Published online before print September 2, 2003, doi: 10.1161/01.HYP.0000091371.53502.D3
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(Hypertension. 2003;42:474.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Serum Uric Acid and Plasma Norepinephrine Concentrations Predict Subsequent Weight Gain and Blood Pressure Elevation
From the Department of Geriatric Medicine, Division of Health Promotion Science, Osaka University Graduate School of Medicine (K.M., H.K., H.M., T.O.), Suita City, Osaka, Japan, and the Sepulveda VA Medical Center and UCLA School of Medicine (M.L.T.), Sepulveda, Calif.
Correspondence to Kazuko Masuo, MD, PhD, c/o Prof Toshio Ogihara, MD, PhD, Department of Geriatric Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan. E-mail kazukom7{at}eb.mbn.or.jp
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Abstract |
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It has been reported that hypertension and obesity often coexist with hyperuricemia. To clarify the relations between serum uric acid, plasma norepinephrine, and insulin or leptin levels in subjects with weight gain–induced blood pressure elevation, we conducted the present longitudinal study. In 433 young, nonobese, normotensive men, body mass index, blood pressure, and levels of serum uric acid, fasting plasma norepinephrine, insulin, and leptin were measured every year for 5 years. Subjects were stratified by significant weight gain and/or blood pressure elevation (>10% in body mass index or mean blood pressure) for 5 years. At entry, blood pressure, uric acid, and norepinephrine values in subjects with blood pressure elevation were greater than in those without it, although body mass index, insulin, and leptin were similar. At entry, body mass index, blood pressure, uric acid, and norepinephrine in subjects with weight gain were greater than in those without weight gain. The increases in body mass index, mean blood pressure, uric acid, norepinephrine, insulin, and leptin for 5 years were greater in subjects with blood pressure elevation and/or weight gain than in subjects without, and those increases were greatest in subjects with weight gain whose blood pressure was elevated. By multiple regression analysis, basal mean blood pressure, norepinephrine, and uric acid were significant determinant factors of changes in mean blood pressure over 5 years, and basal body mass index, norepinephrine, and uric acid were significant determinant factors of changes in body mass index. These results demonstrate that serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.
Key Words: uric acid • sympathetic nervous system • obesity • hypertension, obesity
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Introduction |
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Elevated serum uric acid (UA) is associated with increased rates of cardiovascular events,1–3 and hyperuricemia is frequently observed in obese subjects and hypertensive patients.4–8 Several lines of evidence, both epidemiologic and clinical, point to a close interrelation between hyperuricemia, hypertension, and obesity.2–8 Also, it is known that both hypertension and obesity are related to sympathetic overactivity,9–17 hyperinsulinemia, and insulin resistance.18,19 However, the relation of insulin resistance and sympathetic nervous overactivity to hypertension and obesity is still controversial.11,15,20 These and other investigations have documented the coexistence of elevated UA level, sympathetic overactivity, and hyperinsulinemia in hypertension and obesity, but the precise relation has not been clarified.
The goal of the present longitudinal study was to clarify the interrelation of serum UA level, sympathetic activity, insulin, and leptin levels in subjects with weight gain–induced blood pressure (BP) elevation. We sequentially studied the accompaniments of spontaneous weight gain–induced BP elevation for 5 years, especially focusing on serum UA, sympathetic activity, and plasma levels of insulin and leptin. It was our expectation that by prospectively studying weight gain and BP elevation in this way, any causal contribution of changed sympathetic activity, leptin, and plasma insulin to serum UA would become evident. Second, we hypothesized that the UA level could be a predictor of hypertension (BP elevation), obesity (weight gain), or obesity-related hypertension (weight gain–induced BP elevation).
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Methods |
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Subjects
A cohort of 1121 men who were working in a factory, 2 companies, and 2 nursing homes in Osaka, Japan, were studied during their annual health check-up. The following subjects at study entry were excluded: 125 who were >50 years of age, 218 who were overweight (body mass index [BMI] 25 to 30 kg/m2), 97 with obesity (BMI>30kg/m2), 57 with diabetes mellitus (glycosylated hemoglobin [HbA1c] >6.0%), and 218 with hypertension (
140/90 mm Hg). Additional exclusions were 209 subjects who were taking medications, eg, 193 subjects taking antihypertensive agents, 54 subjects receiving lipid-lowering agents, 37 subjects on UA-lowing agents, 24 subjects receiving medications for liver dysfunction, and 21 subjects on antiarrhythmic agents or digitalis. At study entry, subjects taking the medications listed were excluded, as were subjects who took those medications during the subsequent 5-year follow-up for those severe illnesses. In conclusion, 236 subjects had 2 or more exclusion criteria. After exclusion, 433 young, nonobese (BMI<25 kg/m2), normotensive men without any medications were recruited from the cohort. Informed consent was obtained from each subject, as approved by the Ethics Committee of Osaka University Graduate School of Medicine.
