Published online before print February 9, 2009, doi: 10.1161/CIRCULATIONAHA.108.824730
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(Circulation. 2009;119:978-986.)
© 2009 American Heart Association, Inc.
Hypertension |
Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Obesity-Induced Hypertension
From the Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Correspondence to Toshiro Fujita, MD, PhD, Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. E-mail fujita-dis{at}h.u-tokyo.ac.jp
Received April 9, 2008; accepted December 15, 2008.
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Abstract |
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Background— Obesity is one of the major risk factors for cardiovascular disease and is often associated with increased oxidative stress and sympathoexcitation. We have already suggested that increased oxidative stress in the brain modulates the sympathetic regulation of arterial pressure in salt-sensitive hypertension, which is often associated with obesity. The present study was performed to determine whether oxidative stress could mediate central sympathoexcitation in the initial stage of obesity-induced hypertension.
Methods and Results— Four-week-old male Sprague-Dawley rats were fed a high-fat (45% kcal as fat) or low-fat (10% kcal as fat) diet for 6 weeks. Fat loading elicited hypertension and sympathoexcitation, along with visceral obesity. In urethane-anesthetized and artificially ventilated rats, arterial pressure and renal sympathetic nerve activity decreased in a dose-dependent fashion when 53 or 105 µmol/kg tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. Central tempol reduced arterial pressure and renal sympathetic nerve activity to a significantly greater extent in high-fat diet–fed hypertensive rats than in low-fat diet–fed normotensive rats. Intracerebroventricular apocynin or diphenyleneiodonium, a reduced NADPH oxidase inhibitor, also elicited markedly greater reductions in arterial pressure and renal sympathetic nerve activity in the high-fat diet–fed rats. In addition, fat loading increased NADPH oxidase activity and NADPH oxidase subunit p22phox, p47phox, and gp91phox mRNA expression in the hypothalamus.
Conclusions— In obesity-induced hypertension, increased oxidative stress in the brain, possibly via activation of NADPH oxidase, may contribute to the progression of hypertension through central sympathoexcitation.
Key Words: brain • hypertension • obesity • oxidative stress • sympathetic nervous system
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Introduction |
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Metabolic syndrome, a complex of highly debilitating disorders that consist of hypertension, diabetes mellitus, and dyslipidemia, is associated with the development of visceral obesity.1 All of these features are risk factors for atherosclerosis; therefore, the metabolic syndrome results in a high incidence of cardiovascular events. Although hypertension is one of the major components of the metabolic syndrome, the mechanisms through which obesity contributes to hypertension have not been fully elucidated.
Clinical Perspective p 986
Sympathetic activation is often associated with obesity. For example, studies using microneurography have consistently shown increased muscle sympathetic nerve activity in obese subjects.2 Furthermore, muscle sympathetic nerve activity is closely associated with the level of abdominal visceral fat.3 As expected, a number of studies indicated that sympathetic activation may be involved in obesity-induced hypertension.4 In young, nondiabetic Japanese men, body mass index correlated with not only mean blood pressure but also pulse rate and plasma norepinephrine.5 In an animal study, obese Zucker rats, which display hyperphagia-induced obesity caused by a mutation of the leptin receptor, have elevated sympathetic nerve activity and arterial pressure (AP).6 Autonomic ganglionic blockade decreased mean AP (MAP) to a much greater extent in obese Zucker rats compared with lean rats.7 In addition, bilateral renal denervation prevented the hypertension and sodium retention associated with obesity in dogs fed a high-fat diet (HF).8 Thus, sympathetic activation may play a major role in the pathogenesis of obesity-induced hypertension.
Bodies of evidence have suggested associations of obesity with high oxidative stress in human9 and animal models.10,11 Male Sprague-Dawley rats have exhibited hypertension, along with increased oxidative stress, when fed an HF beginning at 3 weeks of age.12 Furthermore, several studies have demonstrated increased oxidative stress in the kidney and aorta of Fischer rats fed an HF diet with high refined sugar13 and in the aorta of obese Zucker rats.14 Thus, reactive oxygen species (ROS) may be the unifying mechanism underlying the development of hypertension in obesity, although it is unknown how ROS increases AP.
