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Xie J, Chen S, Huan P, Wang S, Zhuang Y. A novel angiotensin I-converting enzyme inhibitory peptide from walnut (Juglans sigillata) protein hydrolysates and its evaluation in Ang II-induced HUVECs and hypertensive rats. Int J Biol Macromol 2024; 266:131152. [PMID: 38556230 DOI: 10.1016/j.ijbiomac.2024.131152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 02/28/2024] [Accepted: 03/25/2024] [Indexed: 04/02/2024]
Abstract
This study aims to seek angiotensin-I-converting enzyme inhibitory (ACEi) peptides from walnut using different enzymatic hydrolysis, and further to validate the potent ACEi peptides identified and screened via peptidomics and in silico analysis against hypertension in spontaneously hypertensive rats (SHRs). Results showed that walnut protein hydrolysate (WPH) prepared by combination of alcalase and simulated gastrointestinal digestion exhibited high ACEi activity. WPH was separated via Sephadex-G25, and four peptides were identified, screened and verified based on their PeptideRanker score, structural characteristic and ACE inhibition. Interestingly, FDWLR showed the highest ACEi activity with IC50 value of 8.02 μg/mL, which might be related to its close affinity with ACE observed in molecular docking. Subsequently, high absorption and non-toxicity of FDWLR was predicted via in silico absorption, distribution, metabolism, excretion and toxicity. Furthermore, FDWLR exhibited positively vasoregulation in Ang II-induced human umbilical vein endothelial cells, and great blood pressure lowering effect in SHRs.
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Affiliation(s)
- Jinxiang Xie
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, No. 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Shupeng Chen
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, No. 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Pengtao Huan
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, No. 727 South Jingming Road, Kunming, Yunnan 650500, China
| | - Shuguang Wang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, No. 727 South Jingming Road, Kunming, Yunnan 650500, China.
| | - Yongliang Zhuang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, No. 727 South Jingming Road, Kunming, Yunnan 650500, China.
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Fan H, Shang N, Davidge ST, Wu J. Chicken Muscle-Derived ACE2-Upregulating Peptide VVHPKESF Reduces Blood Pressure Associated with the ACE2/Ang (1-7)/MasR Axis in Spontaneously Hypertensive Rats. Mol Nutr Food Res 2024; 68:e2300524. [PMID: 38356052 DOI: 10.1002/mnfr.202300524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 12/29/2023] [Indexed: 02/16/2024]
Abstract
SCOPE This study aims to investigate the antihypertensive effect of four chicken muscle-derived angiotensin (Ang)-converting enzymes (ACE)-regulating peptides: Val-Arg-Pro (VRP, ACE inhibition), Leu-Lys-Tyr and Val-Arg-Tyr (LKY and VRY, ACE inhibition and ACE2 upregulation), and Val-Val-His-Pro-Lys-Glu-Ser-Phe (VVHPKESF [V-F], ACE2 upregulation) in spontaneously hypertensive rats. METHODS AND RESULTS Rats (12-14 weeks old) are grouped: 1) untreated, 2) VRP, 3) LKY, 4) VRY, and 5) V-F. Blood pressure (BP) is monitored using implantable telemetry technology. Over 18-day oral administration of 15 mg kg-1 body weight (BW) per day, only peptide V-F significantly (p < 0.05) reduces BP, decreases circulating Ang II, and increases ACE2 and Ang (1-7) levels, and enhances aortic expressions of ACE2 and Mas receptor (MasR). Peptide V-F also attenuates vascular inflammation (TNFα, MCP-1, IL-1α, IL-15, and cyclooxygenase 2 [COX2]) and vascular oxidative stress (nitrotyrosine). The gastrointestinal (GI)-degraded fragment of peptide V-F, Val-Val-His-Pro-Lys (VVHPK), is also an ACE2-upregulating peptide. Peptides VRP, LKY, and VRY do not reduce BP, possibly due to low bioavailability or other unknown reasons. CONCLUSIONS Peptide V-F is the first ACE2-upregulating peptide, purified and fractionated from food proteins based on in vitro ACE2 upregulation, that reduces BP associated with the activation of ACE2/Ang (1-7)/MasR axis; the N-terminal moiety VVHPK may be responsible for the antihypertensive effect of V-F.
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Affiliation(s)
- Hongbing Fan
- Department of Agricultural, Food and Nutritional Science, University of Alberta, 4-10 Ag/For Building, Edmonton, Alberta, T6G 2P5, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, 40546, USA
| | - Nan Shang
- Department of Agricultural, Food and Nutritional Science, University of Alberta, 4-10 Ag/For Building, Edmonton, Alberta, T6G 2P5, Canada
| | - Sandra T Davidge
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
- Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, 4-10 Ag/For Building, Edmonton, Alberta, T6G 2P5, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada
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Fan H, Wu K, Wu J. LRW fails to reduce blood pressure in spontaneously hypertensive rats due to its low gastrointestinal stability and transepithelial permeability. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2022.101964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Spent Hen Muscle Protein-Derived RAS Regulating Peptides Show Antioxidant Activity in Vascular Cells. Antioxidants (Basel) 2021; 10:antiox10020290. [PMID: 33671990 PMCID: PMC7919344 DOI: 10.3390/antiox10020290] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 01/31/2023] Open
Abstract
Spent hens are egg-laying hens reaching the end of their egg-laying cycles, being a major byproduct of the egg industry. Recent studies have been focusing on finding new value-added uses for spent hens. We have previously identified four bioactive peptides from spent hen muscle proteins, including three angiotensin-converting enzyme (ACE) inhibitory (ACEi) peptides (VRP, LKY, and VRY), and one ACE2 upregulating (ACE2u) peptide (VVHPKESF (V-F)). In the current study, we further assessed their antioxidant and cytoprotective activities in two vascular cell lines-vascular smooth muscle A7r5 cells (VSMCs) and endothelial EA.hy926 cells (ECs)-upon stimulation by tumor necrosis factor alpha (TNFα) and angiotensin (Ang) II, respectively. The results from our study revealed that all four peptides attenuated oxidative stress in both cells. None of the investigated peptides altered the expression of TNFα receptors in ECs; however, VRY and V-F downregulated Ang II type 1 receptor (AT1R), while V-F upregulated the Mas receptor (MasR) in VSMCs. Further, we found that the antioxidant effects of VRP, LKY, and VRY were likely through acting as direct radical scavengers, while that of V-F was at least partially ascribed to increased endogenous antioxidant enzymes (GPx4 and SOD2) in both cells. Besides, as an ACE2u peptide, V-F exerted antioxidant effect in a MasR-dependent manner, indicating a possible involvement of the upregulated ACE2-MasR axis underlying its antioxidant action. The antioxidant activities of VRP, LKY, VRY, and V-F in vascular cells indicated their multifunctional properties, in addition to their ACEi or ACE2u activity, which supports their potential use as functional food ingredients against hypertension.
