Aliskiren Group Research Articles

Aliskiren promotes skin-flap survival

BackgroundFlaps are used in clinical wound repair, reconstruction, and plastic surgery but are prone to necrosis after surgery. Aliskiren, a direct renin inhibitor, may promote flap survival. MethodsThirty-eight rats were divided into control and low- and high-dose aliskiren groups (n = 12 rats per group; two rats in the high-dose group died and were replaced). The flap survival rate, neutrophil density, microvessel density, superoxide dismutase activity, and malondialdehyde level were evaluated, and histopathological analysis was performed, on day7 after surgery. Blood perfusion was measured by laser Doppler flowmetry and oxide-gelatin angiography. The levels of vascular endothelial growth factor, tumor necrosis factor-α, interleukin (IL)-6, Nod-like receptor 3, cysteinyl aspartate specific proteinase-1 (caspase-1), IL-1β, and IL-18 were evaluated by immunohistochemical analysis. ResultsAliskiren improved flap survival. Downregulation of the malondialdehyde level and upregulation of the superoxide dismutase level in the experimental groups suggested that aliskiren reduced ischemia–reperfusion injury. Upregulation of the vascular endothelial growth factor level and improvement of blood perfusion in the experimental groups suggested that aliskiren improved flap angiogenesis. Immunohistochemical analysis showed that aliskiren reduced the levels of inflammatory factors such as tumor necrosis factor-α and IL-6. Furthermore, the expression of Nod-like receptor 3 inflammasome components was decreased in the experimental groups. ConclusionAliskiren improved the flap-survival rate.

Long-term outcomes of add-on direct renin inhibition in igA nephropathy: a propensity score-matched cohort study.

The long-term clinical outcomes in biopsy proven IgAN patients treated with aliskiren on top of a maximally tolerated dose of ACEi/ARB remain unknown. Patients with IgAN treated with a direct renin inhibitor and ACEi/ARB for at least 6months were compared with a 1:1 propensityscore-matched cohort (including MEST-C score and the 12-months pre-exposure slope of eGFR matching) who received ACEi/ARB without aliskiren exposure to compute the hazard ratio of reaching the primary endpoint of a composite of 40% reduction in eGFR, initiation of KRT and all-cause mortality. Secondary outcome measures included changes in mean UPCR, blood pressure, eGFR, incidence of hyperkalemia and other adverse events during follow-up. After a median follow-up of 2.5years, 8/36 (22.2%) aliskiren-treated patients and 6/36 (16.7%) control patients reached the primary composite outcome (HR = 1.60; 95% CI 0.52-4.88; P = 0.412). Aliskiren treatment increased the risk of ≥ 40% eGFR decline (HR = 1.60; 95% CI 0.52-4.88; P = 0.412), and hyperkalemia (HR = 8.60; 95% CI 0.99-73.64; P = 0.050). At 10.8years, renal composite outcome was reached in 69.4% vs 58.3% (HR = 2.16; 95% CI 1.18-3.98; P = 0.013) of patients in the aliskiren and control groups, respectively. The mean UPCR reduction between treatment and control was not statistically different (52.7% vs 42.5%; 95% CI 0.63-2.35; P = 0.556). The mean intergroup difference in eGFR decline over 60months was 7.75 ± 3.95ml/min/1.73m2 greater in the aliskiren group (12.83 vs 5.08; 95% CI - 0.17 to 15.66; P = 0.055). Among patients with IgAN, add-on aliskiren was associated with less favorable long-term kidney outcomes despite an initial anti-proteinuric effect.

PS-C21-6: RENOPROTECTIVE EFFECT OF ALISKIREN MONOTHERAPY IN HYPERTENSIVE PATIENTS WITH OBESITY AND TYPE 2 DIABETES MELLITUS

