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Objective: Addressing the rising prevalence of pain disorders and limitations of current analgesics, our study explores repurposing antihypertensive drugs for pain management, inspired by the link between hypertension and pain. We leverage a drug-target Mendelian Randomization (MR) approach to explore their dual benefits and establish causal connections. Methods: A comprehensive compilation of antihypertensive drug classes was undertaken through British National Formulary, with their target genes identified using the DrugBank database. Relevant single nucleotide polymorphisms (SNPs) associated with these targets were selected from published genomic studies on systolic blood pressure (SBP) as genetic instruments. These SNPs were validated through MR against acute coronary artery disease (CAD) to ensure genes not linked to CAD were excluded from acting as proxies for antihypertensive drugs. An MR analysis of 29 pain-related outcomes was conducted using the FinnGen R10 database employing the selected and validated genetic instruments. We utilized the Inverse Variance Weighted (IVW) method for primary analysis, applying Bonferroni correction to control type I error. IVW's multiplicative random effects (MRE) addressed heterogeneity, and MR-PRESSO managed pleiotropy, ensuring accurate causal inference. Results: Our analysis differentiates strong and suggestive evidence in linking antihypertensive drugs to pain disorder risks. Strong evidence was found for adrenergic neuron blockers increasing migraine without aura risk, loop diuretics reducing panniculitis, and vasodilator antihypertensives lowering limb pain risk. Suggestive evidence suggests alpha-adrenoceptor blockers might increase migraine risk, while beta-adrenoceptor blockers could lower radiculopathy risk. Adrenergic neuron blockers also show a potential protective effect against coxarthrosis (hip osteoarthritis) and increased femgenpain risk (pain and other conditions related to female genital organs and menstrual cycle). Additionally, suggestive links were found between vasodilator antihypertensives and reduced radiculopathy risk, and both alphaadrenoceptor blockers and renin inhibitors possibly decreasing dorsalgianas risk (unspecified dorsalgia). These findings highlight the intricate effects of antihypertensive drugs on pain disorders, underlining the need for further research. Conclusion: The findings indicate that antihypertensive medications may exert varied effects on pain management, suggesting a repurposing potential for treating specific pain disorders. The results advocate for further research to confirm these associations and to explore underlying mechanisms, to optimize pain management practices. [ABSTRACT FROM AUTHOR]

Introduction: The risk of thromboembolic events developing limits the dose of antiangiogenic agents, thereby reducing their efficacy. This retrospective study therefore sought to identify predictors for the development of antiangiogenic agent-induced thromboembolic events and to elucidate whether differences in the likelihood of thromboembolic events exist between different antiangiogenic agents or cancer types, to guide future strategies for optimizing safety, efficacy, and quality of life in patients receiving chemotherapy. Methods: This study retrospectively investigated 468 cancer patients who received chemotherapy with bevacizumab, ramucirumab, or aflibercept at our outpatient chemotherapy center between December 2016 and April 2022. Variables related to the development of thromboembolic events were extracted from the medical records, and multivariate logistic regression analysis was performed to identify predictors for the development of thromboembolic events. The Wilcoxon/Kruskal-Wallis test was used to detect significant differences between groups. Results: Significant factors included serum albumin level (odds ratio [OR] = 0.363, 95% confidence interval [CI] = 0.193–0.685; p = 0.0017) and diabetes mellitus (OR = 5.356, 95% CI = 1.711–16.769; p = 0.0039). Renin-angiotensin system inhibitors (OR = 0.307) had low OR, although it was not significant. No difference in the development of thromboembolic events was evident between cancer types (p = 0.0781), but differences were identified between the three antiangiogenic agents (p = 0.0132). Ramucirumab was associated with a lower likelihood of thromboembolic events. Conclusion: Serum albumin level and diabetes mellitus were identified as significant predictors for the development of antiangiogenic agent-induced thromboembolic events. In addition, the likelihood of thromboembolic events did not differ between cancer types but differed between antiangiogenic agents. Plain Language Summary: This retrospective study was designed to identify predictors for the development of antiangiogenic agent-induced thromboembolic events and to elucidate whether differences in the likelihood of thromboembolic events exist between different antiangiogenic agents or cancer types. This study investigated 468 cancer patients who received chemotherapy with bevacizumab, ramucirumab, or aflibercept at our outpatient chemotherapy center between December 2016 and April 2022. Variables related to the development of thromboembolic events were extracted from the medical records, and multivariate logistic regression analysis was performed to identify predictors for the development of thromboembolic events. The Wilcoxon/Kruskal-Wallis test was used to detect significant differences between groups. Significant factors included serum albumin level (odds ratio [OR] = 0.363, 95% confidence interval [CI] = 0.193–0.685) and diabetes mellitus (OR = 5.356, 95% CI = 1.711–16.769). Renin-angiotensin system inhibitors (OR = 0.307) had low OR, although it was not significant. No difference in the development of thromboembolic events was evident between cancer types (p = 0.0781), but differences were identified between the three antiangiogenic agents (p = 0.0132). Ramucirumab was associated with a lower likelihood of thromboembolic events. In conclusion, serum albumin level and diabetes mellitus were identified as significant predictors for the development of antiangiogenic agent-induced thromboembolic events. In addition, the likelihood of thromboembolic events did not differ between cancer types, but differed between antiangiogenic agents. [ABSTRACT FROM AUTHOR]