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Spent Hen Protein Hydrolysate with Good Gastrointestinal Stability and Permeability in Caco-2 Cells Shows Antihypertensive Activity in SHR. Foods 2020; 9:foods9101384. [PMID: 33019511 PMCID: PMC7601532 DOI: 10.3390/foods9101384] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/19/2020] [Accepted: 09/22/2020] [Indexed: 12/17/2022] Open
Abstract
Spent hens are a major byproduct of the egg industry but are rich in muscle proteins that can be enzymatically transformed into bioactive peptides. The present study aimed to develop a spent hen muscle protein hydrolysate (SPH) with antihypertensive activity. Spent hen muscle proteins were hydrolyzed by nine enzymes, either individually or in combination; 18 SPHs were assessed initially for their in vitro angiotensin-converting enzyme (ACE) inhibitory activity, and three SPHs, prepared by Protex 26L (SPH-26L), pepsin (SPH-P), and thermoase (SPH-T), showed promising activity and peptide yield. These three hydrolysates were further assessed for their angiotensin-converting enzyme 2 (ACE2) upregulating, antioxidant, and anti-inflammatory activities; only SPH-T upregulated ACE2 expression, while all three SPHs showed antioxidant and anti-inflammatory activities. During simulated gastrointestinal digestion, ACE2 upregulating, ACE inhibitory and antioxidant activities of SPH-T were not affected, but those of SPH-26L and SPH-P were reduced. ACE inhibitory activity of gastrointestinal-digested SPH-T was not affected after the permeability study in Caco-2 cells, while ACE2 upregulating, antioxidant and anti-inflammatory activities were improved; nine novel peptides with five–eight amino acid residues were identified from the Caco-2 permeate. Among these three hydrolysates, only SPH-T reduced blood pressure significantly when given orally at a daily dose of 1000 mg/kg body weight to spontaneously hypertensive rats. SPH-T can be developed into a promising functional food ingredient against hypertension, contributing to a more sustainable utilization for spent hens while generating extra revenue for the egg industry.
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Yu Z, Wang L, Wu S, Zhao W, Ding L, Liu J. In vivo
anti‐hypertensive effect of peptides from egg white and its molecular mechanism with ACE. Int J Food Sci Technol 2020. [DOI: 10.1111/ijfs.14756] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Zhipeng Yu
- College of Food Science and Engineering Bohai University Jinzhou121013China
| | - Li Wang
- College of Food Science and Engineering Bohai University Jinzhou121013China
| | - Sijia Wu
- College of Food Science and Engineering Bohai University Jinzhou121013China
| | - Wenzhu Zhao
- College of Food Science and Engineering Bohai University Jinzhou121013China
| | - Long Ding
- College of Food Science and Engineering Northwest A&F University Yangling712100China
| | - Jingbo Liu
- Lab of Nutrition and Functional Food Jilin University Changchun130062China
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Kolahdouz-Mohammadi R, Malekahmadi M, Clayton ZS, Sadat SZ, Pahlavani N, Sikaroudi MK, Soltani S. Effect of Egg Consumption on Blood Pressure: a Systematic Review and Meta-analysis of Randomized Clinical Trials. Curr Hypertens Rep 2020; 22:24. [PMID: 32114646 PMCID: PMC7189334 DOI: 10.1007/s11906-020-1029-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW We identified and quantified the results of randomized controlled trials (RCTs) that have assessed the impact of egg consumption on blood pressure in adults. RECENT FINDINGS We conducted a comprehensive search of medical bibliographic databases up to February 2019 for RCTs investigating the effect of egg consumption on blood pressure in adults. Fifteen RCTs were included with a total of 748 participants. Overall, egg consumption had no significant effect on systolic blood pressure (weighted mean difference (WMD) = 0.046 mmHg; 95% CI - 0.792, 0.884) and diastolic blood pressure (WMD = - 0.603 mmHg; 95% CI - 1.521, 0.315). Subgroup analyses had no effect on pooled results and no heterogeneity was found among included studies. Egg consumption has no significant effects on systolic and diastolic blood pressure in adults. Due to several limitations among existing studies, general conclusions cannot be drawn regarding the beneficial or neutral impact of egg consumption on blood pressure in adults.
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Affiliation(s)
- Roya Kolahdouz-Mohammadi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Malekahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Seyede Zahra Sadat
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Naseh Pahlavani
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Sepideh Soltani
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Lee DE, Jung TH, Jo YN, Yun SS, Han KS. Enzymatic Hydrolysis of Egg White Protein Exerts a Hypotensive Effect in Spontaneously Hypertensive Rats. Food Sci Anim Resour 2019; 39:980-987. [PMID: 31950113 PMCID: PMC6949517 DOI: 10.5851/kosfa.2019.e91] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/25/2019] [Accepted: 11/27/2019] [Indexed: 12/12/2022] Open
Abstract
This study was conducted to investigate the hypotensive effect of egg white
protein (EWP) hydrolysate (EWH) in spontaneously hypertensive rats (SHRs). The
hydrolysis of EWP was effectively performed with a combination of 0.5% bromelain
and 1% papain at 50°C for 60 min. The resulting hydrolysate did not
elicit an allergic reaction as confirmed by human mast cell activation test. The
systolic and diastolic blood pressures of the SHRs fed the EWH diet were
observed to be significantly or numerically lower than those of the other groups
during the experimental period of 28 d. EWH treatment significantly
(p<0.05) upregulated the nitric oxide levels in hCMEC/D3 cells and the
plasma of the SHRs compared to those in the control. Moreover, EWH ingestion
significantly (p<0.01) reduced the plasma angiotensin II level of the
SHRs compared with that in the control. In conclusion, beyond its basic
nutritional value, EWH prevents and manages hypertension, and thus can be an
invaluable resource for functional food development.