Objective: Renin-angiotensin system inhibitors have been reported to have protective effects from end-organ damages. However, roles of the direct renin inhibitor monotherapy have been still unknown. Therefore, in the present study, we compared effects of aliskiren monotherapy with those of amlodipine monotherapy on visceral fat area (VFA) and end-organ damages in hypertensive patients with obesity and type 2 diabetes. Design: A single-center, prospective, open-label and randomized study. Methods: Adult hypertensive patients with body mass index ≧ 25 kg/m2 and VFA ≧ 100 cm2 or those with type 2 diabetes, who had an office blood pressure 140–160/90–100 mmHg with or without antihypertensive drugs were randomly allocated to 24-week aliskiren or amlodipine monotherapy. The dose of amlodipine or aliskiren was increased up to 10 mg/day and 300 mg/day, respectively, and only doxazosin could be added at maximum to 8 mg/day if needed. The primary outcome of the study was the changes of waist circumference and VFA at 24 weeks of the study period. Changes in outcomes were analyzed using mixed-effects models for repeated measures, which included treatment, time, treatment-by-time interaction and the baseline values as fixed effects. Results: In a total of 62 participants (age, 57 ± 13 y.o.; 40 men; body mass index, 28.8 ± 4.8 kg/m2; waist circumference, 99.3 ± 11.9 cm; VFA, 134.8 ± 47.0 cm2; blood pressure, 141 ± 16/86 ± 13 mmHg), waist circumference and visceral fat area as a primary endpoint did not significantly change from baseline in both groups. Systolic blood pressure significantly decreased at 12 weeks (change in least squares means: -10 mmHg, P = 0.001) and 24 weeks (-10 mmHg, P = 0.001) in the amlodipine group and at 24 weeks (-11 mmHg, P = 0.001) in the aliskiren group. Diastolic blood pressure significantly decreased at 24 weeks (-6 mmHg, P = 0.009) only in the amlodipine group. Estimated glomerular filtration rates were not statistically different between the groups. Logarithm of urinary albumin excretion significantly decreased at 24 weeks only in the aliskiren group (-0.60, P < 0.001). The 24-weeks-changes in logarithm of serum pentraxin 3 levels, an inflammatory marker, were significantly lower in the aliskiren group than in the amlodipine group (-0.09 vs + 0.09, P = 0.017). Conclusions: These data suggested that aliskiren monotherapy may have a better renoprotective effect than amlodipine monotherapy while it does not affect VFA in hypertensive patients with obesity and type 2 diabetes mellitus.

Effects of Aliskiren Monotherapy versus Amlodipine Monotherapy in Hypertensive Patients with Obesity or Type 2 Diabetes Mellitus

Introduction: Renin-angiotensin system inhibitors have been reported to exert protective effects against organ damage and failure; however, the impact of the direct renin inhibitor as monotherapy has not been assessed. Here, we investigated the effects of 24-week monotherapy with aliskiren compared to amlodipine in hypertensive patients with type 2 diabetes or obesity. Methods: In this randomized intervention study, 62 adult hypertensive patients with visceral obesity (defined as a body mass index [BMI] greater than 25 kg/m2 and a visceral adipose tissue area [VFA] greater than 100 cm2) or type 2 diabetes mellitus (age 57 ± 13, 65% men, BMI 28.8 ± 4.8 kg/m2, VFA 134.8 ± 47.0 cm2, blood pressure 141 ± 16/86 ± 13 mm Hg) were randomized to receive 24-week treatment with aliskiren (max. 300 mg) or amlodipine (max. 10 mg). The primary outcome was the change in VFA at 24 weeks post-treatment. Results: Change in VFA did not differ significantly from baseline in either group. Systolic blood pressure significantly decreased at 12 weeks (−10 mm Hg, p = 0.001) and 24 weeks (−10 mm Hg, p = 0.001) in the amlodipine group and at 24 weeks (−11 mm Hg, p = 0.001) in the aliskiren group. Diastolic blood pressure significantly decreased at 24 weeks (−6 mm Hg, p = 0.009) only in the amlodipine group. Although the estimated glomerular filtration rates did not significantly change in either group, the logarithm of urinary albumin excretion significantly decreased at 24 weeks only in the aliskiren group (−0.60, p < 0.001). The 24-week changes in the urinary albumin excretion significantly correlated with the changes in the plasma renin activity in the aliskiren group (r = 0.51, p = 0.008). Conclusion: Aliskiren monotherapy did not show any superiority to amlodipine monotherapy on VFA, estimated glomerular filtration rates, or urinary albumin excretion in obese or type 2 diabetic hypertensive patients.

