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This study investigates the characterization, mechanisms of action, structure-activity relationships, and in vivo antihypertensive effects of ACE inhibitory peptides derived from sufu hydrolysate following simulated gastrointestinal digestion. Sufu was enzymatically digested using pepsin, trypsin, and chymotrypsin to mimic gastrointestinal conditions, followed by ultrafiltration to fractionate the peptides based on molecular weight. The fraction under 1 kDa exhibited the highest ACE inhibitory activity. LC-MS/MS analysis identified 119 peptide fragments, with bioinformatics screening highlighting 41 peptides with potential ACE inhibitory properties. Among these, two peptides, AWR and LLR, were selected and synthesized for in vitro validation, displaying IC 50 values of 98.04 ± 2.56 μM and 94.01 ± 5.07 μM, respectively. Stability tests showed that both peptides maintained their ACE inhibitory activity across various temperatures and pH levels. Molecular docking and Highest Occupied Molecular Orbital analysis indicated strong binding interactions between these peptides and ACE, with the second-position tryptophan in AWR and the N-terminal leucine in LLR identified as key bioactive sites. These findings were further supported by molecular dynamics simulations, which confirmed the stability of the peptide-ACE complexes. In vivo studies using spontaneously hypertensive rats demonstrated significant reductions in both systolic and diastolic blood pressure, indicating that AWR and LLR have strong antihypertensive potential. This study illustrates that ultrafiltration, combined with LC-MS/MS and bioinformatics analysis, is an effective approach for the rapid screening of ACE inhibitory peptides. These results not only enhance our understanding of sufu-derived peptides but also offer promising implications for hypertension management.

The study examined the antihypertensive effect of peptides derived from pepsin-hydrolyzed corn gluten meal, namely KQLLGY and PPYPW, and their in silico gastrointestinal tract digested fragments, KQL and PPY, respectively. KQLLGY and PPYPW showed higher angiotensin I-converting enzyme (ACE)-inhibitory activity and lower ACE inhibition constant (K i ) values when compared to KQL and PPY. Only KQL showed a mild antihypertensive effect in spontaneously hypertensive rats with -7.83 and - 5.71 mmHg systolic and diastolic blood pressure values, respectively, after 8 h oral administration. During passage through Caco-2 cells, KQL was further degraded to QL, which had reduced ACE inhibitory activity. In addition, molecular dynamics revealed that the QL-ACE complex was less stable compared to the KQL-ACE. This study reveals that structural transformation during peptide permeation plays a vital role in attenuating antihypertensive effect of the ACE inhibitor peptide., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Angiotensin I-converting enzyme (ACE) regulates blood pressure through the renin-angiotensin system. Douchi, a traditional fermented soybean condiment, may have antihypertensive effects, but research on ACE inhibitory peptides from Douchi hydrolysates is limited. We hypothesized that enzymatic treatment could enhance ACE inhibitory peptide diversity and efficacy. We tested ten single enzymes and four combinations, finding pepsin-trypsin-chymotrypsin most effective. Hydrolysates were purified using Sephadex G-15 and reversed-phase HPLC, and peptides were identified via LC-MS/MS. Five peptides (LF, VVF, VGAW, GLFG, NGK) were identified, with VGAW as the most potent ACE inhibitor (IC 50 46.6 ± 5.2 μM) showing excellent thermal and pH stability. Lineweaver-Burk plots confirmed competitive inhibition, and molecular docking revealed eight hydrogen bonds between VGAW and ACE. In hypertensive rats, VGAW significantly reduced blood pressure at 12.5, 25, and 50 mg/kg. These findings highlight Douchi as a source of ACE inhibitory peptides and suggest VGAW as a promising functional food ingredient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Abnormal glucose metabolism is a common disease of the endocrine system. The effects of drugs on glucose metabolism have been reported frequently in recent years, and since abnormal glucose metabolism increases the risk of microvascular and macrovascular complications, metabolic disorders, and infection, clinicians need to pay close attention to these effects. A variety of common drugs can affect glucose metabolism and have different mechanisms of action. Hypertension is a common chronic cardiovascular disease that requires long-term medication. Studies have shown that various antihypertensive drugs also have an impact on glucose metabolism. Among them, α-receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers can improve insulin resistance, while β-receptor blockers, thiazides and loop diuretics can impair glucose metabolism. The aim of this review was to discuss the mechanisms underlying the effects of various antihypertensive drugs on glucose metabolism in order to provide reference information for rational clinical drug use., (© 2024 John Wiley & Sons Ltd.)

An amaranth beverage (AB) was subjected to a simulated process of dynamic gastrointestinal digestion DIDGI®, a simple two-compartment in vitro dynamic gastrointestinal digestion system. The structural changes caused to the proteins during digestion and the digesta inhibitory capacity of the angiotensin converting enzyme (ACE) were investigated. In gastric compartment the degree of hydrolysis (DH) was 14.7 ± 1.5 % and in the intestinal compartment, proteins were digests in a greater extent (DH = 60.6 ± 8.4 %). Protein aggregation was detected during the gastric phase. The final digesta obtained both at the gastric and intestinal level, showed ACE inhibitory capacity (IC 50 80 ± 10 and 140 ± 20 μg/mL, respectively). Purified fractions from these digesta showed even greater inhibitory capacity, being eluted 2 (E2) the most active fraction (IC 50 60 ± 10 μg/mL). Twenty-six peptide sequences were identified. Six of them, with potential antihypertensive capacity, belong to A. hypochondriacus, 3 agglutinins and 3 encrypted sequences in the 11S globulin. Results obtained provide new and useful information on peptides released from the digestion of an amaranth based beverage and its ACE bioactivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Scope: High blood pressure (BP) is the main preventable risk factor for cardiovascular diseases (CVDs). Much research is aimed at finding natural alternatives to control or prevent hypertension (HT), since some hypertensive patients do not respond to current pharmacological treatments or show undesirable side effects., Methods and Results: Forty relevant articles have been selected from various scientific literature databases. The results reveal that angiotensin-converting enzyme (ACE) inhibition is the most reported mechanism of action of antihypertensive peptides. The active peptides have a great variety of origins. Biopeptides with a molecular weight of <3 kDa, short chain <20 amino acids, and a hydrophobic amino acid sequence at the C- and N-terminus exhibit higher antihypertensive activity. They also show good stability to enzymatic hydrolysis and gastrointestinal digestion, and no toxicity. To determine antihypertensive effectiveness, in vitro and in vivo animal studies are the most frequent developed, with few in silico studies and only one human clinical trial., Conclusion: There is interesting potential for antihypertensive peptides as promising natural candidates for the development of functional foods, nutraceuticals and drugs for preventive or therapeutic treatment of hypertension. The aim of this review is to study the role of food-derived bioactive peptides in HT., (© 2024 Wiley‐VCH GmbH.)