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Affiliation(s)
- Da-Eon Lee
- Department of Food and Biotechnology, Sahmyook University, Seoul 01795, Korea
| | - Tae-Hwan Jung
- Convergence Research Center, Sahmyook University, Seoul 01795, Korea
| | - Yu-Na Jo
- Department of Food and Biotechnology, Sahmyook University, Seoul 01795, Korea
| | - Sung-Seob Yun
- R&D Department, Bioprofoods Co. Ltd., Seoul 01795, Korea
| | - Kyoung-Sik Han
- Department of Food and Biotechnology, Sahmyook University, Seoul 01795, Korea.,Convergence Research Center, Sahmyook University, Seoul 01795, Korea
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Fan H, Wang J, Liao W, Jiang X, Wu J. Identification and Characterization of Gastrointestinal-Resistant Angiotensin-Converting Enzyme Inhibitory Peptides from Egg White Proteins. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:7147-7156. [PMID: 31140270 DOI: 10.1021/acs.jafc.9b01071] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Egg proteins are recognized as excellent sources of bioactive peptides, such as angiotensin-converting enzyme inhibitory (ACEi) peptides. Oral administration of a thermolysin-digested egg white hydrolysate (T-EWH) caused a significant blood pressure reduction in spontaneously hypertensive rats; a further ACEi assay implied that its ACEi activity was enhanced after in vitro gastrointestinal (GI) digestion. These results indicated that T-EWH contained ACEi peptides resisting GI digestion and/or being further released during GI digestion. Therefore, the objective of this study was to identify these responsible ACEi peptides from T-EWH. The conventionally activity-guided fractionation was applied, coupled with a synchronized GI digestion throughout, during which both peptide yield and ACEi activity before and after the GI digestion were measured. Finally, six ACEi peptides (LAPYK, LKISQ, LKYAT, INKVVR, LFLIKH, and LGHWVY) with good GI resistance were identified with IC50 values <20 μM, especially LKYAT (0.09 μM). The structure-activity relationship of these peptides was discussed. The discovery of GI-resistant ACEi peptides could further support the application of egg white proteins as functional food ingredients.
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Affiliation(s)
- Hongbing Fan
- Department of Agricultural Food and Nutritional Science , University of Alberta , 4-10 Ag/For Building, Edmonton , Alberta T6G 2P5 , Canada
| | - Jiapei Wang
- Department of Agricultural Food and Nutritional Science , University of Alberta , 4-10 Ag/For Building, Edmonton , Alberta T6G 2P5 , Canada
| | - Wang Liao
- Department of Agricultural Food and Nutritional Science , University of Alberta , 4-10 Ag/For Building, Edmonton , Alberta T6G 2P5 , Canada
| | - Xu Jiang
- Department of Agricultural Food and Nutritional Science , University of Alberta , 4-10 Ag/For Building, Edmonton , Alberta T6G 2P5 , Canada
| | - Jianping Wu
- Department of Agricultural Food and Nutritional Science , University of Alberta , 4-10 Ag/For Building, Edmonton , Alberta T6G 2P5 , Canada
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Liao W, Bhullar KS, Chakrabarti S, Davidge ST, Wu J. Egg White-Derived Tripeptide IRW (Ile-Arg-Trp) Is an Activator of Angiotensin Converting Enzyme 2. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:11330-11336. [PMID: 30295033 DOI: 10.1021/acs.jafc.8b03501] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Angiotensin converting enzyme 2 (ACE2) plays beneficial roles in the renin angiotensin aldosterone system. Our previous studies indicated that egg white-derived antihypertensive peptide IRW (Ile-Arg-Trp) could upregulate ACE2 mRNA level in mesenteric artery of spontaneously hypertensive rats (SHRs), suggesting the potential of IRW as an in vivo ACE2 activator. In this study, the effects of IRW on activity and protein expression of ACE2 were investigated. Results indicated that IRW activated human recombinant ACE2 with an EC50 value of 7.24 × 10-5 M. In rat aortic vascular smooth muscle cell line A7r5 cells, IRW treatment (50 μM) significantly increased the expression and activity of ACE2. Oral administration of IRW to SHRs upregulated ACE2 protein levels in kidney and aorta. Molecular docking study suggested that IRW might activate ACE2 through interaction with the subdomain I near the active site through hydrogen bonds. Overall, this study established IRW as the first food-derived ACE2 activating peptide.
