Sirirat Reungjui*,
Carlos A. Roncal*,
Wei Mu*,
Titte R. Srinivas*,
Dhavee Sirivongs,
Richard J. Johnson* and
Takahiko Nakagawa*
* Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, Florida; and Division of Nephrology, Khon Kaen University, Khon Kaen, Thailand
Correspondence: Dr. Sirirat Reungjui, current address is Division of Nephrology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand 40002. Phone: +66-43-363746; Fax: +66-43-347542; E-mail: sirirt_a{at}kku.ac.th
Received for publication April 6, 2007.
Accepted for publication June 20, 2007.
Fructose is a commonly used sweetener associated with dietsthat increase the prevalence of metabolic syndrome. Thiazidediuretics are frequently used in these patients for treatmentof hypertension, but they also exacerbate metabolic syndrome.Rats on high-fructose diets that are given thiazides exhibitpotassium depletion and hyperuricemia. Potassium supplementationimproves their insulin resistance and hypertension, whereasallopurinol reduces serum levels of uric acid and ameliorateshypertension, hypertriglyceridemia, hyperglycemia, and insulinresistance. Both potassium supplementation and treatment withallopurinol also increase urinary nitric oxide excretion. Wesuggest that potassium depletion and hyperuricemia in rats exacerbatesendothelial dysfunction and lowers the bioavailability of nitricoxide, which blocks insulin activity and causes insulin resistanceduring thiazide usage. Addition of potassium supplements andallopurinol with thiazides might be helpful in the managementof metabolic syndrome.
The metabolic syndrome (MS) is a constellation of risk factorsfor cardiovascular disease and type 2 diabetes and consistsof abdominal obesity, hypertriglyceridemia, low HDL cholesterol,high BP, insulin resistance, and hyperglycemia.1,2 Endothelialdysfunction and hyperuricemia also are closely associated withMS.3,4
Hydrochlorothiazide (HCTZ) is beneficial in patients with hypertensionbecause it reduces morbidity and mortality, especially the frequencyof stroke and congestive heart failure.5,6 As a result, thiazidesare recommended as the first-line therapy for hypertension.6However, many patients with hypertension have MS. In turn, HCTZusage, although critical in the management of hypertension,can have several adverse effects, such as electrolyte disorders(hypokalemia, hyponatremia, and hypomagnesemia), hyperuricemia,hyperlipidemia, and impairment of glucose metabolism in additionto volume depletion.7–10 These adverse effects resultin the development or exacerbation of MS. Although low-dosagethiazides have led to a reduction of these adverse effects,they increase the incidence of new onset of diabetes9 and canbe associated with hypokalemia, hyperuricemia, and hyperlipidemia.11
Understanding the precise mechanisms by which HCTZ exacerbatesMS is important. Some evidence suggests that thiazide-inducedhypokalemia may mediate insulin resistance.12,13 In addition,experimental hyperuricemia can cause endothelial dysfunction,3,14hypertension,15 and hyperinsulinemia.3,16 Furthermore, we recentlyreported that hyperuricemia causes the development of MS, andallopurinol, which lowers uric acid levels, improves these featuresof MS in fructose (F)-fed rats.3 We therefore hypothesized thathypokalemia and hyperuricemia may be primary mechanisms by whichthe thiazides facilitate the MS and that acceleration of MSby thiazides may be prevented by potassium (K) supplementationand allopurinol.
In this study, we administered thiazides to rats with MS, becausethis syndrome is common in patients with hypertension and itis important to determine whether thiazides can exacerbate itsfeatures. Although there are various models of MS in animals,we selected the F-induced model of MS. Indeed, the increasingincidence of MS in humans in the past two decades coincideswith a marked increase in F intake.17,18 Importantly, that highF consumption causes features of the MS has been documentedin clinical studies.19–21 Similarly, high-F diets causeMS in rodents, including hypertension, insulin resistance, andhypertriglyceridemia.3,22,23 In this study, we hypothesizedthat HCTZ use exacerbates F-induced MS and examined the roleof hypokalemia and hyperuricemia in this process.
Body Weights
All rats were pair fed to eliminate effects of food intake onthe results, which can influence glucose, insulin, and triglyceridelevels. Although this will not allow us to determine whetherthiazides can cause weight gain because access was not ad libitum,it did allow us to determine whether thiazides alter triglycerideand glucose levels independent of effects on food intake. Assuch, the average body weights were similar in all groups atweek 20, as shown in Table 1.
