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Pontes RB, Colombari DSA, De Paula PM, Colombari E, Andrade CAF, De Luca LA, Menani JV. Sympathetic and angiotensinergic activity in spontaneously hypertensive rats treated with 3-amino-1,2,4-triazole. Auton Neurosci 2023; 248:103107. [PMID: 37454409 DOI: 10.1016/j.autneu.2023.103107] [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: 04/12/2023] [Revised: 06/28/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
Previous studies from our laboratory have shown that the pressor response to intracerebroventricular (icv) administered ANG II in normotensive rats or spontaneously hypertensive rats (SHRs) is attenuated by increased central H2O2 concentration, produced either by direct H2O2 icv injection or by increased endogenous H2O2 centrally in response to local catalase inhibition with 3-amino-1,2,4-triazole (ATZ). In the present study, we evaluated the effects of ATZ administered peripherally on arterial pressure and sympathetic and angiotensinergic activity in SHRs. Male SHRs weighing 280-330 g were used. Mean arterial pressure (MAP) and heart rate (HR) were recorded in conscious freely moving SHRs. Acute intravenous injection of ATZ (300 mg/kg of body weight) did not modify MAP and HR during the next 4 h, however, the treatment with ATZ (300 mg/kg of body weight twice per day) for 3 days reduced MAP (144 ± 6, vs. saline, 183 ± 13 mmHg), without changing HR. Intravenous hexamethonium (ganglionic blocker) produced a smaller decrease in MAP 4 h after ATZ (-25 ± 3, vs saline -38 ± 4 mmHg). Losartan (angiotensinergic AT1 receptor blocker) produced a significant depressor response 4 h after ATZ (-22 ± 4, vs. saline: -2 ± 4 mmHg) and in 3-day ATZ treated SHRs (-25 ± 5, vs. saline: -9 ± 4 mmHg). The results suggest that the treatment with ATZ reduces sympathetic activity in SHRs and simultaneously increases angiotensinergic activity.
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Affiliation(s)
- Roberto Braz Pontes
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Débora S A Colombari
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Patrícia M De Paula
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Eduardo Colombari
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Carina A F Andrade
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Laurival A De Luca
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - José V Menani
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil.
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Lauar MR, Colombari DSA, De Paula PM, Colombari E, Andrade CAF, De Luca LA, Menani JV. Chronic administration of catalase inhibitor attenuates hypertension in renovascular hypertensive rats. Life Sci 2023; 319:121538. [PMID: 36868399 DOI: 10.1016/j.lfs.2023.121538] [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: 12/20/2022] [Revised: 02/18/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023]
Abstract
AIMS Reactive oxygen species like hydrogen peroxide (H2O2) are produced endogenously and may participate in intra- and extracellular signaling, including modulation of angiotensin II responses. In the present study, we investigated the effects of chronic subcutaneous (sc) administration of the catalase inhibitor 3-amino-1,2,4-triazole (ATZ) on arterial pressure, autonomic modulation of arterial pressure, hypothalamic expression of AT1 receptors and neuroinflammatory markers and fluid balance in 2-kidney, 1clip (2K1C) renovascular hypertensive rats. MATERIALS AND METHODS Male Holtzman rats with a clip occluding partially the left renal artery and chronic sc injections of ATZ were used. KEY FINDINGS Subcutaneous injections of ATZ (600 mg/kg of body weight/day) for 9 days in 2K1C rats reduced arterial pressure (137 ± 8, vs. saline: 182 ± 8 mmHg). ATZ also reduced the sympathetic modulation and enhanced the parasympathetic modulation of pulse interval, reducing the sympatho-vagal balance. Additionally, ATZ reduced mRNA expression for interleukins 6 and IL-1β, tumor necrosis factor-α, AT1 receptor (0.77 ± 0.06, vs. saline: 1.47 ± 0.26 fold change), NOX 2 (0.85 ± 0.13, vs. saline: 1.75 ± 0.15 fold change) and the marker of microglial activation, CD 11 (0.47 ± 0.07, vs. saline, 1.34 ± 0.15 fold change) in the hypothalamus of 2K1C rats. Daily water and food intake and renal excretion were only slightly modified by ATZ. SIGNIFICANCE The results suggest that the increase of endogenous H2O2 availability with chronic treatment with ATZ had an anti-hypertensive effect in 2K1C hypertensive rats. This effect depends on decreased activity of sympathetic pressor mechanisms and mRNA expression of AT1 receptors and neuroinflammatory markers possibly due to reduced angiotensin II action.
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Affiliation(s)
- Mariana R Lauar
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Débora S A Colombari
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Patrícia M De Paula
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Eduardo Colombari
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Carina A F Andrade
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Laurival A De Luca
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - José V Menani
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil.