Studies have confirmed that yogurt has the activity of regulating blood pressure because it is rich in probiotic-fermented food-derived active peptides. There are also studies on angiotensin-converting enzyme inhibition (ACEI) peptide milk, but the bioactive molecules in it are still unclear. Therefore, in this study, we developed a peanut yogurt with ACEI activity, analyzed 1877 differential peptides and their antihypertensive pathways before and after fermentation using peptidomics, and identified three peptides (FLPYPY, QPPPSPPPFL and APFPEVFGK) with potential antihypertensive activity using molecular docking and chemical synthesis techniques. These results first elucidated the relationship between peanut yogurt peptides and antihypertensive function, demonstrated the benefits of peanut yogurt, and provided a theoretical basis for the application of probiotic fermented plant yogurt in health care.

As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC 50 1.87 and 2.03 μM, respectively). 17b (IC 50 0.078 μM) and 17 f (IC 50 0.094 μM) inhibited ACE-1 comparable to perindopril (PER) (IC 50 0.048 μM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to  l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME., (© 2024 Wiley Periodicals LLC.)

Hypertension remains a significant global health concern, contributing significantly to cardiovascular diseases and mortality rates. The inhibition of angiotensin-converting enzyme (ACE) plays a crucial role in alleviating high blood pressure. We investigated the potential of finger millets (Eleusine coracana) as a natural remedy for hypertension by isolating and characterizing its ACE-inhibitory compound. First, we evaluated the ACE-inhibitory activity of the finger millet ethanol extract and subsequently proceeded with solvent fractionation. Among the solvent fractions, the ethyl acetate fraction exhibited the highest ACE inhibitory activity and was further fractionated. Using preparative high-performance liquid chromatography, the ethyl acetate fraction was separated into four subfractions, with fraction 2 (F2) exhibiting the highest ACE inhibitory activity. Subsequent 1 H-nuclear magnetic resonance (NMR) and 13 C-NMR analyses confirmed that the isolated compound from F2 was catechin. Furthermore, molecular docking studies indicated that catechin has the potential to act as an ACE inhibitor. These findings suggest that finger millets, particularly as a source of catechin, have the potential to be used as a natural antihypertensive., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown., Methods and Results: In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys., Conclusion: Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks., Competing Interests: Conflict of interest: There are no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The salty oligopeptides from Stropharia rugosoannulata have been proven to be potential ACE inhibitors. To investigate the ACE receptor binding properties and interaction mechanisms of salty oligopeptides, the molecular interaction, dynamics simulation, and antihypertensive evaluation cross-validation strategy were employed to reveal the oligopeptides' binding reactions and modes with the ACE receptor. Single oligopeptide (ESPERPFL, KSWDDFFTR) had exothermic and specific binding reactions with the ACE receptor, driven by hydrogen bonds and van der Waals forces. The coexistence of the multiple oligopeptide molecules did not produce the apparent ACE receptor competition binding reactions. The molecular dynamics simulation verified that the two oligopeptides disturbed the ACE receptor's different residue regions. Both oligopeptides could form stable complexes with the ACE receptor. Based on the classification of 50 oligopeptides' binding modes, ESPERPFL and KSWDDFFTR belonged to different classes, and their receptor binding modes and sites complemented, resulting in a potential synergistic effect on ACE inhibition. The antihypertensive effect of KSWDDFFTR and its distribution in the body were evaluated using SHR rats orally and ICR mice by tail vein injection, and KSWDDFFTR had antihypertensive effects within 8 h. The study provides a theoretical basis for understanding salty oligopeptides' ACE receptor binding mechanism and their antihypertensive effects.

Peptides possessing antihypertensive attributes via inhibiting the angiotensin-converting enzyme (ACE) were derived through the enzymatic degradation of Trichiurus lepturus (ribbonfish) using alkaline protease. The resulting mixture underwent filtration using centrifugation, ultrafiltration tubes, and Sephadex G-25 gels. Peptides exhibiting ACE-inhibitory properties and DPPH free-radical-scavenging abilities were isolated and subsequently purified via LC/MS-MS, leading to the identification of over 100 peptide components. In silico screening yielded five ACE inhibitory peptides: FAGDDAPR, QGPIGPR, IFPRNPP, AGFAGDDAPR, and GPTGPAGPR. Among these, IFPRNPP and AGFAGDDAPR were found to be allergenic, while FAGDDAPRR, QGPIGPR, and GPTGPAGP showed good ACE-inhibitory effects. IC 50 values for the latter peptides were obtained from HUVEC cells: FAGDDAPRR (IC 50 = 262.98 μM), QGPIGPR (IC 50 = 81.09 μM), and GPTGPAGP (IC 50 = 168.11 μM). Peptide constituents derived from ribbonfish proteins effectively modulated ACE activity, thus underscoring their therapeutic potential. Molecular docking and modeling corroborated these findings, emphasizing the utility of functional foods as a promising avenue for the treatment and prevention of hypertension, with potential ancillary health benefits and applications as substitutes for synthetic drugs.

Enzyme-Treated Soymilk (ETS) was produced from Commercial Soymilk (CSM) with the treatment of proteinase PROTIN SD-NY10 (Bacillus amyloliquefaciens). Previously, we have isolated novel peptides from ETS but data related to isolated-peptides are scant. In this study, bio-informatics and in vivo analysis of isolated-peptides showed strong binding affinity to the active site of the Angiotensin Converting Enzyme (ACE). Among four peptides, tetrapeptide Phe-Phe-Tyr-Tyr (FFYY) showed strong binding affinity and inhibitory activity to the ACE-enzyme (binding affinity -9.5 Kcal/mol and inhibitory concentration of 1.9 µM respectively) as well as showed less toxicity compared to other peptides. The animal experiment revealed that single oral dose of FFYY (80 µg/kg body weight/day) effectively ameliorates the systolic, diastolic and mean blood pressure in the spontaneously hypertensive rat (SHR) model. Chronic oral administration of FFYY (80 µg/kg body weight/day for 3 weeks) reduced the systolic blood pressure elevation and ACE activity without any adverse side effects on the physiological and biological parameters of SHR. In conclusion, both in silico and in vivo experiments of soymilk-isolated FFYY peptide showed a promising option as a potential alternative for hypertension treatment without adverse side effects on SHR., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely β-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.