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Li Q, Liao W, Fan H, Wu J. Optimization and Scale-Up Preparation of Egg White Hydrolysate with Angiotensin I Converting Enzyme Inhibitory Activity. J Food Sci 2018; 83:1762-1768. [DOI: 10.1111/1750-3841.14158] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 03/09/2018] [Accepted: 03/21/2018] [Indexed: 11/30/2022]
Affiliation(s)
- Qiyi Li
- Dept. of Agricultural, Food & Nutritional Science; Univ. of Alberta; Edmonton Alberta Canada
| | - Wang Liao
- Dept. of Agricultural, Food & Nutritional Science; Univ. of Alberta; Edmonton Alberta Canada
| | - Hongbing Fan
- Dept. of Agricultural, Food & Nutritional Science; Univ. of Alberta; Edmonton Alberta Canada
| | - Jianping Wu
- Dept. of Agricultural, Food & Nutritional Science; Univ. of Alberta; Edmonton Alberta Canada
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Liao W, Jahandideh F, Fan H, Son M, Wu J. Egg Protein-Derived Bioactive Peptides: Preparation, Efficacy, and Absorption. ADVANCES IN FOOD AND NUTRITION RESEARCH 2018; 85:1-58. [PMID: 29860972 DOI: 10.1016/bs.afnr.2018.02.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The hen's egg is an important protein source of human diet. On average one large egg contains ~6g protein, which contributes to ~11% of daily protein intake. As a high-quality protein, egg proteins are well recognized as excellent sources of bioactive peptides. The objectives of this chapter are to introduce generation, bioactivities, and absorption of egg protein-derived bioactive peptides. Research on egg protein-derived bioactive peptides has been progressed during the past decades. Enzymatic hydrolysis is the major technique to prepare bioactive peptides from egg protein. Quantitative structure-activity relationships-aided in silico prediction is increasingly applied as a promising tool for efficient prediction of novel bioactive peptides. A number of bioactive peptides from egg proteins have been characterized for antioxidant, immunomodulatory, antihypertensive, antidiabetic, anticancer, and antimicrobial activities. Egg protein-derived peptides that can improve bone health have been reported as well. However, molecular mechanisms of many peptides are not fully understood. The stability and absorption routes, bioavailability, safety, and production of bioactive peptides await further investigation.
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Affiliation(s)
- Wang Liao
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - Forough Jahandideh
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - Hongbing Fan
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - Myoungjin Son
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.
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Chakrabarti S, Liao W, Davidge ST, Wu J. Milk-derived tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro) differentially modulate angiotensin II effects on vascular smooth muscle cells. J Funct Foods 2017. [DOI: 10.1016/j.jff.2016.12.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
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Jahandideh F, Chakrabarti S, Majumder K, Li Q, Panahi S, Morton JS, Davidge ST, Wu J. Egg white protein hydrolysate reduces blood pressure, improves vascular relaxation and modifies aortic angiotensin II receptors expression in spontaneously hypertensive rats. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.10.019] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Liao W, Chakrabarti S, Davidge ST, Wu J. Modulatory Effects of Egg White Ovotransferrin-Derived Tripeptide IRW (Ile-Arg-Trp) on Vascular Smooth Muscle Cells against Angiotensin II Stimulation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:7342-7347. [PMID: 27649793 DOI: 10.1021/acs.jafc.6b03513] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
The renin angiotensin system (RAS) is a key mediator of blood pressure regulation. Angiotensin II (Ang II), the active component of RAS, is a potent vasoconstrictor that also causes abnormal proliferation, oxidative stress, and inflammation in vascular smooth muscle cells (VSMCs) that contribute to atherosclerotic changes. Egg white ovotransferrin-derived tripeptide IRW (Ile-Arg-Trp) was previously shown to exert antihypertensive effect by reducing Ang II synthesis as well as endothelial cell inflammation and endothelial dysfunction. However, the effects of IRW on VSMCs are still unclear. In the present study, we evaluated the antiproliferative, antioxidant, and anti-inflammatory effects of IRW on VSMCs in the presence of Ang II stimulation. It was found that IRW treatment could attenuate Ang II-stimulated proliferation, superoxide production, and inflammation in VSMCs. These beneficial effects appeared to involve modulation of the NF-κB pathway. These findings could further our understanding on the antihypertensive mechanism of IRW beyond vascular endothelium.
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Affiliation(s)
- Wang Liao
- Department of Agricultural, Food & Nutritional Science, ‡Department of Obstetrics & Gynecology, §Department of Physiology, ∥Cardiovascular Research Centre, and ⊥Women and Children's Health Research Institute, University of Alberta , Edmonton, Alberta T6G 2P5, Canada
| | - Subhadeep Chakrabarti
- Department of Agricultural, Food & Nutritional Science, ‡Department of Obstetrics & Gynecology, §Department of Physiology, ∥Cardiovascular Research Centre, and ⊥Women and Children's Health Research Institute, University of Alberta , Edmonton, Alberta T6G 2P5, Canada
| | - Sandra T Davidge
- Department of Agricultural, Food & Nutritional Science, ‡Department of Obstetrics & Gynecology, §Department of Physiology, ∥Cardiovascular Research Centre, and ⊥Women and Children's Health Research Institute, University of Alberta , Edmonton, Alberta T6G 2P5, Canada
| | - Jianping Wu
- Department of Agricultural, Food & Nutritional Science, ‡Department of Obstetrics & Gynecology, §Department of Physiology, ∥Cardiovascular Research Centre, and ⊥Women and Children's Health Research Institute, University of Alberta , Edmonton, Alberta T6G 2P5, Canada
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Chakrabarti S, Wu J. Bioactive peptides on endothelial function. FOOD SCIENCE AND HUMAN WELLNESS 2016. [DOI: 10.1016/j.fshw.2015.11.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Kanso H, Mallem MY, Thorin C, Rabesona H, Haertle T, Chobert JM, Desfontis JC. Vasorelaxant effects of camel and bovine casein tryptic hydrolysates in rat thoracic aorta and their antihypertensive effect in awake spontaneously hypertensive rats. Int Dairy J 2016. [DOI: 10.1016/j.idairyj.2015.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Turgut F, Yaprak M, Abdel-Rahman E. Management of hypertension: Current state of the art and challenges. World J Hypertens 2016; 6:53-59. [DOI: 10.5494/wjh.v6.i1.53] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 12/04/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023] Open
Abstract
Hypertension is a major modifiable cardiovascular risk factor. Hypertension is also recognized as the most important risk factor for global disease burden. It is well established that a sustained reduction in blood pressure by drugs reduces the incidence of cardiovascular morbidity and mortality. In recent years, studies and new guidelines published for the management of hypertension. Awareness, treatment and control of hypertension are very poor, despite the new guidelines. We highlighted the management of hypertension in the light of current literature.