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Kawakami K, Matsuo H, Yamada T, Matsumoto KI, Sasaki D, Nomura M. Effects of hydrogen-rich water and ascorbic acid treatment on spontaneously hypertensive rats. Exp Anim 2022; 71:347-355. [PMID: 35264492 PMCID: PMC9388348 DOI: 10.1538/expanim.21-0187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Hydrogen-rich water (HW) has been suggested to possess antioxidant properties of value in treatments of lifestyle diseases and for prevention of latent pathologies. To date, the potential
benefits of HW against the deleterious effects of excessive salt intake and hypertension have not been investigated. Here, we first examined the effects of HW or HW supplemented with 0.1%
ascorbic acid (HWA) on spontaneously hypertensive rats (SHR) that had been fed a normal diet. In comparison to control rats given distilled water (DW), we found that HW did not significantly
influence systolic blood pressure (SBP) or diastolic blood pressure (DBP) in SHR; however, the increase in SBP and DBP were inhibited in the HWA group. Next, four groups of SHR were given
DW, 0.1% ascorbic acid-added DW (DWA), HW, or HWA in combination with a 4% NaCl-added diet. SHR fed the 4% NaCl-added diet showed increased hypertension; HWA treatment resulted in a
significant reduction in blood pressure. The HWA group tended to have lower plasma angiotensin II levels than the DW group. In addition, urinary volumes and urinary sodium levels were
significantly lower in the HWA group than the DW group. Urinary isoprostane, an oxidative stress marker, was also significantly lower in the HWA group, suggesting that the inhibitory effect
of HWA on blood pressure elevation was caused by a reduction in oxidative stress. These findings suggest a synergistic interaction between HW and ascorbic acid, and also suggest that HWA
ingestion has potential for prevention of hypertension.
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Affiliation(s)
- Kohei Kawakami
- Department of Experimental Animals, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University
| | - Hiroyuki Matsuo
- Department of Experimental Animals, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University
| | - Takaya Yamada
- Department of Experimental Animals, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University
| | - Ken-Ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University
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Anti-hypertensive effect of hydrogen peroxide acting centrally. Hypertens Res 2020; 43:1192-1203. [PMID: 32461634 DOI: 10.1038/s41440-020-0474-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 04/20/2020] [Accepted: 04/29/2020] [Indexed: 11/09/2022]
Abstract
Intracerebroventricular (icv) injection of hydrogen peroxide (H2O2) or the increase of endogenous H2O2 centrally produced by catalase inhibition with 3-amino-1,2,4-triazole (ATZ) injected icv reduces the pressor responses to central angiotensin II (ANG II) in normotensive rats. In the present study, we investigated the changes in the arterial pressure and in the pressor responses to ANG II icv in spontaneously hypertensive rats (SHRs) and 2-kidney, 1-clip (2K1C) hypertensive rats treated with H2O2 injected icv or ATZ injected icv or intravenously (iv). Adult male SHRs or Holtzman rats (n = 5-10/group) with stainless steel cannulas implanted in the lateral ventricle were used. In freely moving rats, H2O2 (5 μmol/1 μl) or ATZ (5 nmol/1 μl) icv reduced the pressor responses to ANG II (50 ng/1 µl) icv in SHRs (11 ± 3 and 17 ± 4 mmHg, respectively, vs. 35 ± 6 mmHg) and 2K1C hypertensive rats (3 ± 1 and 16 ± 3 mmHg, respectively, vs. 26 ± 2 mmHg). ATZ (3.6 mmol/kg of body weight) iv alone or combined with H2O2 icv also reduced icv ANG II-induced pressor response in SHRs and 2K1C hypertensive rats. Baseline arterial pressure was also reduced (-10 to -15 mmHg) in 2K1C hypertensive rats treated with H2O2 icv and ATZ iv alone or combined and in SHRs treated with H2O2 icv alone or combined with ATZ iv. The results suggest that exogenous or endogenous H2O2 acting centrally produces anti-hypertensive effects impairing central pressor mechanisms activated by ANG II in SHRs or 2K1C hypertensive rats.