Measurements
After an overnight fast of >12 hours, BMI, BP, heart rate, and venous blood sampling for measurement of serum UA, blood urea nitrogen (BUN), creatinine, plasma norepinephrine (NE), insulin, and leptin levels were obtained after a 30-minute rest in the supine position in a quiet room. Measurements were made at entry and every year for 5 years. BP was measured at each review 3> times and was averaged. Those who had a wide variability in BP were asked to return for repeated measurements on >3 separate visits to exclude chance variation.
BP and heart rate were measured with an automated sphygmomanometer (TM-2711 or TM-2713, A&D) which had been standardized against a mercury sphygmomanometer. Plasma NE was measured by high-performance liquid chromatography with a fluorometric method (intra-assay coefficient of variation [CV]=2.1%; interassay CV=3.6%; sensitivity=0.06 to 120 nmol/L), and plasma immunoreactive insulin was measured by a standard radioimmunoassay method (insulin RIABEAD II, Dinabott; intra-assay CV=1.9%; interassay CV=2.2%; sensitivity=0.75 to 300 µU/mL). Plasma leptin was measured by radioimmunoassay (human leptin RIA kit, Linco: intra-assay CV=5.0%, interassay CV=4.5%, and sensitivity=0.03 to 6 nmol/L). Serum UA, BUN, and creatinine were measured by autoanalyzer (Hitachi-7050).
Statistical Analyses
Values are shown as mean±SD. Changes in variables within each group and differences among groups were examined by 2-way ANOVA. When significant, the Dunnett test was used to determine whether values at year 1 and year 5 differed significantly from values at entry. Multiple linear-regression analysis was performed to examine relations among variables by using changes in mean BP at 5 years from the values at entry as a dependent variable in all participants (n=433) to evaluate the role of the parameters in BP elevation. In addition, using changes in BMI for 5 years as a dependent variable, we performed multiple linear-regression analysis to evaluate the role of the parameters in weight gain. Multiple linear-regression analysis was also done to examine the relation among variables by using BP levels (systolic and diastolic BP separately) and BMI at year 5 as dependent variables to determine whether basal values of the aforementioned variables predicted levels of BP and BMI. Statistical analyses to compare the prevalence of BP elevations were performed by the 
2 test. Values of P<0.05 were considered significant.
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Results |
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Prevalence of Weight Gain and BP Elevation
Significant weight gain and BP elevation over 5 years were defined as a >10% increase in BMI or mean BP compared with values at entry. The prevalences of significant weight gain and significant BP elevation at year 5 are summarized in Table 1. The prevalence of BP elevation was greater in subjects with weight gain than in subjects without weight gain, but the prevalence of subjects with weight gain was similar between subjects with and without BP elevation.
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Demographic Characteristics of the Subjects
Table 2 shows the demographic characteristics for all subjects (n=433) who entered this longitudinal study at entry, 1 year, and 5 years.
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Comparisons of Demographic Characteristics Between Subjects With and Without BP Elevation
Table 3 shows the demographic characteristics of the 2 groups subdivided by significant BP elevation (>10%) for 5 years. At entry, systolic BP, diastolic BP, mean BP, heart rate, serum UA, and plasma NE were significantly greater in the group with BP elevation than in the group without BP elevation. Increases in BP levels, heart rate, and plasma NE were abrupt. Actual mean BP changes for 5 years were 8.2±2.1 mm Hg in the group with significant BP elevation and 3.5±2.2 mm Hg in the group without significant BP elevation.
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In addition, with hypertension defined as a BP of 140 and/or 90 mm Hg or more, 51 nonhypertensive subjects became hypertensive at 5 years. They had higher levels of systolic BP, diastolic BP, mean BP, serum UA, and plasma NE at entry compared with the subjects with continuing normal BP levels (<140/90 mm Hg; data not shown).