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Majumder K, Chakrabarti S, Morton JS, Panahi S, Kaufman S, Davidge ST, Wu J. Egg-derived ACE-inhibitory peptides IQW and LKP reduce blood pressure in spontaneously hypertensive rats. J Funct Foods 2015. [DOI: 10.1016/j.jff.2014.12.028] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Chakrabarti S, Wu J. Milk-derived tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro) promote adipocyte differentiation and inhibit inflammation in 3T3-F442A cells. PLoS One 2015; 10:e0117492. [PMID: 25714093 PMCID: PMC4340623 DOI: 10.1371/journal.pone.0117492] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 12/24/2014] [Indexed: 01/17/2023] Open
Abstract
Milk derived tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro) have shown promise as anti-hypertensive agents due to their inhibitory effects on angiotensin converting enzyme (ACE). Due to the key inter-related roles of hypertension, chronic inflammation and insulin resistance in the pathogenesis of metabolic syndrome, there is growing interest in investigating established anti-hypertensive agents for their effects on insulin sensitivity and inflammation. In this study, we examined the effects of IPP and VPP on 3T3-F442A murine pre-adipocytes, a widely used model for studying metabolic diseases. We found that both IPP and VPP induced beneficial adipogenic differentiation as manifested by intracellular lipid accumulation, upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) and secretion of the protective lipid hormone adiponectin by these cells. The observed effects were similar to those induced by insulin, suggesting potential benefits in the presence of insulin resistance. IPP and VPP also inhibited cytokine induced pro-inflammatory changes such as reduction in adipokine levels and activation of the nuclear factor kappa B (NF-κB) pathway. Taken together, our findings suggest that IPP and VPP exert insulin-mimetic adipogenic effects and prevent inflammatory changes in adipocytes, which may offer protection against metabolic disease.
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Affiliation(s)
- Subhadeep Chakrabarti
- Department of Agricultural, Food & Nutritional Science (AFNS) and the Cardiovascular Research Centre (CVRC), University of Alberta, Edmonton, AB, Canada
| | - Jianping Wu
- Department of Agricultural, Food & Nutritional Science (AFNS) and the Cardiovascular Research Centre (CVRC), University of Alberta, Edmonton, AB, Canada
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Jahandideh F, Majumder K, Chakrabarti S, Morton JS, Panahi S, Kaufman S, Davidge ST, Wu J. Beneficial effects of simulated gastro-intestinal digests of fried egg and its fractions on blood pressure, plasma lipids and oxidative stress in spontaneously hypertensive rats. PLoS One 2014; 9:e115006. [PMID: 25502445 PMCID: PMC4263718 DOI: 10.1371/journal.pone.0115006] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 11/17/2014] [Indexed: 12/11/2022] Open
Abstract
Background We have previously characterized several antihypertensive peptides in simulated digests of cooked eggs and showed blood pressure lowering property of fried whole egg digest. However, the long-term effects of this hydrolysate and its fractions on blood pressure are not known. Therefore, the objectives of the study were to determine the effects of long term administration of fried whole egg hydrolysate and its fractions (i.e. egg white and egg yolk) on regulation of blood pressure and associated factors in cardiovascular disease such as plasma lipid profile and tissue oxidative stress. Methods and Results We used spontaneously hypertensive rats (SHR), an animal model of essential hypertension. Hydrolysates of fried egg and its fractions were prepared by simulated gastro-intestinal digestion with pepsin and pancreatin. 16–17 week old male SHRs were orally administered fried whole egg hydrolysate, non-hydrolyzed fried whole egg, egg white hydrolysate or egg yolk hydrolysates (either defatted, or not) daily for 18 days. Blood pressure (BP) and heart rate were monitored by telemetry. Animals were sacrificed at the end of the treatment for vascular function studies and evaluating plasma lipid profile and tissue oxidative stress. BP was reduced by feeding fried whole egg hydrolysate but not by the non-hydrolyzed product suggesting a critical role for in vitro digestion in releasing anti-hypertensive peptides. Egg white hydrolysate and defatted egg yolk hydrolysate (but not egg yolk hydrolysate) also had similar effects. Reduction in BP was accompanied by the restoration of nitric oxide (NO) dependent vasorelaxation and reduction of plasma angiotensin II. Fried whole egg hydrolysate also reduced plasma levels of triglyceride although it was increased by the non-hydrolyzed sample. Additionally the hydrolyzed preparations attenuated tissue oxidative stress. Conclusion Our results demonstrate that fried egg hydrolysates exert anti-hypertensive effects, improve plasma lipid profile and attenuate tissue oxidative stress in vivo.
