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BACKGROUND The rehospitalization rate in a hypertensive emergency is high, indicating the necessity for optimizing its long-term management. The role of the renin–angiotensin system (RAS) blockade in this disorder remains uncertain. METHODS We conducted a retrospective analysis involving 20 admitted patients who received aliskiren, a direct renin inhibitor (DRI), for the management of hypertensive emergency associated with elevated plasma renin activity (PRA). We analyzed the changes in blood pressure (BP), kidney function, and RAS activity in the subacute and chronic phases. RESULTS The use of DRI was associated with a marked reduction in PRA (median, from 25.0 to 1.2 ng/ml/h) and serum aldosterone levels (from 404 to 130 pg/ml) during the index admission. BP also decreased from 226/143 to 142/80 mm Hg. A comparison of clinical characteristics according to the renal function indicated that dialysis-dependent patients had higher aldosterone levels than non-dialysis-dependent patients at admission, despite comparable BP levels. After a median follow-up of 567 days in non-dialysis-dependent patients with DRI, eGFR levels were significantly increased from 14.3 to 23.1 ml/min/1.73 m2. PRA levels were consistently suppressed at 0.8 ng/ml/h. We found a significant correlation between the degree of PRA suppression and changes in eGFR (r  = –0.58), indicating that the effective blockade of RAS is associated with the preservation of eGFR in the study subjects. CONCLUSIONS DRI can successfully suppress PRA in patients with high-renin hypertensive emergency in both subacute and chronic phases. An efficient RAS blockade is associated with preserved renal function in these patients. [ABSTRACT FROM AUTHOR]

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

The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure. [ABSTRACT FROM AUTHOR]

Renin is an aspartyl protease of the renin–angiotensin system (RAS) and the first enzyme of the biochemical pathway for the generation of angiotensin II – a potent vasoconstrictor involved in the maintenance of cardiovascular homeostasis and the regulation of blood pressure. High enzymatic specificity of renin and its involvement in the catalysis of the rate-limiting step of the RAS hormone system qualify it as a good target for inhibition of hypertension and other associated diseases. Ligand-based pharmacophore model (Hypo1) was generated from a training set of 24 compounds with renin inhibitory activity. The best hypothesis consisted of one Hydrogen Bond Acceptor (HBA), three Hydrophobic Aliphatic (HY-Al) and one Ring Aromatic (AR) features. This well-validated pharmacophore hypothesis (correlation coefficient 0.95) was further utilized as a 3D query to screen database compounds, which included structures from two natural product repositories. These screened compounds were further analyzed for drug-likeness and ADMET studies. The compounds which satisfied the qualifying criteria were then subjected to molecular docking and Density Functional Theory (DFT) analysis in order to discern their atomic level interactions at the active site of the 3D structure of rennin. The pharmacophore-based modelling that has been used to generate the novel findings of the present study would be an avant-garde approach towards the development of potent inhibitors of renin. [ABSTRACT FROM AUTHOR]

Background: In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. Methods: We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria. Results: Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients. Conclusion: DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen. [ABSTRACT FROM AUTHOR]

Context:The health effects ofSambucus nigraL. (Caprifoliaceae) could be due to polyphenols whose modes of action differ from the traditional one proposed for exogenous antioxidants. Objective:The study emphasizes the effects of the association between the renin inhibitor and the polyphenolic extract on biochemical parameters and systolic (TAS) and diastolic (TAD) blood pressure within anLNAME-induced experimental model of arterial hypertension (AHT). Materials and methods:The polyphenols are extracted with ethanol from isolated and purified vegetable material represented by the mature fruit of theS. nigrawith a dosage of 0.046 g/kg body weight (PS), every 2 days, for 8 weeks. The dose represents 1/20 of LD50. The Wistar white rat blood pressure values were recorded using a CODA™ system, which uses a non-invasive blood pressure measuring method. Results and discussion:The total antioxidant capacity levels were significantly decreased (p < 0.001) in AHT group as compared to the rats in the AHT + PS group. A combination of a renin inhibitor (Aliskiren) and polyphenolic extract generated a superior antioxidant effect compared to administering the two separately. Both TAS and TAD in rats with drug-induced hypertension were reduced by polyphenolic extract. The homogeneous values of TAS record a significant decrease (p < 0.001) of the average values in AHT + PS group or AHT + Aliskiren group. Conclusion:The combination of two different classes of substances, namely, renin inhibitors and natural polyphenol extracts, reduces arterial pressure and also might reduce the side effects of the major classes of antihypertensive agents and improve the quality of live. [ABSTRACT FROM AUTHOR]