Blood pressure and fluid balance are regulated hormonally by renin-angiotensin system (RAS). Influence on this system could be achieved by different compounds that act as angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers and renin inhibitors. The purpose of the present study is to predict the structures of the potent ACE inhibitors on the base of His-Leu peptide structural element of angiotensine I using computational methods. Different modifications were made in the structure of this dipeptide and the energy of binding with the enzyme were calculated. The docking results were analyzed and it was found that along with the important amino acid residue of the receptor molecule Arg167, the Tyr residues (35, 87, 88 and 92) as well as Cys180 are extremely important for the strong binding to the receptor and, accordingly, the manifestation of antagonistic action by the analogues. To block the receptor, the ligand molecule must have an intact terminal carboxyl group and an imidazole nucleus to participate in appropriate interactions. The inclusion of functional groups in the side chains of the amino acid residues of the dipeptide create an additional site for binding to the receptor. With the help of docking, the ligand molecule can be optimized, and this process is fast, saving the synthesis of many compounds and their biological testing. And finally, the most potent analogues will be synthesized and biologically tested. [ABSTRACT FROM AUTHOR]

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

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]

In the last decades, several classifications and definitions have been proposed for advanced heart failure (ADVHF) patients, including clinical, functional, hemodynamic, imaging, and electrocardiographic features. Despite different inclusion criteria, ADVHF is characterized by some common items, such as drug intolerance, low arterial pressure, multiple organ dysfunction, chronic kidney disease, and diuretic use dependency. Additional features include fatigue, hypotension, hyponatremia, and unintentional weight loss associated with a specific laboratory profile reflecting systemic multiorgan dysfunction. Notably, studies evaluating guideline-directed medical therapy recently endorsed by guidelines in stable HF, including the 4 drug classes all together (i.e., betablocker, mineral corticoid antagonist, renin angiotensin inhibitors/neprilysin inhibitors, and sodium glucose transporter inhibitors), remain scarcely analyzed in ADVHF and New York Heart Association (NYHA) Class IV. Additionally, due to the common conditions associated with advanced stages, the balance between drug tolerance and potential benefits of the contemporary use of all agents is questioned. Therefore, less hard endpoints, such as exercise tolerance, quality of life (QoL) and self-competency, are not clearly demonstrated. Specific analyses evaluating outcome and rehospitalization of each drug provided conflicting results and are often limited to subjects with stable conditions and less advanced NYHA class. Current European Society of Cardiology/American Heart Association (ESC/AHA) Guidelines do not indicate the type of treatment, dosage, and administration modalities, and they do not suggest specific indications for ADVHF patients. Due to these concerns, there is an impelling need to understand what drugs may be used as the first line, what management leads to the better outcome, and what is the best treatment algorithm in this setting. In this paper, we summarize the most common pitfalls and limitations for the use of the traditional agents, and we propose a personalized approach aiming at preserve drug tolerance and maintaining adverse event protection and satisfactory QoL. [ABSTRACT FROM AUTHOR]

We aimed to determine effects of aliskiren, a direct renin inhibitor, loaded onto polymeric nanoparticles on the (pro)renin receptor (Atp6ap2), angiotensin II type 1 receptor (Agtr1), and angiotensin-converting enzyme (ACE) gene expression in the heart of spontaneously hypertensive rats (SHR). Twelve-week-old male SHRs were divided into an untreated group and groups treated with powdered aliskiren or aliskiren-loaded nanoparticles (25 mg/kg/day). After three weeks, the accumulation of aliskiren, distribution of polymeric nanoparticles, gene expression of Atp6ap2 and Agtr1 receptors and ACE, and protein expression of NADPH oxidase along with the conjugated diene (CD) concentration were analyzed. The accumulation of aliskiren in the heart was higher in the aliskiren-loaded nanoparticle group than in the powdered group. The fluorescent signals of nanoparticles were visible in cardiomyocytes, vessel walls, and erythrocytes. Aliskiren-loaded nanoparticles decreased the gene expression of Atp6ap2 and ACE, while not affecting Agtr1. Both forms of aliskiren decreased the protein expression of NADPH oxidase, with a more pronounced effect observed in the aliskiren-loaded nanoparticle group. CD concentration was decreased only in the aliskiren-loaded nanoparticle group. We hypothesize that aliskiren-loaded nanoparticle-mediated downregulation of Atp6ap2 and ACE may contribute to a decrease in ROS generation with beneficial effects in the heart. Moreover, polymeric nanoparticles may represent a promising tool for targeted delivery of aliskiren. [ABSTRACT FROM AUTHOR]

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Background: Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of this analysis is to compare drug treatments of DKD by means of a systemic review and a network meta-analysis. Methods: We searched Medline, CENTRAL and clinicaltrials.gov for randomized, controlled studies including adults with DKD treated with the following drugs of interest: single angiotensin-converting-enzyme-inhibitor or angiotensin-receptor-blocker (single ACEi/ARB), angiotensin-converting-enzyme-inhibitor and angiotensin-receptor-blocker combination (ACEi+ARB combination), aldosterone antagonists, direct renin inhibitors, non-steroidal mineralocorticoid-receptor-antagonists (nsMRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). As primary endpoints, we defined: overall mortality and end-stage kidney disease, as secondary endpoints: renal composite outcome and albuminuria and as safety endpoints: acute kidney injury, hyperkalemia and hypotension. Under the use of a random effects model, we computed the overall effect estimates using the statistic program R4.1 and the corresponding package "netmeta". Risk of bias was assessed using the RoB 2 tool and the quality of evidence of each pairwise comparison was rated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). Results: Of initial 3489 publications, 38 clinical trials were found eligible, in total including 42346 patients. Concerning the primary endpoints overall mortality and end stage kidney disease, SGLT2i on top of single ACEi/ARB compared to single ACEi/ARB was the only intervention significantly reducing the odds of mortality (OR 0.81, 95%CI 0.70–0.95) and end-stage kidney disease (OR 0.69, 95%CI 0.54–0.88). The indirect comparison of nsMRA vs SGLT2i in our composite endpoint suggests a superiority of SGLT2i (OR 0.60, 95%CI 0.47–0.76). Concerning safety endpoints, nsMRA and SGLT2i showed benefits compared to the others. Conclusions: As the only drug class, SGLT2i showed in our analysis beneficial effects on top of ACEi/ARB treatment regarding mortality and end stage kidney disease and by that reconfirmed its position as treatment option for diabetic kidney disease. nsMRA reduced the odds for a combined renal endpoint and did not raise any safety concerns, justifying its application. [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]