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Mickelson B, Herfel TM, Booth J, Wilson RP. Nutrition. THE LABORATORY RAT 2020:243-347. [DOI: 10.1016/b978-0-12-814338-4.00009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Wang X, Zhang G, Zhu C, Lin L, Zhao Z, Yu X, Liu G, Zhang H, Li Q, Dong W, Wang J. Vitamin C Prevents Hydrocortisone-Induced Injury in HMEC-1 through Promoting Bestrophin-3 Expression. Nutr Cancer 2019; 71:852-860. [PMID: 30672332 DOI: 10.1080/01635581.2018.1539184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVE To investigate the protective effects and underlying mechanisms of Vitamin C (VC) on hydrocortisone (HC)-induced cell injury in human microvascular endothelial cells (HMEC). METHODS Cell viability was measured by CCK-8 assay and the expression of Best-3 was detected by Western blotting assay. The experiment was divided into normal control, HC injury group, VC treatment groups, HC + Best-3 siRNA group, HC + VC + Best-3 siRNA group, HC + pcDNA3.1 Best-3 group, and HC + VC + pcDNA3.1 Best-3 group. RESULTS HC inhibited HMEC-1 cell viability was balanced with lower expression of Best-3 in a dose-dependent manner. Conversely, VC promoted HMEC-1 cell viability was paralleled to higher expression of Best-3 in a dose-dependent manner. Silencing Best-3 with Best-3 siRNA inhibited HMEC-1 cell viability, however, over-expression of Best-3 with pcDNA3.1 Best-3 promoted HMEC-1 cell viability. Moreover, VC and over-expression of Best-3 prevented HC-induced HMEC-1 cell apoptosis; however, silencing Best-3 further enhanced HC-induced HMEC-1 cell apoptosis. HC reduced Best-3 expression, which was alleviated by VC treatment. HC treatment decreased Bcl-2 expression, facilitated Bax expression. Both of VC and over-expression of Best-3 promoted Bcl-2 expression and decreased Bax expression. Additionally, VC and Best-3 expression have a synergistic effect. CONCLUSIONS VC can efficiently attenuate HC-induced HMEC-1 cell injury, which may be related to promote Best-3 expression.
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Affiliation(s)
- Xuexin Wang
- a Department of Rehabilitation Medicine , Yuhuangding Hospital , Yantai , PR China
| | - Guoping Zhang
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Chaohua Zhu
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Lei Lin
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Zhenshuan Zhao
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Xiaoguang Yu
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Guobin Liu
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Haijing Zhang
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Quanhai Li
- c Department of Cell Therapy Center , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Wei Dong
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
| | - Jian Wang
- b Department of Orthopedics , The First Hospital of Hebei Medical University , Shijiazhuang , PR China
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Ahmad KA, Yuan Yuan D, Nawaz W, Ze H, Zhuo CX, Talal B, Taleb A, Mais E, Qilong D. Antioxidant therapy for management of oxidative stress induced hypertension. Free Radic Res 2017; 51:428-438. [PMID: 28427291 DOI: 10.1080/10715762.2017.1322205] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hypertension is considered as the most common risk factor for cardiovascular diseases, also is regarded as a leading cause of the mortality and morbidity worldwide. The mechanisms underlying the pathological process of hypertension are not completely explained. However, there is growing evidence that increased oxidative stress plays an important role in the pathophysiology of hypertension. Several preclinical studies and clinical trials have indicated that antioxidant therapy is important for management of hypertension, using antioxidants compounds such as alpha tocopherol (Vit E) and ascorbic acid (Vit C), polyphenols with others and some antihypertensive drugs that are now in clinical use (e.g. ACEIs, ARBs, novel B-blockers, dihydropyridine CCBs) which have antioxidative pleiotropic effects. The purpose of this review is to highlight the importance of antioxidant therapy for management of oxidative stress induced hypertension. Furthermore, we review the current knowledge in the oxidative stress and its significance in hypertension.