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Affiliation(s)
- Forough Jahandideh
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Kaustav Majumder
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Subhadeep Chakrabarti
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
- Women & Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Jude S. Morton
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
- Women & Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Sareh Panahi
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Susan Kaufman
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Sandra T. Davidge
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
- Women & Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
- * E-mail:
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Suzuki H, Shimada K, Fujiwara K. Antihypertensive effectiveness of combination therapy with losartan/hydrochlorothiazide for 'real world' management of isolated systolic hypertension. Ther Adv Cardiovasc Dis 2014; 9:10-8. [PMID: 25367171 DOI: 10.1177/1753944714558244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVES The guidelines for hypertension require the presence of compelling indications for pharmacological management of hypertension associated with various diseases. Data mainly obtained through randomized controlled trials have provided evidence supporting effectiveness of the combination of losartan (Lo) and hydrochlorothiazide (HCTZ) for management of hypertensive patients. However, there have been few reports discussing the effectiveness of Lo/HTCZ (losartan 50 mg/hydrochlorothizide 12.5 mg) in the 'real world' in the management of isolated systolic hypertension (ISH). This study was designed to investigate the 'real world' effectiveness of Lo/HTCZ-based treatment of ISH associated with various diseases. METHODS This was a retrospective, uncontrolled analysis of data derived from a large, cross-sectional web-based clinical database collected by physicians. RESULTS Of 24,825 eligible patients, 20,726 were followed during a 6-month period. Among these, subjects for analysis included those with systolic blood pressure (SBP) >140 mmHg and diastolic BP (DBP) <90 mmHg; patients with diabetes mellitus and chronic kidney disease were excluded. A total of 15,846 patients were analysed. Among the various complications, hypercholesterolemia was the most frequent concomitant cardiovascular (CV) risk factor (48.1%), followed by obesity (16.3%). Associated clinical conditions were cerebrovascular diseases (9.6%), ischemic heart disease (7.9%) and left ventricular hypertrophy (4.6%). Total numbers of patients exhibiting any type of complications were 62% (≤64 years old), 69% (65-74 years old) and 67% (≥75 years old) (stratification of age). Mean SBP/DBP measurements (mm Hg) were 156/78 at the start, 140/72 at 1 month and 134/72 at 6 months. Blood pressure (BP) reductions associated with various diseases were similar among patients. Laboratory data including serum levels of total cholesterol, uric acid, hemoglobin A1c and serum potassium did not change during the study. Adverse effects such as orthostatic hypotension and considerable reductions in BP (>30 mmHg SBP) were rare. CONCLUSIONS Lo/HTCZ is safe and effective in reducing and improving BP control in a 'real world' setting. Treatment with Lo/HTCZ enabled a substantial proportion of hypertensive patients with associated diseases to achieve the recommended goal of <140 mm Hg.
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Affiliation(s)
- Hiromichi Suzuki
- Department of Nephrology, Saitama Medical University 38 Morohonngo, Moroyama machi, Iruma gun, Saitama 350-0495, Japan
| | - Kazuyuki Shimada
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
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Kim YH, Hwang JH, Kim KS, Noh JR, Gang GT, Oh WK, Jeong KH, Kwak TH, Choi HS, Lee IK, Lee CH. Enhanced activation of NAD(P)H: quinone oxidoreductase 1 attenuates spontaneous hypertension by improvement of endothelial nitric oxide synthase coupling via tumor suppressor kinase liver kinase B1/adenosine 5'-monophosphate-activated protein kinase-mediated guanosine 5'-triphosphate cyclohydrolase 1 preservation. J Hypertens 2014; 32:306-17. [PMID: 24241058 DOI: 10.1097/hjh.0000000000000018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
AIMS Guanosine 5'-triphosphate cyclohydrolase-1 (GTPCH-1) is a rate-limiting enzyme in de-novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase (eNOS) coupling. Adenosine 5'-monophosphate-activated protein kinase (AMPK) is crucial for GTPCH-1 preservation, and tumor suppressor kinase liver kinase B1 (LKB1), an upstream kinase of AMPK, is activated by NAD-dependent class III histone deacetylase sirtuin 1 (SIRT1)-mediated deacetylation. β-Lapachone has been shown to increase cellular NAD/NADH ratio via NAD(P)H quinone oxidoreductase 1 (NQO1) activation. In this study, we have evaluated whether β-lapachone-induced NQO1 activation modulates blood pressure (BP) through preservation of GTPCH-1 in a hypertensive animal model. METHODS AND RESULTS Spontaneously hypertensive rats (SHRs), primary aortic endothelial cells, and endothelial cell line were used to investigate the hypotensive effect of β-lapachone and its action mechanism. β-Lapachone treatment dramatically lowered BP and vascular tension in SHRs and induced eNOS activation in endothelial cells. Consistent with these effects, β-lapachone treatment also elevated levels of both aortic cGMP and plasma nitric oxide in SHRs. Meanwhile, β-lapachone-treated SHRs showed significantly increased levels of aortic NAD, LKB1 deacetylation, and AMPK Thr phosphorylation followed by increased GTPCH-1 and tetrahydrobiopterin/dihydrobiopterin ratio. In-vitro study revealed that AMPK inhibition by overexpression of dominant-negative AMPK nearly abolished GTPCH-1 protein conservation. Enhanced LKB1 deacetylation and AMPK activation were also elicited by β-lapachone in endothelial cells. However, inhibition of LKB1 deacetylation by blocking of NQO1 or SIRT1 blunted AMPK activation by β-lapachone. CONCLUSION This is the first study demonstrating that eNOS coupling can be regulated by NQO1 activation via LKB1/AMPK/GTPCH-1 modulation, which is possibly correlated with relieving hypertension. These findings provide strong evidence to suggest that NQO1 might be a new therapeutic target for hypertension.
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Affiliation(s)
- Yong-Hoon Kim
- aLaboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon bKorea Bioactive Natural Material Bank, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul cDiabetes and Metabolic Disease Research Center, Lee Gil Ya Cancer & Diabetes Institute, Gachon University of Medicine, Incheon dKT&G Life Sciences Corporation/R&D Center, Suwon eHormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju fDepartment of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea
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Majumder K, Chakrabarti S, Morton JS, Panahi S, Kaufman S, Davidge ST, Wu J. Egg-derived tri-peptide IRW exerts antihypertensive effects in spontaneously hypertensive rats. PLoS One 2013; 8:e82829. [PMID: 24312436 PMCID: PMC3843735 DOI: 10.1371/journal.pone.0082829] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 11/07/2013] [Indexed: 02/07/2023] Open
Abstract
Background There is a growing interest in using functional food components as therapy for cardiovascular diseases such as hypertension. We have previously characterized a tri-peptide IRW (Ile-Arg-Trp) from egg white protein ovotransferrin; this peptide showed anti-inflammatory, anti-oxidant and angiotensin converting enzyme (ACE) inhibitor properties invitro. Given the pathogenic roles played by angiotensin, oxidative stress and inflammation in the spontaneously hypertensive rat (SHR), we tested the therapeutic potential of IRW in this well-established model of hypertension. Methods and Results 16–17 week old male SHRs were orally administered IRW at either a low dose (3 mg/Kg BW) or a high dose (15 mg/Kg BW) daily for 18 days. Blood pressure (BP) and heart rate were measured by telemetry. Animals were sacrificed at the end of the treatment for vascular function studies and measuring markers of inflammation. IRW treatment attenuated mean BP by ~10 mmHg and ~40 mmHg at the low- and high-dose groups respectively compared to untreated SHRs. Heart rate was not affected. Reduction in BP was accompanied by the restoration of diurnal variations in BP, preservation of nitric oxide dependent vasorelaxation, as well as reduction of plasma angiotensin II, other inflammatory markers and tissue fibrosis. Conclusion Our results demonstrate anti-hypertensive effects of IRW invivo likely mediated through ACE inhibition, endothelial nitric oxide synthase and anti-inflammatory properties.