Comparisons of Demographic Characteristics Between Subjects With and Without Weight Gain
Table 4 shows the demographic characteristics in the 2 groups subdivided by significant weight gain (>10% in BMI) regardless of BP elevation. By definition, BMI increased significantly in subjects with weight gain, but systolic BP, diastolic BP, mean BP, heart rate, serum UA, plasma NE, insulin, and leptin also increased significantly at 5 years in subjects with weight gain. Actual weight gain was 7.4±2.2 kg for 5 years in the group with significant weight gain and 1.8±1.1 kg in the group without weight gain.
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Comparisons of Demographic Characteristics Among the 4 Study Groups Stratified by Significant Weight Gain and/or BP Elevation
At entry, BMI was greater in subjects with weight gain than in subjects without weight gain, although entering BMI was similar between subjects with and without BP elevation (Tables 3 through 5 
). The absolute increases in BMI in groups with significant BP elevation and with significant weight gain were greater than in those without significant BP elevation or without significant weight gain (Tables 3 and 4).
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On the other hand, BP levels (systolic, diastolic, and mean) and heart rates were significantly greater at entry and throughout the study in subjects with BP elevation and in subjects with weight gain compared with those in subjects without BP elevation or without weight gain. In both groups with significant BP elevation and weight gain, although mean BP levels and heart rates rose significantly throughout the study, the absolute increase in mean BP and heart rates at the first year were the greatest, with lesser elevations for the next 4 years, in contrast to progressive increases in BMI (Tables 3 and 4).
Serum UA levels at entry in subjects with significant BP elevation and with weight gain were already higher than those in subjects without subsequent BP elevation or weight gain. Of importance, serum UA levels rose with BP elevation or weight gain in subjects with significant BP elevation or weight gain but did not in subjects without significant BP elevation or weight gain. Plasma NE levels at entry in subjects with BP elevation and in subjects with weight gain were greater than in subjects without BP elevation or weight gain. Plasma NE increased with BP elevation or weight gain significantly. However, the increase in plasma NE for the first year was greater than that over the next 4 years (Tables 3 through 5 ).
At entry, fasting plasma insulin and leptin levels were similar between groups with and without BP elevation and between groups with and without weight gain (Tables 3 through 5). However, the increases in plasma insulin and leptin in groups with BP elevation and weight gain were greater than in those without BP elevation or weight gain for both the first year and the next 4 years. Of importance, in groups without significant BP elevation (
10%) or significant weight gain (10%), plasma insulin and leptin did not increase significantly, although mean BP rose. The increases in plasma leptin in the weight gain group were greater than those in the group with BP elevation. The subjects with BP elevation who gained weight significantly for 5 years had the greatest increases in BMI, BP levels, heart rate, serum UA, plasma NE, and insulin among the 4 stratified groups. BUN and creatinine as indices of renal function were similar among the 4 groups at all times during the present study, and those were always within the normal range. These values did not change for 5 years with a significant BP elevation or with a significant weight gain in our nonobese, normotensive population.
What Predicts Obesity and BP Elevation? Correlation and Multiple Regression Analysis
Serum UA levels were correlated significantly with plasma NE levels in subjects with significant BP elevation (n=56; at entry, r=0.46, P<0.05; at 5 years, r=0.48, P<0.05), in subjects with significant weight gain (n=74; at entry, r=0.38, P<0.01; at 5 years, r=0.43, P<0.01), and in all subjects enrolled in the study (n=433; at entry, r=0.22, P<0.05; at 5 years, r=0.26, P<0.01). In all subjects enrolled in the study (n=433), serum UA levels at entry were correlated with mean BP levels at 5 years (r=0.26, P<0.01), with BMI at 5 years (r=0.20, P<0.05), and with plasma NE levels at 5 years (r=0.21, P<0.05). In addition, serum UA was correlated with heart rates in this population (n=433; at entry, r=0.32, P<0.05; at 5 years, r=0.36, P<0.05). Plasma NE was correlated with heart rates in all subjects enrolled in the study (at entry; r=0.22, P<0.05; at 5 years, r=0.26, P<0.01).
When analyzed by multiple linear-regression analysis by using changes in mean BP for 5 years, basal mean BP, basal plasma NE, and basal serum UA levels were significant determinant variables for changes in mean BP (Table 6a, left column). Basal BMI, basal plasma NE, and basal serum UA levels were significant determinant variables for changes in BMI for 5 years as the dependent variable (Table 6a, right column). In addition, changes in BMI for 5 years, changes in plasma NE, and changes in serum UA were significant determinant variables for changes in mean BP for 5 years (Table 6b, left column). Changes in mean BP, changes in plasma NE, and changes in serum UA were significant determinant variables for changes in BMI for 5 years (Table 6b, right column).