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Affiliation(s)
- Khalil Ali Ahmad
- a Department of Pharmacology, School of Pharmacy , China Pharmaceutical University , Nanjing , China
| | - Dai Yuan Yuan
- a Department of Pharmacology, School of Pharmacy , China Pharmaceutical University , Nanjing , China
| | - Waqas Nawaz
- b School of Basic Medicine and Clinical Pharmacy , China Pharmaceutical University , Nanjing , China
| | - Hong Ze
- a Department of Pharmacology, School of Pharmacy , China Pharmaceutical University , Nanjing , China
| | - Chen Xue Zhuo
- a Department of Pharmacology, School of Pharmacy , China Pharmaceutical University , Nanjing , China
| | - Bashar Talal
- c Department of Pharmacy Practice, JSS College of Pharmacy , JSS University , Mysuru , India
| | - Abdoh Taleb
- a Department of Pharmacology, School of Pharmacy , China Pharmaceutical University , Nanjing , China
| | - Enos Mais
- d Department of Pharmacognosy, School of Pharmacy , China Pharmaceutical University , Nanjing , China
| | - Ding Qilong
- a Department of Pharmacology, School of Pharmacy , China Pharmaceutical University , Nanjing , China
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González J, Valls N, Brito R, Rodrigo R. Essential hypertension and oxidative stress: New insights. World J Cardiol 2014; 6:353-366. [PMID: 24976907 PMCID: PMC4072825 DOI: 10.4330/wjc.v6.i6.353] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 03/01/2014] [Accepted: 05/08/2014] [Indexed: 02/06/2023] Open
Abstract
Essential hypertension is a highly prevalent pathological condition that is considered as one of the most relevant cardiovascular risk factors and is an important cause of morbidity and mortality around the world. Despite the fact that mechanisms underlying hypertension are not yet fully elucidated, a large amount of evidence shows that oxidative stress plays a central role in its pathophysiology. Oxidative stress can be defined as an imbalance between oxidant agents, such as superoxide anion, and antioxidant molecules, and leads to a decrease in nitric oxide bioavailability, which is the main factor responsible for maintaining the vascular tone. Several vasoconstrictor peptides, such as angiotensin II, endothelin-1 and urotensin II, act through their receptors to stimulate the production of reactive oxygen species, by activating enzymes like NADPH oxidase and xanthine oxidase. The knowledge of the mechanism described above has allowed generating new therapeutic strategies against hypertension based on the use of antioxidants agents, including vitamin C and E, N-Acetylcysteine, polyphenols and selenium, among others. These substances have different therapeutic targets, but all represent antioxidant reinforcement. Several clinical trials using antioxidants have been made. The aim of the present review is to provide new insights about the key role of oxidative stress in the pathophysiology of essential hypertension and new clinical attempts to demonstrate the usefulness of antioxidant therapy in the treatment of hypertension.
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Tveden-Nyborg P, Lykkesfeldt J. Does vitamin C deficiency increase lifestyle-associated vascular disease progression? Evidence based on experimental and clinical studies. Antioxid Redox Signal 2013; 19:2084-104. [PMID: 23642093 DOI: 10.1089/ars.2013.5382] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
SIGNIFICANCE Despite continuous advances in the prevention of cardiovascular disease (CVD), critical issues associated with an unhealthy lifestyle remain an increasing cause of morbidity and mortality in industrialized countries. RECENT ADVANCES A growing body of literature supports a specific role for vitamin C in a number of reactions that are associated with vascular function and control including, for example, nitric oxide bioavailability, lipid metabolism, and vascular integrity. CRITICAL ISSUES A large body of epidemiological evidence supports a relationship between poor vitamin C status and increased risk of developing CVD, and the prevalence of deficiency continues to be around 10%-20% of the general Western population although this problem could easily and cheaply be solved by supplementation. However, large intervention studies using vitamin C have not found a beneficial effect of supplementation. This review outlines the proposed mechanism by which vitamin C deficiency worsens CVD progression. In addition, it discusses problems with the currently available literature, including the discrepancies between the large intervention studies and the experimental and epidemiological literature. FUTURE DIRECTIONS Increased insights into vitamin C deficiency-mediated CVD progression will enable the design of future randomized controlled trials that are better suited to test the efficacy of vitamin C in disease prevention as well as the identification of high-risk individuals which could possibly benefit from supplementation.
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Affiliation(s)
- Pernille Tveden-Nyborg
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Frederiksberg, Denmark
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de Queiroz TM, Monteiro MMO, Braga VA. Angiotensin-II-derived reactive oxygen species on baroreflex sensitivity during hypertension: new perspectives. Front Physiol 2013; 4:105. [PMID: 23717285 PMCID: PMC3651964 DOI: 10.3389/fphys.2013.00105] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 04/24/2013] [Indexed: 12/12/2022] Open
Abstract
Hypertension is a multifactorial disorder, which has been associated with the reduction in baroreflex sensitivity (BRS) and autonomic dysfunction. Several studies have revealed that increased reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase, following activation of type 1 receptor (AT1R) by Angiotensin-(Ang) II, the main peptide of the Renin–Angiotensin–Aldosterone System (RAAS), is the central mechanism involved in Ang-II-derived hypertension. In the present review, we will discuss the role of Ang II and oxidative stress in hypertension, the relationship between the BRS and the genesis of hypertension and how the oxidative stress triggers baroreflex dysfunction in several models of hypertension. Finally, we will describe some novel therapeutic drugs for improving the BRS during hypertension.