POS-203 LONG-TERM OUTCOMES OF ADD-ON DIRECT RENIN INHIBITION IN IMMUNOGLOBULIN A NEPHROPATHY: A RETROSPECTIVE, PROPENSITY SCORE-MATCHED COHORT STUDY

The addition of the direct renin inhibitor (DRI) aliskiren to an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEi) in IgA nephropathy (IgAN) has been shown to confer additional antiproteinuric effects in two short-term clinical trials. The long-term effect of this combination remains unknown and hence neglected in clinical practice. Thirty six patients with IgAN who had been treated with DRI and ARB for at least 6 months between 2009 to 2010 were identified and retrieved from a linked electronic database. A 1:1 propensity-score matching cohort from the same period that received ARB without aliskiren exposure was used to calculate the hazard ratio of reaching the primary endpoint, defined as a composite of a 40% reduction in estimated glomerular filtration rate (eGFR), initiation of kidney replacement therapy (KRT) and all-cause mortality. Secondary outcome measures included changes in mean urine protein-to-creatinine ratio (UPCR), blood pressure, eGFR, incidence of hyperkalemia and other adverse events during follow-up. After a median follow-up of 10.8 years, 25/36 (69.4%) patients in the aliskiren group and 21/36 (58.3%) patients in the control group reached the primary composite outcome (HR=2.17; 95% CI: 1.18 to 3.98; P=0.013). Aliskiren treatment was associated with an increased risk of >40% eGFR decline (HR=2.17; 95% CI: 1.18 to 3.98; P=0.013), initiation of KRT (HR=1.97; 95% CI: 0.92 to 4.21; P=0.079), and all-cause mortality (HR=2.08; 95% CI: 0.19 to 22.70; P=0.556). The incidence of hyperkalemia was significantly higher in the aliskiren group (HR=5.13; 95%CI: 1.68 to 15.63; P=0.004). After a follow up of 60 months, 16/36 (44.4%) in aliskiren and 9/36 (25.0%) in control group subjects reached the primary composite outcome (HR=2.19; 95%CI: 0.94 to 5.13, P=0.070). The mean UPCR reduction was 10.2% more in the aliskiren group (52.7% vs 42.5%; 95%CI: 0.63 to 2.35;P=0.556). Mean intergroup difference in eGFR decline over 60 months was 7.75±3.95 ml/min/1.73m 2 more in the aliskiren group (12.83 vs 5.08; 95%CI: -0.17 to 15.66; P=0.055). Although add-on aliskiren reduced proteinuria in short-term studies, it was associated with less favourable long-term kidney outcomes among patients with IgAN.

MP53-20 RENOPROTECTIVE EFFECT OF DIRECT RENIN INHIBITOR (ALISKIREN) DURING ACUTE AND CHRONIC PARTIAL URETERAL OBSTRUCTION IN RAT SOLITARY KIDNEY

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Ureter (including Pyeloplasty) and Bladder Reconstruction (including fistula), Augmentation, Substitution, Diversion II (MP53)1 Sep 2021MP53-20 RENOPROTECTIVE EFFECT OF DIRECT RENIN INHIBITOR (ALISKIREN) DURING ACUTE AND CHRONIC PARTIAL URETERAL OBSTRUCTION IN RAT SOLITARY KIDNEY Mohamed Essam, Nashwa Barakat, Ahmed Elkashef, Amira Awadalla, A. E. Behery, and Mahmoud Abdel-Maboud Mohamed EssamMohamed Essam More articles by this author , Nashwa BarakatNashwa Barakat More articles by this author , Ahmed ElkashefAhmed Elkashef More articles by this author , Amira AwadallaAmira Awadalla More articles by this author , A. E. BeheryA. E. Behery More articles by this author , and Mahmoud Abdel-MaboudMahmoud Abdel-Maboud More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002083.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Obstructive uropathy is a major clinical problem that can result in permanent renal damage. The renoprotective effect of direct renin inhibitor (aliskiren) has been demonstrated in many experimental animal models mainly renal ischemia/reperfusion injury. Therefore, we studied the effect of aliskiren on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. METHODS: 60 male Sprague–Dawley rats were randomly allocated into 3 groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. 10 rats from each group were sacrificed after 2 weeks, while the remaining rats were sacrificed after 4 weeks. Left kidneys were harvested for histopathological examination, BCL-2, IL-6, TGF-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. RESULTS: After 2 and 4 weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration (table 1). Aliskiren group showed significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin gene expression (table 2). Aliskiren also significantly increased GSH and SOD activity and reduced MDA and NO activity (table 2). Moreover, aliskiren administration for 4 weeks after PUO significantly yielded more renoprotective effect compared to its administration for 2 weeks. CONCLUSIONS: Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e947-e947 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mohamed Essam More articles by this author Nashwa Barakat More articles by this author Ahmed Elkashef More articles by this author Amira Awadalla More articles by this author A. E. Behery More articles by this author Mahmoud Abdel-Maboud More articles by this author Expand All Advertisement Loading ...