Ethnopharmacological Relevance: Hypertension is the most common and chronic severe health problem globally. Corn silk (CS), the silky fibers of corn (Zea mays L.), has a long history of traditional usage as a remedy for edema and hypertension., Aim of the Study: The aim of the study was to explore the underlying mechanism by which CS exerts its anti-hypertensive effects and investigate the presence of bioactive molecules in CS aqueous extract., Materials and Methods: We analyzed the effects of boiling water extract of CS on angiotensin-converting enzyme (ACE) activities, the critical enzyme involved in the regulation of blood pressure. ACE inhibitory peptides from CS extract were identified using proteomics and bioinformatics tools. The binding interfaces between these peptides and ACE were defined by hydrogen-deuterium exchange mass spectrometry (HDX-MS). Subsequently, the anti-hypertensive effects of peptides were further investigated in spontaneously hypertensive rats (SHR)., Results: Our data showed that CS extract exhibited dose-dependent inhibition of ACE activity. Liquid chromatography-tandem mass spectrometry identified a heat-stable peptide bank with 1313 distinct peptide fragments within the CS boiling water extract. Among these, CS-1 (LVPGWTKPICIGR) was selected through PeptideRanker and BIOPEP-UWM analyses. In vitro ACE inhibitory assays confirmed that CS-1 exhibited dose-dependent ACE inhibition, with IC50 values of 10.32 ± 0.41 μmol/L (using HHL as the substrate) and 13.74 ± 1.87 μmol/L (using ZFHL as the substrate). Oral administration of CS-1 led to a significant dose-dependent reduction in blood pressure, with the maximal decrease (42.33 ± 13.08 mmHg) occurring 0.5 h after ingestion. HDX-MS analysis revealed that CS-1 interacted with the zinc-binding motif of ACE, and hydrogen bond interactions were predicted between CS-1 and specific residues, including His361 in the N-domain, as well as His382, Gly386, and His387 in the C-domain of ACE. These findings suggested that the interaction of CS-1 with the residues in the zinc-binding motif of ACE led to ACE activity inhibition and a subsequent decrease in blood pressure in rats., Conclusions: A novel heat-stable ACE inhibitory peptide, which interacted with the zinc-binding motif of ACE and reduced blood pressure in SHR, was identified in the CS extract. The presence of ACE inhibitory peptides in the CS extract supports its traditional use in ethnopharmacology for hypertension., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Moxonidine, an imidazoline I 1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic., Aims: This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes., Methods: Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment., Results: Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average -3.5 bpm, p  = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters., Conclusion: Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PV discloses the following potential conflicts of interest: lectures for Abbott, AstraZeneca, Bayer, Eli Lilly, Hikma Pharmaceuticals, Merck Sharp & Dohme, Novo Nordisk, Novartis, Pfizer, Sanofi, Servier; research grants from Abbott, Bristol-Myers Squibb–AstraZeneca, Novo Nordisk; participation in expert committees for AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, Servier.

Objective: The goal of this research was to purify and characterize the novel angiotensin-converting enzyme (ACE)-inhibitory and antioxidant peptides from fermented whey protein concentrate produced by Lactobacillus paracasei and Saccharomyces cerevisiae in a co-fermentation system., Method: Whey protein fermented with lactic acid bacteria and yeast culture was analyzed for antioxidative, ACE inhibition, as well as anti-inflammatory activity followed by SDS-PAGE, isoelectric focusing, and 2-dimensional (2D) analysis. Anti-inflammatory activity of whey protein fermentate was also studied on the RAW 264.7 cell line. The bioactive peptides were separated from the whey protein fermentate using reverse-phase high-performance liquid chromatography (RP-HPLC) and reverse-phase liquid chromatography mass spectrometry (RPLC/MS), and thus identification and characterization of purified bioactive peptide was performed., Results: Whey protein fermentate samples' bioactivity was analyzed at specific time intervals at 12, 24, 36, and 48 hours at 37 °C for M11 and at 25 °C for WBS2A. The development settings (incubation time [12, 24, 36, and 48 hours) and inoculation rates [1.5%, 2.0%, and 2.5%]) were optimized for peptide synthesis via the o-phthaldialdehyde (OPA) method (proteolytic activity). Maximum proteolytic activity was observed at 37 °C for M11 (6.50 mg/mL) and at 25 °C for WBS2A (8.59 mg/mL) for 48 hours of incubation. Protein profiling was carried out using SDS-PAGE and 2D gel electrophoresis, in which Sodium dodecyl-sulfate (SDS) exhibited protein bands in the 10- to 55-kDa range, while 2D showed protein bands varying from 10 to 70 kDa. Every spot from 2D was digested by trypsin and identified by RPLC/MS. Protein fractionations (3- and 10-kDa permeates) were carried out employing RP-HPLC. Whey protein fermentate has anti-inflammatory action in RAW 264.7 macrophages that have been exposed to lipopolysaccharide. A molecular docking system was also used to investigate the interactions of peptides (AFLDSRTR, ILGAFIQIITFR) with human myeloperoxidase enzyme., Conclusions: The antihypertensive and antioxidative peptides discovered from whey protein fermentate may be helpful in the design of pharmacologically active healthy ingredients in the upcoming years.

Consumption of legumes has been shown to enhance health and lower the risk of cardiovascular disease and specific types of cancer. ACE inhibitors, antioxidants, and synthetic anti-inflammatories are widely used today; however, they have several undesirable side effects. Thus, researchers have focused on finding ACE inhibitors, antioxidant, and anti-inflammatory peptides from natural sources, such as legumes. Recently, in vitro and in vivo research has shown the bioactive peptides generated from legume protein hydrolysates, such as antioxidant, anti-hypertensive, anticancer, anti-proliferative, anti-inflammatory, etc., in the context of different disease mitigation. Therefore, this review aims to describe the recent advances in in vitro and in vivo studies of antioxidant, anti-hypertensive and anti-inflammatory peptides isolated from legume-derived protein hydrolysates. The results indicated that antioxidant legumes peptides are characterized by short-chain sequence amino acids and possess anti-hypertensive properties by reducing systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR).

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

The authors performed a meta-analysis to assess the efficacy of non-atenolol β-blockers as add-on to monotherapy or as a component of combination antihypertensive therapy in patients with hypertension. The authors searched and identified relevant randomized controlled trials from PubMed until November 2021. Studies comparing blood pressure lowering effects of β-blockers with diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) were included. The analysis included 20 studies with 5544 participants. β-blockers add-on to monotherapy significantly reduced systolic and diastolic blood pressure as compared with non-β-blocker monotherapy (weighted mean difference in mm Hg [95% confidence interval]: -4.1 [-6.0, -2.2] and -3.7 [-4.6, -2.8], respectively). These results were consistent across the comparisons with diuretics (systolic pressure, -10.2 [-14.2, -6.2]; diastolic pressure, -5.4 [-8.2, -2.6]), CCBs (systolic pressure, -4.1 [-7.1, -1.0]; diastolic pressure, -2.8 [-4.1, -1.5]), and ACEIs/ARBs (systolic pressure, -2.9 [-4.3, -1.5]; diastolic pressure, -4.2 [-5.0, -3.4]). There was no significant difference in blood pressure lowering effects between combinations with and without a β-blocker (systolic pressure, -1.3 mm Hg [-5.8, 3.2]; diastolic pressure, -.3 mm Hg [-2.7, 2.1]). Metoprolol add-on or combination therapy had a significantly greater blood pressure reduction than non-β-blocker therapy (systolic pressure, -3.6 mm Hg [-5.9, -1.3]; diastolic pressure, -2.1 mm Hg [-3.5, -.7]). In conclusion, non-atenolol β-blockers are effective in lowering blood pressure as add-on to monotherapy or as a component of combination antihypertensive therapy. In line with the current hypertension guideline recommendations, β-blockers can and should be used in combination with other antihypertensive drugs., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