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Affiliation(s)
- Thyago M de Queiroz
- Department of Biotechnology, Biotechnology Center, Federal University of Paraiba João Pessoa, Brazil
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Larson AJ, Symons JD, Jalili T. Therapeutic potential of quercetin to decrease blood pressure: review of efficacy and mechanisms. Adv Nutr 2012; 3:39-46. [PMID: 22332099 PMCID: PMC3262612 DOI: 10.3945/an.111.001271] [Citation(s) in RCA: 161] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epidemiological studies beginning in the 1990s have reported that intake of quercetin, a polyphenolic flavonoid found in a wide variety of plant-based foods, such as apples, onions, berries, and red wine, is inversely related to cardiovascular disease. More recent work using hypertensive animals and humans (>140 mm Hg systolic and >90 mm Hg diastolic) indicates a decrease in blood pressure after quercetin supplementation. A number of proposed mechanisms may be responsible for the observed blood pressure decrease such as antioxidant effects, inhibition of angiotensin-converting enzyme activity, and improved endothelium-dependent and -independent function. The majority of these mechanisms have been identified using animal models treated with quercetin, and relatively few have been corroborated in human studies. The purpose of this review is to examine the evidence supporting the role of quercetin as a potential therapeutic agent and the mechanisms by which quercetin might exert its blood pressure-lowering effect.
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Affiliation(s)
- Abigail J. Larson
- Department of Nutrition, Exercise, and Health Science, Central Washington University, Ellensburg, WA
| | - J. David Symons
- Division of Nutrition, University of Utah, Salt Lake City, UT
| | - Thunder Jalili
- Division of Nutrition, University of Utah, Salt Lake City, UT,To whom correspondence should be addressed. E-mail:
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Campos RR, Oliveira-Sales EB, Nishi EE, Boim MA, Dolnikoff MS, Bergamaschi CT. The role of oxidative stress in renovascular hypertension. Clin Exp Pharmacol Physiol 2011; 38:144-52. [PMID: 20678153 DOI: 10.1111/j.1440-1681.2010.05437.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
1. There is mounting evidence that increased oxidative stress and sympathetic nerve activity play important roles in renovascular hypertension. In the present review, we focus on the importance of oxidative stress in two distinct populations of neurons involved with cardiovascular regulation: those of the rostral ventrolateral medulla (RVLM) and those of the paraventricular nucleus of the hypothalamus (PVN) in the maintenance of sympathoexcitation and hypertension in two kidney-one clip (2K1C) hypertensive rats. Furthermore, the role of oxidative stress in the clipped kidney is also discussed. 2. In the studies reviewed in this article, it was found that hypertension and renal sympathoexcitation in 2K1C rats were associated with an increase in Angiotensin II type one receptor (AT(1) ) expression and in oxidative markers within the RVLM, PVN and in the clipped kidneys of 2K1C rats. Furthermore, acute or chronic anti-oxidant treatment decreased blood pressure and sympathetic activity, and improved the baroreflex control of heart rate and renal sympathetic nerve activity in 2K1C rats. Tempol or vitamin C administration in the RVLM, PVN or systemically all reduced blood pressure and renal sympathetic activity. Cardiovascular improvement in response to chronic anti-oxidant treatment was associated with a downregulation of AT(1) receptors, as well as oxidative markers in the central nuclei and clipped kidney. 3. The data discussed in the present review support the idea that an increase in oxidative stress within the RVLM, PVN and in the ischaemic kidney plays a major role in the maintenance of sympathoexcitation and hypertension in 2K1C rats.
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Affiliation(s)
- Ruy R Campos
- Department of Physiology, Cardiovascular Division Department of Medicine, Nephrology Division, Federal University of São Paulo, São Paulo, Brazil.
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Rodrigo R, González J, Paoletto F. The role of oxidative stress in the pathophysiology of hypertension. Hypertens Res 2011; 34:431-40. [PMID: 21228777 DOI: 10.1038/hr.2010.264] [Citation(s) in RCA: 284] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hypertension is considered to be the most important risk factor in the development of cardiovascular disease. An increasing body of evidence suggests that oxidative stress, which results in an excessive generation of reactive oxygen species (ROS), has a key role in the pathogenesis of hypertension. The modulation of the vasomotor system involves ROS as mediators of vasoconstriction induced by angiotensin II, endothelin-1 and urotensin-II, among others. The bioavailability of nitric oxide (NO), which is a major vasodilator, is highly dependent on the redox status. Under physiological conditions, low concentrations of intracellular ROS have an important role in the normal redox signaling maintaining vascular function and integrity. However, under pathophysiological conditions, increased levels of ROS contribute to vascular dysfunction and remodeling through oxidative damage. In human hypertension, an increase in the production of superoxide anions and hydrogen peroxide, a decrease in NO synthesis and a reduction in antioxidant bioavailability have been observed. In turn, antioxidants are reducing agents that can neutralize these oxidative and otherwise damaging biomolecules. The use of antioxidant vitamins, such as vitamins C and E, has gained considerable interest as protecting agents against vascular endothelial damage. Available data support the role of these vitamins as effective antioxidants that can counteract ROS effects. This review discusses the mechanisms involved in ROS generation, the role of oxidative stress in the pathogenesis of vascular damage in hypertension, and the possible therapeutic strategies that could prevent or treat this disorder.
