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Fouladi M, Mahmoudabady M, Gholamnezhad Z, Shabab S, Niazmand S, Salmani H. Impact of Endurance Exercise Training on Biomarkers of Aortic Endothelial Damage in Diabetic Rats. Cardiovasc Ther 2024; 2024:6025911. [PMID: 39742025 PMCID: PMC11251799 DOI: 10.1155/2024/6025911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 04/09/2024] [Accepted: 05/07/2024] [Indexed: 01/03/2025] Open
Abstract
Given the heightened risk of diabetes-related cardiovascular events associated with inactivity, this study investigates the molecular mechanisms of vascular damage in streptozotocin (STZ)-induced diabetic rats. The aim is to elucidate the impact of different exercises (interval and continuous training) and metformin on biochemical parameters, aortic injury, oxidative stress, and inflammation to provide insights into potential therapeutic interventions for diabetes-associated vascular complications. Male Wistar rats were administered a single dose of STZ (60 mg/kg) to induce diabetes. Diabetic rats underwent either interval training or continuous training (40 min/day, 5 days/week, 6 weeks), received metformin (300 mg/kg), or a combination of metformin and exercise. After 6 weeks, biochemical parameters in serum and oxidative stress markers and mRNA expression of endothelial nitric oxide synthase (eNOS), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and intercellular adhesion molecule-1 (ICAM-1) in aorta tissue were assessed. Serum levels of fasting blood sugar (FBS), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), TG/HDL, TC/HDL, and LDL/HDL ratios were significantly reduced in all treatment groups compared to the diabetes group. Both types of exercises, metformin, and exercise+metformin combinations, significantly reduced oxidative stress by decreasing malondialdehyde (MDA) and enhancing the antioxidant status in the aortic tissue compared to the diabetic group. In addition, in exercise groups, metformin, and combination groups, the expression of eNOS was significantly elevated, while LOX-1 and ICAM-1 expression significantly decreased compared to the diabetic group. In most cases, the combination of exercise and metformin (especially interval training) was more effective than exercise alone. It seems that exercise along with taking metformin can be considered as a therapeutic method by improving hyperglycemia and hyperlipidemia and reducing oxidative stress and vascular inflammatory responses, leading to ameliorating biomarkers function related to endothelial damage in experimental diabetes conditions.
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Affiliation(s)
- Mahtab Fouladi
- Department of PhysiologyFaculty of MedicineMashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Mahmoudabady
- Department of PhysiologyFaculty of MedicineMashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research CenterMashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Gholamnezhad
- Department of PhysiologyFaculty of MedicineMashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research CenterMashhad University of Medical Sciences, Mashhad, Iran
| | - Sadegh Shabab
- Department of PhysiologyFaculty of MedicineMashhad University of Medical Sciences, Mashhad, Iran
| | - Saeed Niazmand
- Department of PhysiologyFaculty of MedicineMashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research CenterMashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Salmani
- Department of Physiology and PharmacologyFaculty of MedicineSabzevar University of Medical Sciences, Sabzevar, Iran
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Sonobe T, Kakinuma Y. Non-neuronal cell-derived acetylcholine, a key modulator of the vascular endothelial function in health and disease. Front Cardiovasc Med 2024; 11:1388528. [PMID: 38812748 PMCID: PMC11133745 DOI: 10.3389/fcvm.2024.1388528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/06/2024] [Indexed: 05/31/2024] Open
Abstract
Vascular endothelial cells play an important role in regulating peripheral circulation by modulating arterial tone in the microvasculature. Elevated intracellular Ca2+ levels are required in endothelial cells to induce smooth muscle relaxation via endothelium-dependent mechanisms such as nitric oxide production, prostacyclin, and endothelial cell hyperpolarization. It is well established that exogenous administration of acetylcholine can increase intracellular Ca2+ concentrations, followed by endothelium-dependent vasodilation. Although endogenous acetylcholine's regulation of vascular tone remains debatable, recent studies have reported that endogenously derived acetylcholine, but not neuronal cell-derived acetylcholine, is a key modulator of endothelial cell function. In this minireview, we summarize the current knowledge of the non-neuronal cholinergic system (NNCS) in vascular function, particularly vascular endothelial cell function, which contributes to blood pressure regulation. We also discuss the possible pathophysiological impact of endothelial NNCS, which may induce the development of vascular diseases due to endothelial dysfunction, and the potential of endothelial NNCS as a novel therapeutic target for endothelial dysfunction in the early stages of metabolic syndrome, diabetes, and hypertension.
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Affiliation(s)
- Takashi Sonobe
- Department of Bioregulatory Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
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O'Brien MW, Shivgulam ME. Mechanistic, participant, and movement-related factors that contribute to low-flow-mediated constriction. Eur J Appl Physiol 2023; 123:2687-2697. [PMID: 37804365 DOI: 10.1007/s00421-023-05332-y] [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: 04/21/2023] [Accepted: 09/21/2023] [Indexed: 10/09/2023]
Abstract
Endothelial function is commonly determined via the ultrasound-based flow-mediated dilation (FMD) technique which assesses arterial dilation in response to a hyperemia response following distal cuff occlusion. However, the low-flow-mediated constriction (L-FMC) response during cuff-induced ischemia is often overlooked. L-FMC provides unique information regarding endothelial function, but vascular researchers may be unclear on what this metric adds. Therefore, the objective of this review was to examine the mechanistic determinants and participant-level factors of L-FMC. Existing mechanistic studies have demonstrated that vasoreactivity to low flow may be mediated via non-nitric oxide vasodilators (i.e., endothelial hyperpolarizing factors and/or prostaglandins), inflammatory markers, and enhancement of vasoconstriction via endothelin-1. In general, participant-level factors such as aging and presence of cardiovascular conditions generally are associated with attenuated L-FMC responses. However, the influence of sex on L-FMC is unclear with divergent results between L-FMC in upper versus lower limb vessels. The ability of aerobic exercise to augment L-FMC (i.e., make more negative) is well supported, but there is a major gap in the literature concerning the mechanistic underpinnings of this observation. This review summarizes that while larger L-FMC responses are generally healthy, the impact of interventions to augment/attenuate L-FMC has not included mechanistic measures that would provide insight into non-nitric oxide-based endothelial function. Clarifications to terminology and areas of further inquiry as it relates to the specific pharmacological, individual-level factors, and lifestyle behaviors that impact L-FMC are highlighted. A greater integration of mechanistic work alongside applied lifestyle interventions is required to better understand endothelial cell function to reductions in local blood flow.
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Affiliation(s)
- Myles W O'Brien
- School of Physiotherapy (Faculty of Health) and Department of Medicine (Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
- Geriatric Medicine Research, Dalhousie University & Nova Scotia Health, Halifax, NS, B3H 4R2, Canada.
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Razan MR, Amissi S, Islam RA, Graham JL, Stanhope KL, Havel PJ, Rahimian R. Moderate-Intensity Exercise Improves Mesenteric Arterial Function in Male UC Davis Type-2 Diabetes Mellitus (UCD-T2DM) Rats: A Shift in the Relative Importance of Endothelium-Derived Relaxing Factors (EDRF). Biomedicines 2023; 11:biomedicines11041129. [PMID: 37189747 DOI: 10.3390/biomedicines11041129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/01/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
The beneficial cardiovascular effects of exercise are well documented, however the mechanisms by which exercise improves vascular function in diabetes are not fully understood. This study investigates whether there are (1) improvements in blood pressure and endothelium-dependent vasorelaxation (EDV) and (2) alterations in the relative contribution of endothelium-derived relaxing factors (EDRF) in modulating mesenteric arterial reactivity in male UC Davis type-2 diabetes mellitus (UCD-T2DM) rats, following an 8-week moderate-intensity exercise (MIE) intervention. EDV to acetylcholine (ACh) was measured before and after exposure to pharmacological inhibitors. Contractile responses to phenylephrine and myogenic tone were determined. The arterial expressions of endothelial nitric oxide (NO) synthase (eNOS), cyclooxygenase (COX), and calcium-activated potassium channel (KCa) channels were also measured. T2DM significantly impaired EDV, increased contractile responses and myogenic tone. The impairment of EDV was accompanied by elevated NO and COX importance, whereas the contribution of prostanoid- and NO-independent (endothelium-derived hyperpolarization, EDH) relaxation was not apparent compared to controls. MIE 1) enhanced EDV, while it reduced contractile responses, myogenic tone and systolic blood pressure (SBP), and 2) caused a shift away from a reliance on COX toward a greater reliance on EDH in diabetic arteries. We provide the first evidence of the beneficial effects of MIE via the altered importance of EDRF in mesenteric arterial relaxation in male UCD-T2DM rats.
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Affiliation(s)
- Md Rahatullah Razan
- Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA
| | - Said Amissi
- Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA
| | - Rifat Ara Islam
- Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA
| | - James L Graham
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
- Department of Nutrition, University of California, Davis, CA 95616, USA
| | - Kimber L Stanhope
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
- Department of Nutrition, University of California, Davis, CA 95616, USA
| | - Peter J Havel
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
- Department of Nutrition, University of California, Davis, CA 95616, USA
| | - Roshanak Rahimian
- Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA
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Sonobe T, Tsuchimochi H, Maeda H, Pearson JT. Increased contribution of KCa channels to muscle contraction induced vascular and blood flow responses in sedentary and exercise trained ZFDM rats. J Physiol 2022; 600:2919-2938. [PMID: 35551673 DOI: 10.1113/jp282981] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/04/2022] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Microvascular dysfunction in type 2 diabetes impairs blood flow redistribution during exercise and limits the performance of skeletal muscle and may cause early fatigability. Endothelium-dependent hyperpolarization (EDH), which mediates vasodilation in resistance arteries is known to be depressed in animals with diabetes. Here we report that low-intensity exercise training in ZFDM rats increased KCa channel-derived component in the vasodilator responses to muscle contraction than in sedentary rats, partly due to the increase in KCNN3 expression. These results suggest that low-intensity exercise training improves blood flow redistribution in contracting skeletal muscle in metabolic disease with diabetes via upregulation of EDH. ABSTRACT In resistance arteries, endothelium-dependent hyperpolarization (EDH) mediated vasodilation is depressed in diabetes. We hypothesized that downregulation of KCa channel derived EDH reduces exercise-induced vasodilation and blood flow redistribution in diabetes. To test this hypothesis, we evaluated vascular function in response to hindlimb muscle contraction, and the contribution of KCa channels in anaesthetised ZFDM, metabolic disease rats with type 2 diabetes. We also tested whether exercise training ameliorated the vascular response. Using in vivo microangiography, the hindlimb vasculature was visualized before and after rhythmic muscle contraction (0.5 s tetanus every 3 sec, 20 times) evoked by sciatic nerve stimulation (40 Hz). Femoral blood flow of the contracting hindlimb was simultaneously measured by an ultrasonic flowmeter. The contribution of KCa channels was investigated in the presence and absence of apamin and charybdotoxin. We found that vascular and blood flow responses to muscle contraction were significantly impaired at the level of small artery segments in ZFDM fa/fa rats compared to its lean control fa/+ rats. The contribution of KCa channels was also smaller in fa/fa than in fa/+ rats. Low-intensity exercise training for 12 weeks in fa/fa rats demonstrated minor changes in the vascular and blood flow response to muscle contraction. However, KCa-derived component in the response to muscle contraction was much greater in exercise trained than in sedentary fa/fa rats. These data suggest that exercise training increases the contribution of KCa channels among endothelium-dependent vasodilatory mechanisms to maintain vascular and blood flow responses to muscle contraction in this metabolic disease rat model. Abstract figure legend Low-intensity exercise training in ZFDM, metabolic disease rats with type 2 diabetes increases KCa channel-derived component of endothelium-dependent hyperpolarization in the vascular and blood flow responses to skeletal muscle contraction than the responses in sedentary rats, partly due to upregulation of KCNN3 protein expression. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Takashi Sonobe
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Hirotsugu Tsuchimochi
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - Hisashi Maeda
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
| | - James T Pearson
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.,Victoria Heart Institute and Monash Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, Australia
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Wan T, Hong KD, Lu SY. Exercise Prescription Intervention Rehabilitation Suggestions for Fatty Liver Patients. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:2506327. [PMID: 35469163 PMCID: PMC9034938 DOI: 10.1155/2022/2506327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/29/2022] [Indexed: 12/02/2022]
Abstract
In this study, the exercise prescription intervention rehabilitation suggestions for fatty liver patients were summarized as follows: first, basic exercises (brisk walking and jogging.), sports (swimming, badminton, and cycling), traditional Chinese medicine exercises (Taichi boxing and eight-section brocade), the aim of which is to improve overall physical strength and endurance of the body; second, exercise intensity, duration, and frequency; third, exercise precautions; and fourth, exercise prescription selection and suggestion.