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Affiliation(s)
- Kaustav Majumder
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Subhadeep Chakrabarti
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Jude S. Morton
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Sareh Panahi
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Susan Kaufman
- Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Sandra T. Davidge
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
- Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Jianping Wu
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
- Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
- * E-mail:
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Sicras-Mainar A. Farmacoeconomía de olmesartán en combinaciones a dosis fijas para el tratamiento de la hipertensión arterial. HIPERTENSION Y RIESGO VASCULAR 2013. [DOI: 10.1016/s1889-1837(13)70018-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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[Relationship of polymedication in controlling blood pressure: compliance, persistence, costs and incidence of new cardiovascular events]. Med Clin (Barc) 2012; 141:53-61. [PMID: 22766057 DOI: 10.1016/j.medcli.2012.04.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 04/25/2012] [Accepted: 04/26/2012] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND OBJECTIVE To determine the relationship of polypharmacy on blood pressure (BP) control, compliance, persistence, the cost and incidence of cardiovascular events (CVD) in patients with moderate/severe hypertension. PATIENTS AND METHODS An observational multicenter retrospective study. We evaluated patients > 30 years who started a third antihypertensive treatment during 2004-2006. Depending on the number of chronic medications, we established 3 groups: regular consumption of 3-6 drugs, including between 7-10 and ≥ 11. Top-measures: sociodemographic, comorbidity, BP, compliance and persistence. For each group we determined the incidence of new CVD totals and total costs. RESULTS We evaluated 1,906 patients, 765 between 3-6 drugs, 624 between 7-10 and 517 in ≥ 11 (P<.001). Overage age: 69.4 years and 55.5% women. The group of 3-6 drugs showed better BP control (51.8 vs. 47.0 and 41.1%, P<.001), compliance (71.4 vs. 69.9 and 67.1%, P=.017), persistence (50.1 vs. 45.5 and 46.2%, P=.044) and lower incidence of CVD (12.2 vs. 19.7 and 30.2%, P<.001), respectively. The average/unit total costs was 3,369.1 vs. 4,362.1 and € 4,902.3 (P<.001). The presence of CVD was associated with therapy noncompliance (odds ratio [OR] 1.9, 95% confidence interval [95%CI] 1.1 to 3.6) and controlled by the lower BP control (OR 1.4 (95%CI 1.1-2.0) (P < .05). The use of antihypertensive fixed dose has greater compliance (72.8 vs. 68.2%), persistence (64.4 vs. 39.3%) and degree of BP control (52.6 vs. 43, 8%) (p<.001). CONCLUSIONS Polypharmacy is associated with lower compliance and persistence to antihypertensive treatment, cardiovascular disease and increased health care costs.
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Sica D, Bakris GL, White WB, Weber MA, Cushman WC, Huang P, Roberts A, Kupfer S. Blood pressure-lowering efficacy of the fixed-dose combination of azilsartan medoxomil and chlorthalidone: a factorial study. J Clin Hypertens (Greenwich) 2012; 14:284-92. [PMID: 22533654 DOI: 10.1111/j.1751-7176.2012.00616.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
This study compared the efficacy and safety of fixed-dose combinations (FDCs) of the angiotensin II receptor blocker azilsartan medoxomil (AZL-M) and the thiazide-like diuretic chlorthalidone (CLD) with the individual monotherapies in a double-blind factorial study. A total of 1714 patients with clinic systolic blood pressure (SBP) 160 mm Hg to 190 mm Hg inclusive were randomized to AZL-M 0 mg, 20 mg, 40 mg, or 80 mg and/or chlorthalidone 0 mg, 12.5 mg, or 25 mg. The primary efficacy end point was change from baseline to 8 weeks in trough (hour 22-24) SBP by ambulatory blood pressure (BP) monitoring (ABPM). Patients' mean age was 57 years; 47% were men and 20% were black. Baseline trough BP was approximately 165/95 mm Hg and 151/91 mm Hg by clinic and ABPM measurements, respectively. For the pooled AZL-M/CLD 40/25-mg and 80/25-mg FDC groups, SBP reduction by ABPM at trough was 28.9 mm Hg and exceeded AZL-M 80 mg and CLD 25 mg monotherapies by 13.8 mm Hg and 13 mm Hg, respectively (P<.001 for both comparisons). Discontinuation rates and elevations in serum creatinine were dose-dependent and occurred more often in the AZL-M/CLD groups. In patients with stage 2 hypertension, treatment with the combination of AZL-M and CLD resulted in substantially greater SBP reduction compared with either agent alone.
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Affiliation(s)
- Domenic Sica
- Division of Nephrology, Department of Medicine and Pharmacology, Virginia Commonwealth University, Richmond, VA, USA.