Background and Objectives Dual renin-angiotensin-aldosterone system (RAAS) blockade involves dual therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin-receptor blockers (ARBs), direct renin inhibitors (DRIs), or mineralocorticoid receptor antagonists (MRAs). It is hypothesized that dual RAAS blockade would result in a more complete inhibition of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have shown increased risk of acute kidney injury (AKI) and hyperkalemia without additional benefit on mortality, cardiovascular events, or chronic kidney disease (CKD) progression compared to RAAS inhibitor monotherapy in patients with diabetic kidney disease (DKD). The development of newer, more selective non-steroidal MRAs as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. We conducted a systematic review and meta-analysis of the risks of AKI and hyperkalemia with dual RAAS blockade in patients with DKD. Design, setting, participants, and measurements This is a systematic review and meta-analysis of the randomized controlled trials (RCT) published from 1 January 2006 to 30 May 2022. The study population included adult patients with DKD receiving dual RAAS blockade. A total of 31 RCTs and 33   048 patients were included in the systematic review. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random effects. Results There were 208 AKI events in 2690 patients on ACEi + ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48, 95% CI: 1.23–1.39). There were 304 hyperkalemia events in 2818 patients on ACEi + ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97, 95% CI: 1.32–2.94). A non-steroidal MRA + ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97, 95% CI: 0.81–1.16) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05, 95% CI: 1.84–2.28). A steroidal MRA + ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus five events in 248 at risk in monotherapy (pooled RR 5.42 95% CI: 2.15–13.67). Conclusion Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and non-steroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs. [ABSTRACT FROM AUTHOR]

The Renin–Angiotensin System (RAS) has attracted considerable interest beyond its traditional cardiovascular role due to emerging data indicating its potential involvement in neurodegenerative diseases, including Alzheimer's dementia (AD). This review investigates the therapeutic implications of RAS modulators, specifically focusing on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors in AD. ACEIs, commonly used for hypertension, show promise in AD by reducing angiotensin (Ang) II levels. This reduction is significant as Ang II contributes to neuroinflammation, oxidative stress, and β-amyloid (Aβ) accumulation, all implicated in AD pathogenesis. ARBs, known for vasodilation, exhibit neuroprotection by blocking Ang II receptors, improving cerebral blood flow and cognitive decline in AD models. Renin inhibitors offer a novel approach by targeting the initial RAS step, displaying anti-inflammatory and antioxidant effects that mitigate AD degeneration. Preclinical studies demonstrate RAS regulation's favorable impact on neuroinflammation, neuronal damage, cognitive function, and Aβ metabolism. Clinical trials on RAS modulators in AD are limited, but with promising results, ARBs being more effective that ACEIs in reducing cognitive decline. The varied roles of ACEIs, ARBs, and renin inhibitors in RAS modulation present a promising avenue for AD therapeutic intervention, requiring further research to potentially transform AD treatment strategies. [ABSTRACT FROM AUTHOR]

This review considers the chiral phosphorus-containing drugs used to treat patients in the clinic, as well as the promising and experimental drugs that are in the process of being researched. Natural and synthetic representatives of phosphorus-containing drugs, such as tenofovir (hepatitis B and HIV treatment), fosfomycin (antibiotic), valinofos (antibiotic), phosphazinomycin A (antibiotic), (R)-phospholeucine, various antibacterial and antifungal agents, renin inhibitors, etc., have found practical applications as medicines and bioregulators and other medicines. The influence of the chirality of both carbon atoms and phosphorus atoms on the pharmacodynamics, pharmacokinetics, and toxicological properties of phosphorus drugs has been demonstrated. Therefore, the choice of enantiomers is critical since the wrong choice of a chiral drug can lead to undesirable consequences, carcinogenicity, and teratogenicity. New chiral technologies affecting drug development are discussed, such as the "chiral switch" of racemates already on the market, as well as phosphorus-containing prodrugs with a higher biological selectivity and low adverse effects. [ABSTRACT FROM AUTHOR]