Hypertension is the main cause of human death and the Renin- Angiotensin- Aldosterone System (RAAS) has a key role in the control of human blood pressure. In this research a multi-step virtual screening strategy was applied in order to find new potential renin inhibitors. The crystal structure of renin-aliskiren complex was explored and receptor-ligand pharmacophore model was developed and validated using pharmit. ZINC database was screened by pharmacophore model and Lipinski's rule of five. Thereafter, the retrieved hits were docked in the active site of renin by using Vina. ADME parameters and toxicity of the filtered compounds were approximated using in silico methods and the selected compounds were subjected to high performance docking in order to improve the accuracy of screening. The non-bond interactions of the hit molecules with renin were explored and the compounds with the highest affinity and appropriate interactions were selected. In the last step, molecular dynamic simulation studies were performed on the complex of renin with aliskiren and three top-ranked structures including ZINC6085004, ZINC426421106, and ZINC5481346. RMSD, RMSF, Rg and number of hydrogen bonds were calculated. The binding free energy was calculated using the MM/PBSA method. The result of MD simulation indicated the stable binding of ZINC426421106 and ZINC5481346 with the active site of renin. According to this in-silico study these two compounds are drug-like, nontoxic, and have a high potential for inhibiting renin and could serve as appropriate lead molecules for the development of renin inhibitors as antihypertensive agents. Representation of the overall virtual screening process. [Display omitted] • A structure-based pharmacophore model was developed and validated for the renin-aliskiren complex. • ZINC database was screened by the pharmacophore model. • Molecular dynamic simulation studies were performed on the complex of renin with top-ranked structures. • The binding free energy was calculated using the MM/PBSA method. • Two molecules had a high potential for inhibition of human renin. [ABSTRACT FROM AUTHOR]

This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin-angiotensin-aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials. [ABSTRACT FROM AUTHOR]

We conducted a systematic review and meta-analysis of double-blind randomized controlled trials to quantify the dose-related systolic (SBP) and diastolic blood pressure (DBP) lowering efficacy of renin inhibitors vs placebo in the treatment of adults with primary hypertension. Databases searched were Medline (1966–March 2008), EMBASE (1988–March 2008) and Cochrane Central Register of Controlled Trials (CENTRAL). Six trials in 3694 patients met the inclusion criteria. All examined aliskiren, the only renin inhibitor licensed for marketing in Canada and the United States. Aliskiren caused a dose-related SBP/DBP lowering effect compared to placebo: weighted mean difference with 95% CI: aliskiren 75 mg, −2.9 (−4.6, −1.3)/−2.3 (−3.3, −1.3) mm Hg; aliskiren 150 mg, −5.5 (−6.5, −4.4)/−3.0 (−3.7, −2.3) mm Hg; aliskiren 300 mg, −8.7 (−9.7,−7.6)/−5.0 (−5.6, −4.3) and aliskiren 600 mg, −11.4 (−13.5, −9.2)/−6.6 (−7.9, −5.2) mm Hg. Aliskiren 300 mg significantly lowered both SBP −3.0 (−4.0, −2.0) and DBP −1.7 (−2.3, −1.0) as compared to aliskiren150 mg. Aliskiren has no effect on blood pressure variability. No data were available to assess the effect of aliskiren on heart rate or pulse pressure. This review found weak evidence that during 4- to 8-week use, aliskiren did not increase withdrawals due to adverse effects as compared to placebo. We concluded that aliskiren has a dose-related blood pressure lowering effect better than placebo and magnitude of effect is similar to that determined for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.Journal of Human Hypertension (2009) 23, 495–502; doi:10.1038/jhh.2008.162; published online 22 January 2009 [ABSTRACT FROM AUTHOR]

Renin catalyzes the rate‐determining step in the renin–angiotensin–aldosterone system that regulates mammalian blood pressure by converting angiotensinogen to angiotensin I (Ang I). Excessive plasma levels of Ang I is a causative factor in hypertension development. Therefore, inhibition of renin activity can lower blood pressure and provide relief from clinical symptoms associated with hypertension. Synthetic compounds are currently the most used group of renin inhibitors; however, only aliskiren is approved as a drug for hypertension treatment. But some negative side effects are associated with aliskiren therapy, which have necessitated the search for alternative natural compounds such as food protein‐derived renin‐inhibitory peptides with blood pressure‐reducing effects. This paper is a concise review of the currently known sources and methods of production of renin‐inhibitory peptides including their potential in vitro and in vivo extent of renin inhibition. Practical applications: Hypertension is a major human chronic disease that leads to severe cardiovascular impairment and ultimately death if not managed properly. Current therapeutic approach to hypertension management involves the use of drugs that inhibit excessive activities of renin and angiotensin converting enzyme (ACE), the two main enzymes that control mammalian blood pressure. Since renin catalyzes a single reaction that is the rate‐determining step in the renin–angiotensin system, inhibition of this enzyme activity could be a highly effective strategy for controlling blood pressure without severe negative side effects. However, therapeutic control of renin activity remains difficult with only one approved drug. Some food protein‐derived peptides have been found to inhibit renin activity inhibition, which could offer a drug‐free treatment for hypertension. Therefore, this review provides a summary of recent developments in the advances and efficacy testing of renin‐inhibitory peptides. [ABSTRACT FROM AUTHOR]