Functional and molecular evaluation of using aliskiren during acute and chronic partial ureteral obstruction in rat solitary kidney

AimsTo study the effect of direct renin inhibitor (aliskiren) on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. Main methodsSixty male Sprague–Dawley rats were randomly allocated into three groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. Ten rats from each group were sacrificed after two weeks, while the remaining rats were sacrificed after four weeks. Left kidneys were harvested for histopathological examination, BCL-2, interleukin (IL)-6, transforming growth factor (TGF)-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. Key findingsAfter two and four weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration. Aliskiren group showed statistically significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin relative gene expression. Aliskiren significantly increased GSH and SOD activity and reduced MDA and NO activity. Moreover, aliskiren administration for four weeks after PUO significantly yielded more renoprotective effect compared to its administration for two weeks. SignificanceAliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney.

The Potential Effects of Aliskiren on Atrial Remodeling Induced by Chronic Intermittent Hypoxia in Rats.

PurposeAtrial remodeling takes part in the pathogenesis of atrial fibrillation (AF). Aliskiren, as a direct renin inhibitor, has been shown to exert protective effects against arrhythmia. The aim of this study was to investigate the potential role of aliskiren in atrial remodeling in a chronic intermittent hypoxia (CIH) rat model.MethodsA total of 45 Sprague–Dawley rats were randomly assigned into three groups (n=15 per group): control group; CIH group; and CIH with aliskiren (CIH-A) group. CIH and CIH-A rats were subjected to CIH for 6 h per day for 4 weeks. Atrial fibrosis was evaluated using Masson’s trichrome staining. Electrophysiological tests were conducted in the isolated perfused hearts to assess the atrial effective refractory period and inducibility of AF. Atrial ionic remodeling was measured using the whole-cell patch-clamp technique, and Western blotting and real-time quantitative polymerase chain reactionwere performed to evaluate changes in ion channels.ResultsCIH induced obvious collagen deposition, and the abnormal fibrosis was significantly attenuated by aliskiren. The inducibility of AF was increased significantly in the CIH group compared with the control and CIH-A groups (23±24.5% vs 2.0±4.2% vs 5.0±7.0%, respectively; P<0.05). Compared with the control group, the densites of the calcium current (ICaL) and sodium current (INa) were reduced significantly in the CIH group (ICaL: −3.16±0.61 pA/pF vs −7.13±1.98 pA/pF; INa: −50.97±8.71 pA/pF vs −132.58±25.34 pA/pF, respectively; all P<0.05). Following intervention with aliskiren, the reductions in ICaL and INa were significantly improved, and the ionic modeling changes assessed at the mRNA and protein levels were also significantly improved.ConclusionCIH could alter atrial modeling and subsequently promote the occurrence and development of AF, which could be attenuated by treatment with aliskiren.

Direct Renin Inhibition in Non-diabetic chronic Kidney disease (DRINK): a prospective randomized trial.

The potential long-term safety and efficacy of aliskiren in nondiabetic chronic kidney disease (CKD) are unknown. We sought to investigate the renoprotective effect of aliskiren on nondiabetic CKD patients. In this open-label, parallel, randomized controlled trial, nondiabetic CKD Stages 3-4 patients were randomized to receive aliskiren added to an angiotensin II receptor blocker (ARB) at the maximal tolerated dose, or ARB alone. Primary outcome was the rate of change in estimated glomerular filtration rate (eGFR). Secondary endpoints included rate of change in urine protein-to-creatinine ratio (UPCR), cardiovascular events and hyperkalemia. Composite renal outcomes of doubling of baseline serum creatinine or a 40% reduction in eGFR or incident end-stage renal disease or death were analyzed as post hoc analysis. Seventy-six patients were randomized: 37 to aliskiren (mean age 55.1 ± 11.1 years) and 39 to control (mean age 55.0 ± 9.4 years). Their baseline demographics were comparable to eGFR (31.9 ± 9.0 versus 27.7 ± 9.0 mL/min/1.73 m2, P = 0.05) and UPCR (30.7 ± 12.6 versus 47.8 ± 2.8 mg/mmol, P = 0.33) for treatment versus control subjects. After 144 weeks of follow-up, there was no difference in the rate of eGFR change between groups. Six patients in the aliskiren group and seven in the control group reached the renal composite endpoint (16.2% versus 17.9%, P = 0.84). The cardiovascular event rate was 10.8% versus 2.6% (P = 0.217). The hyperkalemia rate was 18.9% versus 5.1% with an adjusted hazard ratio of 7.71 (95% confidence interval 1.14 to 52.3, P = 0.04) for the aliskiren arm. Aliskiren neither conferred additional renoprotective benefit nor increased adverse events, except for more hyperkalemia in nondiabetic CKD patients.