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Multiple regression analyses were also performed to examine relations among variables by using systolic BP and diastolic BP levels separately and BMI at 5 years as dependent variables to determine whether their basal values predicted levels of systolic BP, diastolic BP, and BMI. Basal systolic BP, basal diastolic BP, basal plasma NE, and basal UA were significant determinant factors for changes in systolic BP for 5 years (R=0.2389, F=13.60, P=0.0001), for changes in diastolic BP for 5 years (R=0.1863, F=8.27, P=0.0001), and for changes in BMI (R=0.1651, F=7.31, P=0.0001; data not shown).
In addition, from our analysis, a 1.0 mg/dL change (increase) in serum UA predicted a 27.5 mm Hg change (elevation) in systolic BP, a 15.2 mm Hg change (elevation) in diastolic BP, and a 18.8 mm Hg change (elevation) in mean BP elevation for 5 years. In addition, a 1.00 pmol/mL change (increase) in plasma NE predicted a 28.0 mm Hg change (elevation) in systolic BP, a 15.3 mm Hg change (elevation) in diastolic BP, and a 19.1 mm Hg change (elevation) in mean BP for 5 years.
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Discussion |
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The main finding in this study was that serum UA and plasma NE level were predictors of BP elevation, weight gain, and weight gain–induced BP elevation in originally nonobese, normotensive, healthy men. Serum UA and plasma NE levels at entry were already significantly greater in subjects who subsequently gained weight over the following 5 years and in subjects whose BP subsequently rose. The increases in serum UA and plasma NE in subjects with weight gain–induced BP elevation were the greatest among the 4 study groups. In addition, by multiple regression analysis, basal serum UA level and basal plasma NE level were significant determinant factors for both changes in mean BP and changes in BMI, suggesting that basal serum UA and basal plasma NE level could predict subsequent BP and BMI increase in the future. Second, a significantly greater elevation in serum UA levels was noted along with BP elevation or weight gain over 5 years when compared with the changes in UA levels in subjects without progressive BP elevation or weight gain. In addition, the present longitudinal study presents evidence that weight gain (obesity) and BP elevation (hypertension) contribute not only to an elevated serum UA level but also to sympathetic overactivity, hyperinsulinemia, and hyperleptinemia, even in nonobese subjects. The strength of the present study lies in its longitudinal design, allowing sequential and concurrent measurements of body weight, BP, and their possible determinants, such as UA, sympathetic activity, insulin, and leptin at the same time.
It is well documented that serum UA level is determined by the balance between its production and urinary excretion.21–23 The pathophysiologic mechanism of increased serum UA level in hypertensive patients is suggested to be related to impaired renal tubular handling of UA, leading to impaired renal UA excretion.24 In obese subjects, it is suggested to be due to overproduction of UA.21,22 Insulin resistance and hyperinsulinemia enhance the tubular sodium-hydrogen exchanger and facilitate the active reabsorption of UA.23,25 Recently, it has been reported that hyperuricemia in obese subjects is mainly attributable to impaired renal clearance of UA owing to the influence of hyperinsulinemia secondary to insulin resistance.21,25
Insulin resistance and/or hyperinsulinemia have been reported to be strongly associated with BP,18,19 whereas other investigators have reported a weaker relation or none at all.12,17 The differences among the various studies might possibly be due to the multiple mechanisms and heterogeneous factors involved in the regulation of BP.11,15,18 In the present study, fasting plasma insulin levels at entry were similar between those with and without weight gain and between those with and without BP elevation. However, the absolute increases in plasma insulin with weight gain were significantly greater in the group with significant weight gain and in the group with BP elevation whose BMI significantly increased. Specifically, the increases in plasma insulin were noted progressively over 5 years, whereas the increases in plasma NE were noted primarily in the first year, suggesting that BP elevation with weight gain later in the 5 years of follow-up appears to be causally related to hyperinsulinemia.