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

Angiotensin-converting enzyme inhibitors are widely used for treatment of hypertension and related diseases. Here, six karnamicins E 1 -E 6 (1-6), which bear fully substituted hydroxypyridine and thiazole moieties are characterized from the rare actinobacterium Lechevalieria rhizosphaerae NEAU-A2. Through a combination of isotopic labeling, genome mining, and enzymatic characterization studies, the programmed assembly of the fully substituted hydroxypyridine moiety in karnamicin is proposed to be due to sequential operation of a hybrid polyketide synthase-nonribosomal peptide synthetase, two regioselective pyridine ring flavoprotein hydroxylases, and a methyltransferase. Based on AlphaFold protein structures predictions, molecular docking, and site-directed mutagenesis, we find that two pyridine hydroxylases deploy active site residues distinct from other flavoprotein monooxygenases to direct the chemo- and regioselective hydroxylation of the pyridine nucleus. Pleasingly, karnamicins show significant angiotensin-converting enzyme inhibitory activity with IC 50 values ranging from 0.24 to 5.81 μM, suggesting their potential use for the treatment of hypertension and related diseases., (© 2023. The Author(s).)

Background: Elevated blood pressure (BP) was associated with higher risk of heart failure, but the relationship between BP-lowering via antihypertensive drugs and diminution of heart failure was inconclusive. This study aimed to estimate the causal association of BP with heart failure, and explore the effects of BP-lowering through different antihypertensive drug classes on heart failure risk using Mendelian randomization analysis with genetic variants as instrument variables., Methods: Genetic variants associated with BP were derived from UK Biobank ( n  = 317 754) and the genome-wide association study (GWAS) meta-analysis of UK Biobank and International Consortium of Blood Pressure ( n  = 757 601). Heart failure summary association data were contributed by HERMES Consortium (47 309 heart failure cases and 930 014 controls). Inverse variance weighted (IVW) was performed to estimate causality between exposure and outcome, and weighted median was utilized as sensitivity analysis, and Mendelian randomization-Egger regression was used to identify pleiotropy of instrument variables. Multivariable Mendelian randomization (MVMR) was applied to control for the confounders., Results: Genetically predicted SBP and DBP were associated with heart failure [SBP: odds ratio (OR) = 1.355, 95% confidence interval (CI) 1.201-1.529; DBP: OR = 1.348, 95% CI 1.213-1.498] in UK Biobank. Likewise, in the GWAS meta-analysis of UK Biobank and International Consortium of Blood Pressure, the causal associations were observed between SBP, DBP and heart failure (SBP: OR = 1.237, 95% CI 1.188-1.289; DBP: OR = 1.337, 95% CI 1.245-1.437). Genetically determined β-blockers and calcium channel blockers (CCBs) were associated with lower risk of heart failure (β-blockers: OR = 0.617, 95% CI 0.453-0.839; CCBs: OR = 0.730, 95% CI 0.625-0.851). No association was found between angiotensin receptor blockers (ARBs) and heart failure (OR = 1.593, 95% CI 0.647-3.924). When adjusted for smoking, alcohol, physical activity, fruit and vegetable intake, the results were stable., Conclusion: Our study indicates causal associations between SBP, DBP, and heart failure, and suggests the preventive effects of heart failure by BP-lowering using β-blockers and CCBs., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Hypertension, defined as persistent systolic blood pressure (SBP) at least 130 mm Hg or diastolic BP (DBP) at least 80 mm Hg, affects approximately 116 million adults in the US and more than 1 billion adults worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death., Observations: First-line therapy for hypertension is lifestyle modification, including weight loss, healthy dietary pattern that includes low sodium and high potassium intake, physical activity, and moderation or elimination of alcohol consumption. The BP-lowering effects of individual lifestyle components are partially additive and enhance the efficacy of pharmacologic therapy. The decision to initiate antihypertensive medication should be based on the level of BP and the presence of high atherosclerotic CVD risk. First-line drug therapy for hypertension consists of a thiazide or thiazidelike diuretic such as hydrochlorothiazide or chlorthalidone, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker such as enalapril or candesartan, and a calcium channel blocker such as amlodipine and should be titrated according to office and home SBP/DBP levels to achieve in most people an SBP/DBP target (&lt;130/80 mm Hg for adults &lt;65 years and SBP &lt;130 mm Hg in adults ≥65 years). Randomized clinical trials have established the efficacy of BP lowering to reduce the risk of CVD morbidity and mortality. An SBP reduction of 10 mm Hg decreases risk of CVD events by approximately 20% to 30%. Despite the benefits of BP control, only 44% of US adults with hypertension have their SBP/DBP controlled to less than 140/90 mm Hg., Conclusions and Relevance: Hypertension affects approximately 116 million adults in the US and more than 1 billion adults worldwide and is a leading cause of CVD morbidity and mortality. First-line therapy for hypertension is lifestyle modification, consisting of weight loss, dietary sodium reduction and potassium supplementation, healthy dietary pattern, physical activity, and limited alcohol consumption. When drug therapy is required, first-line therapies are thiazide or thiazidelike diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blockers, and calcium channel blockers.

Previous work has shown that egg white-derived peptide QIGLF has significant in vivo antihypertensive activity. This study aimed to clarify the antihypertensive mechanisms of QIGLF on spontaneously hypertensive rats (SHRs) by a serum proteomic approach. Here, the tandem mass tag (TMT) quantitative proteomic was performed to discover serum protein changes in SHRs with QIGLF. As a result, SHRs with 4 weeks of QIGLF treatment have distinct serum protein expression profiles by principal component and Pearson's correlation coefficient analysis. Based on Gene Ontology (GO) annotation, oxygen transport and organelle fusion were found to be a regulated major biological process. Besides, aldosterone regulated sodium reabsorption, mitophagy, gap junction, and tight junction were significantly regulated based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. QIGLF might exert antihypertensive effects in the SHRs by inhibiting Na + reabsorption and oxidative stress, restoring gap junction and tight junction., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

VGINYW is a highly active angiotensin I-converting enzyme (ACE) inhibitory peptide discovered from α-lactalbumin by an in vitro - in silico high throughput screening strategy. The aim of this study was to evaluate the antihypertensive effect of the peptide and the α-lactalbumin hydrolysates under 3 kDa (LH-3k), and illustrate the possible mechanism in spontaneously hypertensive rats (SHRs). SHRs were administered with VGINYW and LH-3k at doses of 5 mg per kg BW and 100 mg per kg BW, respectively. VGINYW and LH-3k could markedly decrease the systolic blood pressure (SBP) of the SHRs, and the maximal drops of 21 mmHg (2 h after administration) and 17 mmHg (4 h after administration) were achieved during the 8 hour test, respectively. When the agents were given once per day for 4 weeks, they caused a long-term decrease of 16 mmHg of SBP. VGINYW and LH-3k control the blood pressure through regulating the renin-angiotensin system by inhibiting the ACE activity and diminishing the angiotensin II level, and further upregulating the expression levels of the angiotensin-converting enzyme 2 and angiotensin type 2 receptor, and downregulating the expression of the angiotensin type 1 receptor. VGINYW and LH-3k could notably ameliorate the oxidative stress in the SHR as well. It is more important that the gavage of VGINYW and LH-3k could alleviate hypertension-associated intestinal microbiota dysbiosis by recovering the diversity of the gut microbiota and altering the key floras which are short chain fatty acid producers. In conclusion, VGINYW and LH-3k are effective functional ingredients for blood pressure control.