Table 1. Renal function, serum K, serum Mg2+, and urinary uric acid excretion evaluated at week 20 of the study
F-Induced Features of MS in Rats
At week 4, the F-fed rats developed early features of MS, includinghypertension (Figure 1), hypertriglyceridemia (normal diet 125± 55 versus F 325 ± 104 mg/dl; P < 0.001) andhyperuricemia (normal diet 1.7 ± 0.3 versus F 2.2 ±0.4 mg/dl; P = 0.01). Serum cholesterol was significantly higherat week 14 (Figure 2). No significant difference in serum glucosewas observed between the F group and the normal diet group (Figure 2).
Figure 1. SBP at weeks 4 and 16. The rats receiving F develop hypertension. HCTZ reduces the SBP. KCL further reduces BP at week 16. Similarly, allopurinol reduces BP reduction at both weeks 4 and 16. Data are means ± SD. P at least <0.05 *versus normal diet, &versus F, $versus F+HCTZ, and #versus F+HCTZ+KCL.
Figure 2. Time courses of serum uric acid (A), serum glucose (B), serum cholesterol (C), and serum triglycerides (D). The rats receiving F developed hyperuricemia and hypertriglyceridemia throughout the study. Hypercholesterolemia was detected at week 14. The combination of HCTZ with F causes more hyperuricemia and hyperglycemia as shown at weeks 14 and 20. Serum cholesterol and triglyceride are numerically higher with HCTZ use but did not reach statistical significance. KCL tends to reduce serum glucose at week 20 (P = 0.06). Allopurinol treatment significantly reduces serum uric acid and triglycerides at all time points and serum glucose at week 20. Data are means ± SD. P at least <0.05 *versus normal diet, &versus F, $versus F+HCTZ, and #versus F+HCTZ+KCL.
HCTZ Reduced Systolic BP but Aggravated F-Induced MS
HCTZ use reduced systolic BP (SBP) in the F+HCTZ group comparedwith the F group at weeks 4 and 16 (Figure 1). The level ofserum K was significantly lower in the F+HCTZ and F+HCTZ+allopurinolgroups at week 20, whereas all HCTZ-treated rats also developedhypomagnesemia (Table 1). An increase of serum HCO3– wasalso observed (F 23.0 ± 0.9; F+HCTZ 24.7 ± 1.1;F+HCTZ+KCL 25.6 ± 1.8; F+HCTZ+allopurinol 25.7 ±1.5 mEq/L; all P <0.05 versus the F group).
HCTZ use did not exacerbate MS early at week 4; the metabolicprofile of the F group and the F+HCTZ group was similar at thistime. However, HCTZ aggravated insulin resistance (Figure 3)and hyperuricemia at week 14 (F 2.2 ± 0.5 versus F+HCTZ2.7 ± 0.5 mg/dl; P = 0.04) and at week 20 (F 2.2 ±0.6 versus F+HCTZ 2.8 ± 0.6 mg/dl; P = 0.02). Serum glucosewas also increased by HCTZ at week 14 (F 150 ± 10 versusF+HCTZ 176 ± 13 mg/dl; P = 0.006) and at week 20 (F 160± 26 versus F+HCTZ 186 ± 22 mg/dl; P = 0.02).Although serum triglycerides were higher in the F+HCTZ group,they did not reach statistical significance (Figure 2).
Figure 3. QUICKI at week 14. The combination of F+HCTZ significantly lowers insulin sensitivity than the normal diet or the F. Treatment with allopurinol improves insulin sensitivity. KCL tends to improve insulin sensitivity, but this was NS. Data are means ± SD. P < 0.05 *versus normal diet, &versus F, and $versus F+HCTZ.
K Supplementation Reduced SBP and Improved Insulin Resistance
K supplementation significantly reduced SBP in F+HCTZ+KCL ratsat week 16 (F+HCTZ 136 ± 4 versus F+HCTZ+KCL 131 ±5 mmHg; P = 0.04), whereas no effect was observed at week 4(F+HCTZ 129 ± 5 versus F+HCTZ+KCL 127 ± 3 mmHg;P > 0.05). By insulin tolerance test, serum glucose was notdecreased despite insulin administration in the F+HCTZ group,whereas insulin-induced reduction of serum glucose was observedin the F+HCTZ+KCL group (Figure 4). These data suggest thatK supplementation improves insulin sensitivity, which was deterioratedby fructose with HCTZ. Compatibly, K supplementation tendedto lower serum glucose at week 20 (F+HCTZ 186 ± 22 versusF+HCTZ+KCL 166 ± 20 mmHg; P = 0.06). No significant changeof serum uric acid and serum triglycerides was observed in theF+HCTZ+KCL group compared with the F+HCTZ group.