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Affiliation(s)
- Ramón Rodrigo
- Renal Pathophysiology Laboratory, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
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Oliveira-Sales EB, Colombari DSA, Davisson RL, Kasparov S, Hirata AE, Campos RR, Paton JFR. Kidney-induced hypertension depends on superoxide signaling in the rostral ventrolateral medulla. Hypertension 2010; 56:290-6. [PMID: 20606111 DOI: 10.1161/hypertensionaha.110.150425] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2010] [Accepted: 06/01/2010] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species in peripheral cardiovascular tissues are implicated in the pathogenesis of 2 kidney-1 clip hypertension. We recently identified an imbalance between reactive oxygen species generation and oxidant scavenging in the rostral ventrolateral medulla (RVLM) of 2 kidney-1 clip in rats. We tested whether enhanced superoxide signaling in RVLM of 2 kidney-1 clip rats contributes to the chronic hypertension via sympathetic activation in conscious rats. We enhanced superoxide scavenging in RVLM by overexpressing cytoplasmically targeted superoxide dismutase using an adenoviral vector (Ad-CMV-CuZnSOD) in Wistar rats (male, 150 to 180 g) in which the left renal artery was occluded partially 3 weeks earlier. Hypertension was documented using radiotelemetry recording of arterial pressure in conscious rats for 6 weeks. Renovascular hypertension elevated both serine phosphorylation of p47phox subunit of NADPH and superoxide levels in RVLM. The elevated superoxide levels were normalized by expression of CuZnSOD in RVLM. Moreover, the hypertension produced in the 2 kidney-1 clip rats was reversed 1 week after viral-mediated expression of CuZnSOD. This antihypertensive effect was maintained and associated with a decrease in the low-frequency spectra of systolic blood pressure variability, suggesting reduced sympathetic vasomotor tone. The expression of CuZnSOD was localized to RVLM neurons, of which some contained tyrosine hydroxylase. None of the above variables changed in control rats receiving Ad-CMV-eGFP in RVLM. In Goldblatt hypertension, superoxide signaling in the RVLM plays a major role in the generation of sympathetic vasomotor tone and the chronic sustained hypertension in this animal model.
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Affiliation(s)
- Elizabeth B Oliveira-Sales
- Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, University of Bristol, UK
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Nounou HA, Deif MM, Arafah M. The influence of dexamethasone and the role of some antioxidant vitamins in the pathogenesis of experimental bronchial asthma. J Exp Pharmacol 2010; 2:93-103. [PMID: 27186095 PMCID: PMC4863291 DOI: 10.2147/jep.s8313] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Bronchial asthma is a disease characterized by paroxysmal and reversible obstruction of the airways. The imbalance between the oxidant and antioxidant system that is called oxidative stress is critical in asthma pathogenesis. It is likely, therefore, that antioxidants may be effective in the treatment of asthma. Systemic treatment with glucocorticoids has been reported to inhibit smooth muscle hypercontraction which may account partially for their beneficial effects in the treatment of asthma. OBJECTIVE The present study was conducted in order to study the effect of dexamethasone and some antioxidant vitamins on interleukin-4 (IL-4), immunoglobulin E (IgE) and heat shock protein 70 (Hsp70) in bronchial asthma in rats, and to recognize their possible beneficial role. METHOD The study was conducted on 60 adult male albino rats randomly divided into 4 groups (15 for each group): including normal control group (group A); asthma model group where rats were sensitized by ovalbumin and challenged with antigen aerosol producing bronchial asthma (group B); asthma model group treated with antioxidant vitamins (vitamin E and vitamin C) (group C); asthma model group treated with dexamethasone (group D). Blood and lung samples were collected from all groups. RESULTS AND CONCLUSION Our results revealed a significant decrease of serum reduced glutathione (GSH) levels among groups B, C and D as compared to group A, while there was a significant increase in group C and D as compared to group B. Antioxidant and dexamethasone treatment resulted in a significant decrease of serum IL-4, malondialdehyde (MDA), and serum IgE levels in group C and D as compared to group B. Antioxidant treatment resulted in a significant decrease of serum Hsp70 level as compared to group B, while dexamethasone treatment resulted in a significant increase of serum Hsp70 level as compared to group B. This study suggests that it is likely that a combination of antioxidant vitamins may be effective in the treatment of asthma, considering their reported effects on lowering MDA, IL-4, and IgE levels, and the similar beneficial effects of dexamethasone in addition to increasing the expression of Hsp70 in the studied model of bronchial asthma.