The role of central ROS in sympathetic regulation of AP has been suggested in some types of hypertensive animal models.15–20 The ROS level was increased in the brain of stroke-prone spontaneously hypertensive rats.17 The pressor and sympathoexcitatory effects of centrally administered angiotensin II were completely abolished by adenoviral vector-mediated expression of superoxide dismutase18,19 and by central administration of 4-hydroxy-2,2,6,6-tetramethylpiperindine-N-oxyl (tempol), a membrane-permeable superoxide dismutase mimetic, or polyethylene glycol–superoxide dismutase.20 Furthermore, we have previously demonstrated that salt loading stimulated an increase in AP induced by central sympathoexcitation possibly through brain ROS overproduction in adrenomedullin-knockout mice, an animal model of increased oxidative stress.15 We have also suggested that increased ROS in the brain elevates AP possibly through central sympathoexcitation in a salt-sensitive hypertensive model, Dahl salt-sensitive rats.16
Obesity-induced hypertension showed enhancement of salt sensitivity of blood pressure.21 Conversely, a number of studies, including ours, have demonstrated that salt-sensitive hypertension exhibits the metabolic disorder22–25 and sympathoexcitation.16,26,27 In a manner similar to salt-sensitive hypertension,16 increased oxidative stress10,12–14 and sympathoexcitation3,4 may be important pathogenic mechanisms in the progression of obesity-induced hypertension. High dietary fat has been reported to actually induce reduced NADPH oxidase–associated oxidative stress and inflammation in the brain of rats.28 However, the exact role of increased brain ROS in obesity remains to be elucidated. We hypothesized that ROS overproduction in the brain might contribute to central sympathetic activation and AP elevation in obesity-induced hypertension. In the present study, to clarify our hypothesis, we examined the response of renal sympathetic nerve activity (RSNA) and AP to intracerebroventricular administration of antioxidant agents and the level of NADPH oxidase activity and mRNA expression in obesity-induced hypertensive model rats fed an HF.
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Methods |
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Animals
Four-week-old male Sprague-Dawley rats (Tokyo Laboratory Animals Science, Tokyo, Japan) were randomly assigned to receive an HF (45% kcal as fat; Research Diets, New Brunswick, NJ) or a low-fat diet (LF; 10% kcal as fat) for 6 weeks. All rats were housed in a room maintained at 23°C to 25°C with a 12-hour light/dark cycle and were given food and water ad libitum. All experimental procedures were approved by the Ethics Committees on Animal Research of Faculty of Medicine, University of Tokyo.
Measurement of Blood Pressure and Biochemical Parameters
Body weight and systolic blood pressure measured by the tail-cuff method (P-98A, Softron, Tokyo, Japan) were recorded every week. Urinary norepinephrine excretion was measured at 4 and 6 weeks of dietary loading as an indicator of sympathetic nerve activity. At 6 weeks of treatment, in some rats anesthetized with sodium pentobarbital (50 mg/kg IP), blood samples were obtained by cardiac puncture to measure the following metabolic parameters after an overnight fast. Blood glucose concentrations were measured with a Quickauto NEO GLU-HK kit (Shino-Test Inc, Tokyo, Japan). Serum insulin and leptin concentrations were measured with an insulin and a leptin ELISA kit (Morinaga Institute of Biological Science, Inc, Yokohama, Japan), respectively. Serum cholesterol, triglycerides, and free fatty acids were assayed with routine enzymatic assays. At the end of the study, the retroperitoneal, epididymal, and total mesenteric fats were harvested, and their wet weights were measured to evaluate visceral fat.
Ganglionic Blockade With Hexamethonium Hydrochloride
In some conscious rats, we examined the response of MAP to ganglionic blockade to evaluate sympathetic nerve activity. The femoral artery and vein were cannulated under ether anesthesia. The experiment was begun at least 3 hours after recovery from anesthesia.16 After the baseline MAP measurement, 30 mg/kg hexamethonium was administered into the femoral vein. The maximal decrease in the MAP was considered an index of sympathetic activity.29
Intracerebroventricular Administration of Antioxidant Agents
In urethane-anesthetized (1 g/kg) and artificially ventilated rats, MAP, heart rate (HR), and RSNA were recorded, as mentioned in our previous reports.15,16,26 After recording the basal MAP, HR, and RSNA during a 30-minute stabilization period, we infused artificial cerebrospinal fluid (ACSF) or tempol (53 or 105 µmol/kg in 10 µL ACSF) into the lateral ventricle in 10 minutes and recorded changes in the parameters. The dose of tempol was determined as described previously.15,16,30 The effect of intracerebroventricular apocynin (1.05 or 2.1 µmol/kg in ACSF) or diphenyleneiodonium (DPI; 13 µmol/kg in ACSF),16 an inhibitor of NADPH oxidase, was also examined. Accuracy of the intracerebroventricular injection was confirmed by injection of Evans blue dye after each experiment.