Figure 4. The insulin tolerance test at week 18. Blood glucose levels were not lowered by insulin in rats receiving F with or without HCTZ, consistent with insulin resistance. In contrast, KCL and allopurinol treatment improve the insulin response similar to that observed with the normal diet group. Data are means ± SD. P at least <0.05 *versus normal diet, &versus fructose diet, and $versus F+HCTZ.
Lowering Uric Acid with Allopurinol Improved Hypertension, Hypertriglyceridemia, Hyperglycemia, and Insulin Resistance
Allopurinol treatment significantly reduced the level of serumuric acid in the F+HCTZ group. In addition, allopurinol significantlyreduced SBP (Figure 1), and serum triglycerides were also significantlylower than the F+HCTZ group at weeks 4, 14, and 20 (Figure 2).
Insulin resistance was improved by allopurinol (Figures 3 and4). In addition, serum glucose was significantly lower at week20 (F+HCTZ 186 ± 22 versus F+HCTZ+allopurinol 166 ±14 mg/dl; P = 0.04).
To investigate further the role of uric acid, we examined thecorrelation between uric acid and other factors. When individualdata on rats were examined at week 20, serum uric acid positivelycorrelated with serum triglycerides, serum cholesterol, andserum glucose (Figure 5). Furthermore, there was a significantcorrelation between serum uric acid and SBP at week 4 (r = 0.53,P = 0.003) and serum insulin at week 14 (r = 0.42, P = 0.009).
Figure 5. Correlations of various metabolic factors in fructose/HCTZ-induced MS in the rat.
Insulin and Other Factors
At week 14, serum insulin concentrations in normal, F, F+HCTZ,F+HCTZ+KCL, and F+HCTZ+allopurinol groups were 1846 ±452, 2561 ± 1286, 3449 ± 1200, 3058 ± 1514,and 2319 ± 971 pg/ml, respectively. Significant differencesof serum insulin were detected between F+HCTZ and normal (P= 0.002) and borderline significance between F+HCTZ and F+HCTZ+allopurinol(P = 0.05). Serum insulin levels positively correlated not onlywith serum glucose but also with serum triglycerides and serumcholesterol (Figure 5), suggesting an association between insulinresistance and dyslipidemia.24,25
Renal Function and Urinary Excretion of Sodium, K, and Uric Acid
Although there was no significant difference in serum creatininebetween groups, an increased urinary protein excretion by Fsuggests renal dysfunction. However, an elevation of blood ureanitrogen (BUN) in all HCTZ-treated groups (groups 3, 4, and5) could be attributed to volume depletion induced by HCTZ,because F did not raise BUN.
With respect to urinary electrolytes, HCTZ significantly increaseddaily urinary sodium excretion at week 1 (normal 0.4 ±0.2; F 0.5 ± 0.1; F+HCTZ 0.8 ± 0.4; F+HCTZ+KCL0.8 ± 0.2; and F+HCTZ+allopurinol 0.9 ± 0.3 mEq/d;all P < 0.05 versus normal or F). Urinary K excretion wasalso significantly higher in the F+HCTZ group (1.5 ±0.4 mEq/d) and the F+HCTZ+allopurinol group (1.4 ± 0.3mEq/d) as compared with the F group (1.2 ± 0.1 mEq/d).Because of K supplementation, the F+HCTZ+KCL group had normalserum K level with high urine K (3.1 ± 1.1).
The F group developed hyperuricemia (Figure 2) with higher urinaryuric acid excretion per day and uric acid clearance comparedwith the normal group (Table 1), which suggested an increaseof uric acid production. Similar to that observed in humans,HCTZ enhanced hyperuricemia (Figure 2), which could be attributedto a reduction of urinary uric acid excretion (Table 1). Allopurinolacutely reduced 32.3% of urinary uric acid excretion comparedwith the F+HCTZ group during the first week (P < 0.05), whichcould be due to a reduced production of uric acid by allopurinol.However, it is of note that urinary uric acid excretion anduric acid clearance increased during the chronic phase despiteallopurinol use (Table 1).