Renin inhibitors derived from natural ingredients often belong to the saponin or polyphenol chemical class. Pegagan (Centella asiatica) is a natural plant in Indonesia that contains saponins and polyphenols. The active compounds of Pegagan include asiaticoside, madasiatic acid, madecassoside, madecassic acid, and asiatic acid. This study investigates the possible renin-inhibitory properties of phytochemicals from Centella asiatica using in-silico molecular docking. Using AutoDock v4.2.6, up to five C. asiatica compounds were docked with 2V0Z Renin with Inhibitor 10 (Aliskiren) in human subjects (Homo sapiens 6LU7). These compounds included asiaticoside, madasiatic acid, madecassoside, madecassid acid, and asiatic acid. SwissADME was used to evaluate these drugs' pharmacokinetic characteristics. The molecular docking results of 5 test ligands obtained affinity energy values from -8.7 kcal/mol to -10.4 kcal/mol. In contrast, the affinity energy value for the comparison ligand (aliskiren) is -9.0 kcal/mol. Madecasosside has an affinity energy value of -10.4 kcal/mol, asiaticoside of -9.6 kcal/mol and asiatic acid of -9.2 kcal/mol. Based on this energy affinity value, the active compound C. asiatica has the potential as a renin inhibitor. Pharmacokinetic analysis revealed that asiatic acid, madecassic acid, madasiatic acid, and asiatic acid have good pharmacokinetic properties. It may be concluded based on in silico molecular docking and pharmacokinetics investigation that the molecule most strongly suggested for additional in vitro renin inhibitor research was asiatic acid. Keywords: Renin Inhibitor, Centella asiatica, Molecular Docking. [ABSTRACT FROM AUTHOR]

Aliskiren is referred to as a direct renin inhibitor. renin catalysis the conversion of angiotensinogen to angiotensin-1 Aliskiren and Valsartan use as hypertension. Valsartan belongs to the angiotensin 2 receptor blocker family. Which prevent the protein angiotensin 2. Cardiac stimulation and renal reabsorption of sodium. This review article represents the collection and discussion of various analytical methods available in the literature for the determination of Aliskiren and Valsartan in pharmaceutical and biological samples consisting of UV spectroscopy, RP-HPLC, HPTLC, LCMS/MS methods. The anticipated review provides details about the comparative utilization of various analytical techniques for the determination of Aliskiren and Valsartan alone and in combination. The present review article can be effectively explored to conduct future analytical investigation for the estimation of Aliskiren and Valsartan. [ABSTRACT FROM AUTHOR]

Flavonoids have various pharmacological activities, such as antihypertensive, anticancer, and and antidiabetic effects. Several studies have shown that luteolin, quercetin, kaempferol, myricetin, naringenin, hesperetin, and epicatechin have antihypertensive effects, but the mechanism of action has yet to be discovered with certainty. This study aims to identify flavonoids from luteolin, quercetin, kaempferol, myricetin, naringenin, hesperetin, and epicatechin as renin inhibitors through in silico study; seven flavonoid compounds were docked with 2V0Z with renin inhibitor (Aliskiren) in humans (Homo sapiens 6 LU7) using AutoDock v4.2.6. SwissADME was used to evaluate the pharmacokinetic characteristics of these substances. Results molecular binding of luteolin, quercetin, kaempferol, myricetin, naringenin, hesperetin, and epicatechin, has potential as renin inhibitors with affinity energy values lower than those of aliskiren of -9.3; -9.3; -10.0; -9.2; -9.9; -9.3; and -9.7 kcal/mol. The interactions of these seven compounds have the same catalytic activity as aliskiren on two aspartic acid residues, Asp32 and Asp215. The analysis of pharmacokinetic profiles and the search for physical and chemical properties showed that the seven compounds violated three of the five Lipinski rules, while aliskiren violated one. Hesperitin, kaempferol, and naringenin had similarities with aliskiren on the amino-acid residues in the renin-binding pocket. However, based on pharmacokinetic analysis, the three compounds had an oral pharmacokinetic profile that could have been better than aliskiren. [ABSTRACT FROM AUTHOR]

This article is a response to a letter from A.H. Jan Danser and Ingrid M. Garrelds regarding the clinical impact of sample storage at -20 °C on renin reference intervals and aldosterone-renin ratio calculations. The authors of the response paper argue that cryoactivation of prorenin is a preanalytical risk for renin measurements in plasma samples stored at -20 °C. They cite experiments that show highly variable increases in renin concentration when samples are frozen at -20 °C, but no cryoactivation when samples are snap-frozen or defrosted at ambient temperature. Based on this evidence, the authors advise laboratories to store plasma samples for renin analyses in a -70 °C freezer or snap-freeze samples and store them in a -20 °C freezer. [Extracted from the article]

The article discusses the phenomenon of cryoactivation, which refers to a cold-induced change in prorenin, the inactive precursor of renin. The authors explain that storing plasma samples at low temperatures for a long time can lead to the inactivation of serine protease inhibitors, resulting in the generation of kallikrein, which can cleave the prosegment of prorenin. The authors argue that storing samples at -20 °C is sufficient and that there is no advantage to storing them at -70 °C. They also mention that renin inhibitors can bind to the active site of prorenin, leading to overestimation of renin levels in certain assays. [Extracted from the article]

Genetic variants in the third intron of the PRDM6 gene have been associated with BP traits in multiple GWAS. By combining fine mapping, massively parallel reporter assays, and gene editing, we identified super enhancers that drive the expression of PRDM6 and are partly regulated by STAT1 as the causal variants for hypertension. The heterozygous disruption of Prdm6 in mice expressing Cre recombinase under the control of mouse smooth muscle cell protein 22-a promoter (Prdm6fl/+ SM22- Cre) exhibited a markedly higher number of renin-producing cells in the kidneys at E18.5 compared with WT littermates and developed salt-induced systemic hypertension that was completely responsive to the renin inhibitor aliskiren. Strikingly, RNA-Seq analysis of the mouse aortas identified a network of PRDM6-regulated genes that are located in GWAS-associated loci for blood pressure, most notably Sox6, which modulates renin expression in the kidney. Accordingly, the smooth muscle cell-specific disruption of Sox6 in Prdm6fl/+ SM22-Cre mice resulted in a dramatic reduction of renin. Fate mapping and histological studies also showed increased numbers of neural crest-derived cells accompanied by increased collagen deposition in the kidneys of Prdm6fl/+ Wnt1Cre-ZsGreen1Cre mice compared with WT mice. These findings establish the role of PRDM6 as a regulator of renin-producing cell differentiation into smooth muscle cells and as an attractive target for the development of antihypertensive drugs. [ABSTRACT FROM AUTHOR]