Measurement of NADPH-Induced Superoxide Production
Production of NADPH-induced (final concentration, 100 µmol/L) superoxide anions was measured by bis-N-methylacridinium (lucigenin) chemiluminescence in the isolated hypothalamus, where several nuclei critically involved in cardiovascular regulation are known to be located,31 as described previously.11,16
Real-Time Quantitative Reverse-Transcriptase Polymerase Chain Reaction for NADPH Oxidase Subunits
NADPH oxidase subunit p22phox, p47phox, gp91phox mRNA expression in the isolated hypothalamus was evaluated by real-time quantitative reverse-transcription polymerase chain reaction according to the procedure described previously.16 Assay-on-demand primers and probes sets (Applied Biosystems, Tokyo, Japan) were used for the rat p22phox, p47phox, gp91phox, and β-actin.
Statistical Analysis
All values are presented as mean±SEM. In the intracerebroventricular administration experiments, the baseline value was defined as the mean value over a 1-minute stabilization period before administration of drugs, and the peak value was defined as a mean value for 10 seconds around the maximum response. Magnitudes of changes were expressed as percentage change of the peak values from the baseline values. The Student unpaired t test was used for comparisons between HF- and LF-fed rats. The data from intracerebroventricular tempol experiments were analyzed with a mixed model performed with JMP (SAS Institute, Cary, NC) computer software. Values of P<0.05 were considered statistically significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Effects of HF on Total Body Weight, Visceral Fat Weight, and Blood Pressure
The body weight in HF-fed rats increased significantly after 3 weeks of treatment (3 weeks: 286.4±2.1 versus 264.6±6.4 g for HF- and LF-fed rats, respectively; P=0.004; 6 weeks: 436.2±5.8 versus 391.8±9.0 g; P<0.001; n=10, respectively). The visceral fat weight was significantly greater in HF-fed rats (n=10) than in LF-fed rats (n=8) (retroperitoneal fat, 12.4±0.8 versus 6.1±0.9 g; P<0.001; epididymal fat, 9.0±0.6 versus 5.3±0.6 g; P<0.001; total mesenteric fat, 8.5±0.4 versus 5.6±0.8 g; P=0.003). Thus, the larger body weight in the rats was associated with a greater accumulation of visceral fat mass in the present study.
Like body weight, systolic blood pressure was significantly elevated in HF-fed rats (n=10) compared with LF-fed rats (n=10) from 3 (148±3 versus 126±2 mm Hg; P<0.001) to 6 (148±3 versus 129±3 mm Hg; P<0.001) weeks of treatment. In the conscious state, MAP also was significantly elevated in HF-fed rats (n=4) compared with the LF-fed rats (n=4) by direct measurement (113±2 versus 94±8 mm Hg; P=0.048).
Effects of HF on Metabolic Parameters
Fasting blood glucose tended to be higher in HF-fed rats compared with LF-fed rats (P=0.058; the Table). Moreover, serum insulin was apparently higher in HF-fed rats (P<0.001). Thus, insulin resistance was enhanced in HF-fed rats as indicated by the homeostasis model assessment of insulin resistance (P<0.001). Serum leptin concentrations also were elevated in HF-fed rats (P<0.001). However, no significant differences were found in serum cholesterol, triglycerides, and free fatty acids between HF- and LF-fed rats.
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Twenty-Four-Hour Urinary Norepinephrine and Effects of Ganglionic Blockade With Hexamethonium Hydrochloride
Urinary norepinephrine excretion increased in HF-fed rats (n=10) compared with LF-fed rats (n=10) (4 weeks of treatment: 1.1±0.1 versus 0.7±0.1 µg/24 h; P=0.003; 6 weeks: 1.4±0.0 versus 1.1±0.1 µg/24 hours; P=0.032). Moreover, the MAP reduction induced by hexamethonium was significantly greater in HF-fed rats (–62±1.5 versus –46±3.5 mm Hg; P=0.006; n=4). Both results suggest that sympathetic activity increased significantly in HF-fed rats compared with LF-fed rats.