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Affiliation(s)
- Tian Wan
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Kun-Da Hong
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Si-Yu Lu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
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O’Brien MW, Petterson JL, Wu Y, Bray NW, Kimmerly DS. What is the impact of aerobic fitness and movement interventions on low-flow-mediated vasoconstriction? A systematic review of observational and intervention studies. Vasc Med 2022; 27:193-202. [PMID: 35209754 PMCID: PMC11909780 DOI: 10.1177/1358863x211073480] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The cardiovascular benefits of physical exercise are well established. The vasoreactivity that occurs during reductions in local arterial blood flow, termed low-flow-mediated constriction (L-FMC), is a measure of endothelial-dependent vasoconstrictor function. It is unclear whether aerobic fitness and movement (or lack thereof) influences L-FMC. We systematically reviewed studies examining the impact of physical behaviours on L-FMC. To be included, cross-sectional and interventional studies had to examine the impact of a physical behaviour on L-FMC in adults. There were no language or date of publication restrictions. Sources were searched in May, 2021 and included Scopus, Embase, MEDLINE, CINAHL, and Academic Search Premier. National Institutes of Health quality assessment tools were used. Fourteen studies (15 arms; 313 participants; 398 total observations from four arteries) met the inclusion criteria. The study quality varied from four out of 14 (controlled intervention scoring) to nine out of 12 (longitudinal intervention with no control group scoring) with the total points dependent upon the study design. Conflicting results were reported for acute prolonged sitting studies (attenuated L-FMC: n = 1; no change: n = 1) and resistance exercise (increased L-FMC: n = 2; no change: n = 2). Most observational studies examining aerobic fitness (3/4 studies) and aerobic exercise interventions (4/5 studies) observed a favourable effect on L-FMC. Overall, the included studies support that higher aerobic fitness and engaging in aerobic exercise training may augment L-FMC responses. Our systematic review highlights the heterogeneity between studies and identifies current gaps and future directions to better our understanding of (in)activity, exercise, and posture on endothelial vasoconstrictor function. PROSPERO Registration No.: CRD42021248241.
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Affiliation(s)
- Myles W O’Brien
- Division of Kinesiology, Dalhousie University, Halifax, NS, Canada
| | | | - Yanlin Wu
- Division of Kinesiology, Dalhousie University, Halifax, NS, Canada
| | - Nick W Bray
- Faculty of Professional Studies, School of Kinesiology, Acadia University, Wolfville, NS, Canada
| | - Derek S Kimmerly
- Division of Kinesiology, Dalhousie University, Halifax, NS, Canada
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Is physical activity a future therapy for patients with Marfan syndrome? Orphanet J Rare Dis 2022; 17:46. [PMID: 35144638 PMCID: PMC8832740 DOI: 10.1186/s13023-022-02198-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/30/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction The international recommendations tend to avoid physical activity (PA) for patients with Marfan syndrome (MFS). However, exceptions have recently been made in the most recent recommendations for these patients, suggesting benefits from doing PA at low intensity only. Furthermore, there is no evidence that moderate aerobic or weight training can worsen the disease symptoms and increase mortality of MFS patients. The present review sums up the work carried out in the field of PA and MFS. The review aims to (1) identify the different types of exercise testing and training protocols and (2) discuss the feasibility and potentially beneficial nature of PA as an innovative way to manage MFS patients.
Methods The scientific literature was reviewed using the following words: Marfan syndrome, training, physical activity, evaluation, weight training, arterial disease, aneurysms, lung damage, aortic dissection, rupture. A total of 345 studies were prospected and 43 studies were included. Conclusions A limited number of studies were done in humans, however one demonstrated the feasibility of the management of MFS patients with PA. There were potential beneficial effects of PA on arterial structures, but this review also showed deleterious effects when PA was conducted at high intensities, corresponding to 75–85% of the maximal oxygen uptake. However, these effects have only been reported in animal studies.
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Impact of Lifestyles (Diet and Exercise) on Vascular Health: Oxidative Stress and Endothelial Function. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1496462. [PMID: 33062134 PMCID: PMC7533760 DOI: 10.1155/2020/1496462] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/25/2020] [Accepted: 08/28/2020] [Indexed: 02/07/2023]
Abstract
Healthy lifestyle and diet are associated with significant reduction in risk of obesity, type 2 diabetes, and cardiovascular diseases. Oxidative stress and the imbalance between prooxidants and antioxidants are linked to cardiovascular and metabolic diseases. Changes in antioxidant capacity of the body may lead to oxidative stress and vascular dysfunction. Diet is an important source of antioxidants, while exercise offers many health benefits as well. Recent findings have evidenced that diet and physical factors are correlated to oxidative stress. Diet and physical factors have debatable roles in modulating oxidative stress and effects on the endothelium. Since endothelium and oxidative stress play critical roles in cardiovascular and metabolic diseases, dietary and physical factors could have significant implications on prevention of the diseases. This review is aimed at summarizing the current knowledge on the impact of diet manipulation and physical factors on endothelium and oxidative stress, focusing on cardiovascular and metabolic diseases. We discuss the friend-and-foe role of dietary modification (including different diet styles, calorie restriction, and nutrient supplementation) on endothelium and oxidative stress, as well as the potential benefits and concerns of physical activity and exercise on endothelium and oxidative stress. A fine balance between oxidative stress and antioxidants is important for normal functions in the cells and interfering with this balance may lead to unfavorable effects. Further studies are needed to identify the best diet composition and exercise intensity.
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Huang J, Zhang H, Tan X, Hu M, Shen B. Exercise restores impaired endothelium-derived hyperpolarizing factor-mediated vasodilation in aged rat aortic arteries via the TRPV4-K Ca2.3 signaling complex. Clin Interv Aging 2019; 14:1579-1587. [PMID: 31564840 PMCID: PMC6731547 DOI: 10.2147/cia.s220283] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 08/25/2019] [Indexed: 12/28/2022] Open
Abstract
Background Aging leads to structural and functional changes in the vasculature characterized by arterial endothelial dysfunction and stiffening of large elastic arteries and is a predominant risk factor for cardiovascular disease, the leading cause of morbidity and mortality in modern societies. Although exercise reduces the risk of many age-related diseases, including cardiovascular disease, the mechanisms underlying the beneficial effects of exercise on age-related endothelial function fully elucidated. Purpose The present study explored the effects of exercise on the impaired endothelium-derived hyperpolarizing factor (EDHF)–mediated vasodilation in aged arteries and on the involvement of the transient receptor potential vanilloid 4 (TRPV4) channel and the small-conductance calcium-activated potassium (KCa2.3) channel signaling in this process. Methods Male Sprague-Dawley rats aged 19–21 months were randomly assigned to a sedentary group or to an exercise group. Two-month-old rats were used as young controls. Results We found that TRPV4 and KCa2.3 isolated from primary cultured rat aortic endothelial cells pulled each other down in co-immunoprecipitation assays, indicating that the two channels could physically interact. Using ex vivo functional arterial tension assays, we found that EDHF-mediated relaxation induced by acetylcholine or by the TRPV4 activator GSK1016790A was markedly decreased in aged rats compared with that in young rats and was significantly inhibited by TRPV4 or KCa2.3 blockers in both young and aged rats. However, exercise restored both the age-related and the TRPV4-mediated and KCa2.3-mediated EDHF responses. Conclusion These results suggest an important role for the TRPV4-KCa2.3 signaling undergirding the beneficial effect of exercise to ameliorate age-related arterial dysfunction.
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Affiliation(s)
- Junhao Huang
- Guangdong Provincial Key Laboratory of Sports and Health Promotion, Scientific Research Center, Department of Sports and Health, Guangzhou Sport University, Guangzhou, Guangdong, People's Republic of China
| | - Hai Zhang
- Department of Physical Education, Guangdong University of Petrochemical Technology, Maoming, Guangdong, People's Republic of China
| | - Xianming Tan
- Guangdong Provincial Key Laboratory of Sports and Health Promotion, Scientific Research Center, Department of Sports and Health, Guangzhou Sport University, Guangzhou, Guangdong, People's Republic of China
| | - Min Hu
- Guangdong Provincial Key Laboratory of Sports and Health Promotion, Scientific Research Center, Department of Sports and Health, Guangzhou Sport University, Guangzhou, Guangdong, People's Republic of China
| | - Bing Shen
- Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, People's Republic of China
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Endothelium-Dependent Hyperpolarization (EDH) in Diabetes: Mechanistic Insights and Therapeutic Implications. Int J Mol Sci 2019; 20:ijms20153737. [PMID: 31370156 PMCID: PMC6695796 DOI: 10.3390/ijms20153737] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/25/2019] [Accepted: 07/30/2019] [Indexed: 02/07/2023] Open
Abstract
Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and the hyperpolarization of vascular smooth muscle cells mediated by the endothelium plays a central role in agonist-mediated and flow-mediated vasodilation in resistance-size vessels. Although the mechanisms underlying diabetic vascular complications are multifactorial and complex, impairment of endothelium-dependent hyperpolarization (EDH) of vascular smooth muscle cells would contribute at least partly to the initiation and progression of microvascular complications of diabetes. In this review, we present the current knowledge about the pathophysiology and underlying mechanisms of impaired EDH in diabetes in animals and humans. We also discuss potential therapeutic approaches aimed at the prevention and restoration of EDH in diabetes.