The construction of functionalized cyclopropanes is a hot topic in synthetic chemistry as they are important 3C starting materials and privileged structures in medicinal chemistry. By treating the readily available cyclopropenes with sulfonyl iodides in water, β-iodo cyclopropyl sulfones were diastereoselectively formed via a syn-addition process in high yields. Employment of water as the sole solvent, avoidance of transition metals and air-sensitive reagents, and chromatography-free purification of the products make this transformation quite operationally convenient and environmentally benign. This method could be extended to various styrenes and alkynes, and the reactions with alkynes exhibited excellent anti-addition selectivity. It should be noted that post-modification of several natural products and drugs has been achieved, and this transformation has been successfully applied as a key step in the synthesis of a quinolinone MAT2A inhibitor and in the formal synthesis of a dipeptide renin inhibitor. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hypertension is a silent killer that causes kidney, heart, and stroke damage if not handled properly. In Indonesia, the prevalence of the population with high blood pressure is 34.11% with women 36.85% higher than men 31.34%, this shows a fairly high value so that special attention is needed on hypertension therapy. It is known that currently there are 6 types of pharmacological therapy for hypertension and one of the newest is the renin inhibitor class (Aliskiren). Indonesia has diverse natural wealth in the form of flora and fauna, with a wealth of more than 30,000 types of medicinal plants with 9500 potential herbal medicines that have not been utilized optimally, with the largest exporter of herbal medicines in the world. Centella asiatica plants containing triterpenoid saponins have high renin inhibitor activity, namely the content of Asiaticoside and Madecasoside. The research method was carried out in silico using molecular simulation and in vitro with fluorometry (328/552 nm) to test the activity of asiaticoside and madecasoside compounds as well as a mixture of asiaticoside and madecasoside in Centella asiatica plants. This is supported by the docking outcome. The docking results show that madecososide compounds have a gibbs energy close to the positive control aleskiren (-8.356 kcal/mol) and aleskiren (-9.44 kcal/mol). The experiment results showed that the triterpenoid saponin compound (madecassoside) contained an IC value of 0.71, at a concentration of 5 µg/µl, and absorbance of 1.35 A in the first minute. The strongest renin inhibition was Madecasoside compound with a concentration of 5 µg/µl with an average value of fluorescent adsorption and an average percent inhibition of 135% with the best renin inhibition at Madecasoside 5 ug/ul the first minute with absorbance values 1.19 A. Finally, the in silico result corresponded to the in vitro experiment. Centella asiatica plants have renin inhibitor activity as antihypertensive, especially in secondary metabolites of triterpene saponins with pure madecasoside compounds compared with aliskiren as a renin inhibitor. So that the compound madecasoside has renin inhibitor activity as an antihypertensive. [ABSTRACT FROM AUTHOR]

The natriuretic peptide system (NPS) is the key driving force of the heart's endocrine function. Recent developments in NPS-targeted therapies have been found promising and effective against cardiovascular diseases, including hypertension. Notably, after discovering crosstalk between NPS and the renin-angiotensin-aldosterone system (RAAS), various combinations such as neprilysin/angiotensin II receptor type 1 AT 1 receptor inhibitors and neprilysin/renin inhibitors have been preclinically and clinically tested against various cardiac complications. However, the therapeutic effects of such combinations on the pathophysiology of hypertension are poorly understood. Furthermore, the complicated phenomena underlying NPS regulation and function, particularly in hypertension, are still unexplored. Mounting evidence suggests that numerous regulatory mechanisms modulate the expression of NPS, which can be used as potential targets against hypertension and other cardiovascular diseases. Therefore, this review will specifically focus on epigenetic and other regulators of NPS, identifying prospective regulators that might serve as new therapeutic targets for hypertension. More importantly, it will shed light on recent developments in NPS-targeted therapies, such as M-atrial peptides, and their latest combinations with RAAS modulators, such as S086 and sacubitril-aliskiren. These insights will aid in the development of effective therapies to break the vicious cycle of high blood pressure during hypertension, ultimately addressing the expanding global heart failure pandemic. [ABSTRACT FROM AUTHOR]