Attenuation of atrial remodeling by aliskiren via affecting oxidative stress, inflammation and PI3K/Akt signaling pathway.

Atrial fibrillation (AF) is the most common type of arrhythmia. Atrial remodeling is a major factor to the AF substrate. The purpose of the study is to explore whether aliskiren (ALS) has a cardioprotective effect and its potential molecular mechanisms on atrial remodeling. In acute experiments, dogs were randomly assigned to Sham, Paced and Paced+aliskiren (10mgkg-1) (Paced+ALS) groups, with 7 dogs in each group. Rapid atrial pacing (RAP) was maintained at 600bpm for 2h for paced and Paced+ALS groups and atrial effective refractory periods (AERPs), inducibility of AF (AFi) and average duration time (ADT) were measured. In chronic experiments, there were 5 groups: Sham, Sham+ALS, Paced, Paced+ALS and Paced+ALS+PI3K antagonist wortmannin (WM) (70μgkg-1day-1). RAP at 500 beats/min was maintained for 2weeks. Inflammation and oxidative stress indicators were measured by ELISA assay, echocardiogram and pathology were used to assess atrial structural remodeling, phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/Akt) signaling pathways were studied by RT-PCR and western blotting to evaluate whether the cardioprotective effect of ALS works through PI3K/Akt signaling pathway. The electrophysiological changes were observed after 2-h pacing. The AERP shortened with increased AFi and ADT, which was attenuated by ALS (P < 0.05). After pacing for 2weeks, oxidative stress and inflammation markers in the Paced group were significantly higher than those in the Sham group (P < 0.01) and were reduced by ALS treatment (P < 0.01). The reduced level of antioxidant enzymes caused by RAP was also found to be elevated in ALS-treated group (P < 0.01). The results of pathology and echocardiography showed that RAP can cause atrial enlargement, fibrosis (P < 0.01), and were attenuated in ALS treatment group. The PI3K/Akt signaling pathway were downregulated induced by RAP. ALS could upregulate the PI3K/Akt pathway expression (P < 0.05). Furthermore, the cardioprotective effects in structural remodeling of ALS were suppressed by WM. ALS may offer cardioprotection in RAP-induced atrial remodeling, which may partly be ascribed to its anti-inflammatory and anti-oxidative stress action and the regulation of PI3K/Akt signaling pathway.

Aliskiren and captopril improve cognitive deficits in poorly controlled STZ-induced diabetic rats via amelioration of the hippocampal P-ERK, GSK3β, P-GSK3β pathway

Learning and memory deficits are obvious symptoms that develop over time in patients with poorly controlled diabetes. Hyperactivity of the renin-angiotensin system (RAS) is directly associated with β-cell dysfunction and diabetic complications, including cognitive impairment. Here, we investigated the protective and molecular effects of two RAS modifiers, aliskiren; renin inhibitor and captopril; angiotensin converting enzyme inhibitor, on cognitive deficits in the rat hippocampus. Injection of low dose streptozotocin for 4 days resulted in type 1 diabetes. Then, poorly controlled diabetes was mimicked with ineffective daily doses of insulin for 4 weeks. The hyperglycaemia and pancreatic atrophy caused memory disturbance that were identifiable in behavioural tests, hippocampal neurodegeneration, and the following significant changes in the hippocampus, increases in the inflammatory marker interleukin 1β, cholinesterase, the oxidative stress marker malondialdehyde and protein expression of phosphorylated extracellular-signal-regulated kinase and glycogen synthase kinase-3 beta versus decrease in the antioxidant reduced glutathione and protein expression of phosphorylated glycogen synthase kinase-3 beta. Blocking RAS with either drugs along with insulin amended all previously mentioned parameters. Aliskiren stabilized the blood glucose level and restored normal pancreatic integrity and hippocampal malondialdehyde level. Aliskiren showed superior protection against the hippocampal degeneration displayed in the earlier behavioural modification in the passive avoidance test, and the aliskiren group outperformed the control group in the novel object recognition test. We therefore conclude that aliskiren and captopril reversed the diabetic state and cognitive deficits in rats with poorly controlled STZ-induced diabetes through reducing oxidative stress and inflammation and modulating protein expression.