Subjects with significant weight gain and with BP elevation had greater levels of plasma NE at entry compared with those values in subjects without weight gain or without BP elevation. In addition, the absolute increases in plasma NE in subjects with weight gain and BP elevation were significantly greater in the early stage. These results suggest that the nonobese, normotensive subjects predisposed to obesity and hypertension have sympathetic overactivity and that this sympathetic overactivity operates in the early stage, during the initial development of weight gain or BP. It is perhaps counterintuitive that increased sympathetic activity predicts weight gain, given that sympathetic stimulation is thermogenic and would be expected to favor negative caloric balance. However, we have previously reported this surprising observation.13 Using microneurography at the peroneal nerve, Grassi et al9 reported that baseline muscle sympathetic nerve activity in obese, normotensive subjects was twice that seen in lean control subjects. It was concluded that even in the absence of any BP alteration, human obesity is characterized by a marked sympathetic activation, possibly because of an impairment of reflex sympathetic restraint. The authors speculated that another possible factor is an enhancement of sympathetic drive due to an increase in levels of circulating insulin, angiotensin II, or both. Using NE spillover methods, Esler’s group (Rumantir et al10) reported that an absence of suppression of cardiac sympathetic outflow seen in normotensive, obese individual might be important in obesity-related hypertension. Increases in renal sympathetic activity in obesity might be a necessary cause for the development of hypertension in obese individuals.10 Previously, we reported that plasma NE as well as fasting plasma insulin and leptin in obese subjects (normotensives and hypertensives) were significantly higher than those in lean subjects at entry in weight reduction studies26,27 and also in a cross-sectional study.28 Recently, we also reported that obese subjects had higher levels of plasma NE, heart rate, and BP at entry as well as greater changes during weight gain in those parameters,13 suggesting that stimulated sympathetic activity caused by obesity plays an important role in obesity-related hypertension.
Recently, Watanabe et al29 reported that mild hyperuricemia in rats acutely increased blood pressure by a renin-dependent mechanism that was most manifest under low-sodium dietary conditions. Although many studies have shown that hyperuricemia is a predictor of cardiovascular diseases,1–3 controversy has existed over its causative role. Several epidemiologic studies failed to show UA as a risk independent of other factors, such as hypertension, for predicting cardiovascular events. Some investigators have suggested that hyperuricemia might be a secondary response to the reduced renal blood flow that is a characteristic hemodynamic finding in hypertension.1,30 However, Johnson et al31 hypothesized that vasoconstriction reduces renal blood flow, leading to renal microvascular and tubulointerstitial injury and resultant hypertension, and that hyperuricemia might be an independent predictor of hypertension. They also reviewed more recently the pathogenic role of UA in hypertension in both human and animal models.32 It has also been well documented that sympathetic overactivity causes vasoconstriction. Taken together, subjects with relative sympathetic overactivity, such as those groups with weight gain and BP elevation in the present study, appear to have already existing renal microvascular damage, even though their renal function was within the normal range. Our results that both plasma NE and serum UA at entry were greater in subjects who gained weight or whose BP rose compared with those values in subjects whose BMI and BP did not change significantly might give supportive evidence for the hypothesis. Our findings could be construed to mean that the elevated UA level was due to sympathetic overactivity and the resultant neurogenic renal vasoconstriction. There is strong evidence that renal vasoconstriction results in increased proximal urate reabsorption and an increase in serum UA.30 In addition, our data in the present study are in a good accordance with the studies of Jossa et al6 and Selby et al,7 that UA is an independent predictor of hypertension in the general population, and also the studies in which a high heart rate, which is a known marker of sympathetic overactivity, predicts hypertension.
Perspectives
Our results showed that relatively higher serum UA concentration and sympathetic overactivity predict subsequent BP rise and weight gain in nonobese, normotensive, Japanese men. Sympathetic nervous activation and hyperuricemia are linked as predictors of weight gain (obesity), BP elevation (hypertension), and weight gain–induced BP elevation (obesity-related hypertension). However, the precise mechanisms leading to hyperuricemia and the underlying interrelations between hyperuricemia, sympathetic overactivity, and leptin in developing hypertension or obesity are still controversial. Whether lowering of serum UA or reversal of sympathetic overactivity confers protection against the development of either obesity or hypertension remains untested.
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Acknowledgments |
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The authors thank Prof Murray D. Esler, Baker Heart Research Institute, Melbourne, Australia, for his thorough review of and his constructive comments on this research and manuscript.
Received October 17, 2002; first decision October 25, 2002; accepted August 1, 2003.