K Supplementation or Allopurinol Increase Urinary Nitric Oxide Excretion
Urine nitrate/nitrite excretion is a marker of nitric oxide(NO) bioavailability as well as endothelial function.26,27 Fdecreased urine nitrate/nitrites, which were further loweredby HCTZ. However, K supplementation or allopurinol treatmentincreased urinary nitrate/nitrite excretion (Figure 6).
Figure 6. Urine nitrate/nitrite level. The levels of urinary nitrate and nitrite in rats receiving F are lower than that observed in the normal diet group. HCTZ induces a further reduction of urinary nitrate and nitrite. KCL and allopurinol treatment increases the level of urinary nitrate and nitrite compared with the F+HCTZ. Data are means ± SD. P at least <0.05 *versus normal diet, &versus F, and $versus F+HCTZ.
The principal new finding in this study is that we can showexperimentally that correcting the serum K and uric acid abnormalitiesin F-induced MS in rats can largely prevent the metabolic abnormalitiesthat are associated with thiazides. The beneficial effects ofthese treatments were associated with an increase in urine nitrite/nitrates,suggesting the involvement of endothelial dysfunction on thedevelopment of MS with thiazide usage.
Hypokalemia occurs in 6.5 to 50% of patients receiving diuretics,28–30with the average reduction of serum K from thiazides reportedat approximately 0.3 to 1.1 mEq/L.6,31,32 Previous studies suggestedthat hypokalemia may be a factor causing hyperglycemia, hyperinsulinemia,and insulin resistance in patients receiving thiazides, becausethese features can be improved with K supplements.13,33 It alsohas been shown that K depletion, even without frank hypokalemia,can cause insulin resistance.34 In our experiments, HCTZ produceda significant reduction in serum K (0.3 mEq/L), although thisdid not reach the criteria of hypokalemia (serum K <3.5 mEq/L).Our important finding is that this mild K depletion was significantlyassociated with exacerbation of hyperglycemia, insulin resistance,and a reduction of urine NO excretion, all of which were correctedby K supplementation. The observation that K supplements preventedthe reduction of urine NO in F-fed rats receiving HCTZ is consistentwith an improvement in endothelial function. K supplementationhas been shown to act as an endothelium-derived hyperpolarizingfactor35 and release NO to preserve endothelial function,36whereas K depletion was found to attenuate endothelial-dependentvasorelaxation.37 In turn, an inhibition of endothelial NO isknown to cause insulin resistance.38
Unlike glucose, F is the only sugar that rapidly increases serumuric acid in humans as well as rodents.3 Recently, we foundthat F-induced hyperuricemia has a causal role in the pathogenesisof MS.3 This study demonstrated that HCTZ enhanced hyperuricemiain rats receiving a high-F diet by reducing urinary uric acidexcretion, although F likely increases the production of uricacid. Decreased urinary uric acid excretion could be due toan increase in uric acid reabsorption in proximal tubule, whichmay be mediated by thiazide-induced volume contraction.39
Another important finding is that the lowering of serum uricacid by allopurinol was associated with an improvement of thefeatures of MS. We also found that a lowering of uric acid byallopurinol was associated with an increase in urinary NO excretion.Given that uric acid inhibits endothelial NO bioavailabilityas well as endothelial function,3,14,40 a lowering of uric acidcould improve endothelial function in this model. Collectively,these findings suggest that hyperuricemia, by virtue of reducingNO, plays a role in the pathogenesis of the MS aggravated withHCTZ.
The inhibition of uric acid production by allopurinol likelyaccounts for the reduction of urinary uric acid excretion duringthe first week. However, with long-term allopurinol treatment,the reduction in uric acid excretion was not observed. Althoughthe precise mechanism remains unknown, hyperuricemic rats areknown to develop renal vasoconstriction with a reduction ofrenal blood flow, and this is reversed by allopurinol.41 Inturn, an increase in renal blood flow will result in increaseduric acid excretion.42 In this scenario, by improving endothelialdysfunction and renal blood flow, the lowering of uric acidcould paradoxically enhance excretion.