Blood pressure control, which can induce a slight decrease in the glomerular filtration rate (GFR), plays a nephron- and cardioprotective role. However, the more important early decline in GFR associated with antihypertensive therapy and strict blood pressure targets is still of concern. Since few data are available from trials and observational studies, and the phenomenon is relatively rare, we performed a meta-analysis of available studies. We conclude that major reductions in the glomerular filtration rate occurring soon after starting angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and/or under intensive blood pressure control predict end-stage kidney disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Certain classes of antihypertensive drug may exert specific, blood pressure (BP)-independent protective effects on end-organ damages such as left ventricular hypertrophy, although the overall evidence has not been definitive in clinical trials. To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains (ie, hypertensive and normotensive) of rats. We chose 6 antihypertensive classes: enalapril (angiotensin-converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating β-blocker), and hydralazine. In the tested rat strains, 4 of 6 drugs, including 2 renin-angiotensin system inhibitors, were effective for BP lowering, whereas the remaining 2 drugs were not. Besides BP lowering, there appeared to be some interdrug heterogeneity in phenotypic changes, such as suppressed body weight gain and body weight-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by renin-angiotensin system blockade, for example, for genes in the natriuretic peptide system ( Nppb and Corin ) in the heart and for those in the renin-angiotensin system/kallikrein-kinin system ( Ren and rat Klk1 paralogs) and those related to calcium ion binding ( Calb1 and Slc8a1 ) in the kidney. The research resources constructed here will help corroborate occasionally inconclusive evidence in clinical settings.

Background: Bradykinin-potentiating peptides (BPPs) are snake venom peptides inhibiting the angiotensin-converting enzyme (ACE). ACE plays an important role in the regulation of blood pressure. BPPs lead to the development of ACE inhibitors for the treatment of hypertension., Objective: The objective of the present work was to carry out a comprehensive comparative study of four synthesised snake venom BPPs in vivo., Methods: Four synthesised snake venom BPPs were administered to rats via the intraperitoneal route for 15 days at a fixed dose. Lisinopril was used as a comparative standard. Thirty male albino rats were divided into six groups: A, B, C, D, E (lisinopril), and F (control). Group F was maintained as the control group and given only saline. After 15 days, blood samples and tissues were removed for the study of selective biochemical parameters and histomorphometric analysis. Statistical evaluation of all results was also performed., Results: The results indicated that peptide I, with the sequence ZSAPGNEAIPP, was highly toxic and adversely affected all the biochemical and histological parameters studied in this work. Peptide II (ZNWPHPQIPP) and peptide IV (ZQWAQGRAPHPP) showed lower toxicity. None of the BPPs raised the serum creatinine level and exhibited nephroprotective effects. Although lisinopril raised the creatinine level, it showed a protective role towards the pancreas and lungs in parallel., Conclusion: The present work shows that although there is a high sequence similarity between the four BPPs, their in vivo activity varies. The sequences of peptide II and peptide IV can be used to improve the design of current ACE inhibitors used for hypertension treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Food proteins are sources for ACE-I inhibitory peptides that can be extracted by enzymatic hydrolysis exhibiting anti-hypertensive activity. However, these peptides are prone to further degradation by gastrointestinal enzymes during oral consumption. Bio-activity of these peptides is dependent on the resultant peptide post gastrointestinal digestion. To exhibit the bio-activity, they need to be absorbed in intact form. Although studies suggest di and tri-peptides show better ACE-I inhibitory activity, few peptides show altered IC 50 values under simulated gastrointestinal digestion. Moreover, ACE-I inhibitory peptides with low IC 50 values have not shown effective anti-hypertensive activity in spontaneously hypertensive rats when administered orally. Few ACE-I inhibitory peptides have reported effective reduction in systolic blood-pressure when administered through intravenously. During oral consumption of such peptides, the actual peptide sequence responsible for reducing blood-pressure is a result of breakdown in gastrointestinal tract. The fate of targeted peptides during digestion depends on amino acid sequence of the protein containing the specific site for cleavage where the action of digestive enzymes takes place. Therefore, this review attempts to explain the factors that affect the anti-hypertensive activity of ACE-I inhibitory peptides during oral consumption. It also highlights subsequent absorption of ACE-I inhibitory peptides after gastrointestinal digestion.

Angiotensin I-converting enzyme (ACE) catalyses the biosynthesis of angiotensin II, a potent blood vessel constrictor, from angiotensin I, and ACE inhibitors were recognised as medications for hypertension. Undescribed bis- γ -pyrone polypropionate compounds, callypyrones A and B were purified from the organic extract of Callyspongiidae sponge species Callyspongia diffusa by repeated chromatographic purification. Callypyrone A exhibited significantly greater attenuation potential against ACE (IC 50 0.48 mM) than that displayed by callypyrone B (IC 50 0.57 mM) and showed comparable activity with standard ACE inhibitor captopril (IC 50 0.36 mM). Higher electronic parameters of callypyrone A (topological surface area of 108.36) combined with balanced hydrophilic-lipophilic parameter (octanol-water coefficient, log P ow 1.9), as deduced from the structure-activity relationship analyses, could further indicate the improved ligand-receptor interactions resulting in its prospective ACE inhibitory activity. In silico docking analyses of the callypyrones with ACE recorded lowest binding energy (-12.58 kcal mol -1 ) for callypyrone A, which further supported the antihypertensive potential of the compound.