Protective Effects of Nanoparticle-Loaded Aliskiren on Cardiovascular System in Spontaneously Hypertensive Rats.

Aliskiren, a renin inhibitor, has been shown to have cardioprotective and blood pressure (BP) lowering effects. We aimed to determine the effects of nanoparticle-loaded aliskiren on BP, nitric oxide synthase activity (NOS) and structural alterations of the heart and aorta developed due to spontaneous hypertension in rats. Twelve week-old male spontaneously hypertensive rats (SHR) were divided into the untreated group, group treated with powdered or nanoparticle-loaded aliskiren (25 mg/kg/day) and group treated with nanoparticles only for 3 weeks by gavage. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions, and collagen content were determined in both the heart and aorta. Vasoactivity of the mesenteric artery and wall thickness, inner diameter, and cross-sectional area (CSA) of the aorta were analyzed. After 3 weeks, BP was lower in both powdered and nanoparticle-loaded aliskiren groups with a more pronounced effect in the latter case. Only nanoparticle-loaded aliskiren increased the expression of nNOS along with increased NOS activity in the heart (by 30%). Moreover, nanoparticle-loaded aliskiren decreased vasoconstriction of the mesenteric artery and collagen content (by 11%), and CSA (by 25%) in the aorta compared to the powdered aliskiren group. In conclusion, nanoparticle-loaded aliskiren represents a promising drug with antihypertensive and cardioprotective effects.

Effect of Aliskiren on Renal Cortical Ischemia/Reperfusion Injury in Albino Rats: A Histological and Immunohistochemical Study

Background: Ischemia/reperfusion injury (IRI) is a foremost reason for acute kidney injury, which is a common clinical complication having high morbidity rate and lacks effective therapy. Renin-angiotensin system (RAS) activation and angiotensin II level elevation are important risk factors in IRI. Aliskiren (ALS) is the first oral direct rennin inhibitor that blocks the first step in RAS and has been approved for treating hypertension.Aim of work: Investigating whether ALS pretreatment protects the renal cortex of adult male albino rats subjected to IRI.Material and Methods: Thirty adult male albino rats were divided into 3 groups: group I (control group), group II (IRI group): were subjected to IRI procedure, group III (ALS group): rats were pretreated with aliskiren (ALS, 100 mg/kg) twice orally 24h and 1h before IRI and left for 24h of reperfusion before scarification. Blood samples were taken to estimate the levels of blood urea nitrogen (BUN), serum creatinine (SCr) and superoxide dismutase enzyme (SOD). Kidneys sections were stained with HandE and PAS stains and immunohistochemical staining against COX-2 and caspase-3. This was followed by morphometric and statistical analysis.Results: IRI group showed deterioration in renal function tests with massive histological alterations in the Malpighian renal corpuscles and the convoluted tubules. There was significant decrease in optical density of PAS reaction, with significant increase in the mean area% of COX-2 and caspase-3 immunoexpression. ALS group showed significant improvement in renal function tests with preserved normal histology of the renal cortex. There was significant increase in the optical density of PAS reaction, with significant decrease in the mean area% of COX-2 and caspase-3 immunoexpression.Conclusion: A protective effect of ALS was detected in IRI-induced renal cortical damage in adult male albino rats. This was evidenced by laboratory results, histological and immunohistochemical evaluation.

Greater reductions in plasma aldosterone with aliskiren in hypertensive patients with higher soluble (Pro)renin receptor level.

The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

Formulation and in vivo evaluation of aliskiren-loaded poly(lactic-co-glycolic) acid nanoparticles