Effects of Intracerebroventricular Tempol on MAP, HR, and RSNA
MAP, integrated RSNA, and HR values started decreasing a few minutes after intracerebroventricular tempol administration and reached their lowest level within 
15 minutes, after which they gradually returned to the respective control levels within 30 minutes (Figure 1). However, in some cases of HF-fed rats, the reduction continued for >30 minutes. In all of the rats, MAP, HR, and RSNA values decreased in a dose-dependent fashion (Figure 2). The reduction in MAP was significantly (P<0.001) greater in HF-fed rats than in LF-fed rats (–13.3±2.1% versus –5.5±2.0% at 53 µmol/kg tempol and –32.7±3.0% versus –13.4±2.4% at 105 µmol/kg tempol). Similarly, the reduction in RSNA was significantly (P<0.001) greater in HF-fed rats (–8.8±2.4% versus –1.9±0.5% and –13.4±1.7% versus –5.1±1.0%). The reduction in HR also was stimulated (P=0.004) in HF-fed rats (–7.9±1.8% versus –0.8±1.7% and –13.4±3.1% versus –4.5±0.6%). Thus, downward shifts were observed in the dose-response curves of the MAP, RSNA, and HR values for intracerebroventricular tempol in HF-fed rats compared with LF-fed rats (Figure 2).
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Effects of Intracerebroventricular Apocynin or DPI on MAP, HR, and RSNA
Intracerebroventricular apocynin or DPI, an NADPH oxidase inhibitor, also elicited remarkably greater reductions in MAP and RSNA in HF-fed rats. As with tempol, intracerebroventricular apocynin decreased MAP and RSNA in a dose-dependent fashion (Figure 3). The sample size of the intracerebroventricular apocynin experiment was too small (n=3) to analyze statistically. Therefore, we have presented the scatterplot of the percentage change in MAP and RSNA against dose with a line joining the results of each rat in the online-only Data Supplement (Figure I). The rats from the same group demonstrated very similar responses by dose, and the dose-response curves of the MAP and RSNA values showed markedly greater downward shifts in HF-fed rats compared with LF-fed rats. Intracerebroventricular DPI also decreased MAP and RSNA values in HF-fed rats but not in LF-fed rats; intracerebroventricular DPI-induced reductions in the MAP and RSNA values were significantly greater in HF-fed rats (MAP, P=0.004; RSNA, P=0.015; Figure 4). The response of HR to intracerebroventricular apocynin or DPI varied with each animal even in the same groups and did not show any difference between HF- and LF-fed rats.
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Measurement of NADPH-Induced Superoxide Production in the Isolated Hypothalamus
NADPH-induced superoxide production increased significantly in the isolated hypothalamus from HF-fed rats compared with LF-fed rats (3.30±0.28x106 versus 2.20±0.11x106 relative light units per 10 minutes per 1 g; P=0.005; Figure 5).
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mRNA Expression for NADPH Oxidase Subunits in the Hypothalamus
The mRNA expression levels for the NADPH oxidase subunits p22phox, p47phox, and gp91phox were significantly increased in the hypothalamus from HF-fed rats compared with LF-fed rats (p22phox, P=0.039; p47phox, P=0.036; gp91phox, P<0.001; Figure 6).
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Discussion |
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In the present study, we have demonstrated 3 major findings. First, high fat loading caused sympathoexcitation and hypertension, along with obesity-related metabolic disorder. Second, reductions in RSNA and AP values elicited by intracerebroventricular administration of the antioxidant tempol, apocynin, or DPI were significantly greater in HF-fed rats than in LF-fed rats. Third, hypothalamic NADPH oxidase activity and mRNA expression were higher in HF-fed rats than LF-fed rats. These results suggest that obesity enhances ROS generation in the brain via activation of NADPH oxidase, which leads to central sympathoexcitation and hypertension. To best of our knowledge, these are the first findings providing evidence that there may be a close association between oxidative stress and sympathoexcitation in the brain of obesity-induced hypertensive subjects.