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O'Brien MW, Mekary S, Robinson SA, Johns JA, Kimmerly DS. The relationship between aerobic fitness and low-flow-mediated constriction in older adults. Eur J Appl Physiol 2018; 119:351-359. [PMID: 30535655 DOI: 10.1007/s00421-018-4044-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 11/26/2018] [Indexed: 10/27/2022]
Abstract
PURPOSE Aerobic fitness is directly related to favorable vasodilatory (i.e., flow-mediated dilation; FMD) and vasoconstrictor functions (i.e., low-flow-mediated constriction; L-FMC) in young adults. Furthermore, aerobically fit older adults (OA) have larger FMD responses than their less fit peers. However, the relationship between aerobic fitness and vasoconstrictor responsiveness is unknown in OA. We hypothesized that OA who are more aerobically fit will exhibit a greater L-FMC response than their less fit counterparts. METHODS Forty-seven healthy OA (67 ± 5 years) were divided into less (LF; n = 27) and more aerobically fit (MF; n = 20) groups based on peak oxygen consumption (VO2peak). VO2peak was determined from an incremental maximal cycle ergometer test via indirect calorimetry. FMD and L-FMC were assessed in the brachial artery via high-resolution duplex ultrasonography. RESULTS VO2peak (18.3 ± 3.2 versus 29.1 ± 5.8 ml/kg/min; P < 0.001) and L-FMC were both greatest in the MF versus LF groups (-1.2 ± 0.9 vs. - 0.5 ± 0.6%; P = 0.01). Furthermore, the MF group had an enhanced FMD response (5.6 ± 1.5 versus 3.9 ± 1.2%; P < 0.001). In the pooled sample, there was a negative correlation (r = - 0.52; P < 0.001) between VO2peak (22.9 ± 7.0 ml/kg/min) and L-FMC (-0.8 ± 0.8%). CONCLUSIONS In an older population, greater aerobic fitness was associated with a more favorable vasoconstrictor response to low-flow conditions. Interventional or longitudinal aerobic exercise training studies are warranted in this population to determine the impact of training-induced increases in VO2peak on L-FMC.
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Affiliation(s)
- Myles W O'Brien
- Autonomic Cardiovascular Control and Exercise Laboratory, School of Health and Human Performance, Division of Kinesiology, Faculty of Health, Dalhousie University, 6230 South Street, Halifax, NS, B3H 4R2, Canada
| | - Said Mekary
- School of Kinesiology, Acadia University, Wolfville, NS, Canada
| | - Susan A Robinson
- Autonomic Cardiovascular Control and Exercise Laboratory, School of Health and Human Performance, Division of Kinesiology, Faculty of Health, Dalhousie University, 6230 South Street, Halifax, NS, B3H 4R2, Canada
| | - Jarrett A Johns
- Autonomic Cardiovascular Control and Exercise Laboratory, School of Health and Human Performance, Division of Kinesiology, Faculty of Health, Dalhousie University, 6230 South Street, Halifax, NS, B3H 4R2, Canada
| | - Derek Stephen Kimmerly
- Autonomic Cardiovascular Control and Exercise Laboratory, School of Health and Human Performance, Division of Kinesiology, Faculty of Health, Dalhousie University, 6230 South Street, Halifax, NS, B3H 4R2, Canada.
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Simanenkova AV, Makarova MN, Vasina LV, Butomo MI, Shlyakhto EV, Vlasov TD. Microcirculatory dopplerography as a method to evaluate drugs endothelial protective properties in type 2 diabetic patients. ACTA ACUST UNITED AC 2018. [DOI: 10.24884/1682-6655-2018-17-3-120-128] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Objective - to identify the most accurate way of drugs endothelial protective properties evaluation. Material and methods. Blood endothelin-1 (E) and acetylcholine-induced endothelial dependent vasodilation (EDV) were measured for 9 months in type 2 diabetic patients receiving either metformin (MET) (group 1) or MET and liraglutide (LIR) (group 2). Results. E was normal in group 1 at baseline and decreased only with glycaemia decline, in group 2 it was primarily increased and declined independently on glycaemia dynamics. In both groups E normalized in 6 months. EDV was impaired primarily in groups 1 and 2 and normalized only in group 2 in 9 months. Conclusions. LIR improves endothelial function, independently on glycaemia. Dopplerography in more accurate in drugs endothelial protective effects evaluation than circulating markers.
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Affiliation(s)
- A. V. Simanenkova
- Federal State Budgetary Educational Institution of Higher Education «Pavlov First Saint Petersburg State Medical University»
| | - M. N. Makarova
- Federal State Budgetary Educational Institution of Higher Education «Pavlov First Saint Petersburg State Medical University»
| | - L. V. Vasina
- Federal State Budgetary Educational Institution of Higher Education «Pavlov First Saint Petersburg State Medical University»; Federal State Budgetary Institution «Almazov National Medical Research Centre» of the Ministry of Health of the Russian Federation
| | - M. I. Butomo
- Federal State Budgetary Educational Institution of Higher Education «Pavlov First Saint Petersburg State Medical University»
| | - E. V. Shlyakhto
- Federal State Budgetary Educational Institution of Higher Education «Pavlov First Saint Petersburg State Medical University»; Federal State Budgetary Institution «Almazov National Medical Research Centre» of the Ministry of Health of the Russian Federation
| | - T. D. Vlasov
- Federal State Budgetary Educational Institution of Higher Education «Pavlov First Saint Petersburg State Medical University»; Federal State Budgetary Institution «Almazov National Medical Research Centre» of the Ministry of Health of the Russian Federation
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Fujita N, Aono S, Karasaki K, Sera F, Kurose T, Fujino H, Urakawa S. Changes in lipid metabolism and capillary density of the skeletal muscle following low-intensity exercise training in a rat model of obesity with hyperinsulinemia. PLoS One 2018; 13:e0196895. [PMID: 29718998 PMCID: PMC5931644 DOI: 10.1371/journal.pone.0196895] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 04/20/2018] [Indexed: 02/06/2023] Open
Abstract
Although exercise is effective in improving obesity and hyperinsulinemia, the exact influence of exercise on the capillary density of skeletal muscles remains unknown. The aim of this study was to investigate the effects of low-intensity exercise training on metabolism in obesity with hyperinsulinemia, focusing specifically on the capillary density within the skeletal muscle. Otsuka Long-Evans Tokushima fatty (OLETF) rats were used as animal models of obesity with hyperinsulinemia, whereas Long-Evans Tokushima Otsuka (LETO) rats served as controls (no obesity, no hyperinsulinemia). The animals were randomly assigned to either non-exercise or exercise groups (treadmill running for 60 min/day, for 4 weeks). The exercise groups were further divided into subgroups according to training mode: single bout (60 min, daily) vs. multiple bout (three bouts of 20 min, daily). Fasting insulin levels were significantly higher in OLETF than in LETO rats. Among OLETF rats, there were no significant differences in fasting glucose levels between the exercise and the non-exercise groups, but the fasting insulin levels were significantly lower in the exercise group. Body weight and triacylglycerol levels in the liver were significantly higher in OLETF than in LETO rats; however, among OLETF rats, these levels were significantly lower in the exercise than in the non-exercise group. The capillary-to-fiber ratio of the soleus muscle was significantly higher in OLETF than in LETO rats; however, among OLETF rats, the ratio was lower in the exercise group than in the non-exercise group. No significant differences in any of the studied parameters were noted between the single-bout and multiple-bout exercise training modes among either OLETF or LETO rats. These results suggest that low-intensity exercise training improves insulin sensitivity and fatty liver. Additionally, the fact that attenuation of excessive capillarization in the skeletal muscle of OLETF rats was accompanied by improvement in increased body weight.
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Affiliation(s)
- Naoto Fujita
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
- * E-mail:
| | - Saki Aono
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Kohei Karasaki
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Fumi Sera
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Tomoyuki Kurose
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
| | - Hidemi Fujino
- Life and Medical Science Area, Health Sciences Discipline, Kobe University, Suma-ku, Kobe, Japan
| | - Susumu Urakawa
- Department of Musculoskeletal Functional Research and Regeneration, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
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Takamine Y, Ichinoseki-Sekine N, Tsuzuki T, Yoshihara T, Naito H. Effects of voluntary running exercise on bone histology in type 2 diabetic rats. PLoS One 2018; 13:e0193068. [PMID: 29447298 PMCID: PMC5814042 DOI: 10.1371/journal.pone.0193068] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 02/02/2018] [Indexed: 12/22/2022] Open
Abstract
The incidence of obesity in children and adolescents, which may lead to type 2 diabetes, is increasing. Exercise is recommended to prevent and improve diabetes. However, little is known about the bone marrow environment at the onset of diabetes in the young, and it is unclear whether exercise training is useful for maintaining bone homeostasis, such as mechanical and histological properties. Thus, this study clarified the histological properties of bone and whether exercise contributes to maintaining bone homeostasis at the onset of type 2 diabetes in rats. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF; n = 21) rats as a diabetic model and Long-Evans Tokushima Otsuka (LETO; n = 18) rats as a control were assigned randomly to four groups: the OLETF sedentary group (O-Sed; n = 11), OLETF exercise group (O-Ex; n = 10), LETO sedentary group (L-Sed; n = 9), and LETO exercise group (L-Ex; n = 9). All rats in the exercise group were allowed free access to a steel running wheel for 20 weeks (5-25 weeks of age). In the glucose tolerance test, blood glucose level was higher in the O-Sed group than that in the L-Sed and L-Ex groups, and was markedly suppressed by the voluntary running exercise of O-Ex rats. The energy to fracture and the two-dimensional bone volume at 25 weeks of age did not differ significantly among the groups, though the maximum breaking force and stiffness were lower in OLETF rats. However, bone marrow fat volume was greater in O-Sed than that in L-Sed and L-Ex rats, and was markedly suppressed by wheel running in the O-Ex rats. Our results indicate that exercise has beneficial effects not only for preventing diabetes but also on normal bone remodeling at an early age.