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References |
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 R. J. Johnson, S. E. Perez-Pozo, Y. Y. Sautin, J. Manitius, L. G. Sanchez-Lozada, D. I. Feig, M. Shafiu, M. Segal, R. J. Glassock, M. Shimada, et al. Hypothesis: Could Excessive Fructose Intake and Uric Acid Cause Type 2 Diabetes? Endocr. Rev., February 1, 2009; 30(1): 96 - 116. [Abstract] [Full Text] [PDF]
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 J. P. Forman, H. Choi, and G. C. Curhan Uric Acid and Insulin Sensitivity and Risk of Incident Hypertension Arch Intern Med, January 26, 2009; 169(2): 155 - 162. [Abstract] [Full Text] [PDF]
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N. E Straznicky, G. W Lambert, K. Masuo, T. Dawood, N. Eikelis, P. J Nestel, M. T McGrane, J. A Mariani, F. Socratous, R. Chopra, et al. Blunted sympathetic neural response to oral glucose in obese subjects with the insulin-resistant metabolic syndrome Am. J. Clinical Nutrition, January 1, 2009; 89(1): 27 - 36. [Abstract] [Full Text] [PDF]
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 D. I. Feig, D.-H. Kang, and R. J. Johnson Uric Acid and Cardiovascular Risk N. Engl. J. Med., October 23, 2008; 359(17): 1811 - 1821. [Full Text] [PDF]
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 A. Flaa, I. K. Eide, S. E. Kjeldsen, and M. Rostrup Sympathoadrenal Stress Reactivity Is a Predictor of Future Blood Pressure: An 18-Year Follow-Up Study Hypertension, August 1, 2008; 52(2): 336 - 341. [Abstract] [Full Text] [PDF]
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D. E. Weiner, H. Tighiouart, E. F. Elsayed, J. L. Griffith, D. N. Salem, and A. S. Levey Uric Acid and Incident Kidney Disease in the Community J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1204 - 1211. [Abstract] [Full Text] [PDF]
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 L. G. Sanchez-Lozada, E. Tapia, P. Bautista-Garcia, V. Soto, C. Avila-Casado, I. P. Vega-Campos, T. Nakagawa, L. Zhao, M. Franco, and R. J. Johnson Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome Am J Physiol Renal Physiol, April 1, 2008; 294(4): F710 - F718. [Abstract] [Full Text] [PDF]
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R. J Johnson, M. S Segal, Y. Sautin, T. Nakagawa, D. I Feig, D.-H. Kang, M. S Gersch, S. Benner, and L. G Sanchez-Lozada Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease Am. J. Clinical Nutrition, October 1, 2007; 86(4): 899 - 906. [Abstract] [Full Text] [PDF]
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 Y. Y. Sautin, T. Nakagawa, S. Zharikov, and R. J. Johnson Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress Am J Physiol Cell Physiol, August 1, 2007; 293(2): C584 - C596. [Abstract] [Full Text] [PDF]
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 A. Canales, J. Benedi, M. Nus, J. Librelotto, J. M Sanchez-Montero, and F. J. Sanchez-Muniz Effect of Walnut-Enriched Restructured Meat in the Antioxidant Status of Overweight/Obese Senior Subjects with at Least One Extra CHD-Risk Factor J. Am. Coll. Nutr., June 1, 2007; 26(3): 225 - 232. [Abstract] [Full Text] [PDF]
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 C. L. Gentile, J. S. Orr, B. M. Davy, and K. P. Davy Modest weight gain is associated with sympathetic neural activation in nonobese humans Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2007; 292(5): R1834 - R1838. [Abstract] [Full Text] [PDF]
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E. Krishnan, C. K. Kwoh, H. R. Schumacher, and L. Kuller Hyperuricemia and Incidence of Hypertension Among Men Without Metabolic Syndrome Hypertension, February 1, 2007; 49(2): 298 - 303. [Abstract] [Full Text] [PDF]
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J. P. Forman, H. Choi, and G. C. Curhan Plasma Uric Acid Level and Risk for Incident Hypertension Among Men J. Am. Soc. Nephrol., January 1, 2007; 18(1): 287 - 292. [Abstract] [Full Text] [PDF]