A number of reports suggest that ROS overproduction in the kidneys,10,13,24 heart,11 and arteries10,12–14,25 is involved in obesity-induced hypertension. However, the role of ROS in the brain has never been elucidated, although high dietary fat has been reported to induce NADPH oxidase–derived oxidative stress and inflammation in the brain.28 Our viewpoint that oxidative stress in the brain exerts an effect on central sympathoexcitation in obesity-induced hypertension is plausible because recent studies have also implicated the contribution of ROS overproduction in the brain to activation of the sympathetic nervous system. For example, microinjection of tempol into the dorsomedial hypothalamus32 or the rostral ventrolateral medulla33 attenuated the pressor and sympathoexcitatory responses to emotional stress in rabbits. Microinjection of superoxide dismutase into rostral ventrolateral medulla of anesthetized pigs reduced AP, HR, and RSNA values.34 Intracerebroventricular infusion of antioxidants, including in this study, elicited a direct sympathoinhibitory effect, suggesting that ROS might directly stimulate central sympathetic nerve activity.16,35 Moreover, in stroke-prone spontaneously hypertensive rats, the ROS level was increased in the rostral ventrolateral medulla, and bilateral microinjection of tempol into the rostral ventrolateral medulla decreased AP.17
Intracerebroventricular administration can act in the hypothalamic area, which is supposed to contain sodium sensors and osmosensors and several nuclei critically involved in the cardiovascular regulation system such as the subfornical organ, paraventricular hypothalamic nuclei, and organum vasculosum of the stria terminalis.31,36 Other regions of the brain such as the rostral ventrolateral medulla17,33,34 have also been recognized as key areas in the normal and reflex control of AP. In contrast, previous studies, including those in our laboratory, with intracerebroventricular infusion of antioxidants suggest that the hypothalamus is a critical area in the ROS generation and maintenance of sympathetic control of the cardiovascular system.15,16,19,20,30,35 These results are compatible with the present data although the region-related functions of the brain are complicated and remain unknown.
Although the present study has demonstrated that ROS generation may be mediated through the activation of NADPH oxidase, the potential mechanisms underlying ROS generation in the brain of obese rats remain unclear. Emerging bodies of evidence suggest that several possible factors contribute to the excessive formation of ROS in obesity,9,37 although the mechanism may be complicated. Several studies have shown that the central renin-angiotensin system mediates ROS generation,18,19,33,38 and it is well known that adipose tissue can secrete angiotensinogen.39,40 In obese Zucker rats, brain angiotensin II type 1 receptor mRNA expression and pressor response to intracerebroventricular angiotensin II were partially increased compared with lean rats.41 Although centrally administered angiotensin II exhibited a sympathoexcitatory action possibly through its ROS-generating effect,18–20,33 the central renin-angiotensin system has not been fully investigated in obese hypertensive animals. On the other hand, insulin resistance may be critical in ROS overproduction and sympathoexcitation because HF-fed rats exhibited significantly elevated homeostasis model assessment of insulin resistance. Rats fed a high fructose diet, a model of insulin resistance, have in fact increased ROS generation42 and attenuated baroreflex function.43 In addition, a peroxisome proliferator-activated receptor-
agonist, pioglitazone, which ameliorates insulin resistance, prevented hypertension and oxidative stress in diet-induced obese rats.44 Although no reports have suggested that insulin acts as an antioxidant, insulin resistance may be related to ROS generation through several mechanisms. For example, one of the plausible candidates to stimulate ROS generation in the brain may be leptin, a polypeptide hormone mediator produced by adipocytes, because serum leptin concentrations were elevated in HF-fed rats. Leptin can generate oxidative stress, as has been reported for endothelial cells in culture.45 In addition, leptin indirectly stimulates production of inflammatory cytokines such as interleukin-6 and tumor necrosis factor-
, which increase NADPH oxidase production.9 However, no data suggest that leptin stimulates ROS generation in the brain. High blood glucose, which marginally increased in HF-fed rats, could generate ROS through synthesis of advanced glycation end product (AGE). The receptor for AGE also exists in neural cells, and AGE has been shown to stimulate p47phox expression in neuroblastoma cells.46 However, no reports exist on AGE or the receptor for AGE in the brain of obesity-induced hypertensive animal models. Moreover, any abnormality in the ROS-scavenging system might contribute to ROS upregulation in obesity. Thus, further study is needed to clarify the mechanisms underlying ROS generation in the brain of obese hypertensive animals.