• Acute kidney injury (AKI) during the aging process is particularly of significant concern. • Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. • Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the AKI risk. Aging-related physiological changes, such as decline in renal function, not only exacerbates pre-existing comorbidities but also escalate the susceptibility to adverse events. Previous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI), and the concomitant use of renin-angiotensin system blockade or diuretics may further potentiate the risk. However, studies evaluating the risk of AKI associated with NSAIDs (including routes, concomitant use of different NSAIDs, categories (traditional NSAIDs or COX-2 inhibitors), and cumulative doses of NSAIDs) are limited, particularly the risk of AKI associated with the dual or triple combination of NSAIDs with renin-angiotensin system blockade (RAS blockades) and/or diuretics. A case-crossover study utilized two sets of longitudinal data from Taiwan's National Health Insurance Research Database (NHIRD). Newly admitted patients with a primary AKI diagnosis were included, with the index date defined as the first admission date. The 1–7 days and 181–187 days prior to the index date served as the case and control periods. Exposure to NSAIDs and co-exposures of RAS blockade and/or diuretics were assessed in both periods. Multivariable conditional logistic regression models, adjusting for potential confounders, estimated adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) for AKI associated with NSAIDs, dual, or triple combinations. Sensitivity analyses explored result robustness by varying case and control period lengths. The study included 1,284 newly diagnosed AKI patients. NSAIDs showed a 3.55-fold increased risk of AKI (aOR: 3.55; 95 % CI 2.70–4.65), with similar risks for traditional NSAIDs and COX-2 inhibitors. Use of multiple NSAIDs, parenteral dosage forms, and higher cumulative doses increased AKI risk. Dual combination with either RAS blockade or diuretics resulted in a 2.90-fold (aOR: 2.90; 95 %CI 1.47–5.70) and 12.68-fold (aOR: 12.68; 95 %CI 6.15–26.12) risk, respectively. The highest risk occurred with triple combination (aOR: 29.22; 95 %CI 12.82–66.64). NSAIDs, including both non-selective NSAIDs and COX2 inhibitors, elevate the risk of AKI. Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the risk, with the latter associated with the highest risk of AKI. [ABSTRACT FROM AUTHOR]

Depression is considered a neuropsychic disease that has global prevalence and is associated with disability. The pathophysiology of depression is not well understood; however, emerging evidence has indicated that neuroinflammation could contribute to developing depression symptoms. One of the factors that have a role in the development of neuroinflammation is the renin–angiotensin system. Therefore, the goal of the current study is to determine the antidepressant-like effects of Aliskiren, a renin inhibitor, against lipopolysaccharide (LPS)-induced depressive-like behavior in mice, glial cell activation, and the upregulation of proinflammatory cytokines in the prefrontal cortex. For behavioral studies, the open field test (OFT), tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT) were used. Inflammatory markers were assessed using real-time polymerase chain reaction (RT-PCR). LPS administration (0.5 mg/kg, intraperitoneal injection (i.p.)) sufficiently reduced the number of crossings in OFT, whereas Aliskiren pretreatment (10 mg/kg, i.p.) attenuated the LPS effect for two hours after LPS injection. The treatments did not show effects on locomotor activity in OFT 24 h after LPS administration. LPS increased the immobility time in TST and FST or reduced sucrose consumption in SPT after 24 h. Aliskiren reversed the effects induced by LPS in TST, FST, and SPT. CD11 b mRNA, a microglial marker, GFAP mRNA, an astroglial marker, and proinflammatory cytokines genes (TNF-α, IL-1β, and IL-6) were upregulated in the prefrontal cortex in LPS exposed animals. However, Aliskiren reduced LPS-induced inflammatory genes in the prefrontal cortex. Hence, the outcomes conclude that Aliskiren prevents depressive illness associated with neuroinflammation in humans. [ABSTRACT FROM AUTHOR]

The renin--angiotensin--aldosterone system (RAAS) cascade has a significant effect on several systems. Angiotensin II (AngII) has appeared as not only a vasoactive peptide but also as a multifunctional cytokine that displays several non-hemodynamic properties beyond renal hemodynamic properties. The kidney includes total components of the RAAS such as aldosterone and AngII not only adjust renal hemodynamics and reabsorption of sodium but also activating various inflammatory and fibrotic responses. Inhibition of the RAAS is one of the most potent methods to impede the development of renal diseases such as chronic kidney disease (CKD) and its related problems such as high blood pressure and heart disorders. Aliskiren, an octanamide, nonpeptide piperidine, orally, active, first commercially available, and direct renin inhibitor (DRI), impedes RAAS and operates by attaching to the active sites of renin and may be effective for the management of renal disease because of blocking the RAAS at its point of start and most sensitive step. Based on numerous studies, aliskiren is the greatest powerful inhibitor of AngII extents among RAAS inhibitors, even though it is unable to prevent the (pro) renin receptor-mediated extracellular signal-regulated kinase 1 and 2 (ERK1/2) activations. In this review, it is described renoprotective effects of aliskiren against different types of nephropathy such as acute kidney injury, diabetic nephropathy, and hypertensive nephropathy. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has urged for the repurposing of existing drugs for rapid management and treatment. Renin inhibitors down regulation of ACE2, which is an essential receptor for SARS-CoV-2 infection that is responsible for COVID-19, in addition to their ability to act as protease inhibitors were encouraging aspects for their investigation as possible inhibitors of main protease of SARS-CoV-2 via computational studies. A Pharmacophore model was generated using the newly released SARS-COV-2 main protease inhibitors. Virtual screening was performed on renin inhibitors, and Drug likeness filter identified remikiren and 0IU as hits. Molecular docking for both compounds showed that the orally active renin inhibitor remikiren (Ro 42–5892) of Hoffmann–La Roche exhibited good molecular interaction with Cys145 and His41 in the catalytic site of SARS-CoV-2 main protease. Molecular dynamics simulation suggested that the drug is stable in the active site of the enzyme. Image 1 • For rapid management of COVID-19, drug repurposing was widely carried out. • Renin inhibitors downregulate ACE2, decreasing the risk of SARS-COV-2 infection. • SARS-COV-2 main protease is a potential target for renin inhibitors. • Pharmacophore model was generated and virtually screened on renin inhibitors. • Remikiren was a hit, furtherly studied through molecular docking and dynamics. [ABSTRACT FROM AUTHOR]