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Affiliation(s)
- Yuri Takamine
- Graduate School of Health and Sports Science, Juntendo University, Inzai, Chiba, Japan
| | - Noriko Ichinoseki-Sekine
- Graduate School of Health and Sports Science, Juntendo University, Inzai, Chiba, Japan
- Faculty of Liberal Arts, The Open University of Japan, Chiba, Chiba, Japan
| | - Takamasa Tsuzuki
- Graduate School of Health and Sports Science, Juntendo University, Inzai, Chiba, Japan
| | - Toshinori Yoshihara
- Graduate School of Health and Sports Science, Juntendo University, Inzai, Chiba, Japan
| | - Hisashi Naito
- Graduate School of Health and Sports Science, Juntendo University, Inzai, Chiba, Japan
- * E-mail:
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16
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Piao SJ, Kim SH, Suh YJ, Hong SB, Ahn SH, Seo DH, Park IS, Nam M. Beneficial Effects of Aerobic Exercise Training Combined with Rosiglitazone on Glucose Metabolism in Otsuka Long Evans Tokushima Fatty Rats. Diabetes Metab J 2017; 41:474-485. [PMID: 29199408 PMCID: PMC5741557 DOI: 10.4093/dmj.2017.41.6.474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 07/26/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Regular aerobic exercise is essential for the prevention and management of type 2 diabetes mellitus and may be particularly beneficial for those treated with thiazolidinediones, since it may prevent associated weight gain. This study aimed to evaluate the effect of combined exercise and rosiglitazone treatment on body composition and glucose metabolism in obese diabetes-prone animals. METHODS We analyzed metabolic parameters, body composition, and islet profiles in Otsuka Long Evans Tokushima Fatty rats after 28 weeks of aerobic exercise, rosiglitazone treatment, and combined exercise and rosiglitazone treatment. RESULTS Combined exercise with rosiglitazone showed significantly less increase in weight and epididymal fat compared to rosiglitazone treatment. Aerobic exercise alone and combined rosiglitazone and exercise treatment led to similar retention of lean body mass. All experimental groups showed a decrease in fasting glucose. However, the combined exercise and rosiglitazone therapy group showed prominent improvement in glucose tolerance compared to the other groups. Rescue of islet destruction was observed in all experimental groups, but was most prominent in the combined therapy group. CONCLUSION Regular aerobic exercise combined with rosiglitazone treatment can compensate for the adverse effect of rosiglitazone treatment and has benefit for islet preservation.
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Affiliation(s)
- Shan Ji Piao
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
- Qingdao Endocrine and Diabetes Hospital, Qingdao, China
| | - So Hun Kim
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Young Ju Suh
- Department of Biomedical Sciences, Inha University School of Medicine, Incheon, Korea
| | - Seong Bin Hong
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Seong Hee Ahn
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Da Hae Seo
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - In Sun Park
- Department of Anatomy, Inha University School of Medicine, Incheon, Korea.
| | - Moonsuk Nam
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.
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17
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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18
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Reyes LM, Morton JS, Kirschenman R, DeLorey DS, Davidge ST. Vascular effects of aerobic exercise training in rat adult offspring exposed to hypoxia-induced intrauterine growth restriction. J Physiol 2015; 593:1913-29. [PMID: 25616117 DOI: 10.1113/jphysiol.2014.288449] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 01/20/2015] [Indexed: 12/22/2022] Open
Abstract
KEY POINTS Prenatal hypoxia, one of the most common consequences of complicated pregnancies, leads to intrauterine growth restriction (IUGR) and impairs later-life endothelium-dependent vascular function. Early interventions are needed to ultimately reduce later-life risk for cardiovascular disease. Aerobic exercise training has been shown to prevent cardiovascular diseases. Whether exercise can be used as an intervention to reverse the vascular phenotype of this susceptible population is unknown. Aerobic exercise training enhanced endothelium-derived hyperpolarization-mediated vasodilatation in gastrocnemius muscle arteries in male IUGR offspring, and did not improve nitric oxide-mediated vasodilatation in IUGR offspring. Understanding the mechanisms by which exercise impacts the cardiovascular system in a susceptible population and the consideration of sexual dimorphism is essential to define whether exercise could be used as a preventive strategy in this population. ABSTRACT Hypoxia in utero is a critical insult causing intrauterine growth restriction (IUGR). Adult offspring born with hypoxia-induced IUGR have impaired endothelium-dependent vascular function. We tested whether aerobic exercise improves IUGR-induced endothelial dysfunction. Pregnant Sprague-Dawley rats were exposed to control (21% oxygen) or hypoxic (11% oxygen) conditions from gestational day 15 to 21. Male and female offspring from normoxic and hypoxic (IUGR) pregnancies were randomized at 10 weeks of age to either an exercise-trained or sedentary group. Exercise-trained rats ran on a treadmill for 30 min at 20 m min(-1) , 5 deg gradient, 5 days week(-1) , for 6 weeks. Concentration-response curves to phenylephrine and methylcholine were performed in second order mesenteric and gastrocnemius muscle arteries, in the presence or absence of l-NAME (100 μm), MnTBAP (peroxynitrite scavenger; 10 μm), apamin (0.1 μm) and TRAM-34 (an intermediate-conductance calcium-activated potassium channel blocker; 10 μm), or indomethacin (5 μm). In adult male IUGR offspring, prenatal hypoxia had no effect on total vasodilator responses in either vascular bed. Aerobic exercise training in IUGR males, however, improved endothelium-derived hyperpolarization (EDH)-mediated vasodilatation in gastrocnemius muscle arteries. Female IUGR offspring had reduced NO-mediated vasodilatation in both vascular beds, along with decreased total vasodilator responses and increased prostaglandin-mediated vasoconstriction in gastrocnemius muscle arteries. In contrast to males, aerobic exercise training in IUGR female offspring had no effect on either vascular bed. Exercise may not prove to be a beneficial therapy for specific vascular pathways affected by prenatal hypoxia, particularly in female offspring.
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Affiliation(s)
- Laura M Reyes
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
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van Waveren A, Duncan MJ, Coulson FR, Fenning A. Moderate intensity physical activity prevents increased blood glucose concentrations, fat pad deposition and cardiac action potential prolongation following diet-induced obesity in a juvenile-adolescent rat model. BMC OBESITY 2014. [PMID: 26217503 PMCID: PMC4511067 DOI: 10.1186/2052-9538-1-11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Both obesity and a lack of physical activity have been associated with an elevated risk of cardiovascular disease (CVD). The incidence of obesity is increasing, especially in juvenile-adolescents. While there is limited research examining the chronic effects of obesity in adolescent humans and animal models of this condition, little is also known concerning how moderate physical activity might prevent or attenuate secondary cardiovascular complications induced by obesity during adolescence. We investigated the effects of diet-induced obesity (consisting of a high-fat, high-carbohydrate diet (HFHC)) on biometric indices, vascular and airway function, cardiovascular function, systemic oxidative stress and markers of inflammation in a juvenile-adolescent rodent model. Four groups were used: control (CON), physical activity (PA) treated, HFHC and HFHC + PA (n = 16 per group). HFHC feeding started at 4 weeks of age for a period of 12 weeks. Physical activity treatment was initiated (PA and HFHC + PA groups) when the animals were 8 weeks of age, for 8 weeks. Results Physical activity in juvenile-adolescent healthy rats showed no change in comparison to the CON group in all experimental parameters except for increases in lipid peroxidation, decreases in inflammatory cytokines, improvements in vascular reactivity and decreased atrial responses to positive chronotropic agents. The HFHC animals were mildly hyperglycemic, hypertensive, displayed renal hypertrophy and showed increased retroperitoneal fat pad deposition compared to the CON group. HFHC + PA rats were also hypertensive, however showed improvements in cardiac electrophysiology, body weight, fat pad deposition and inflammatory signaling, in comparison to the HFHC fed rats and CON animals. Conclusion In conclusion, in a juvenile-adolescent animal model of diet-induced obesity engagement in physical activity is beneficial in reducing the inflammatory effects of obesity.
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Affiliation(s)
- Alannah van Waveren
- Central Queensland University, Institute of Health and Social Science Research, Rockhampton, Queensland 4702 Australia
| | - Mitch J Duncan
- School of Medicine & Public Health, Priority Research Centre in Physical Activity and Nutrition, The University of Newcastle, Newcastle, Australia
| | - Fiona R Coulson
- School of Medical and Applied Sciences, Central Queensland University, Rockhampton, Queensland 4702 Australia
| | - Andrew Fenning
- Central Queensland University, Institute of Health and Social Science Research, Rockhampton, Queensland 4702 Australia ; School of Medical and Applied Sciences, Central Queensland University, Rockhampton, Queensland 4702 Australia
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20
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The diabetic vasculature: physiological mechanisms of dysfunction and influence of aerobic exercise training in animal models. Life Sci 2014; 102:1-9. [PMID: 24583313 DOI: 10.1016/j.lfs.2014.02.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/30/2014] [Accepted: 02/15/2014] [Indexed: 02/08/2023]
Abstract
Diabetes mellitus (DM) is associated with a number of complications of which chronic vascular complications are undoubtedly the most complex and significant consequence. With a significant impact on health care, 50-80% of people with diabetes die of cardiovascular disease (including coronary artery disease, stroke, peripheral vascular disease and other vascular disease), making it the major cause of morbidity and mortality in diabetic patients. A healthy lifestyle is essential in the management of DM, especially the inclusion of aerobic exercise, which has been shown effective in reducing the deleterious effects in vasculature. Interest in exercise studies has increased significantly with promising results that demonstrate a future for investigation. Considering the importance of this emerging field, the aim of this mini-review is to summarize and integrate animal studies investigating physiological mechanisms of vascular dysfunction and remodeling in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and how these are influenced by chronic aerobic exercise training.
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Zguira MS, Vincent S, Le Douairon Lahaye S, Malarde L, Tabka Z, Saïag B. Intense exercise training is not effective to restore the endothelial NO-dependent relaxation in STZ-diabetic rat aorta. Cardiovasc Diabetol 2013; 12:32. [PMID: 23399712 PMCID: PMC3599941 DOI: 10.1186/1475-2840-12-32] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Accepted: 02/04/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The aim of this study was to examine the effects of intense physical training on vascular function in streptozotocin-diabetic rats. We focused on the endothelium-dependent relaxation (EDR) induced by acetylcholine (ACh) and stable ADP adenosine-5'- O - (2-thiodiphosphate) (ADPβS). METHODS Control or diabetic male Wistar rats (n=44) were randomly assigned to sedentary or trained groups. The training program consisted in a regular period of running on a treadmill during 8 weeks (10° incline and up to 25 m/min, 60 min/day). The reactivity of isolated thoracic aorta rings of healthy, diabetic and/or trained has been tested. RESULTS ACh and ADPβS-induced EDR were observed in phenylephrine (PE) pre-contracted vessels. As compared to sedentary control group, diabetic rats showed an increase in PE-induced contraction and a decrease in ACh and ADPβS-induced EDR (p<0.05). Moreover, there were no increase in ACh and ADPβS-induced EDR in diabetic rats. N-Nitro-L-Arginine Methyl Ester inhibited the nitric oxide synthase in diabetic and control rats, thereby resulting in a strong inhibition of the EDR induced by ACh and ADPβS (10-6 M). CONCLUSION Diabetes induced an endothelium dysfunction. Nevertheless, our intense physical training was not effective to restore the aorta endothelial function.