Aliskiren (ALS) is a direct renin inhibitor with low bioavailability and high drug cost. The goal of this study was to increase the bioavailability of ALS through nanoformulation. The optimized formulation was then evaluated in spontaneously hypertensive rats (SHRs). We developed an ALS poly(lactic- co-glycolic) acid nanoparticle (ALS-NP) through the emulsion–diffusion–evaporation method with various solvents, stabilizer concentrations, and centrifugation speeds. SHRs were orally dosed with 30 mg/kg ALS or dose equivalent ALS-NP. Several parameters were assayed in plasma and/or urine at baseline and 24 h post-dose, while pharmacokinetic analysis included serial sampling. The optimum formulation was found with ethyl acetate, a 1.00% w/v didodecyldimethylammonium bromide concentration, and a 10,000 r/min (15,554 g) centrifugation speed. A 168% relative bioavailability was observed as a result of ALS-NP administration along with significant, as determined by Student’s t-test, increases in the maximum ALS plasma concentration ( p = 0.0189) and the area under the plasma concentration–time curve from 0 to infinity ( p = 0.0095). Conversely, a reduction was found in oral volume of distribution ( p = 0.0009) and oral clearance ( p = 0.0298). Blood urea nitrogen increased significantly after dosing in both groups ( p &lt; 0.0001 and p &lt; 0.0001); however, no statistical difference was found between endpoint levels ( p &gt; 0.05) following one-way analysis of variance (ANOVA). Kidney injury molecule-1 increased following ALS dosing ( p = 0.0486), while ALS-NP showed a decrease ( p = 0.027) which was also significantly decreased compared to ALS-Final ( p = 0.0008) when examined using two-way ANOVA. Urinary potassium excretion decreased significantly, as shown by two-way ANOVA, only in the ALS group ( p = 0.0274) which was also significantly reduced compared to ALS-NP-Final ( p = 0.016). Using the current formulation and at the dosage tested, ALS-NP showed a more favorable pharmacokinetic profile and positive kidney changes compared to ALS in regard to select outcomes. Thus, NP formulation may further improve ALS renoprotection in addition to increasing bioavailabilty.

Aliskiren alone or in combination with enalapril vs. enalapril among patients with chronic heart failure with and without diabetes: a subgroup analysis from the ATMOSPHERE trial.

Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes. ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71-1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups. In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Aliskiren for heart failure: a systematic review and meta-analysis of randomized controlled trials.

ObjectiveTo systematically review and synthesize the currently available evidence of aliskiren for the treatment of heart failure.Materials and MethodsWe systematically searched the Cochrane, Embase and PubMed databases to identify the randomized controlled trials (RCT) on the effects of aliskiren on heart failure. Data were synthesized with random effects model and presented in forest plot. Publication bias was evaluated with funnel plot. Heterogeneity was evaluated with Begg's test and Egger's test.ResultsOf 124 studies, 6 RCT of 9845 heart failure patients were included for meta-analysis, including 3727 patients receiving aliskiren. Compared with the controls, aliskiren did not significantly reduce the all-cause mortality (1.02 [0.91–1.14], I2 = 0%) or cardiovascular mortality (1.02 [0.88–1.17], I2 = 7.3%) of heart failure patients. Total adverse events, renal dysfunction, hypotension and hyperkalaemia were not significantly different between the aliskiren group and control group. Begg's test and Egger's test indicated low heterogeneity. Funnel plots indicated low publication bias.ConclusionsAliskiren, either used alone or combined with standard medical therapy, does not significantly reduce the all-cause mortality or cardiovascular mortality of heart failure patients. Although aliskiren does not cause statistically higher adverse events, its adverse events may not be neglected.

Inhibition of Angiotensin-II Production Increases Susceptibility to Acute Ischemia/Reperfusion Arrhythmia.

BackgroundMyocardial ischemia and reperfusion lead to impairment of electrolyte balance and, eventually, lethal arrhythmias. The aim of this study was to investigate the effects of pharmacological inhibition of angiotensin-II (Ang-II) production on heart tissue with ischemia-reperfusion damage, arrhythmia, and oxidative stress.Material/MethodsRats were divided into 4 groups: only ischemia/reperfusion (MI/R), captopril (CAP), aliskiren (AL), and CAP+AL. The drugs were given by gavage 30 min before anesthesia. Blood pressure and electrocardiography (ECG) were recorded during MI/R procedures. The heart tissue and plasma was kept so as to evaluate the total oxidant (TOS), antioxidant status (TAS), and creatine kinase-MB (CK-MB).ResultsCreatine kinase-MB was not different among the groups. Although TAS was not affected by inhibition of Ang-II production, TOS was significantly lower in the CAP and/or AL groups than in the MI/R group. Furthermore, oxidative stress index was significantly attenuated in the CAP and/or AL groups. Captopril significantly increased the duration of VT during ischemia; however, it did not have any effect on the incidence of arrhythmias. During reperfusion periods, aliskiren and its combinations with captopril significantly reduced the incidence of other types of arrhythmias. Captopril alone had no effect on the incidence of arrhythmias, but significantly increased arrhythmias score and durations of arrhythmias during reperfusion. MAP and heart rate did not show changes in any groups during ischemic and reperfusion periods.ConclusionsAngiotensin-II production appears to be associated with elevated levels of reactive oxygen species, but Ang-II inhibitions increases arrhythmia, mainly by initiating ventricular ectopic beats.