Seven novel potential renin inhibitors, having a structure based on the peptide fragment 8-13 of human angiotensinogen - a natural substrate for renin, have been designed and synthesized. All peptides were obtained by the carbodiimide method in solution and purified by chromatography on the SiO2 column. In P1-P3' positions, they contain esters or N-alkyl amides of modified (3S, 4S)-4-amino-3-hydroxyacids. The achieved inhibitory activity IC50 was of 10-6-10-7M Inhibitory activity of the compounds was measured in vitro by high-performance liquid chromatography (HPLC) determination of lowering the concentration of substrate in the presence of renin and the potential rennin inhibitor. Their resistance to enzymatic degradation was assayed by the determination of stability against chymotrypsin activity. Their hydrophobicity evaluated as a Log P-value was calculated by a computer method. The theoretical binding affinity of thus obtained inhibitors was elaborated based on docking to the S3-S3' pocket of the renin active site. [ABSTRACT FROM AUTHOR]

The recurrence of colorectal liver metastasis (CRLM) following liver resection is common; approximately 40% of patients will experience tumor recurrence post-surgery. Renin-angiotensin inhibitors (RASis) have been shown to attenuate the growth and progression of CRLM in pre-clinical models following liver resection. This study examined the efficacy of the RASi captopril on patient-derived colorectal liver metastasis organoids. Patient-derived organoids (PDOs) were established using fresh samples of colorectal liver metastasis from appropriately consented patients undergoing liver resection. To mimic the regenerating liver post-CRLM liver resection, PDOs were cultured under hepatocyte regeneration conditions in vitro. CRLM PDOs were established from three patients' parent tissue. CRLM PDOs and parent tissue expressed markers of colorectal cancer, CDX2 and CK20, consistently. Furthermore, CRLM PDOs treated with captopril showed a dose dependent reduction in their expansion in vitro. In conclusion, CRLM PDOs recapitulate in vivo disease and displayed a dose-dependent response to treatment with captopril. RASis may be an additional viable treatment for patients with CRLM.

1. The pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, was investigated in rats with subcutaneously injected turpentine oil, which was an inflammation animal model. 2. Following intravenous administration of TAK-272 to the turpentine-treated rats, the systemic clearance and volume of distribution decreased with the elevated plasma a1-acid glycoprotein (AGP) levels. The elevated plasma AGP levels were negatively correlated with the plasma unbound fraction of TAK-272 in the rats. Although the AUCs of total TAK-272 in the turpentine-treated rats were higher than those in the control rats after intravenous and oral administration, those of unbound TAK-272, which seem to directly contribute to the pharmacological effect and safety, were nearly equal between the turpentine-treated and control rats in the respective dose routes. TAK-272 has been shown to primarily bind to AGP in the human plasma. 3. These results strongly suggested that the pharmacokinetic of TAK-272 in humans would also be affected by the variation in the plasma AGP levels and should be discussed with not only the total concentrations but also the unbound concentrations in the clinical trial for patients with elevated plasma AGP levels. [ABSTRACT FROM AUTHOR]

It has been demonstrated that certain angiotensin‐converting enzyme (ACE) inhibitors and angiotensin AT1 receptor antagonists can possess anticonvulsant activity. The purpose of the current study was to examine the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, against pentylenetetrazole (PTZ)‐induced clonic seizures in mice and on the protective activity of conventional antiepileptic drugs (AEDs) in this seizure model. Effects of aliskiren on the PTZ threshold and the protective efficacy of AEDs, such as clonazepam (CLO), phenobarbital (PB), valproate (VPA), and ethosuximide (ETX) in the PTZ test, were evaluated in adult Swiss mice. Aliskiren and AEDs were administered intraperitoneally (i.p.) while PTZ (50–100 mg/kg) was injected subcutaneously (s.c.). The rota‐rod and passive avoidance test were used to assess the adverse effects of the combined treatment with aliskiren and AEDs. Aliskiren, at the dose of 75 mg/kg, significantly raised the PTZ threshold (P < 0.05). Furthermore, aliskiren, at the subthreshold dose of 50 mg/kg, significantly enhanced the protective action of CLO (P < 0.01), PB (P < 0.01), and VPA (P < 0.05) but not ETX (P > 0.05) in the s.c. PTZ test. Motor coordination in the rota‐rod test and long‐term memory in the passive avoidance task were not impaired by the combined treatment of the drugs. This study suggests that treatment with aliskiren can be useful in hypertensive patients with myoclonic seizures. Certainly, a clinical verification of using aliskiren in such patients would be necessary. [ABSTRACT FROM AUTHOR]

Patients with decompensated cirrhosis are at risk of developing acute kidney injury (AKI). Studies have suggested that inhibition of the Renin-Angiotensin System (RAS) has certain nephro- and hepatoprotective effects in patients with compensated liver disease. This study aimed to investigate the clinical impact of RAS-Inhibitors in individuals with decompensated liver cirrhosis. Overall, 1181 consecutive hospitalized patients with ascites that underwent paracentesis were considered for this retrospective study. In total, 667 patients with decompensated cirrhosis fulfilled the inclusion criteria and were finally analyzed. RAS-Inhibitor intake was documented in 41 patients (7%). First, 28-day incidences of AKI and grade III AKI of all patients with RAS-Inhibitors were compared to those without intake. Afterwards, propensity score matching was conducted in a 3:1 manner. Here, incidence of further renal endpoints such as need of hemodialysis were analyzed in detail. In the unmatched setting, intake of RAS-Inhibitors was not associated with an increased 28 day-incidence of AKI (P = 0.76) or LTx-free survival (P = 0.60). However, 28 day-incidence of grade III AKI was significantly lower in patients with RAS-Inhibitor intake (P < 0.001). In the matched setting, 28 day-incidence of AKI did not differ (P = 0.81), while grade III AKI was significantly less frequent in the RAS-Inhibitor group (P < 0.001). Need for hemodialysis was also significantly lower in patients with RAS-Inhibitors (P = 0.03) and LTx-free survival was comparable between both groups (P = 0.52). Thus, this study suggests that intake of RAS-Inhibitors is associated with decreased incidences of grade III AKI and need of hemodialysis in patients with decompensated liver disease., (© 2023. Springer Nature Limited.)

Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative neoplasms (MPNs) characterized by thrombotic and hemorrhagic complications, leading to a high risk of disability and mortality. Although arterial hypertension was found to be the most significant modifiable cardiovascular (CV) risk factor in the general population, little is known about its role in MPNs as well as a possible role of renin-angiotensin system inhibitors (RASi) in comparison with other anti-hypertensive treatments. We investigated a large cohort of 404 MPN adult patients, 133 diagnosed with PV and 271 with ET. Over half of the patients (53.7%) reported hypertension at MPN diagnosis. The 15-year cumulative incidence of thrombotic-adverse events (TAEs) was significantly higher in patients with hypertension (66.8 ± 10.3% vs 38.5 ± 8.4%; HR = 1.83; 95%CI 1.08-3.1). Multivariate analysis showed that PV diagnosis and hypertension were independently associated with a higher risk of developing TAEs (HR = 3.5; 95%CI 1.928-6.451, p < 0.001 and HR = 1.8; 95%CI 0.983-3.550, p = 0.05, respectively). In multivariate analysis, the diagnosis of PV confirmed a significant predictive role in developing TAEs (HR = 4.4; 95%CI 1.92-10.09, p < 0.01), also considering only MPN patients with hypertension. In addition, we found that the use of RASi showed a protective effect from TAEs both in the whole cohort of MPN with hypertension (HR = 0.46; 95%CI 0.21-0.98, p = 0.04) and in the subgroup of thrombotic high-risk score patients (HR = 0.49; 95%CI 0.24-1.01, p = 0.04). In particular, patients with ET and a high risk of thrombosis seem to benefit most from RASi treatment (HR = 0.27; 95%CI 0.07-1.01, p = 0.03). Hypertension in MPN patients represents a significant risk factor for TAEs and should be adequately treated., (© 2023. The Author(s).)

Imarikiren hydrochloride (TAK‐272/SCO‐272) is a novel direct renin inhibitor with potential indications for cardiovascular and renal diseases. This phase I study evaluated the pharmacokinetics, pharmacodynamics and safety of a single oral administration of imarikiren in healthy Japanese male subjects. The Dose‐Ascending part (double‐blind, placebo‐controlled, parallel‐group design; n = 60) comprised six steps from 5 to 200 mg (n = 8 for imarikiren and n = 2 for placebo per step). The Food Effect part (n = 12) was an open‐label, 2 × 2 crossover design with a dose of 50 mg to evaluate the effect of food on the pharmacokinetics and safety of imarikiren. There was a generally linear relationship between dose and area under the plasma concentration–time curve (0 to infinity) or maximum plasma concentration of imarikiren. Food had no clinically significant effect on the exposure of imarikiren. Inhibition of plasma renin activity was rapid and lasted up to 24 hr at all doses. Plasma active renin concentration increased, reaching a maximum at approximately 6 hr, in a nearly dose‐dependent manner. Across both study parts, the number of subjects with treatment‐emergent adverse events ranged from 0 to 3 per group with no dependency on dose. All treatment‐emergent adverse events except two were mild in intensity; there were no serious adverse events or deaths. Single oral administration of imarikiren from 5 to 200 mg was safe and well tolerated. These findings suggest that further clinical development of a once‐daily imarikiren regimen is warranted. [ABSTRACT FROM AUTHOR]

Legumes are rich sources of protein in human diet and their consumption has been associated with the prevention of chronic diseases attributable to their bioactive components. Pigeon pea (Cajanus cajan) is an underutilized legume with relatively high protein content (~24%). Protein hydrolysates were prepared from pea isolate by enzymatic hydrolysis using pepsin and pancreatin. Hydrolysates were evaluated for their amino acid composition, antioxidant properties, in vitro and in vivo antihypertensive properties. The hydrolysates had high hydrophobic amino acids, especially isoleucine, phenylalanine, and leucine. Pepsin‐pancreatin‐hydrolyzed pea protein (PPHPp) showed significantly higher ability to scavenge DPPH˙ while pancreatin‐hydrolyzed pea protein (PPHPa) had higher ˙OH, ABTS˙+ scavenging, Fe3+ reducing and linoleic acid peroxidation inhibition. PPHPp exhibited superior angiotensin‐converting enzyme inhibition (61.82%) while PPHPa showed higher renin inhibition (14.28%). PPHPp exhibited strong antihypertensive effect, showing an instantaneous systolic blood pressure lowering effect (−26.12 mmHg) within 2‐h post‐oral administration. Pigeon pea protein hydrolysate (especially from pancreatin digest) could therefore, be a promising source of bioactive peptides and potential ingredient for formulation of functional foods against oxidative stress and hypertension. Bioactive peptides were obtained from pigeon pea isolate via enzymatic hydrolysis. Pigeon pea peptides showed good inhibitory activity against ACE and renin. Hydrolysates exhibited systolic blood pressure reduction in hypertensive rats. [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]