Obesity-induced hypertension has been demonstrated to elicit salt-sensitive hypertension and vice versa.22–25 Both exhibit increased oxidative stress and sympathoexcitation. We have recently suggested that in salt-sensitive hypertension, increased oxidative stress in the brain, possibly via activation of NADPH oxidase, might mediate AP elevation through central sympathetic activation,16 which is quite similar to the HF-fed rats. Thus, our series of studies,16 including the present one, suggest a possible common pathogenic background: increased ROS production in the brain and central sympathoexcitation in obesity-induced and salt-sensitive hypertension.
Dobrian et al10,25 demonstrated that HF caused obesity in approximately half of the Sprague-Dawley rats but not in the other half. However, in our study, all Sprague-Dawley rats fed HF gained more weight compared with LF-fed rats. This discrepancy may be due to the difference of age (adulthood versus childhood) at the beginning of HF loading. In the former studies, rats with a body weight of 300 to 350 g were used at the start of fat loading, whereas the mean body weight of rats used in the present study was 79.4 g (range, 67 to 87 g). In all rats, which began to eat HF at 3 weeks of age and had been loaded for 10 weeks, body weight gain was accelerated12 in a manner similar to that in our study. These findings suggested that HF feeding from a juvenile age may induce a greater risk for the progression of obesity and hypertension beyond any individual genetic difference. Currently, hypertension in young children is increasing in prevalence, along with an obesity epidemic.47,48 Moreover, juvenile hypertensive patients with left ventricular hypertrophy have a greater body mass index and a greater number of metabolic syndrome components.49 Juvenile hypertension with obesity is associated with an increased risk of cardiovascular disease. Moreover, obesity in youth tends to be maintained into adulthood, further increasing the risk of adult cardiovascular disease.50 Therefore, the present study involving HF-fed young rats implies that strategies to control body weight in youth are critical to control sympathetic overactivity possibly caused by ROS upregulation in the brain, which leads to adult hypertension and resultant cardiovascular disease.
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Conclusions |
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The present study suggests for the first time that in obesity-induced hypertension, increased oxidative stress in the brain, possibly via activation of NADPH oxidase, may mediate AP elevation through central sympathetic activation. Based on our new insights, a novel strategy such as administration of an antioxidant factor with a sympathoinhibitory effect may be useful for preventing and managing hypertension associated with the metabolic disorder.
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Acknowledgments |
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We express our sincere thanks to Dr Hiroshi Ohtsu (assistant professor in the Department of Clinical Trial Data Management, University of Tokyo) for help with the statistical analysis.
Source of Funding
This work was supported by grants from the Daiichi Sankyo Co Ltd.
Disclosures
None.
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References |
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1. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005; 111: 1448–1454.
2. Grassi G, Seravalle G, Colombo M, Bolla G, Cattaneo BM, Cavagnini F, Mancia G. Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans. Circulation. 1998; 97: 2037–2042.
3. Alvarez GE, Beske SD, Ballard TP, Davy KP. Sympathetic neural activation in visceral obesity. Circulation. 2002; 106: 2533–2536.
4. Esler M, Straznicky N, Eikelis N, Masuo K, Lambert G, Lambert E. Mechanisms of sympathetic activation in obesity-related hypertension. Hypertension. 2006; 48: 787–796.
5. Masuo K, Mikami H, Itoh M, Ogihara T, Tuck ML. Sympathetic activity and body mass index contribute to blood pressure levels. Hypertens Res. 2000; 23: 303–310.[Medline] [Order article via Infotrieve]
6. Morgan DA, Anderson EA, Mark AL. Renal sympathetic nerve activity is increased in obese Zucker rats. Hypertension. 1995; 25: 834–838.
7. Carlson SH, Shelton J, White CR, Wyss JM. Elevated sympathetic activity contributes to hypertension and salt sensitivity in diabetic obese Zucker rats. Hypertension. 2000; 35: 403–408.
8. Kassab S, Kato T, Wilkins FC, Chen R, Hall JE, Granger JP. Renal denervation attenuates the sodium retention and hypertension associated with obesity. Hypertension. 1995; 25: 893–897.
9. Vincent HK, Taylor AG. Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes (Lond). 2006; 30: 400–418.[CrossRef][Medline] [Order article via Infotrieve]
10. Dobrian AD, Davies MJ, Schriver SD, Lauterio TJ, Prewitt RL. Oxidative stress in a rat model of obesity-induced hypertension. Hypertension. 2001; 37: 554–560.