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Affiliation(s)
- Mohamed Sami Zguira
- Laboratory Movement Sport and Health Sciences, UFR APS University of Rennes 2, Avenue Charles Tillon, Rennes cedex, France.
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da Silva CA, Ribeiro JP, Canto JCAU, da Silva RE, Silva Junior GB, Botura E, Malschitzky MAR. High-intensity aerobic training improves endothelium-dependent vasodilation in patients with metabolic syndrome and type 2 diabetes mellitus. Diabetes Res Clin Pract 2012; 95:237-45. [PMID: 22041126 DOI: 10.1016/j.diabres.2011.09.034] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2011] [Revised: 09/24/2011] [Accepted: 09/29/2011] [Indexed: 10/15/2022]
Abstract
BACKGROUND The aim of this study is to compare the effect of physical exercise program on the endothelial function of patients with metabolic syndrome and type 2 diabetes mellitus. METHODS Patients were randomized for high intensity aerobic training (HI: 80% maximum heart rate, n=10), low intensity aerobic training (LI: 55% of maximum heart rate, n=10) and control (n=11). Before and after 6 weeks of training, subjects performed the maximal exercise test and a study of the endothelial function, through a high resolution ultrasound of the brachial artery, which was assessed after reactive hyperemia (endothelium dependent vasodilation) and nitrate administration (endothelium independent vasodilation). RESULTS A total of 31 patients with metabolic syndrome and type 2 diabetes mellitus were studied, with mean age of 58±6 years, The percentage diameter difference of the vessel after hyperemia was significantly higher for the high intensity group (HI before 2.52±2.85% and after 31.81±12.21%; LI before 3.23±3.52% and after 20.61±7.76%; controls before 3.56±2.33% and after 2.43±2.14%; p<0.05). CONCLUSIONS High intensity aerobic training improved the functional capability and endothelium dependent vasodilator response, but it does not improve the endothelium independent vasodilation in patients with metabolic syndrome and type 2 diabetes mellitus.
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Affiliation(s)
- Carlos Alberto da Silva
- Institute of Physical Education and Sports, Federal University of Ceará, Fortaleza, Ceará, Brazil.
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The forgotten face of regular physical exercise: a 'natural' anti-atherogenic activity. Clin Sci (Lond) 2011; 121:91-106. [PMID: 21729002 DOI: 10.1042/cs20100520] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Humans are not programmed to be inactive. The combination of both accelerated sedentary lifestyle and constant food availability disturbs ancient metabolic processes leading to excessive storage of energy in tissue, dyslipidaemia and insulin resistance. As a consequence, the prevalence of Type 2 diabetes, obesity and the metabolic syndrome has increased significantly over the last 30 years. A low level of physical activity and decreased daily energy expenditure contribute to the increased risk of cardiovascular morbidity and mortality following atherosclerotic vascular damage. Physical inactivity leads to the accumulation of visceral fat and consequently the activation of the oxidative stress/inflammation cascade, which promotes the development of atherosclerosis. Considering physical activity as a 'natural' programmed state, it is assumed that it possesses atheroprotective properties. Exercise prevents plaque development and induces the regression of coronary stenosis. Furthermore, experimental studies have revealed that exercise prevents the conversion of plaques into a vulnerable phenotype, thus preventing the appearance of fatal lesions. Exercise promotes atheroprotection possibly by reducing or preventing oxidative stress and inflammation through at least two distinct pathways. Exercise, through laminar shear stress activation, down-regulates endothelial AT1R (angiotensin II type 1 receptor) expression, leading to decreases in NADPH oxidase activity and superoxide anion production, which in turn decreases ROS (reactive oxygen species) generation, and preserves endothelial NO bioavailability and its protective anti-atherogenic effects. Contracting skeletal muscle now emerges as a new organ that releases anti-inflammatory cytokines, such as IL-6 (interleukin-6). IL-6 inhibits TNF-α (tumour necrosis factor-α) production in adipose tissue and macrophages. The down-regulation of TNF-α induced by skeletal-muscle-derived IL-6 may also participate in mediating the atheroprotective effect of physical activity.
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Félétou M. The Endothelium, Part I: Multiple Functions of the Endothelial Cells -- Focus on Endothelium-Derived Vasoactive Mediators. ACTA ACUST UNITED AC 2011. [DOI: 10.4199/c00031ed1v01y201105isp019] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Gao X, Martinez-Lemus LA, Zhang C. Endothelium-derived hyperpolarizing factor and diabetes. World J Cardiol 2011; 3:25-31. [PMID: 21286215 PMCID: PMC3030734 DOI: 10.4330/wjc.v3.i1.25] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 11/30/2010] [Accepted: 12/07/2010] [Indexed: 02/06/2023] Open
Abstract
In addition to its role as a barrier between blood and tissues, the vascular endothelium is responsible for the synthesis and released of a number of vasodilators including prostaglandins, nitric oxide and endothelium-derived hyperpolarizing factor (EDHF). As one of these vasodilators, the specific nature of EDHF has not been fully elucidated, although a number of roles have been proposed. Importantly, many conditions, such as hypertension, hyperlipidemia, heart failure, ischemia-reperfusion and diabetes mellitus comprise vascular endothelial dysfunction with EDHF dysregulation. This article reviews reports on the role of EDHF in diabetes-related endothelial dysfunction.
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Affiliation(s)
- Xue Gao
- Xue Gao, Department of Physiology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100005, China
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Labinskyy N, Hicks S, Grijalva J, Edwards J. The Contrary Impact Of Diabetes And Exercise On Endothelial Nitric Oxide Synthase Function. WEBMEDCENTRAL 2010; 1. [PMID: 27683619 DOI: 10.9754/journal.wmc.2010.00137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Mikus CR, Rector RS, Arce-Esquivel AA, Libla JL, Booth FW, Ibdah JA, Laughlin MH, Thyfault JP. Daily physical activity enhances reactivity to insulin in skeletal muscle arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats. J Appl Physiol (1985) 2010; 109:1203-10. [PMID: 20634354 DOI: 10.1152/japplphysiol.00064.2010] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Insulin-mediated glucose disposal is dependent on the vasodilator effects of insulin. In type 2 diabetes, insulin-stimulated vasodilation is impaired as a result of an imbalance in NO and ET-1 production. We tested the hypothesis that chronic voluntary wheel running (RUN) prevents impairments in insulin-stimulated vasodilation associated with obesity and type 2 diabetes independent of the effects of RUN on adiposity by randomizing Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of hyperphagia-induced obesity and type 2 diabetes, to 1) RUN, 2) caloric restriction (CR; diet adjusted to match body weights of RUN group), or 3) sedentary control (SED) groups (n = 8/group) at 4 wk. At 40 wk, NO- and ET-1-mediated vasoreactivity to insulin (1-1,000 μIU/ml) was assessed in the presence of a nonselective ET-1 receptor blocker (tezosentan) or a NO synthase (NOS) inhibitor [N(G)-nitro-L-arginine methyl ester (L-NAME)], respectively, in second-order arterioles isolated from the white portion of the gastrocnemius muscle. Body weight, fasting plasma glucose, and hemoglobin A1c were lower in RUN and CR than SED (P < 0.05); however, the glucose area under the curve (AUC) following the intraperitoneal glucose tolerance test was lower only in the RUN group (P < 0.05). Vasodilator responses to all doses of insulin were greater in RUN than SED or CR in the presence of a tezosentan (P < 0.05), but group differences in vasoreactivity to insulin with coadministration of L-NAME were not observed. We conclude daily wheel running prevents obesity and type 2 diabetes-associated declines in insulin-stimulated vasodilation in skeletal muscle arterioles through mechanisms that appear to be NO mediated and independent of attenuating excess adiposity in hyperphagic rats.
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Affiliation(s)
- Catherine R Mikus
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, USA
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Bunker AK, Arce-Esquivel AA, Rector RS, Booth FW, Ibdah JA, Laughlin MH. Physical activity maintains aortic endothelium-dependent relaxation in the obese type 2 diabetic OLETF rat. Am J Physiol Heart Circ Physiol 2010; 298:H1889-901. [PMID: 20304812 DOI: 10.1152/ajpheart.01252.2009] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We tested the hypothesis that physical activity can attenuate the temporal decline of ACh-induced endothelium-dependent relaxation during type 2 diabetes mellitus progression in the Otsuka Long-Evans Tokushima fatty (OLETF) rat. Sedentary OLETF rats exhibited decreased ACh-induced abdominal aortic endothelium-dependent relaxation from 13 to 20 wk of age (20-35%) and from 13 to 40 wk of age (35-50%). ACh-induced endothelium-dependent relaxation was maintained in the physically active OLETF group and control sedentary Long-Evans Tokushima Otsuka (LETO) group from 13 to 40 wk of age. Aortic pretreatment with N(G)-nitro-l-arginine (l-NNA), indomethacin (Indo), and l-NNA + Indo did not alter the temporal decline in ACh-induced endothelium-dependent relaxation. Temporal changes in the protein expression of SOD isoforms in the aortic endothelium or smooth muscle did not contribute to the temporal decline in ACh-induced endothelium-dependent relaxation in sedentary OLETF rats. A significant increase in the 40-wk-old sedentary LETO and physically active OLETF rat aortic phosphorylated endothelial nitric oxide (p-eNOS)-to-eNOS ratio was observed versus 13- and 20-wk-old rats in each group that was not seen in the 40- versus 13- and 20-wk-old sedentary OLETF rats. These results suggest that temporal changes in the antioxidant system, EDHF, and cycloxygenase metabolite production in sedentary OLETF rat aortas do not contribute to the temporal decline in sedentary OLETF rat aortic ACh-induced endothelium-dependent relaxation seen with type 2 diabetes mellitus progression. We also report that physical activity in conjunction with aging in the OLETF rat results in a temporal increase in the aortic endothelial p-eNOS-to-eNOS ratio that was not seen in sedentary OLETF rats. These results suggest that the sustained aortic ACh-induced endothelium-dependent relaxation in aged physically active OLETF rats may be the result of an increase in active aortic eNOS.
