2014 were analyzed retrospectively to determine the effects of MetS and its treatment on CRC survival. Overall survival (OS) by MetS status and by medications for MetS components management was compared with Cox proportional models.Results. Of the 301 patients, 76 (25.2%) had MetS, 20.3% were on insulin, 23.9% were on metformin, 25.6% took statins, 17.9% were on either angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB). Whereas metformin (HR, 0.46, 95% CI, 0.25-0.84) and statins (HR, 0.58; 95% CI, 0.35-0.96) had a protective effect on OS, insulin (HR 1.73, 95% CI, 1.02-2.97) had a detrimental effect. In subgroup analysis of diabetic subjects, a nonsignificant improvement in OS was observed in the metformin treated patients compared to those on other hypoglycemic agents (HR, 0.92, 95% CI, 0.55-1.55). Neither MetS nor antihypertensive drugs had any apparent effect on OS.Conclusions. Our result suggests that, among CRC patients with MetS, taking metformin and statins may improve overall survival, whereas being on insulin may negatively impact CRC prognosis. Further studies are warranted to determine the exact mechanism through which metformin, statins, and insulin exert their effects on CRC survival.

Combined therapy in cardiology is currently the most recognized method of treatment, especially in patients with hypertension. Approximately in 50 % of patients with hypertension, monotherapy is effective. However to achieve the desired effect in the remaining half of patients, simultaneous administration of two and sometimes three drugs is required. Numerous drugs with a fixed combination of two (and even three) antihypertensive drugs, often used in clinical practice, greatly simplify the dosage regimen of drugs and improve patients’ adherence to treatment. Unfortunately, simultaneous prescription of several drugs increases sharply the probability of inter-drug interaction with the increase in the number of prescribed drugs. The result of drug-drug intereaction may be unpredictable. Therefore, the ability to predict the possible adverse reactions in patients with cardiovascular diseases and to prescribe rationally combined pharmacotherapy is a guarantee of highly efficient and safe treatment.Currently, rational combinations of antihypertensive drugs of different groups make hypertension therapy more comfortable and increases patients’ adherence to treatment. The authors present topical combinations of antihypertensive drugs in one drug: angiotensin converting enzyme inhibitor + diuretic, β-adrenoblocker + diuretic; diuretic + angiotensin receptor antagonist; calcium antagonist + angiotensin receptor antagonist; calcium antagonist + β-adrenoblocker, and others.The article presents an overview of both rational (calcium antagonist + diuretic, β-adrenoblocker + diuretic,) and irrational (angiotensin converting enzyme Inhibitor + potassium-sparing diuretic, angiotensin receptor blocker + potassium-sparing diuretic) combinations of antihypertensive drugs. Combinations of some hypotensive and antianginal drugs with drugs of other groups with a high risk of adverse reactions are presented.

Background: Sacubitril/valsartan is a combination drug therapy for heart failure (HF) patients that has been shown to reduce mortality and hospitalisation. Aims: To explore clinically relevant real-life patient data regarding prescribing of sacubitril/valsartan for HF patients in three hospitals, in accordance with national guidelines. Methods: A retrospective multicentre study in three large UK hospital Trusts based in the West Midlands. Findings: A total of 118 symptomatic chronic HF patients with reduced ejection fraction were included in the study. A high proportion of prescribers adhered to NICE guidelines for treatment with sacubitril/valsartan; 99% of patients had a New York Heart Association functional class of at least II; 82% had a left ventricle ejection fraction of under 35%; 100% received an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker before commencing sacubitril/valsartan. The mean age of men and women at the three hospitals was 65 and 59 years, respectively. The proportion of men prescribed sacubitril/valsartan was greater than women: 80% compared to 20%, respectively. The majority of patients on the therapy were white British (65%). Total prescribing of sacubitril/valsartan at the three hospitals was 295 patients, lower than expected. Conclusion: The prescribing of sacubitril/valsartan at the Trusts generally adhered to NICE guidance; however, the prescribing rate was lower than expected compared with the NICE resource tool. Further investigations into the safety and scope of application of sacubitril/valsartan are required to match the prescribing of sacubitril/valsartan with eligible patients who could benefit from the medication.

We assessed the effects of the sacubitril/valsartan combination drug (LCZ696), in comparison to valsartan alone, on the progression of atherosclerotic plaque formation and inflammatory gene expression in apolipoprotein E- deficient mice (apoE−/− mice). Seventy-two apoE−/− mice were fed a western diet and a constrictive silastic tube was used to elicit carotid lesion formation. The animals were separated into a control group, a valsartan group or an LCZ696 group (n = 24 in each group). Plaques in the carotid artery were harvested 12 weeks later for histological examination. The levels of pro-inflammatory genes in the plasma and lesions were detected using real-time PCR and ELISA. Valsartan or LCZ696 treatment remarkably inhibited the expression of pro-inflammatory genes, including interleukin-6, matrix metalloproteinase-8 and monocyte chemotactic protein-1, in comparison with the control group. Meanwhile, both valsartan and LCZ696 suppressed the formation of atherosclerotic plaques by decreasing plaque lipid content and cross-sectional plaque area and increasing the content of plaque collagen and fibrous cap thickness. In particular, LCZ696 performed the best in suppressing atherosclerosis and inhibiting the level of pro-inflammatory genes. LCZ696 significantly ameliorated atherosclerosis and inflammation in apoE−/− mice compared with valsartan.