Bioactive peptides exhibiting angiotensin-converting enzyme (ACE) inhibitory effects and extracted from natural foods have potential as healthy and safe therapeutics for high blood pressure. The aim of this study was to isolate and purify ACE inhibitory peptides from rabbit meat protein hydrolysate, to explore the underlying mechanisms by molecular docking, and to evaluate the antihypertensive effects in vivo . A novel ACE inhibitory tetrapeptide Trp-Gly-Ala-Pro (WGAP) was identified and purified from a bromelain hydrolysate. WGAP acted against ACE in a non-competitive manner with an IC 50 of 140.70 ± 4.51 μM. It was resistant to enzymatic degradation by pepsin and trypsin in vitro . Molecular docking analysis indicated that WGAP formed stable hydrogen bonds with ACE residues His353, Ala354 and ALA356. In vivo , 100 mg kg -1 WGAP significantly reduced systolic and diastolic blood pressure in hypertensive rats by up to 42.66 ± 2.87 and 28.56 ± 2.71 mmHg, respectively, 4 h after oral administration. ACE inhibitory peptides derived from rabbit meat have potential antihypertensive effects and provide a new route for the exploration of novel hypertension inhibitors and the utilization of rabbit meat.

Hypertension has been recognized as one of the most frequent comorbidities and risk factors for the seriousness and adverse consequences in COVID-19 patients. 3,4-dihydropyrimidin-2(1H) ones have attracted researchers to be synthesized via Beginilli reaction and evaluate their antihypertensive activities as bioisosteres of nifedipine a well-known calcium channel blocker. In this study, we report synthesis of some bioisosteres of pyrimidines as novel CCBs with potential ACE2 inhibitory effect as antihypertensive agents with protective effect against COVID-19 infection by suppression of ACE2 binding to SARS-CoV-2 Spike RBD. All compounds were evaluated for their antihypertensive and calcium channel blocking activities using nifedipine as a reference standard. Furthermore, they were screened for their ACE2 inhibition potential in addition to their anti-inflammatory effects on LPS-stimulated THP-1 cells. Most of the tested compounds exhibited significant antihypertensive activity, where compounds 7a, 8a and 9a exhibited the highest activity compared to nifedipine. Moreover, compounds 4a,b, 5a,b, 7a,b, 8a,c and 9a showed promising ACE2:SARS-CoV-2 Spike RBD inhibitory effect. Finally, compounds 5a, 7b and 9a exerted a promising anti-inflammatory effect by inhibition of CRP and IL-6 production. Ultimately, compound 9a may be a promising antihypertensive candidate with anti-inflammatory and potential efficacy against COVID-19 via ACE2 receptor inhibition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The angiotensin-converting enzyme (ACE) inhibitory peptide QIGLF derived from egg white was shown to have significant in vivo antihypertensive effects in our previous study, but the intervention mechanisms at the metabolic level are still unclear. The UPLC-QTOF/MS-based untargeted metabolomics approach was used to clarify the potential antihypertensive mechanisms of QIGLF in the serum of spontaneously hypertensive rats (SHRs). Multivariate statistical analysis showed a clear difference in the metabolite profiles between the QIGLF and model groups. The results suggested that eight potential biomarkers were identified, that is, adrenic acid, ursodeoxycholic acid, glycocholic acid, taurocholic acid, tryptophan, acetylindoxyl, tyrosine, and 2-phenylethanol, which were mainly involved in aromatic amino acid biosynthesis and metabolism, biosynthesis of bile acid, and biosynthesis of unsaturated fatty acids. QIGLF might exert antihypertensive effects by improving endothelial dysfunction. This study provides a theoretical basis for future research and application of ACE inhibitory peptides in the prevention and improvement of hypertension.

Objectives: Considering the complementary nature of signalling mechanisms and the therapeutic effects of nebivolol, a β1-adrenoreceptor antagonist, and valsartan, an angiotensin receptor blocker (ARB), here we aimed to investigate whether nebivolol/valsartan combination would complement the cardioprotective effects of nebivolol on angiotensin II (ANG II)-induced pathology in H9c2 cardiomyoblasts., Methods: H9c2 cardiomyoblasts were used to investigate the protective effects of nebivolol and nebivolol and valsartan combination against ANG II-induced pathology. Reactive oxygen species (ROS) generation was determined by 2',7'-dichlorofluorescein diacetate (DCFDA) and MitoSOX Red staining. Real-time PCR and immunoblotting were employed to quantify the changes in mRNA and protein expression levels, respectively., Key Findings: Our data revealed that pretreatment with nebivolol and nebivolol/valsartan combination significantly reduced ANG II-induced oxidative stress and mTORC1 signalling. Concurrently, ANG II-induced activation of inflammatory cytokines and fetal gene expressions were significantly suppressed by nebivolol and nebivolol/valsartan combination. Pretreatment with nebivolol and nebivolol/valsartan combination alleviated ANG II-induced impairment of mitochondrial biogenesis by restoring the gene expression levels of PGC-1α, TFAM, NRF-1 and SIRT3. Our data further show that nebivolol and nebivolol/valsartan combination mediated up-regulation in mitochondrial biogenesis is accompanied by decrease in ANG II-stimulated mitochondrial ROS generation as well as increase in expression of mitochondrial fusion genes MFN2 and OPA1, indicative of improved mitochondrial dynamics., Summary: These findings suggest that both nebivolol and nebivolol/valsartan combination exert protective effects on ANG II-induced mitochondrial dysfunction by alleviating its biogenesis and dynamics. Moreover, addition of valsartan to nebivolol do not produce any additive effects compared with nebivolol alone on ANG II-induced cardiac pathology., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

[Figure: see text].

Angiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models., (© 2021. The Author(s).)

[Figure: see text].

The present study investigates the chemical composition, anti-inflammatory, and antihypertensive activities, in vitro, from extracts of Cuphea lindmaniana and Cuphea urbaniana leaves. The extraction was performed ultrasound-assisted, and UHPLC/MS analysis was in positive mode ionization. The anti-inflammatory activity of the extracts and miquelianin were assayed at concentrations 0.001-10 μg/mL by chemotaxis on rat polymorphonuclear neutrophils. The antihypertensive activity was performed by angiotensin-converting enzyme (ACE) inhibition. From the nineteen proposed compounds, six of them are described for the first time in this genus. The extracts displayed antichemotactic effect with a reduction of 100 % of the neutrophil migration, in vitro, in most concentrations. The ACE-inhibition presented results ranging from 19.58 to 22.82 %. In conclusion, C. lindmaniana and C. urbaniana extracts contain a rich diversity of flavonoids and display in vitro anti-inflammatory and antihypertensive potential. Thus, this study could serve as a scientific baseline for further investigation, on developmental novel products with therapeutic actions., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