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Affiliation(s)
- Aaron K Bunker
- Dept. of Biomedical Sciences, Univ. of Missouri, E102 Veterinary Medicine Bldg., 1600 E. Rollins Rd., Columbia, MO 65211, USA
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Kajikuri J, Watanabe Y, Ito Y, Ito R, Yamamoto T, Itoh T. Characteristic changes in coronary artery at the early hyperglycaemic stage in a rat type 2 diabetes model and the effects of pravastatin. Br J Pharmacol 2009; 158:621-32. [PMID: 19645710 DOI: 10.1111/j.1476-5381.2009.00348.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Diabetes is a risk factor for the development of coronary artery disease but it is not known whether the functions of endothelium-derived nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in coronary arteries are altered in the early stage of diabetes. Such alterations and the effects of pravastatin were examined in left anterior descending coronary arteries (LAD) from Otsuka Long-Evans Tokushima Fatty (OLETF) rats (type 2 diabetes model) at the early hyperglycaemic stage [vs. non-diabetic Long-Evans Tokushima Otsuka (LETO) rats]. EXPERIMENTAL APPROACH Isometric tension, membrane potential and superoxide production were measured, as were protein expression of NAD(P)H oxidase components and endothelial NO synthase (eNOS). KEY RESULTS Superoxide production and the protein expressions of both the nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] oxidase components and eNOS were increased in OLETF rats. These changes were normalized by pravastatin administration. Not only acetylcholine (ACh)-induced endothelial NO production but also functions of endothelium-derived NO [from (i) the absolute tension induced by epithio-thromboxane A(2) (STA(2)) or high K(+); (ii) enhancement of the STA(2)-contraction by a nitric oxide synthase (NOS) inhibitor; and (iii) the ACh-induced endothelium-dependent relaxation of high K(+)-induced contraction] or EDHF [from (iv) ACh-induced endothelium-dependent smooth muscle cell hyperpolarization and relaxation in the presence of a NOS inhibitor] were similar between LETO and OLETF rats [whether or not the latter were pravastatin-treated or -untreated]. CONCLUSIONS AND IMPLICATIONS Under conditions of increased vascular superoxide production, endothelial function is retained in LAD in OLETF rats at the early hyperglycaemic stage, partly due to enhanced endothelial NOS protein expression. Inhibition of superoxide production may contribute to the beneficial vascular effects of pravastatin.
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Affiliation(s)
- J Kajikuri
- Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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31
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Agosti V, Graziano S, Artiaco L, Sorrentino G. Biological mechanisms of stroke prevention by physical activity in type 2 diabetes. Acta Neurol Scand 2009; 119:213-23. [PMID: 18700881 DOI: 10.1111/j.1600-0404.2008.01080.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The principal modifiable risk factors for stroke are hypertension, diabetes mellitus, hypercholesterolaemia, hyperhomocysteinaemia, smoking and limited physical activity. However, it is not clear whether physical inactivity is a risk factor per se, or because it predisposes to pathological conditions that are risk factors for stroke. The limited availability of effective therapeutic approaches for stroke emphasizes the crucial role of prevention of risk factors. The global burden associated with type 2 diabetes is large and continues to grow. Convincing epidemiologic data support the role of physical activity in preventing type 2 diabetes. The increasing evidence of physical activity in preventing diabetic complications, including stroke, has generated interest in the molecular basis underlying these beneficial effects. The aim of the present review is to discuss the biological mechanisms underlying the effect of physical activity in preventing stroke in type 2 diabetes.
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Affiliation(s)
- V Agosti
- University of Naples Parthenope and Istituto di diagnosi e cura Hermitage Capodimonte, Italy
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Matsumoto T, Ozawa Y, Taguchi K, Kobayashi T, Kamata K. Chronic treatment with losartan (angiotensin II type 1 receptor antagonist) normalizes enhanced acetylcholine-induced coronary vasoconstriction in isolated perfused hearts of type 2 diabetic OLETF rats. J Smooth Muscle Res 2009; 45:197-208. [DOI: 10.1540/jsmr.45.197] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University
| | - Yuta Ozawa
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University
| | - Kumiko Taguchi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University
| | - Tsuneo Kobayashi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University
| | - Katsuo Kamata
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University
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Teixeira de Lemos E, Reis F, Baptista S, Pinto R, Sepodes B, Vala H, Rocha-Pereira P, Correia da Silva G, Teixeira N, Silva AS, Carvalho L, Teixeira F, Das UN. Exercise training decreases proinflammatory profile in Zucker diabetic (type 2) fatty rats. Nutrition 2008; 25:330-9. [PMID: 19062255 DOI: 10.1016/j.nut.2008.08.014] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2008] [Revised: 08/28/2008] [Accepted: 08/29/2008] [Indexed: 01/27/2023]
Abstract
OBJECTIVE In the present study we evaluated the effect of exercise on the plasma levels of proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory molecule uric acid in the Zucker diabetic fatty (ZDF) rats that are more prone to develop type 2 diabetes mellitus. METHODS Sixteen obese ZDF (Gmi fa/fa) rats (8 wk old, 228.40 +/- 4.05 g) were randomly assigned to one of two groups (n = 8 each): an exercise-trained group and a sedentary one. In addition, 16 lean ZDF (Gmi +/+) rats (8 wk old, 199.00 +/- 3.50 g) were subjected to identical sedentary and exercise conditioning (n = 8 each). Initially, rats swam 15 min/d (5 d/wk) in a 36 degrees C bath. The exercise protocol was gradually increased by 15 min/d until a swimming period of 1 h/d (1 wk) was attained. Thereafter, rats swam 1 h/d, 3 d/wk, for an additional period of 11 wk. Rats were sacrificed 48 h after the last training period and the blood and pancreas were collected. Circulating levels of glucose, glycosylated hemoglobin, total cholesterol, triglycerides, insulin, uric acid, IL-6, and TNF-alpha were assessed. The concentrations of proinflammatory cytokines in the pancreas were also evaluated. RESULTS In the diabetic ZDF (fa/fa) rats, exercise decreased hyperuricemia (-37.3%) and IL-6 and TNF-alpha levels (-16.9% and -12.7% respectively) and maintained the weight of the pancreas at near normal. Immunohistochemistry revealed a marked decrease in the expression of TNF-alpha and IL-6 in the pancreatic islet cells of ZDF (fa/fa) rats. CONCLUSION These results indicate that aerobic exercise is anti-inflammatory in nature.
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Affiliation(s)
- E Teixeira de Lemos
- Therapeutics Unit, Institute of Pharmacology and Experimental Therapeutics, Medicine Faculty, Coimbra University, Coimbra, Portugal; Polytechnic Institute of Viseu, Viseu, Portugal
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Grijalva J, Hicks S, Zhao X, Medikayala S, Kaminski PM, Wolin MS, Edwards JG. Exercise training enhanced myocardial endothelial nitric oxide synthase (eNOS) function in diabetic Goto-Kakizaki (GK) rats. Cardiovasc Diabetol 2008; 7:34. [PMID: 19019231 PMCID: PMC2602993 DOI: 10.1186/1475-2840-7-34] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2008] [Accepted: 11/19/2008] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Different mechanisms of diabetic-induced NO dysfunction have been proposed and central to most of them are significant changes in eNOS function as the rate-limiting step in NO bioavailability. eNOS exists in both monomeric and dimeric conformations, with the dimeric form catalyzing the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of superoxide (O2-). Diabetic-induced shifts to decrease the dimer:monomer ratio is thought to contribute to the degradation of nitric oxide (NO) bioavailability. Exercise has long been useful in the management of diabetes. Although exercise-induced increases expression of eNOS has been reported, it is unclear if exercise may alter the functional coupling of eNOS. METHODS To investigate this question, Goto-Kakizaki rats (a model of type II diabetes) were randomly assigned to a 9-week running program (train) or sedentary (sed) groups. RESULTS Exercise training significantly (p < .05) increased plantaris muscle cytochrome oxidase, significantly improved glycosylated hemoglobin (sed: 7.33 +/- 0.56%; train: 6.1 +/- 0.18%), ad improved insulin sensitivity. Exercise increased both total eNOS expression and the dimer:monomer ratio in the left ventricle LV (sed: 11.7 +/- 3.2%; train: 41.4 +/- 4.7%). Functional analysis of eNOS indicated that exercise induced significant increases in nitric oxide (+28%) production and concomitant decreases in eNOS-dependent superoxide (-12%) production. This effect was observed in the absence of tetrahydrobiopterin (BH4), but not in the presence of exogenous BH4. Exercise training also significantly decreased NADPH-dependent O2- activity. CONCLUSION Exercise-induced increased eNOS dimerization resulted in an increased coupling of the enzyme to facilitate production of NO at the expense of ROS generation. This shift that could serve to decrease diabetic-related oxidative stress, which should serve to lessen diabetic-related complications.
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Affiliation(s)
- James Grijalva
- Department of Physiology, New York Medical College, Valhalla NY, USA
| | - Steven Hicks
- Department of Physiology, New York Medical College, Valhalla NY, USA
| | - Xiangmin Zhao
- Department of Physiology, New York Medical College, Valhalla NY, USA
| | - Sushma Medikayala
- Department of Physiology, New York Medical College, Valhalla NY, USA
| | - Pawel M Kaminski
- Department of Physiology, New York Medical College, Valhalla NY, USA
| | - Michael S Wolin
- Department of Physiology, New York Medical College, Valhalla NY, USA
| | - John G Edwards
- Department of Physiology, New York Medical College, Valhalla NY, USA
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Matsumoto T, Kobayashi T, Wachi H, Seyama Y, Kamata K. Vascular NAD(P)H oxidase mediates endothelial dysfunction in basilar arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Atherosclerosis 2006; 192:15-24. [PMID: 16831440 DOI: 10.1016/j.atherosclerosis.2006.06.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2005] [Revised: 04/13/2006] [Accepted: 06/02/2006] [Indexed: 11/20/2022]
Abstract
We examined the responses of basilar arteries taken from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetes model. Both the nitric oxide (NO)-mediated relaxation and the cyclic 3',5'-guanosine monophosphate (cGMP) production elicited by acetylcholine (ACh) were much weaker in OLETF rats than in age-matched control Long Evans Tokushima Otsuka (LETO) rats. The contraction induced by an NO synthase (NOS) inhibitor [N(G)-nitro-L-arginine (L-NNA)] was weaker in the OLETF group. In that group, application of apocynin, an NAD(P)H oxidase inhibitor, normalized (i) ACh-induced relaxation, (ii) L-NNA-induced contraction, and (iii) ACh-induced cGMP production to the LETO levels. Superoxide anion production was greater in basilar arteries from OLETF rats than in those from LETO rats. The protein expression of gp91(phox), an NAD(P)H oxidase subunit, was upregulated in the OLETF arteries (versus LETO ones). These results suggest that the existence of endothelial dysfunction in basilar arteries in type 2 diabetes is related to increased oxidative stress mediated via NAD(P)H oxidase. Possibly, an impairment of NO-dependent relaxation responses and a basal impairment of NO signaling may be responsible for the increased risk of adverse cerebrovascular events in type 2 diabetes.