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Affiliation(s)
- H A Nounou
- Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - M M Deif
- Physiology Department, College of Medicine, Alexandria University, Egypt
| | - M Arafah
- Pathology Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Nishi EE, Campos RR, Bergamaschi CT, de Almeida VR, Ribeiro DA. Vitamin C prevents DNA damage induced by renovascular hypertension in multiple organs of Wistar rats. Hum Exp Toxicol 2010; 29:593-9. [PMID: 20053703 DOI: 10.1177/0960327109358267] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The aim of this study was to investigate, through the single-cell gel (comet) assay, whether vitamin C is able to protect against renovascular hypertension-induced genotoxicity in multiple organs. A total of 32 male Wistar rats were divided into four groups: negative control (n = 6); animals treated with vitamin C (n = 6); hypertensive rats (n = 10) and hypertensive rats and treated with vitamin C (n = 10). Hypertension was induced as a result of partial obstruction of the left renal artery by means of a silver clip during 6 weeks. Vitamin C was administered at 150 mg/kg during 7 consecutive days before the end of the experimental period. The results showed that vitamin C was able to protect blood cells against hypertension-induced genotoxicity. Brain, liver and heart cells were also protected by vitamin C following hypertension-induced genotoxic damage. Regarding blood pressure, vitamin C reduced the hypertensive state. In conclusion, our results suggest that vitamin C can prevent hypertension-induced DNA damage in blood, liver, brain and heart cells as well as to normalize the blood pressure of rats.
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Affiliation(s)
- Erika Emy Nishi
- Department of Physiology, Cardiovascular Division, Paulista Medical School, Federal University of Sao Paulo, UNIFESP, SP, Brazil
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Tian N, Moore RS, Braddy S, Rose RA, Gu JW, Hughson MD, Manning RD. Interactions between oxidative stress and inflammation in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 2007; 293:H3388-95. [PMID: 17921322 DOI: 10.1152/ajpheart.00981.2007] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The goal of this study was to test the hypothesis that increases in oxidative stress in Dahl S rats on a high-salt diet help to stimulate renal nuclear factor-kappaB (NF-kappaB), renal proinflammatory cytokines, and chemokines, thus contributing to hypertension, renal damage, and dysfunction. We specifically studied whether antioxidant treatment of Dahl S rats on high Na intake would decrease renal inflammation and thus attenuate the hypertensive and adverse renal responses. Sixty-four 7- to 8-wk-old Dahl S or R/Rapp strain rats were maintained for 5 wk on high Na (8%) or high Na + vitamins C (1 g/l in drinking water) and E (5,000 IU/kg in food). Arterial and venous catheters were implanted at day 21. By day 35 in the high-Na S rats, antioxidant treatment significantly increased the renal reduced-to-oxidized glutathione ratio and decreased renal cortical H(2)O(2) and O(2)(*-) release and renal NF-kappaB. Antioxidant treatment with vitamins C and E in high-Na S rats also decreased renal monocytes/macrophages in the glomeruli, cortex, and medulla, decreased tumor necrosis factor-alpha by 39%, and decreased monocyte chemoattractant protein-1 by 38%. Vitamin-treated, high-Na S rats also experienced decreases in arterial pressure, urinary protein excretion, renal tubulointerstitial damage, and glomerular necrosis and increases in glomerular filtration rate and renal plasma flow. In conclusion, antioxidant treatment of high-Na Dahl S rats decreased renal inflammatory cytokines and chemokines, renal immune cells, NF-kappaB, and arterial pressure and improved renal function and damage.
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Affiliation(s)
- N Tian
- Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
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Rodrigo R, Guichard C, Charles R. Clinical pharmacology and therapeutic use of antioxidant vitamins. Fundam Clin Pharmacol 2007; 21:111-27. [PMID: 17391284 DOI: 10.1111/j.1472-8206.2006.00466.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The clinical use of antioxidants has gained considerable interest during the last decade. It was suggested from epidemiological studies that diets high in fruits and vegetables might help decrease the risk of cardiovascular disease. Therefore, supplements of vitamins C and E were applied through protocols aimed to prevent diseases such as atherosclerosis, preeclampsia or hypertension, thought to be mediated by oxidative stress. Despite the biological properties of these vitamins could account for an effective protection, as shown by several clinical and experimental studies, their efficacy remains controversial in the light of some recent clinical trials and meta-analyses. However, the methodology of these studies, criteria for selection of patients, the uncertain extent of progression of the disease when initiating supplementation, the lack of mechanistic studies containing basic scientific aspects, such as the bioavailability, pharmacokinetic properties, and the nature of the antioxidant sources of vitamins, could account for the inconsistency of the various clinical trials and meta-analyses assessing the efficacy of these vitamins to prevent human diseases. This review presents a survey of the clinical use of antioxidant vitamins E and C, proposing study models based on the biological effects of these compounds likely to counteract the pathophysiological mechanisms able to explain the structural and functional organ damage.