This study aimed to assess the biological properties of peptide fractions isolated from dried fermented dairy products (jameed) as influenced by processing. Peptide fractions were separated by reversed-phase high-performance liquid chromatography (RP-HPLC) from salted (Sa) and unsalted (Us) cow milk jameed after drying the fermented curd by sun drying (Sd) or freeze-drying (Fd) and were characterized for their antioxidant capacity and inhibitory activity toward angiotensin I-converting enzyme (ACE) and α-amylase. Sd samples showed more numerous peptide peaks in RP-HPLC chromatograms than Fd samples, regardless of the salt content. High antioxidant activity was evidenced in several peptide fractions from FdUs jameed (including fractions 1, 2, 4, 7, 8, 9, and 10), SdUs jameed (1, 2, 5, 7, and 9), and FdSa jameed (2, 5, 6, and 9). By contrast, peptide fractions from SdSa (1, 2, 3, 5, 8, and 9), SdUs (4, 5, and 10), and FdUs (5, 6, and 8) jameed displayed the highest ACE inhibitory activity. Similarly, the highest inhibition of α-amylase was obtained with fractions from SdSa (1, 2, 3, 4, 5, 6, 8, and 9), SdUs (2 and 6), and FdUs (1, 7 and 9) jameed. A significant negative correlation was evidenced between antioxidant activity and anti-α-amylase activity of peptide fractions from SdSa jameed. These findings demonstrate that cow milk jameed is a source of bioactive peptides with antioxidant, anti-ACE, and anti-α-amylase properties in vitro, which can be tailored by adjusting the salt content and the drying conditions. PRACTICAL APPLICATION: This study shows that cow milk jameed, a staple fermented food in several Mediterranean countries, can serve as a useful source of multifunctional bioactive peptides with potential antioxidant, hypotensive, and hypoglycemic effects, which may help prevent and manage chronic health conditions such as hypertension, type 2 diabetes, and the metabolic syndrome. The bioactivities of certain peptide fractions were enhanced by lowering the salt content of jameed or by the drying method. The relatively simple RP-HPLC method described in this study can be used to isolate the peptide fractions of interest for further characterization and use as functional ingredients., (© 2021 Institute of Food Technologists®.)

Fish discards and by-products can be transformed into high value-added products such as fish protein hydrolysates (FPH) containing bioactive peptides. Protein hydrolysates were prepared from different parts (whole fish, skin and head) of several discarded species of the North-West Spain fishing fleet using Alcalase. All hydrolysates had moisture and ash contents lower than 10% and 15%, respectively. The fat content of FPH varied between 1.5% and 9.4% and had high protein content (69.8-76.6%). The amino acids profiles of FPH are quite similar and the most abundant amino acids were glutamic and aspartic acids. All FPH exhibited antioxidant activity and those obtained from Atlantic horse mackerel heads presented the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, reducing power and Cu 2+ chelating activity. On the other hand, hydrolysates from gurnard heads showed the highest ABTS radical scavenging activity and Fe 2+ chelating activity. In what concerns the α-amylase inhibitory activity, the IC 50 values recorded for FPH ranged between 5.70 and 84.37 mg/mL for blue whiting heads and whole Atlantic horse mackerel, respectively. α-Glucosidase inhibitory activity of FPH was relatively low but all FPH had high Angiotensin Converting Enzyme (ACE) inhibitory activity. Considering the biological activities, these FPH are potential natural additives for functional foods or nutraceuticals.

Importance: Observational studies have reported associations between antihypertensive medication and psychiatric disorders, although the reported direction of association appears to be dependent on drug class., Objective: To estimate the potential effect of different antihypertensive drug classes on schizophrenia, bipolar disorder, and major depressive disorder., Design, Setting, and Participants: This 2-sample mendelian randomization study assessed the association between a single-nucleotide variant (SNV) and drug target gene expression derived from existing expression quantitative trait loci (eQTL) data in blood (sample 1) and the SNV-disease association from published case-control genome-wide association studies (sample 2). Significant associations were corroborated using published brain eQTL and protein QTL data. Participants included 40 675 patients with schizophrenia and 64 643 controls, 20 352 patients with bipolar disorder and 31 358 controls, and 135 458 patients with major depressive disorder and 344 901 controls. Blood eQTL levels were measured in 31 684 individuals from 37 cohorts (eQTLGen consortium); prefrontal cortex eQTLs were measured from the PsychENCODE resource in 1387 individuals; and protein QTLs were measured in cerebral spinal fluid from 544 individuals and plasma from 818 individuals. Data were collected from October 4, 2019, to June 1, 2020, and analyzed from October 14, 2019, to June 6, 2020., Exposures: Expression levels of antihypertensive drug target genes as proxies for drug exposure, and genetic variants robustly associated with the expression of these genes as mendelian randomization instruments., Main Outcomes and Measures: Risk for schizophrenia, bipolar disorder, and major depressive disorder., Results: A 1-SD lower expression of the angiotensin-converting enzyme (ACE) gene in blood was associated with lower systolic blood pressure of 4.0 (95% CI, 2.7-5.3) mm Hg, but increased risk of schizophrenia (odds ratio [OR], 1.75; 95% CI, 1.28-2.38; P = 3.95 × 10-4). A concordant direction of association was also observed between ACE expression in prefrontal cortex (OR, 1.33; 95% CI, 1.13-1.56) and ACE protein levels in cerebral spinal fluid (OR per 1-SD decrease, 1.12; 95% CI, 1.05-1.19) and plasma (OR per 1-SD decrease, 1.04; 95% CI, 1.01-1.07). We found no evidence for an association between genetically estimated SBP and schizophrenia risk., Conclusions and Relevance: Findings suggest an adverse association of lower ACE messenger RNA and protein levels with schizophrenia risk. These findings warrant greater pharmacovigilance and further investigation into the effect of ACE inhibitors, particularly those that are centrally acting, on psychiatric symptoms in patients with schizophrenia, as well as the role of ACE inhibitor use in late-onset schizophrenia.

The major anti-hypertensive (AHT) drug classes have been associated with differential risks of psychiatric disorders. However, existing data are limited largely to depression, and confounding variables have not always been controlled for. We sought to fill the evidence gap, using TriNetX Analytics, an electronic health records network. Amongst 58.6 million patients aged 18-90 years, patients prescribed a calcium channel blocker (CCB) were compared with those taking a diuretic, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or β-blocker. Cohorts were propensity score-matched for age, sex, race, and blood pressure. Over a 2-year exposure period, we measured the incidence and risk ratio of a first diagnosis (ICD-10 codes), or a recurrence, of psychotic, affective, and anxiety disorders, as well as substance use disorders and sleep disorders. Cohort sizes ranged from 33,734 to 322,814. CCBs were associated with a lower incidence of psychotic, affective, and anxiety disorders than β-blockers (risk ratios 0.69-0.99) and a higher incidence than ARBs (risk ratios 1.04-2.23) for both first and recurrent diagnoses. Comparisons of CCBs with ACEIs or diuretics showed smaller risk ratios that varied between disorders, and between first episode and recurrence. AHT classes were also associated with the incidence of substance use and sleep disorders. Results remained largely unchanged after more extensive cohort matching for additional potential confounders. In a secondary analysis, a comparison between ARBs and ACEIs showed lower rates of psychotic, affective, and substance use disorders with ARBs, but higher risks of anxiety and sleep disorders. In conclusion, AHT classes are differentially associated with the incidence of psychiatric disorders. ARBs show the most advantageous profile and β-blockers the least. The apparent beneficial effects of ARBs merit further study.