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Affiliation(s)
- Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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Akamine EH, Kawamoto EM, Scavone C, Nigro D, Carvalho MHC, de Cássia A Tostes R, Britto LRG, Fortes ZB. Correction of endothelial dysfunction in diabetic female rats by tetrahydrobiopterin and chronic insulin. J Vasc Res 2006; 43:309-20. [PMID: 16682803 DOI: 10.1159/000093196] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2005] [Accepted: 02/19/2006] [Indexed: 11/19/2022] Open
Abstract
Diabetes-induced vascular dysfunction has mainly been studied in males. However, the mechanisms involved may not correspond to those in females. Here we analyzed the effects of tetrahydrobiopterin (BH(4)) and chronic insulin on the physiology of mesenteric arterioles of alloxan-diabetic female rats. The parameters studied were the mesenteric arteriolar reactivity (intravital microscopy), nitric oxide synthase (NOS) activity (conversion of L-arginine to L-citrulline), eNOS gene expression (RT-PCR), NO production (diaminofluorescein), reactive oxygen species (ROS) generation (intravital fluorescence microscopy) and Cu/Zn superoxide dismutase (SOD) activity (spectrophotometry) and gene expression (RT-PCR). The reduced endothelium-dependent vasodilation of diabetic females was corrected by both BH(4) and insulin. NOS activity was decreased by diabetes, but insulin did not correct it. However, NOS expression was not modified by either diabetes or insulin. Arterioles of diabetic rats exhibited lower NO production, which was fully corrected by BH(4) and only partially by insulin. ROS generation was increased in diabetic rats, and both BH(4) and insulin normalized it. Diabetes did not change SOD activity and gene expression. However, insulin increased SOD activity but not its expression. Our data suggest that, similarly to males, endothelial dysfunction in female diabetic rats involves an altered ROS/NO imbalance. In contrast to males, however, insulin does not regulate NOS in the microcirculation of diabetic females.
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Affiliation(s)
- Eliana H Akamine
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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Matsumoto T, Kobayashi T, Kamata K. Mechanisms underlying the impaired EDHF-type relaxation response in mesenteric arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Eur J Pharmacol 2006; 538:132-40. [PMID: 16678154 DOI: 10.1016/j.ejphar.2006.04.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2005] [Revised: 03/02/2006] [Accepted: 04/03/2006] [Indexed: 12/30/2022]
Abstract
We previously reported that in mesenteric arteries from streptozotocin-induced diabetic rats, the endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP. Here, we observed an impairment of acetylcholine-induced EDHF-type relaxation in mesenteric arteries from a type 2 diabetic model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats [vs. age-matched control Long-Evans Tokushima Otsuka (LETO) rats], and we investigated the mechanism underlying this impairment. In the LETO group, this EDHF-type relaxation was attenuated by 18alpha-glycyrrhetinic acid (a gap-junction inhibitor) and by a protein kinase A (PKA) inhibitor. In both groups (OLETF and LETO), it was enhanced by 3-isobutyl-1-methylxanthine, a cAMP-phosphodiesterase (PDE) inhibitor, but following these enhancements it was still weaker in OLETF rats than in LETO rats. The relaxations induced by cilostamide (a selective PDE3 inhibitor) and 8-bromo-cAMP (a cell-permeant cAMP analog) were reduced in OLETF rats, as was PKA activity. The relaxations induced by two activators of Ca(2+)-activated K(+) channels (K(Ca)) [1-ethyl-2-benzimidazolinone (1-EBIO), intermediate-conductance K(Ca) channel (IK(Ca)) activator, and riluzole, small-conductance K(Ca) channel (SK(Ca)) activator] were also impaired in OLETF rats. We conclude that the impairment of EDHF-type relaxation seen in OLETF rats may be attributable not only to a reduction in cAMP/PKA signaling, but also to reduced endothelial K(Ca) channel activities.
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Affiliation(s)
- Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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Abstract
This review summarizes and examines the evidence from experiments using animal models to determine the effect of endurance exercise training on endothelium-dependent dilation in the arterial circulation. The response of the endothelium to exercise training is complex and depends on a number of factors that include the duration of the training program, the size of the artery/arteriole, the anatomical location of the artery/arteriole, and the health of the individual. In healthy animals, short-term exercise training appears to cause enhanced endothelium-dependent dilation in some vascular beds, but it returns to normal levels as the duration of the training program increases. In general, evidence supports the notion that exercise training causes greater increases in endothelium-dependent dilation in various disease states than in healthy individuals. The evidence of a generalized effect of training on arterial endothelium in all regions of the body is inconsistent and appears to depend on the animal model used. Available results indicate that training duration, artery size, and anatomical location interact in ways not fully understood at this time to determine whether and to what extent endothelium-dependent dilation will be enhanced by exercise training.
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De Moraes R, Gioseffi G, Lopes NDN, Gomes MB, Nóbrega ACL, Tibiriçá E. Exercise training protects the renal circulation against high glucose challenge. Fundam Clin Pharmacol 2005; 19:537-43. [PMID: 16176332 DOI: 10.1111/j.1472-8206.2005.00358.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
It has been shown previously that high glucose causes direct and acute endothelial dysfunction in non-diabetic isolated rabbit kidney. This study assessed whether exercise training is able to maintain normal renal vascular endothelial function despite high glucose exposure. Animals were pen confined (SED) or treadmill trained over a 12-week period (ExT). Kidneys isolated from SED and ExT rabbits were continuously perfused ex vivo during 3 h with Krebs-Henseleit solutions containing normal (5.5 mm) or high (15 mm) concentrations of d-glucose. In the SED 5.5 group, acetylcholine (ACh) induced dose-related vasodilator responses, reaching the maximum of 41+/- 2% (n=10; P<0.05). In the kidneys perfused with high concentrations of glucose (SED 15), endothelium-dependent vasodilation was significantly blunted. Maximal relaxation in the presence of 15 mm glucose was of 19 +/- 2%, which was significantly different from the SED 5.5 group (41+/- 2%, n=10, P<0.01). In the ExT 5.5 group, ACh-induced vasodilation was significantly enhanced when compared with the SED 5.5 group, reaching the maximum of (52+/- 2%, n=10, P<0.05). Moreover, the exposure of the renal circulation of ExT animals to high glucose did not change endothelium-dependent vasodilation induced by ACh (46+/- 3%, n=6), when compared with the ExT 5.5 group. Finally, exercise training prevented the deleterious effects of high glucose on endothelial-dependent renal vasodilation (SED 15: 19+/- 2% vs. ExT 15: 46+/- 3%; P<0.05). It is concluded that exercise training protects the rabbit renal circulation against endothelial dysfunction elicited by acute exposure to moderately elevated glucose levels, corresponding to the postprandial glycemia of diabetes type 2 patients under treatment. The enhanced renal vasodilator reserve elicited by exercise training turns out to be a response that protects the kidney from the deleterious effects of glycemic peaks.
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Affiliation(s)
- Roger De Moraes
- Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, FIOCRUZ, Av. Brasil 4365 - Manguinhos, C.P. 926, 21045-900 Rio de Janeiro, RJ, Brazil
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De Moraes R, Gioseffi G, Nóbrega ACL, Tibiriçá E. Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits. J Appl Physiol (1985) 2004; 97:683-8. [PMID: 15090484 DOI: 10.1152/japplphysiol.00923.2003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Exercise training is known to improve vasodilating mechanisms mediated by endothelium-dependent relaxing factors in the cardiac and skeletal muscle vascular beds. However, the effects of exercise training on visceral vascular reactivity, including the renal circulation, are still unclear. We used the experimental model of the isolated perfused rabbit kidney, which involves both the renal macro- and microcirculation, to test the hypothesis that exercise training improves vasodilator mechanisms in the entire renal circulation. New Zealand White rabbits were pen confined (Sed; n = 24) or treadmill trained (0% grade) for 5 days/wk at a speed of 18 m/min during 60 min over a 12-wk period (ExT; n = 24). Kidneys isolated from Sed and ExT rabbits were continuously perfused in a nonrecirculating system under conditions of constant flow and precontracted with norepinephrine (NE). We assessed the effects of exercise training on renal vascular reactivity using endothelial-dependent [acetylcholine (ACh) and bradykinin (BK)] and -independent [sodium nitroprusside (SNP)] vasodilators. ACh induced marked and dose-related vasodilator responses in kidneys from Sed rabbits, the reduction in perfusion pressure reaching 41 ± 8% ( n = 6; P < 0.05). In the kidneys from ExT rabbits, vasodilation induced by ACh was significantly enhanced to 54 ± 6% ( n = 6; P < 0.05). In contrast, BK-induced renal vasodilation was not enhanced by training [19 ± 8 and 13 ± 4% reduction in perfusion pressure for Sed and ExT rabbits, respectively ( n = 6; P > 0.05)]. Continuous perfusion of isolated kidneys from ExT animals with Nω-nitro-l-arginine methyl ester (l-NAME; 300 μM), an inhibitor of nitric oxide (NO) biosynthesis, completely blunted the additional vasodilation elicited by ACh [reduction in perfusion pressure of 54 ± 6 and 38 ± 5% for ExT and l-NAME + ExT, respectively ( n = 6; P < 0.05)]. On the other hand, l-NAME infusion did not affect ACh-induced vasodilation in Sed animals. Exercise training also increased renal vasodilation induced by SNP [36 ± 7 and 45 ± 10% reduction in perfusion pressure for Sed and ExT rabbits, respectively ( n = 6; P < 0.05)]. It is concluded that exercise training alters the rabbit kidney vascular reactivity, enhancing endothelium-dependent and -independent renal vasodilation. This effect seems to be related not only to an increased bioavailability of NO but also to the enhanced responsiveness of the renal vascular smooth muscle to NO.
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Affiliation(s)
- Roger De Moraes
- Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, FIOCRUZ, Av. Brasil 4365-Manguinhos, C.P. 926, 21045-900 Rio de Janeiro, RJ, Brazil
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Abstract
PURPOSE To investigate whether regular intense physical training induces changes in microvascular reactivity of human glabrous and nonglabrous skin. METHODS Subjects were physically trained competitive cyclists (N = 19) and age-matched sedentary controls (N = 20). We measured cutaneous microvascular blood flow on the dorsum of the hand (nonglabrous skin) and on the finger pulp (glabrous skin) using the laser-Doppler (LD) method. Endothelium-dependent vasodilation was assessed by an iontophoretic application of acetylcholine (ACh) on the dorsum of the hand and by an induction of postocclusive reactive hyperemia (PRH) on the finger pulp. Endothelium-independent vasodilation was assessed on the dorsum of the hand by iontophoretically applied sodium-nitroprusside (SNP). RESULTS The ACh-evoked increase in LD flux (LDF) was significantly greater in the group of cyclists (7.5-fold +/- 0.5 increase) as compared with controls (5.9-fold +/- 0.5). We found no differences in the peak LDF during PRH, whereas the recovery time of PRH was significantly longer (241.5 +/- 21.6 s in trained vs 154.6 +/- 9.3 s in sedentary group) and the area under the PRH curve significantly larger in the group of trained subjects (19,066 +/- 2,653 PU x s in trained vs 12,168 +/- 864 PU x s in sedentary). In contrast, we found a significantly smaller response to SNP in the group of cyclists (6.2-fold +/- 0.5 increase) as compared with sedentary subjects (7.8-fold +/- 0.5 increase). CONCLUSION The results of our study point to a greater vasodilator capacity of endothelium in glabrous as well as in nonglabrous skin in the group of physically trained subjects. In addition, our results indicate that regular physical activity also modifies the reactivity of vascular smooth muscle cells.