11. Matsui H, Ando K, Kawarazaki H, Nagae A, Fujita M, Shimosawa T, Nagase M, Fujita T. Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder. Hypertension. 2008; 52: 287–294.
12. Smith AD, Brands MW, Wang MH, Dorrance AM. Obesity-induced hypertension develops in young rats independently of the renin-angiotensin-aldosterone system. Exp Biol Med (Maywood). 2006; 231: 282–287.
13. Roberts CK, Barnard RJ, Sindhu RK, Jurczak M, Ehdaie A, Vaziri ND. Oxidative stress and dysregulation of NAD(P)H oxidase and antioxidant enzymes in diet-induced metabolic syndrome. Metabolism. 2006; 55: 928–934.[CrossRef][Medline] [Order article via Infotrieve]
14. Chinen I, Shimabukuro M, Yamakawa K, Higa N, Matsuzaki T, Noguchi K, Ueda S, Sakanashi M, Takasu N. Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats. Endocrinology. 2007; 148: 160–165.
15. Fujita M, Kuwaki T, Ando K, Fujita T. Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in the brain. Hypertension. 2005; 45: 1165–1172.
16. Fujita M, Ando K, Nagae A, Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension. Hypertension. 2007; 50: 360–367.
17. Kishi T, Hirooka Y, Kimura Y, Ito K, Shimokawa H, Takeshita A. Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation. 2004; 109: 2357–2362.
18. Zimmerman MC, Lazartigues E, Sharma RV, Davisson RL. Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circ Res. 2004; 95: 210–216.
19. Zimmerman MC, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, Davisson RL. Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res. 2002; 91: 1038–1045.
20. Campese VM, Shaohua Y, Huiquin Z. Oxidative stress mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension. 2005; 46: 533–539.
21. Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med. 1989; 321: 580–585.[Abstract]
22. Ogihara T, Asano T, Ando K, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiro M, Abe M, Fukushima Y, Kikuchi M, Fujita T. High-salt diet enhances insulin signaling and induces insulin resistance in Dahl salt-sensitive rats. Hypertension. 2002; 40: 83–89.
23. Uzu T, Kimura G, Yamauchi A, Kanasaki M, Isshiki K, Araki S, Sugiomoto T, Nishio Y, Maegawa H, Koya D, Haneda M, Kashiwagi A. Enhanced sodium sensitivity and disturbed circadian rhythm of blood pressure in essential hypertension. J Hypertens. 2006; 24: 1627–1632.[Medline] [Order article via Infotrieve]
24. Roberts CK, Vaziri ND, Sindhu RK, Barnard RJ. A high-fat, refined-carbohydrate diet affects renal NO synthase protein expression and salt sensitivity. J Appl Physiol. 2003; 94: 941–946.
25. Dobrian AD, Schriver SD, Lynch T, Prewitt RL. Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity. Am J Physiol Renal Physiol. 2003; 285: F619–F628.
26. Ono A, Kuwaki T, Kumada M, Fujita T. Differential central modulation of the baroreflex by salt loading in normotensive and spontaneously hypertensive rats. Hypertension. 1997; 29: 808–814.
27. Huang BS, Leenen FH. Both brain angiotensin II and "ouabain" contribute to sympathoexcitation and hypertension in Dahl S rats on high salt intake. Hypertension. 1998; 32: 1028–1033.
28. Zhang X, Dong F, Ren J, Driscoll MJ, Culver B. High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. Exp Neurol. 2005; 191: 318–325.[CrossRef][Medline] [Order article via Infotrieve]
29. Sato Y, Ando K, Fujita T. Role of sympathetic nervous system in hypotensive action of taurine in DOCA-salt rats. Hypertension. 1987; 9: 81–87.
30. Lu N, Helwig BG, Fels RJ, Parimi S, Kenney MJ. Central Tempol alters basal sympathetic nerve discharge and attenuates sympathetic excitation to central ANG II. Am J Physiol Heart Circ Physiol. 2004; 287: H2626–H2633.
31. de Wardener HE. The hypothalamus and hypertension. Physiol Rev. 2001; 81: 1599–1658.
32. De Matteo R, Head GA, Mayorov DN. Tempol in the dorsomedial hypothalamus attenuates the hypertensive response to stress in rabbits. Am J Hypertens. 2006; 19: 396–402.[CrossRef][Medline] [Order article via Infotrieve]
33. Mayorov DN, Head GA, De Matteo R. Tempol attenuates excitatory actions of angiotensin II in the rostral ventrolateral medulla during emotional stress. Hypertension. 2004; 44: 101–106.