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Kim YH, Hwang JH, Noh JR, Gang GT, Kim DH, Son HY, Kwak TH, Shong M, Lee IK, Lee CH. Activation of NAD(P)H:quinone oxidoreductase ameliorates spontaneous hypertension in an animal model via modulation of eNOS activity. Cardiovasc Res 2011; 91:519-27. [PMID: 21502369 DOI: 10.1093/cvr/cvr110] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
AIMS Hypertension is one of the most common human diseases worldwide, and extensive research efforts are focused upon the identification and utilizing of novel therapeutic drug targets. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is an important regulator of blood pressure (BP). β-Lapachone (βL), a well-known substrate of NAD(P)H:quinone oxidoreductase (NQO1), increases the cellular NAD(+)/NADH ratio via the activation of NQO1. In this study, we evaluated whether βL-induced activation of NQO1 modulates BP in an animal model of hypertension. METHODS AND RESULTS Spontaneously hypertensive rats (SHR), primary human aortic endothelial cells (HAEC), and endothelial cell lines were used to investigate the hypotensive effect of βL and its mode of action. βL treatment stimulated endothelium-dependent vascular relaxation in response to acetylcholine in aorta of SHR and dramatically lowered BP in SHR, but the hypotensive effect was completely blocked by eNOS inhibition with ω-nitro-l-arginine methyl ester. Aortic eNOS phosphorylation and eNOS protein expression were significantly increased in βL-treated SHR. In vitro studies revealed that βL treatment elevated the intracellular NAD(+)/NADH ratio and concentration of free Ca(2+) ([Ca(2+)]i), and resulted in Akt/AMP-activated protein kinase/eNOS activation. These effects were abolished by NQO1 siRNA and [Ca(2+)]i inhibition through a ryanodine receptor blockade. CONCLUSION This study is the first to demonstrate that NQO1 activation has a hypotensive effect mediated by eNOS activation via cellular NAD(+)/NADH ratio modulation in an animal model. These results provide strong evidence suggesting NQO1 might be a new therapeutic target for hypertension.
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Affiliation(s)
- Yong-Hoon Kim
- Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, 111 Gwahangno, Yuseong-gu, Daejeon, Republic of Korea
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Sicras Mainar A, Galera Llorca J, Muñoz Ortí G, Navarro Artieda R. Influencia del cumplimiento asociado a la incidencia de eventos cardiovasculares y los costes en combinaciones a dosis fijas en el tratamiento de la hipertensión arterial. Med Clin (Barc) 2011; 136:183-91. [DOI: 10.1016/j.medcli.2010.01.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Revised: 01/22/2010] [Accepted: 01/26/2010] [Indexed: 10/18/2022]
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Bhad P, Ayalasomayajula S, Karan R, Leon S, Riviere GJ, Sunkara G, Jarugula V. Evaluation of pharmacokinetic interactions between amlodipine, valsartan, and hydrochlorothiazide in patients with hypertension. J Clin Pharmacol 2010; 51:933-42. [PMID: 20852001 DOI: 10.1177/0091270010376963] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The steady-state pharmacokinetic (PK) interaction potential between amlodipine (10 mg), valsartan (320 mg), and hydrochlorothiazide (HCTZ; 25 mg) was evaluated in patients with hypertension in a multicenter, multiple-dose, open-label, 4-cohort, parallel-group study. Eligible patients were randomly allocated to the dual combination of valsartan + HCTZ, amlodipine + valsartan, or amlodipine + HCTZ and nonrandomly allotted to amlodipine + valsartan + HCTZ triple combination treatment. After 6 days of treatment with a half-maximal dose of different combinations, patients were up-titrated to the maximal drug doses from day 7 through day 17. PK parameters of corresponding analytes from the triple- and dual-treatment groups were estimated on day 17 and compared. Safety and tolerability of all treatments was assessed. The C ( ssmax ) and AUC(0-τ) values of amlodipine or HCTZ remained unaffected when administered with valsartan + HCTZ or valsartan + amlodipine, respectively. On the other hand, valsartan exposure increased by 10% to 25% when coadministered with HCTZ and amlodipine, which is not considered clinically relevant. In conclusion, there were no clinically relevant PK interactions with amlodipine, valsartan, and HCTZ triple combination compared with the corresponding dual combinations. All treatments were safe and well tolerated.
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Affiliation(s)
- Prafulla Bhad
- Translational Medicine-Scientific Operations, Novartis Healthcare Pvt Ltd, Hitech City, India
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Segura de La Morena J, García Donaire JA, Ruilope Urioste LM. Nuevas estrategias terapéuticas para mejorar el control de la hipertensión arterial y simplificar la pauta de tratamiento farmacológico. Med Clin (Barc) 2010; 134:635-42. [DOI: 10.1016/j.medcli.2010.01.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Revised: 01/25/2010] [Accepted: 01/28/2010] [Indexed: 12/01/2022]
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Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol 2008; 52:1749-57. [PMID: 19022154 DOI: 10.1016/j.jacc.2008.08.036] [Citation(s) in RCA: 250] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2008] [Revised: 08/18/2008] [Accepted: 08/26/2008] [Indexed: 02/07/2023]
Abstract
Resistant hypertension is defined as failure to achieve goal blood pressure (BP) when a patient adheres to the maximum tolerated doses of 3 antihypertensive drugs including a diuretic. Although the exact prevalence of resistant hypertension is currently unknown, indirect evidence from population studies and clinical trials suggests that it is a relatively common clinical problem. The prevalence of resistant hypertension is projected to increase, owing to the aging population and increasing trends in obesity, sleep apnea, and chronic kidney disease. Management of resistant hypertension must begin with a careful evaluation of the patient to confirm the diagnosis and exclude factors associated with "pseudo-resistance," such as improper BP measurement technique, the white-coat effect, and poor patient adherence to life-style and/or antihypertensive medications. Education and reinforcement of life-style issues that affect BP, such as sodium restriction, reduction of alcohol intake, and weight loss if obese, are critical in treating resistant hypertension. Exclusion of preparations that contribute to true BP treatment resistance, such as nonsteroidal anti-inflammatory agents, cold preparations, and certain herbs, is also important. Lastly, BP control can only be achieved if an antihypertensive treatment regimen is used that focuses on the genesis of the hypertension. An example is volume overload, a common but unappreciated cause of treatment resistance. Use of the appropriate dose and type of diuretic provides a solution to overcome treatment resistance in this instance.
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Affiliation(s)
- Pantelis A Sarafidis
- Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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