The effect of high F intake on insulin sensitivity is stilldebated. As recently reviewed,43 some groups have observed thathealthy individuals develop insulin resistance after high Fconsumption, whereas others have reported no effect on glucosemetabolism as well as insulin sensitivity. One reason for thisdiscrepancy is dosage. For example, when 1000 kcal is given,insulin resistance develops in 1 wk19; when 864 kcal/d is consumed,insulin resistance is observed only in organs with high fructokinaseactivity (liver, fat cells) and takes 4 wk20; and when lowerdosages are given, no insulin resistance is observed, even after1 mo.21 Similar situations occur in the rat. With high dosages(60% F), insulin resistance occurs within 4 to 8 wk3; with dosagessimilar to that in the current American diet (15% total energyintake), it takes slightly more than 1 yr.44 However, the ratis more resistant because it has low uric acid levels; indeed,if uricase is inhibited, then 20% F will induce hyperinsulinemiarapidly.45 Furthermore, F, by virtue of increasing the circulationof fatty acids, may lead to the ectopic deposition of fat inliver and skeletal muscle that will cause insulin resistanceindirectly.46 This indirect induction of insulin resistanceby F could also account for the discrepancy in some of thesestudies. Because F and its metabolites fructose-3-phosphateand 3-deoxyglucosone cause oxidative stress and nonenzymaticglycation,47 the polyol pathway could also be involved in developmentof MS.
This study demonstrates that HCTZ aggravates the MS in F-fedrats and that K supplementation and reducing uric acid levelsmay provide some protection. Nevertheless, it will be importantto determine whether similar protection can be provided by thesemaneuvers in humans. In this regard, we are involved in a randomized,controlled trial to determine whether lowering of uric acidwill improve features of MS associated with thiazide use inblack individuals with stage 1 hypertension.
All animal studies were approved by the University of FloridaInstitutional Animal Use and Care Committee.
Pilot Studies
Because variable dosages of HCTZ have been commonly used inother studies (e.g., 3 to 80 mg/kg per d48,49), we performedpilot studies to determine the minimum adequate dosage of HCTZfor this study. Because the aim of study was to examine therole of hypokalemia on adverse effects of HCTZ, we identifiedthe lowest dosage that can reduce BP along with a mild reductionof serum K. We therefore gave three different dosages of HCTZ(Sigma-Aldrich, St. Louis, MO) to normal rats. As a result,we found that 10 mg/kg per d HCTZ is the lowest dosage thatreduced BP and induced mild hypokalemia.
Experimental Protocol
Male Sprague-Dawley rats (150 to 200 g; Charles River, Wilmington,MA) were placed on a standard diet (Harlan, Madison, WI) fora 5-d run-in period, then the rats were divided into five groups(n = 8) with similar body weight and baseline blood chemistry:Group 1: Normal standard diet (Harlan); group 2 (F): 60% fructosediet (Harlan); group 3 (F+HCTZ): In addition to 60% fructosediet, HCTZ 10 mg/kg per d was supplied in drinking water; group4 (F+HCTZ+KCL): 60% F diet with HCTZ and 1% K chloride (KCL)in drinking water; the concentration of KCL in drinking waterwas increased at weeks 5 (1.5% KCL), 15 (1.75% KCL), and 17(2% KCL) to maintain normal serum K+ level through the wholestudy; and group 5 (F+HCTZ+allopurinol): 60% F diet plus HCTZand allopurinol 150 mg/L (Sigma-Aldrich) in drinking water.
We pair-fed rats to ensure equivalent caloric intake, therebyavoiding the influence of different food intake on the metabolicabnormalities. Body weight was measured weekly. At weeks 1,4, 14, and 20, metabolic cages were used for urine collectionovernight, where water but no food was freely accessed. After4 h of fasting, serum was also collected from the tail veinat weeks 4, 14, and 20. At the end of week 20, rats were killed.
Tail-Cuff BP Measurement
SBP was measured in conscious rats with tail-cuff sphygmomanometer(Visitech BP2000, Apex, NC) at weeks 4 and 16 as described previously.3
Biochemical Measurements
Serum and urine K concentrations were determined with the atomicabsorption spectrophotometer (Perkin-Elmer 306, Downers Grove,IL). By use of an autoanalyzer (VetAce; Alfa Wassermann, WestCaldwell, NJ), the routine chemistries including glucose, cholesterol,triglycerides, uric acid, BUN, and creatinine were measuredin serum. In addition, urine protein concentration and urinecreatinine were determined.
Serum Insulin and the Quantitative Insulin Sensitivity Check Index
Fasting serum glucose and insulin were obtained at week 14.Serum insulin was determined with the rat insulin ELISA kit(Crystal Chem, Chicago, IL). Quantitative Insulin SensitivityCheck Index (QUICKI) is a mathematical model based on log-transformedfasting plasma glucose and insulin values by equal 1/(log [glucose]+ log [insulin]). QUICKI predicts insulin sensitivity, withlower values representing more insulin resistance. QUICKI showsa good correlation with the hyperinsulinemic-euglycemic clampmethod, especially in individuals with impaired glucose tolerance.50
Insulin Tolerance Test
At week 18, 0.75 U/kg recombinant human insulin (Novolin; NovoNordisk, Princeton, NJ) was administered intraperitoneally afterrats had been fasted for 16 h. Blood glucose was determinedon tail blood via hand-held blood glucose monitor (OneTouch;Johnson & Johnson, Milpitas, CA) at five points: 0, 15,30, 45, and 60 min after insulin injection.