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Affiliation(s)
- Ramón Rodrigo
- Laboratory of Renal Pathophysiology, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, Santiago, Chile.
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Paliege A, Pasumarthy A, Parsumathy A, Mizel D, Yang T, Schnermann J, Bachmann S. Effect of apocynin treatment on renal expression of COX-2, NOS1, and renin in Wistar-Kyoto and spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 2006; 290:R694-700. [PMID: 16467505 DOI: 10.1152/ajpregu.00219.2005] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Macula densa (MD) cells of the juxtaglomerular apparatus (JGA) synthesize type 1 nitric oxide synthase (NOS1) and type 2 cyclooxygenase (COX-2). Both nitric oxide (NO) and prostaglandins have been considered to mediate or modulate the control of renin secretion. Reactive oxygen species (ROS) produced locally by NADPH oxidase may influence NO bioavailability. We have tested the hypothesis that in hypertension elevated ROS levels may modify the expression of NOS1 and COX-2 in the JGA, thereby interacting with juxtaglomerular signaling. To this end, spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY) received the specific NADPH oxidase inhibitor, apocynin, during 3 wk. Renal functional and histochemical parameters, plasma renin activity (PRA), and as a measure of ROS activity, urinary isoprostane excretion (IP) were evaluated. Compared with WKY, IP levels in untreated SHR were 2.2-fold increased, and NOS1 immunoreactiviy (IR) of JGA 1.5-fold increased, whereas COX-2 IR was reduced to 35%, renin IR to 51%, and PRA to 7%. Apocynin treatment reduced IP levels in SHR to 52%, NOS1 IR to 69%, and renin IR to 62% of untreated SHR, whereas renin mRNA, COX-2 IR, glomerular filtration rate, PRA, and systolic blood pressure remained unchanged. WKY revealed no changes under apocynin treatment. These data show that NADPH oxidase is an important contributor to elevated levels of ROS in hypertension. Upregulation of MD NOS1 in SHR may have the potential of blunting the functional impact of ROS at the level of bioavailable NO. Downregulated COX-2 and renin levels in SHR are apparently unrelated to oxidative stress, since apocynin treatment had no effect on these parameters.
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Affiliation(s)
- A Paliege
- Medical Faculty of the Charité, Department of Vegetative Anatomy, Berlin, Germany
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Tian N, Thrasher KD, Gundy PD, Hughson MD, Manning RD. Antioxidant Treatment Prevents Renal Damage and Dysfunction and Reduces Arterial Pressure in Salt-Sensitive Hypertension. Hypertension 2005; 45:934-9. [PMID: 15837840 DOI: 10.1161/01.hyp.0000160404.08866.5a] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The goal of this study was to test the hypothesis that oxidative stress in Dahl salt-sensitive (SS) rats on a high-sodium intake contributes to the progression of renal damage, the decreases in renal hemodynamics, and the development of hypertension. We specifically studied whether antioxidant therapy, using vitamins C and E, could help prevent renal damage and glomerular filtration rate (GFR) and renal plasma flow reductions and attenuate the increases in arterial pressure. Thirty-three 7- to 8-week old Dahl SS/Rapp strain rats were placed on either a high-sodium (8%) or a low-sodium (0.3%) diet with or without vitamin E (111 IU/d) in the food and 98 mg/d vitamin C in the drinking water for 5 weeks. Rats were equipped with indwelling arterial and venous catheters at day 21. By day 35 in the rats with high-sodium diet, vitamin C and E treatment significantly decreased renal cortical and medullary O2*- release, mean arterial pressure, urinary protein excretion, glomerular necrosis, and renal tubulointerstitial damage. At this time, GFR significantly decreased in the high-sodium diet group (1.6+/-0.2 mL/min) when compared with either the high-sodium plus vitamins C and E (2.9+/-0.2 mL/min) or the low-sodium diet group (2.9+/-0.3 mL/min). In SS rats on high-sodium diet, renal plasma flow decreased 40%, and this reduced flow was restored by vitamin treatment. In Dahl salt-sensitive hypertension, increased oxidative stress plays an important role in the renal damage, decreases in renal hemodynamics, and increases in arterial pressure that occur. Antioxidant treatment with vitamins C and E improves renal dysfunction, lessens renal injury, and decreases arterial pressure in Dahl salt-sensitive hypertension.
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Affiliation(s)
- Niu Tian
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, USA
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