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P. Cirillo, W. Sato, S. Reungjui, M. Heinig, M. Gersch, Y. Sautin, T. Nakagawa, and R. J. Johnson Uric Acid, the Metabolic Syndrome, and Renal Disease J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S165 - S168. [Abstract] [Full Text] [PDF]
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T. S. Perlstein, O. Gumieniak, G. H. Williams, D. Sparrow, P. S. Vokonas, M. Gaziano, S. T. Weiss, and A. A. Litonjua Uric Acid and the Development of Hypertension: The Normative Aging Study Hypertension, December 1, 2006; 48(6): 1031 - 1036. [Abstract] [Full Text] [PDF]
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P. B. Mellen, A. J. Bleyer, T. P. Erlinger, G. W. Evans, F. J. Nieto, L. E. Wagenknecht, M. R. Wofford, and D. M. Herrington Serum Uric Acid Predicts Incident Hypertension in a Biethnic Cohort: The Atherosclerosis Risk in Communities Study Hypertension, December 1, 2006; 48(6): 1037 - 1042. [Abstract] [Full Text] [PDF]
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M. Esler, N. Straznicky, N. Eikelis, K. Masuo, G. Lambert, and E. Lambert Mechanisms of Sympathetic Activation in Obesity-Related Hypertension Hypertension, November 1, 2006; 48(5): 787 - 796. [Full Text] [PDF]
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D. I. Feig, M. Mazzali, D.-H. Kang, T. Nakagawa, K. Price, J. Kannelis, and R. J. Johnson Serum Uric Acid: A Risk Factor and a Target for Treatment? J. Am. Soc. Nephrol., April 1, 2006; 17(4_suppl_2): S69 - S73. [Abstract] [Full Text] [PDF]
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T. Nakagawa, H. Hu, S. Zharikov, K. R. Tuttle, R. A. Short, O. Glushakova, X. Ouyang, D. I. Feig, E. R. Block, J. Herrera-Acosta, et al. A causal role for uric acid in fructose-induced metabolic syndrome Am J Physiol Renal Physiol, March 1, 2006; 290(3): F625 - F631. [Abstract] [Full Text] [PDF]
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 M. Pladevall, B. Singal, L. K. Williams, C. Brotons, H. Guyer, J. Sadurni, C. Falces, M. Serrano-Rios, R. Gabriel, J. E. Shaw, et al. A Single Factor Underlies the Metabolic Syndrome: A confirmatory factor analysis Diabetes Care, January 1, 2006; 29(1): 113 - 122. [Abstract] [Full Text] [PDF]
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 N. E. Straznicky, E. A. Lambert, G. W. Lambert, K. Masuo, M. D. Esler, and P. J. Nestel Effects of Dietary Weight Loss on Sympathetic Activity and Cardiac Risk Factors Associated with the Metabolic Syndrome J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5998 - 6005. [Abstract] [Full Text] [PDF]
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K. Masuo, T. Katsuya, Y. Fu, H. Rakugi, T. Ogihara, and M. L. Tuck Lys418Asn Polymorphism of the {alpha}2-Adrenoceptor Gene Relates to Serum Uric Acid Levels But Not to Insulin Sensitivity Hypertension, July 1, 2005; 46(1): 144 - 150. [Abstract] [Full Text] [PDF]
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 K. Masuo, T. Katsuya, Y. Fu, H. Rakugi, T. Ogihara, and M. L. Tuck {beta}2- and {beta}3-Adrenergic Receptor Polymorphisms Are Related to the Onset of Weight Gain and Blood Pressure Elevation Over 5 Years Circulation, June 28, 2005; 111(25): 3429 - 3434. [Abstract] [Full Text] [PDF]
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F. Viazzi, D. Parodi, G. Leoncini, A. Parodi, V. Falqui, E. Ratto, S. Vettoretti, G. P. Bezante, M. Del Sette, G. Deferrari, et al. Serum Uric Acid and Target Organ Damage in Primary Hypertension Hypertension, May 1, 2005; 45(5): 991 - 996. [Abstract] [Full Text] [PDF]
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R. J. Johnson, D. I. Feig, J. Herrera-Acosta, and D.-H. Kang Resurrection of Uric Acid as a Causal Risk Factor in Essential Hypertension Hypertension, January 1, 2005; 45(1): 18 - 20. [Full Text] [PDF]
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J. Sundstrom, L. Sullivan, R. B. D'Agostino, D. Levy, W. B. Kannel, and R. S. Vasan Relations of Serum Uric Acid to Longitudinal Blood Pressure Tracking and Hypertension Incidence Hypertension, January 1, 2005; 45(1): 28 - 33. [Abstract] [Full Text] [PDF]
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