34. Zanzinger J, Czachurski J. Chronic oxidative stress in the rostral ventrolateral medulla modulates sympathetic control of circulation in pigs. Pflugers Arch. 2000; 439: 489–494.[CrossRef][Medline] [Order article via Infotrieve]
35. Campese VM, Ye S, Zhong H, Yanamadala V, Ye Z, Chiu J. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. Am J Physiol Heart Circ Physiol. 2004; 287: H695–H703.
36. Huang BS, Amin MS, Leenen FH. The central role of the brain in salt-sensitive hypertension. Curr Opin Cardiol. 2006; 21: 295–304.[Medline] [Order article via Infotrieve]
37. Eriksson JW. Metabolic stress in insulin’s target cells leads to ROS accumulation: a hypothetical common pathway causing insulin resistance. FEBS Lett. 2007; 581: 3734–3742.[CrossRef][Medline] [Order article via Infotrieve]
38. Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH. Superoxide mediates sympathoexcitation in heart failure: roles of angiotensin II and NAD(P)H oxidase. Circ Res. 2004; 95: 937–944.
39. Frederich RC Jr, Kahn BB, Peach MJ, Flier JS. Tissue-specific nutritional regulation of angiotensinogen in adipose tissue. Hypertension. 1992; 19: 339–344.
40. Boustany CM, Bharadwaj K, Daugherty A, Brown DR, Randall DC, Cassis LA. Activation of the systemic and adipose renin-angiotensin system in rats with diet-induced obesity and hypertension. Am J Physiol Regul Integr Comp Physiol. 2004; 287: R943–R949.
41. Bokil HS, Porter JP. Brain angiotensin type 1 receptor expression and function in the Zucker obese rat. Neurosci Lett. 2000; 281: 139–142.[CrossRef][Medline] [Order article via Infotrieve]
42. Delbosc S, Paizanis E, Magous R, Araiz C, Dimo T, Cristol JP, Cros G, Azay J. Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis. 2005; 179: 43–49.[CrossRef][Medline] [Order article via Infotrieve]
43. Miller AW, Sims JJ, Canavan A, Hsu T, Ujhelyi MR. Impaired vagal reflex activity in insulin-resistant rats. J Cardiovasc Pharmacol. 1999; 33: 698–702.[CrossRef][Medline] [Order article via Infotrieve]
44. Dobrian AD, Schriver SD, Khraibi AA, Prewitt RL. Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. Hypertension. 2004; 43: 48–56.
45. Lauterio TJ, Davies MJ, DeAngelo M, Peyser M, Lee J. Neuropeptide Y expression and endogenous leptin concentrations in a dietary model of obesity. Obes Res. 1999; 7: 498–505.[Medline] [Order article via Infotrieve]
46. Nitti M, Furfaro AL, Traverso N, Odetti P, Storace D, Cottalasso D, Pronzato MA, Marinari UM, Domenicotti C. PKC delta and NADPH oxidase in AGE-induced neuronal death. Neurosci Lett. 2007; 416: 261–265.[CrossRef][Medline] [Order article via Infotrieve]
47. Hansen ML, Gunn PW, Kaelber DC. Underdiagnosis of hypertension in children and adolescents. JAMA. 2007; 298: 874–879.
48. Din-Dzietham R, Liu Y, Bielo MV, Shamsa F. High blood pressure trends in children and adolescents in national surveys, 1963 to 2002. Circulation. 2007; 116: 1488–1496.
49. Litwin M, Sladowska J, Antoniewicz J, Niemirska A, Wierzbicka A, Daszkowska J, Wawer ZT, Janas R, Grenda R. Metabolic abnormalities, insulin resistance, and metabolic syndrome in children with primary hypertension. Am J Hypertens. 2007; 20: 875–882.[CrossRef][Medline] [Order article via Infotrieve]
50. Beilin L, Huang RC. Childhood obesity, hypertension, the metabolic syndrome and adult cardiovascular disease. Clin Exp Pharmacol Physiol. 2008; 35: 409–411.[CrossRef][Medline] [Order article via Infotrieve]
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Footnotes |
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*Drs Nagae and Fujita contributed equally to this work.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.824730/DC1.
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