Cardiorenal syndrome in patients with heart failure is a regular link in the chain of cardiorenal continuum. Physicians of various specialties may encounter patients with cardiorenal syndrome: general practitioners, cardiologists, nephrologists, resuscitators, anesthetists, cardiac surgeons, etc. The currently definition, classification, pathogenesis, diagnosis and epidemiology of cardiorenal syndrome in patients with heart failure were presented in first part of our review. In the second part, prognosis, approaches to the prevention and treatment of cardiorenal syndrome in patients with heart failure are discussed. They include the treatment of cardiovascular pathology and heart failure in accordance with current guidelines for the prevention of episodes of acute and decompensated chronic heart failure; diet; smoking cessation, alcohol, nephrotoxic substances; body weight, blood pressure and glycemia control; angiotensin converting enzyme inhibitors, angiotensin receptor antagonists or angiotensin receptors and neprilisin inhibitors (ARNI), statins; reducing of the abdominal pressure and others. It is necessary to develop and introduce new approaches to nephroprotection in patients with cardiorenal syndrome, which is possible with the joint work of a multidisciplinary team.

Resistant hypertension is defined as uncontrolled blood pressure despite the use of 3 or more antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, at maximal or maximally tolerated doses. Antihypertensive medication non-adherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. Resistant hypertension is a high risk phenotype, leading to increased all-cause mortality and cardiovascular disease (CVD) outcomes. Healthy lifestyle habits are associated with reduced CV risk in patients with resistant hypertension. Aldosterone excess is common in patients with resistant hypertension, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of 5 or more antihypertensive agents of different classes, including a long acting thiazide-like diuretic and a mineralocorticoid receptor antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying resistant hypertension, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.

Aim.To evaluate the effectiveness of telmisartan as a component of triple antihypertensive therapy in patients with obesity and refractory arterial hypertension.Material and methods.The study included 30 patients with obesity and refractory arterial hypertension. All patients received an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACE inhibitor) in an adequate dosage as part of a triple antihypertensive therapy that also includes a calcium antagonist and thiazide diuretic. Participants were randomly divided into two equal groups. In the main group, telmisartan (Dr. Reddy’s Laboratories) was prescribed at a dosage of 80 mg/day instead of the previously taken ARB or ACE inhibitor. In the control group, patients continued to receive a previously prescribed ARB or an ACE inhibitor. The primary end point was a decrease in mean daily systolic and/or diastolic blood pressure (SBP and DBP) according to 24-hour blood pressure monitoring at 10 mm Hg and more than 20 weeks after the start of the study. The secondary end point was a decrease in the concentration of inflammatory markers and an increase in the level of adiponectin by 15%.Results.After 20 weeks, in the telmisartan group, we noted a significant decrease in the average daily SBP and DBP: in the main group from 145,9±5,4/95,6±4,8 mm Hg to 134,8±3,0/84,9±4,2 mm Hg, in the control group with 147,2±4,9/96,4±5,6 mm Hg to 142,4±4,3/96,9±62 mm Hg. We also determined an increase in the serum adiponectin concentration from 9,3±5,6 μg/ml to 13,4±6,6 μg/ml in the main group and a decrease from 8,8±5,2 μg/ml to 8,6±5,6 μg/ml in the control group, as well as a decrease in the concentration of highly sensitive C-reactive protein (main group from 8,8±3,0 to 6,0±2,8 mg/l and the control group from 7,4±3,8 to 6,9±4,9 mg/l) and interleukin-6 (main group from 16,2±6,1 to 12,3±2,8 pg/ml, control group from 22,5±4,2 to 19,9±5,2 pg/ml).Conclusion.Telmisartan can be considered as a drug of choice as part of multi-component therapy in the treatment of patients with obesity and refractor arterial hypertension.