Comparison of direct renin inhibitor and angiotensin II receptor blocker on clinic and ambulatory blood pressure profiles in hypertension with chronic kidney disease

ABSTRACTWe compared the therapeutic effects of aliskiren (direct renin inhibitor (DRI) group) with angiotensin II (Ang II) type 1 receptor blockers (ARBs) (ARB group) on clinic blood pressure (BP) and ambulatory BP in 36 hypertensive chronic kidney disease (CKD) patients. The baseline clinic BP levels and the after-treatment/baseline (A/B) ratios of clinic BP levels, estimated after 24-week treatment period, were similar in DRI group (n = 18) and ARB group (n = 18). With respect to the effects on ambulatory BP, the A/B ratios of the daytime and nighttime systolic BP in DRI group were significantly higher than those in ARB group. The A/B ratio of ankle-brachial pressure index after the study was higher in the DRI group compared with the ARB group. The results of the present study suggest that DRI therapy is not superior to ARB therapy in lowering ambulatory BP in hypertensive CKD patients, in spite of comparable clinic BP-lowering effects.

Angiotensin II Receptor Blockers or Straight Renin Inhibitor Influence Upon Morphological and Functional Heart and Central Hemodynamics Indices in Hypertensive Patients After Ischemic Stroke

Arterial hypertension (AH) in the world and in Ukraine is the main cause of strokes and chronic cerebral dyscirculation with constantly growing incidence. The risk of recurrent stroke grows with increase of concomitant risk factors and AH target organs damage. Asymptomatic target organs damage, especially, LV hypertrophy, etc., is one the potent factors for cerebral vascular complications in hypertensive patients. That is why treatment of heart anatomy alterations, as a target organ, is of great importance in cardiovascular continuum for primary and secondary prevention of cardiovascular, including cerebrovascular end-points. The objective: of the study was to evaluate the influence of AH medication treatment by angiotensin receptors type II blockers (ARB) and straight renin inhibitor upon morphological and functional heart indices and central hemodynamics in hypertensive patients after ischemic stroke (IS) during 1 year follow-up according to stroke and vascular hospital departments experience. Patients and methods. We prospectively included 135 hypertensive pts. without AF history after IS aged 36-78 years (61,0±9,1 yrs.), hospitalized to stroke and vascular hospital departments of Ternopol regional community psycho-neurological hospital (TRCPNH) over the period Nov. 2011 – Dec. 2013 р. All pts. underwent Doppler EchoCG. Along with fundamental therapy pts. were randomly prescribed Losartan 50-100 mg/day (40 pts.), Olmesartan 20-40 mg/day (48 pts) or Aliskiren 150-300 mg/day. Control EchoCG was performed in 6 and 12 months from trearment start. Results. Among the pts. with AH after IS usually there are pts. with low NYHA class of CHF, with LVEF correlating with NYHA functional class ( –0,47, p&lt;0,0001), with predominantly concentric LV geometry (97,8%), correlating with NYHA functional class. NYHA FC significantly correlates with most morphological and functional left and right remodeling indices, while LV volumes significantly correlate with LV systolic function. ARB administration (Losartan or Olmesartan) for AH treatment leads to marked significant regress of LV hypertrophy and hypertensive remodeling already in 6 months of treatment with central hemodynamics improvement with similar changes in both sartans groups without significant difference between indices. In Aliskiren group (3) in 6 months of treatment pts. Showed significantly higher LA dimensions compared to Losartan group, thicker LV walls compared to both sartan groups, and higher LV RWTh. Central hemodynamics indices, namely, LV diastolic function, LV preload and smaller circulation pressure in 6 months after treatment did not significantly differ between the groups. Conclusions. In Aliskiren group in 12 months of treatment there also were certain positive changes compared to start data, witnessing of reverse LV remodeling. But at the same time Aliskiren group showe significantly higher LV walls thickness (р=0,0051 and р&lt;0,0001 for IVS, and р&lt;0,0001 and р&lt;0,0001 fro LVPW, respectively), and higher LV MMi (р=0,0003 and р=0,0002, respectively) compared both to Losartan and Olmesartan groups, with preservation of concentric LV geometry and LV hypertrophy. Also, Aliskiren group showed significantly worse LV diastolic function and preload indices, allowing to conclude about insufficient cardioprotection with Aliskiren in treating AH after IS, and significant benefit from ARB.