Abstract: This study aimed to determine if açai seed extract (ASE) could reverse pre-existing cardiovascular and renal injury in an experimental model of renovascular hypertension (2 kidney, 1 clip, 2K1C). Young male rats (Wistar) were used to obtain 2K1C and sham groups. Animals received the vehicle, ASE (200 mg/kg/d), or enalapril (30 mg/kg/d) in drinking water from the third to sixth week after surgery. We evaluated systolic blood pressure by tail plethysmography, vascular reactivity in the rat isolated mesenteric arterial bed (MAB), serum and urinary parameters, plasma inflammatory cytokines by ELISA, MAB expression of endothelial nitric oxide synthase and its active form peNOS by Western blot, plasma and MAB oxidative damage and antioxidant activity by spectrophotometry, and vascular and cardiac structural changes by histological analysis. ASE and enalapril reduced the systolic blood pressure, restored the endothelial and renal functions, and decreased the inflammatory cytokines and the oxidative stress in 2K1C rats. Furthermore, both treatments reduced vascular and cardiac remodeling. ASE substantially reduced cardiovascular remodeling and recovered endothelial dysfunction in 2K1C rats probably through its antihypertensive, antioxidant, and anti-inflammatory actions, supplying a natural resource for the treatment of renovascular hypertension., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Since not all proteins are suitable for preparing bioactive peptides by enzymatic degradation, the purpose of this study is to evaluate the necessity of walnut protein (WP) enzymolysis to exert its potential antihypertensive activity. Five proteases were used to hydrolyze WP to produce WP hydrolysate (WPH) enzymatically. The angiotensin-I-converting enzyme (ACE) inhibitory activity of WP and WPH before and after simulated digestion in vitro was measured, and the antihypertensive effect was evaluated in vivo. The results showed that after simulated digestion in vitro, the ACE inhibitory activity of WP digests (44.85%) was not significantly different from that of WPH digests (p > 0.05). In vivo experimental results showed that both WP and WPH had significant blood pressure lowering effects in the acute and long-term administrative experiments. The mechanism of its antihypertensive activities was regulating the balance of the renin-angiotensin-aldosterone system and the kallikrein-kinin system by inhibiting ACE activities in tissues and regulating the level of endothelium-derived vasoconstrictor factors and relaxing factors in serum. It seems unnecessary to carry out enzymatic hydrolysis to produce walnut peptides with antihypertensive activity.

Hypertension causes many deaths worldwide and has shown an increasing trend as a severe non-communicable disease. Conventional antihypertensive drugs inevitably cause side effects, and great efforts have been made to exploit healthier and more-available substitutes. Microalgae have shown great potential in this regard and have been applied in the food and pharmaceutical industries. Some compounds in microalgae have been proven to have antihypertensive effects. Among these natural compounds, peptides from microalgae are promising angiotensin-converting enzyme (ACE) inhibitors because an increasing number of peptides show hypertensive effects and ACE inhibitory-like activity. In addition to acting as ACE inhibitors for the treatment of hypertension, these peptides have other probiotic properties, such as antioxidant and anti-inflammatory properties, that are important for the prevention and treatment of hypertension. Numerous studies have revealed the important bioactivities of ACE inhibitors and their mechanisms. This review discusses the antihypertensive effects, structure-activity relationships, molecular docking studies, interaction mechanisms, and other probiotic properties of microalgal ACE inhibitory peptides according to the current research related to microalgae as potential antihypertensive drugs. Possible research directions are proposed. This review contributes to a more comprehensive understanding of microalgal antihypertensive peptides.

Abstract: Sympathetic activity, arteriolar structure, and angiogenesis are important mechanisms modulating hypertension and this study aimed to analyze the effects of perindopril treatment, associated or not with exercise training, on the mechanisms that control blood pressure (BP) in hypertensive rats. Spontaneously hypertensive rats (SHR) were allocated into 4 groups: 1/sedentary (S); 2/perindopril (P, 3.0 mg/kg/d); 3/trained (T); and 4/trained + perindopril (TP). Wistar rats were used as normotensive sedentary control group. SHR were assigned to undergo a treadmill training (T) or were kept sedentary. Heart rate, BP, sympathetic activity to the vessels (LF-SBP), and skeletal muscle and myocardial morphometric analyses were performed. BP was significantly lower after all 3 strategies, compared with S and was accompanied by lower LF-SBP (-76%, -53%, and -44%, for P, T, and TP, respectively). Arteriolar vessel wall cross-sectional area was lower after treatments (-56%, -52%, and -56%, for P, T, and TP, respectively), and only TP presented higher arteriolar lumen area. Capillary rarefaction was present in soleus muscle and myocardium in S group and both trained groups presented higher vessel density, although perindopril attenuated this increase in soleus muscle. Although myocyte diameter was not different between groups, myocardial collagen deposition area, higher in S group, was lower after 3 strategies. In conclusion, we may suggest that perindopril could be an option for the hypertensive people who practice exercise and need a specific pharmacological treatment to reach a better BP control, mainly because training-induced angiogenesis is an important response to facilitate blood flow perfusion and oxygen uptake and perindopril did not attenuate this response., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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

Enzymatic hydrolysis can liberate bioactive peptides from protein materials, thus, pigeon pea was hydrolysed using thermoase. Crude hydrolysate (PPHT) was subjected to ultrafiltration using different molecular weight cutoffs to collect <1, 1-3, 3-5, 5-10, and >10 kDa peptide fractions. Fractions were analysed for in vitro antioxidative, antihypertensive, and antidiabetic properties. The peptide fractions had stronger DPPH • scavenging and renin inhibition when compared to PPHT. In contrast, ACE inhibition was stronger for the PPHT and <1 kDa peptide fraction while activity decreased as peptide size increased. The <1 kDa peptide also showed significantly stronger ferric reducing antioxidant power, OH • scavenging and inhibition of linoleic acid oxidation when compared to PPHT. α-amylase and α-glucosidase were inhibited by all the peptide fractions, though the 3-5 and >10 kDa had higher values. We conclude that the PPHT and peptide fractions could serve as potential ingredients to formulate antihypertensive and antidiabetic functional foods and nutraceuticals. PRACTICAL APPLICATIONS: Oxidative stress promotes the generation of free radicals, which have a significant impact in the pathogenesis of human chronic diseases such as cardiovascular impairment, cancer, and diabetes. Peptides generated from enzymatic hydrolysis of proteins have been identified to impart beneficial health effects. In this work, we showed that a thermoase digest of pigeon pea protein as well as the fractionated peptides had strong antioxidant properties in addition to exhibiting inhibitory activities against renin and angiotensin converting enzyme, the main therapeutic targets for antihypertensive agents. The peptide products also inhibited α-amylase and α-glucosidase activities, providing potential ingredients that can be used to formulate antidiabetic functional foods., (© 2020 Wiley Periodicals LLC.)