Background Epidemiology of patients with worsening heart failure and reduced ejection fraction (HFrEF) in the real-world setting is not well described. Objectives The purpose of this study was to describe incidence, clinical characteristics, treatment, and outcomes of patients with HFrEF who develop worsening heart failure (HF) in the real-world setting. Methods Data on patients with incident HFrEF from the National Cardiovascular Data Registry PINNACLE were linked to pharmacy, private practitioner, and hospital claims databases. Incidence, clinical characteristics, treatment (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, and mineralocorticoid receptor antagonist) and outcomes of patients with worsening HF, defined as ≥90 days of stable HF with subsequent worsening requiring intravenous diuretic agents, were assessed. Results Of 11,064 HFrEF patients, 1,851 (17%) developed worsening HF on average 1.5 years following initial HF diagnosis. Patients who developed worsening HF were more likely to be African American, be octogenarians, and have higher comorbidity burden (p 50% target dose for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, and mineralocorticoid receptor antagonist, respectively. The 2-year mortality rate was 22.5%, and 56% of patients were rehospitalized within 30 days of the worsening HF event. Conclusions In the real-world setting, 1 in 6 patients with HFrEF develop worsening HF within 18 months of HF diagnosis. These patients have a high risk for 2-year mortality and recurrent HF hospitalizations. The use of standard-of-care therapies both before and after the onset of worsening HF is low. With high unmet medical need, patients with worsening HF require novel treatment strategies as well as greater optimization of existing guideline-directed therapy.

The contribution of the local angiotensin receptor system to neuroinflammation, impaired neurogenesis, and amyloid beta (Aβ) accumulation in Alzheimer’s disease (AD) and in hypertension is consistent with the remarkable neuroprotection provided by angiotensin receptor blockers (ARBs) independent of their blood pressure-lowering effect. Considering the causal relationship between hypertension and AD and that targeting cerebrovascular pathology with ARBs does not necessarily require their systemic effects, we tested intranasal losartan in the rat model of chronic hypertension (spontaneously hypertensive stroke-prone rats, SHRSP). Intranasal losartan at a subdepressor dose decreased mortality, neuroinflammation, and perivascular content of Aβ by enhancing key players in its metabolism and clearance, including insulin-degrading enzyme, neprilysin, and transthyretin. Furthermore, this treatment improved neurologic deficits and increased brain IL-10 concentration, hippocampal cell survival, neurogenesis, and choroid plexus cell proliferation in SHRSP. Losartan (1 μM) also reduced LDH release from cultured astroglial cells in response to toxic glutamate concentrations. This effect was completely blunted by IL-10 antibodies. These findings suggest that intranasal ARB treatment is a neuroprotective, neurogenesis-inducing, and Aβ-decreasing strategy for the treatment of hypertensive stroke and cerebral amyloid angiopathy acting at least partly through the IL-10 pathway. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00723-6) contains supplementary material, which is available to authorized users.

According to current conception, the process of forming of nephrosclerosis despite the origins is detected by the force of the same cellular and molecular mechanisms. Hence primary triggers cause elevated production of range of cellular response mediators, cytokines and growth factors such as transforming plateled-derived growth factor, fibroblast growth factor, interferon gamma, nuclear factor and others, by means of sequential processes, is followed by the replacement of kidney tissue. One of the most studied aspects of the process of nephrosclerosis is the influence of anginotensin II. Therefore, despite the triggering factors, development and progression of nephrosclerosis all children with chronic renal disease are in a risk group with predisposition for renal insufficiency and it is required to prescribe nephroprotective therapy, i.e. the drugs that will influence one of the links of the nephrosclerosis, in order to slow down its progression. Currently, with nephroprotective goal in early age are used the following elements - angiotensin converting enzyme inhibitors and angiotensin receptors, antogonists (blockers). Lately, the active search for effective and safe drugs with nephroprotective effect on one side and great interest towards undiscovered before qualities of Vitamin D caused a huge amount of works that support the effect of Vitamin D. Prescription of Vitamin D to animals with uremia was followed by the drop of apoptosis of podocides and loss of the protein that is contained in the split diaphragm that caused decrease in proteinuria. Vitamin D suppresses protophibrotic TGF-B1 in tubular epithelial cells. The regression of tubulointerstitial phibrosis under the influence of Vitamin D was confirmed based on the cases of animals with obstruction of urethra. Along with the use of the mentioned above groups of drugs, which effectiveness was proved experimentally and clinically, we strongly believe the more thorough study of the Vitamin D drug use is needed, especially to study the prevention and slowing down of the progression of nephrosclerosis in the cases of children with chronic renal disease. It is crucial to detect the exact dosage of the drug, the prescription period and the methods for the control of the effective concentration of the drug.

An application of a specific analysis on recordings obtained from urinary bladder (UB) preparations influenced with Angiotensin II (AngII) and AngII receptor (ATR) blockers was performed.UB preparations were divided as follows: group 1 stimulated with AngII only; group 2:PD123319 (ATR type-2 blocker)+AngII; group 3:Losartan (ATR type-1 blocker)+AngII. The averaged time and force parameters of the contractions were processed by a spline interpolation and graphic images of the different patterns of the contractile activity were obtained.The speed of AngII-induced UB contraction, when PD123319 was administered, was significantly higher than those, registered by the application of AngII alone and Losartan + AngII. The presence of Losartan markedly delayed the speed of the overall AngII-induced contraction.The study indicates the contribution of both ATR subtypes for the development of AngII-induced UB contraction. Our results showed that probably ATR mediate a reciprocal dynamic response to AngII in the bladder.