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Affiliation(s)
- Helena Lenasi
- Institute of Physiology, School of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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42
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Kemi OJ, Haram PM, Wisløff U, Ellingsen Ø. Aerobic fitness is associated with cardiomyocyte contractile capacity and endothelial function in exercise training and detraining. Circulation 2004; 109:2897-904. [PMID: 15173028 DOI: 10.1161/01.cir.0000129308.04757.72] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Physical fitness and level of regular exercise are closely related to cardiovascular health. A regimen of regular intensity-controlled treadmill exercise was implemented and withdrawn to identify cellular mechanisms associated with exercise capacity and maximal oxygen uptake (VO2max). METHODS AND RESULTS Time-dependent associations between cardiomyocyte dimensions, contractile capacity, and VO2max were assessed in adult rats after high-level intensity-controlled treadmill running for 2, 4, 8, and 13 weeks and detraining for 2 and 4 weeks. With training, cardiomyocyte length, relaxation, shortening, Ca2+ decay, and estimated cell volume correlated with increased VO2max (r=0.92, -0.92, 0.88, -0.84, 0.73; P<0.01). Multiple regression analysis identified cell length, relaxation, and Ca2+ decay as the main explanatory variables for VO2max (R2=0.87, P<0.02). When training stopped, exercise-gained VO2max decreased 50% within 2 weeks and stabilized at 5% above sedentary controls after 4 weeks. Cardiomyocyte size regressed in parallel with VO2max and remained (9%) above sedentary after 4 weeks, whereas cardiomyocyte shortening, contraction/relaxation- and Ca2+-transient time courses, and endothelium-dependent vasorelaxation regressed completely within 2 to 4 weeks of detraining. Cardiomyocyte length, estimated cell volume, width, shortening, and Ca2+ decay and endothelium-dependent arterial relaxation all correlated with VO2max (r=0.85, 0.84, 0.75, 0.63, -0.54, -0.37; P<0.01). Multiple regression identified cardiomyocyte length and vasorelaxation as the main determinants for regressed VO2max during detraining (R2=0.76, P=0.02). CONCLUSIONS Cardiovascular adaptation to regular exercise is highly dynamic. On detraining, most of the exercise-gained aerobic fitness acquired over 2 to 3 months is lost within 2 to 4 weeks. The close association between cardiomyocyte dimensions, contractile capacity, arterial relaxation, and aerobic fitness suggests cellular mechanisms underlying these changes.
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Affiliation(s)
- Ole Johan Kemi
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
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43
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Napoli C, Williams-Ignarro S, De Nigris F, Lerman LO, Rossi L, Guarino C, Mansueto G, Di Tuoro F, Pignalosa O, De Rosa G, Sica V, Ignarro LJ. Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice. Proc Natl Acad Sci U S A 2004; 101:8797-802. [PMID: 15169957 PMCID: PMC423275 DOI: 10.1073/pnas.0402734101] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The pathogenic mechanisms by which physical exercise influences atherosclerotic lesion formation remain poorly understood. Because vigorous physical training increases oxidative stress, this study tested the hypothesis that graduated and moderate physical exercise together with metabolic intervention (l-arginine and antioxidants) may contribute to increased vascular protection. Exercise training in mice was induced by graduated swimming. In hypercholesterolemic male mice on an atherogenic high-cholesterol diet, graduated and moderate exercise lowered plasma cholesterol and decreased atherosclerotic lesions compared with sedentary control mice. Antioxidants (1.0% vitamin E added to the chow and 0.05% vitamin C added to the drinking water) and l-arginine (6% in drinking water) supplementation to exercising hypercholesterolemic mice further and synergistically reduced atherosclerosis compared with untreated exercised mice. Arterial oxidation-specific epitopes and systemic oxidative stress were reduced by metabolic intervention. Graduated chronic exercise elicited an increase in production of nitric oxide through increased endothelial nitric oxide synthase expression and ameliorated scavenger activities. Thus, metabolic intervention with l-arginine and antioxidants together with graduated and moderate exercise training reduce atherosclerotic lesion formation.
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Affiliation(s)
- Claudio Napoli
- Department of General Pathology, Medicine, Clinical Pathology, and Human Pathology, University of Naples, 80131 Naples, Italy.
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44
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Matsumoto T, Wakabayashi K, Kobayashi T, Kamata K. Alterations in vascular endothelial function in the aorta and mesenteric artery in type II diabetic rats. Can J Physiol Pharmacol 2004; 82:175-82. [PMID: 15052283 DOI: 10.1139/y04-002] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We used the partial protection exerted by suitable dosages of nicotinamide against the β-cytotoxic effect of streptozotocin (STZ) to create an experimental diabetic syndrome in adult rats that appears closer to type II diabetes mellitus than other available animal models. The dosage of 230 mg/kg of nicotinamide given intraperitoneally 15 min before STZ administration (65 mg/kg i.v.) yielded animals with hyperglycemia (187.8 ± 17.8 vs. 103.8 ± 2.8 mg/dL in controls; P < 0.001) and preservation of plasma insulin levels. This study assessed the relationship between endothelial dysfunction and agonist-induced contractile responses in such rats. In the thoracic aorta, the acetylcholine (ACh) induced relaxation was significantly reduced and the noradrenaline (NA) induced contractile response was significantly increased in diabetic rats compared with age-matched control rats. In the superior mesenteric artery, the ACh-induced relaxation was similar in magnitude between diabetic and age-matched control rats; however, the ACh-induced endothelium-derived hyperpolarizing factor (EDHF) type relaxation was significantly weaker in diabetic rats than in the controls. The phenylephrine (PE) induced contractile response was not different between the two groups. The plasma concentration of NOx (NO2– + NO3–) was significantly lower in diabetic rats than in control rats. We conclude that vasomotor activities in conduit arteries are impaired in this type II diabetes model.Key words: aorta, contraction, endothelium-derived hyperpolarizing factor, endothelium-mediated relaxation, mesenteric artery, type II diabetes.
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MESH Headings
- Acetylcholine/pharmacology
- Animals
- Aorta, Thoracic/drug effects
- Aorta, Thoracic/physiopathology
- Biological Factors/biosynthesis
- Biological Factors/pharmacology
- Chlorides/pharmacology
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Type 2/chemically induced
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/physiopathology
- Hyperglycemia/chemically induced
- Hyperglycemia/complications
- Indomethacin/pharmacology
- Insulin/blood
- Isotonic Solutions/pharmacology
- Male
- Mesenteric Artery, Superior/drug effects
- Mesenteric Artery, Superior/physiopathology
- Muscle Contraction/drug effects
- Muscle Relaxation/drug effects
- Muscle, Smooth, Vascular/drug effects
- Niacinamide/adverse effects
- Nitric Oxide/analogs & derivatives
- Nitric Oxide/blood
- Nitroarginine/pharmacology
- Nitroprusside/pharmacology
- Norepinephrine/pharmacology
- Phenylephrine/pharmacology
- Potassium/pharmacology
- Rats
- Rats, Wistar
- Sodium/pharmacology
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Affiliation(s)
- Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan
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45
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Mahajan H, Richards SM, Rattigan S, Clark MG. T-1032, a cyclic GMP phosphodiesterase-5 inhibitor, acutely blocks physiologic insulin-mediated muscle haemodynamic effects and glucose uptake in vivo. Br J Pharmacol 2003; 140:1283-91. [PMID: 14581178 PMCID: PMC1574135 DOI: 10.1038/sj.bjp.0705548] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
1. Cyclic GMP phosphodiesterase-5 inhibitors have been shown to alter blood flow in specific tissues by potentiating local NO-dependent vasodilatory mechanisms. Since the haemodynamic effects of physiologic insulin, particularly capillary recruitment, may be critical for muscle glucose uptake in vivo and are blocked by inhibitors of nitric oxide synthase, we have explored the acute effects of the specific cGMP phosphodiesterase-5 inhibitor T-1032 on physiologic insulin action in anaesthetized healthy rats in vivo. 2. Whole-body glucose infusion (GIR), femoral blood flow (FBF), hind leg vascular resistance (VR), hind leg glucose uptake (HGU), 2-deoxyglucose uptake into muscles of the lower leg (R'g), hind leg metabolism of infused 1-methylxanthine (1-MX), a measure of capillary recruitment, and muscle cGMP were determined. The experimental groups were T-1032 (10 microg min-1 kg-1) infused for 1 h before and during a euglycaemic insulin clamp (3 mU min-1 kg-1 x 2 h), T-1032 infused for 3 h with saline, T-1032 during a 2 h clamp, T-1032 with saline for 2 h, and a 2 h saline control. 3. Insulin increased GIR from zero to 13 mg min-1 kg-1, HGU from 0.1+/-0.01 to 0.43+/-0.05 micromol min-1, R'g and 1-MX, marginally increased FBF, and had no effect on blood pressure or heart rate. T-1032 alone had no effect on blood pressure, heart rate, FBF, VR, HGU, R'g or 1-MX, but increased muscle cGMP. T-1032 1 h before and during insulin completely blocked GIR (1 h), HGU (2 h), R'g (2 h), and 1-MX (2 h). T-1032 commenced with insulin had only partial blocking activity against insulin. 4. We conclude that T-1032 is a potent acutely acting inhibitor of the muscle effects of physiologic insulin on capillary recruitment and glucose uptake in vivo. These, together with inhibition of whole-body glucose infusion during insulin, may caution against the use of isoenzyme-5-specific cyclic GMP phosphodiesterase inhibitors as therapeutic agents.
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Affiliation(s)
- Hema Mahajan
- Biochemistry, Medical School, University of Tasmania, Private Bag 58, Hobart, Tasmania 7001, Australia
| | - Stephen M Richards
- Biochemistry, Medical School, University of Tasmania, Private Bag 58, Hobart, Tasmania 7001, Australia
| | - Stephen Rattigan
- Biochemistry, Medical School, University of Tasmania, Private Bag 58, Hobart, Tasmania 7001, Australia
| | - Michael G Clark
- Biochemistry, Medical School, University of Tasmania, Private Bag 58, Hobart, Tasmania 7001, Australia
- Author for correspondence:
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