Here, we report that LMK235, a class I and histone deacetylase (HDAC6)‐preferential HDAC inhibitor, reduces hypertension via inhibition of vascular contraction and vessel hypertrophy. Angiotensin II‐infusion mice and spontaneously hypertensive rats (SHRs) were used to test the anti‐hypertensive effect of LMK235. Daily injection of LMK235 lowered angiotensin II‐induced systolic blood pressure (BP). A reduction in systolic BP in SHRs was observed on the second day when SHRs were treated with 3 mg/kg LMK235 every 3 days. However, LMK235 treatment did not affect angiotensin‐converting enzyme 1 and angiotensin II receptor mRNA expression in either hypertensive model. LMK235, acting via the nitric oxide pathway, facilitated the relaxing of vascular contractions induced by a thromboxane A2 agonist in the rat aortic and mesenteric artery ring test. In addition, LMK235 increased nitric oxide production in HUVECs and inhibited the increasing of aortic wall thickness in both animal hypertensive models. LMK235 decreased the enhanced cell cycle‐related genes cyclin D1 and E2F3 in angiotensin II‐infusion mice and restored the decreased p21 expression. In addition, LMK235 suppressed calcium calmodulin‐dependent protein kinase II (CaMKII) α, which is related to vascular smooth muscle cell proliferation. Inhibition or knockdown of HDAC5 blocked the CaMKIIα‐induced cell cycle gene expression. Immunoprecipitation demonstrated that class I HDACs were involved in the inhibition of CaMKII α‐induced HDAC4/5 by LMK235. We suggest that LMK235 should be further investigated for its use in the development of new therapeutic options to treat hypertension via reducing vascular hyperplasia or vasoconstriction.

Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals. Treatments with C21 or vehicle were administered orally, 24 h post-stroke, and continued for 30 days. Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline as well as at different time points post-stroke. Our findings demonstrate that the angiotensin receptor (AT2R) agonist C21 effectively prevents the development of PSCI in aged animals.

Simultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675 mg/day) vs. placebo, sacubitril (360 mg/day), valsartan (900 mg/day), and benazepril (5 mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n = 18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on Day 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on Day 5. Compared with placebo, sacubitril/valsartan (675 mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675 mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675 mg administration was similar to that observed with valsartan 900 mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.

The mechanism underlying thrombosis in atrial fibrillation (AF) is not yet clearly understood. The apelin/APJ axis parallel and counter-regulate with the angiotensin system. The present study hypothesizes that apelin/APJ axis exert its anti-thrombus effect in normal left atrial tissue and is disrupted by up-regulated renin-angiotensin-aldosterone system (RAAS) signaling during AF. The specimens of left atrial appendages collected from patients with rheumatic mitral stenosis who underwent valve replacement were divided into 3 groups: sinus rhythm, AF+/thrombus-, and AF+/thrombus+. The amounts of angiotensin II receptor subtype 1 (AT1), apelin/APJ and its downstream plasminogen activator inhibitor-1 (PAI-1) were detected by western blot. The expression of apelin/APJ was significantly decreased in the AF+/thrombus+ group compared with the sinus rhythm and AF+/thrombus- groups. Meanwhile the expressions of AT1 and PAI-1 were highest in the AF+/thrombus+ group compared to the other two groups. Taken together, the present study reveals apelin/APJ axis might be correlated with thrombosis in patients with AF mediated by PAI-1.

Ag2S nanodots have already been demonstrated as promising near-infrared (NIR-II, 1.0–1.45 μm) emitting nanoprobes with low toxicity, high penetration and high resolution for in vivo imaging of, for example, tumors and vasculature. In this work, we have systematically investigated the potential application of functionalized Ag2S nanodots for accurate imaging of damaged myocardium tissues after a myocardial infarction induced by either partial or global ischemia. Ag2S nanodots surface-functionalized with the angiotensin II peptide (ATII) have shown over 10-fold enhanced binding efficiency to damaged tissues than non-specifically (PEG) functionalized Ag2S nanodots due to their interaction with the upregulated angiotensin II receptor type I (AT1R). It is demonstrated how the NIR-II images generated by ATII-functionalized Ag2S nanodots contain valuable information about the location and extension of damaged tissue in the myocardium allowing for a proper identification of the occluded artery as well as an indirect evaluation of the damage level. The potential application of Ag2S nanodots in the near future for in vivo imaging of myocardial infarction was also corroborated by performing proof of concept whole body imaging experiments.