Measurement of Urinary NO
Urine was determined for NO by using the nitrate/nitrite colorimetricassay kit (Cayman Chemical Co., Ann Arbor, MI).
Statistical Analyses
All data are shown as means ± SD. One-way ANOVA (SPSS14.0; SPSS, Chicago, IL) and post hoc multiple comparisons wereused to determine the significance between the mean of multiplegroups with the least-significant difference test for equaland Dunnett test for unequal variances. The homogeneity of variancewas clarified by Levene test. The paired and unpaired t testswere used to compare the continuous variables of the specifictwo groups. Pearson correlation was used to address potentialassociations between groups. Statistical significance was definedas P < 0.05.
T.N., S.R., and R.J.J. are listed as inventors on several patentapplications related to uric acid and cardiovascular diseasefrom the University of Florida or University of Washington.R.J.J. is also on the Scientific Board of Nephromics, Inc.
Acknowledgments
The work was supported by funding from the National Institutesof Health grants DK-52121, HL-68607, and HL-79352 and fundsfrom Gatorade. S.R. is supported by a fellowship from the AnandamahidolFoundation of Thailand.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
See related editorial, "The Fructose Nation," on pages 2619–2621.
Hall WD, Watkins LO, Wright JT Jr, Wenger NK, Kumanyika SK, Gavin JR 3rd, Ferdinand KC, Watson K, Clark LT, Flack JM, Reed JW, Horton EW, Saunders E; African-American Lipid and Cardiovascular Council: The metabolic syndrome: Recognition and management.
Dis Manag 9
: 16
–33, 2006[CrossRef][Medline]
Liberopoulos EN, Mikhailidis DP, Elisaf MS: Diagnosis and management of the metabolic syndrome in obesity.
Obes Rev 6
: 283
–296, 2005[CrossRef][Medline]
Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ: A causal role for uric acid in fructose-induced metabolic syndrome.
Am J Physiol Renal Physiol 290
: F625
–F631, 2006[Abstract/Free Full Text]
Deedwania PC: Mechanisms of endothelial dysfunction in the metabolic syndrome.
Curr Diab Rep 3
: 289
–292, 2003[Medline]
Turnbull F: Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomized trials.
Lancet 362
: 1527
–1535, 2003[CrossRef][Medline]
The ALLHAT Study Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium-channel blocker vs. diuretic.
JAMA 288
: 2981
–2997, 2002[Abstract/Free Full Text]
Punzi HA, Punzi CF; Antihypertensive and Lipid-Lowering Heart Attack Trial Study; Trinity Hypertension Research Institute: Metabolic issues in the Antihypertensive and Lipid-Lowering Heart Attack Trial Study.
Curr Hypertens Rep 6
: 106
–110, 2004[Medline]
Verdecchia P, Reboldi G, Angeli F, Borgioni C, Gattobigio R, Filippucci L, Norgiolini S, Bracco C, Porcellati C: Adverse prognostic significance of new diabetes in treated hypertensive subjects.
Hypertension 43
: 963
–969, 2004[Abstract/Free Full Text]
Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB: Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program.
J Hypertens 18
: 1149
–1154, 2000[CrossRef][Medline]
Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O: Metabolic outcome during 1 year in newly detected hypertensives: Results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).
J Hypertens 21
: 1563
–1574, 2003[CrossRef][Medline]
Amery A, Birkenhager W, Brixko P, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Fagard R, Forette F, Forte J: Glucose intolerance during diuretic therapy in elderly hypertensive patients. A second report from the European Working Party on high blood pressure in the elderly (EWPHE).
Postgrad Med J 62
: 919
–924, 1986[Abstract]
Andersson OK, Gudbrandsson T, Jamerson K: Metabolic adverse effects of thiazide diuretics: The importance of normokalaemia.
J Intern Med Suppl 735
: 89
–96, 1991[Medline]
Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ: Hyperuricemia induces endothelial dysfunction.
Kidney Int 67
: 1739
–1742, 2005[CrossRef][Medline]
Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.
Hypertension 38
: 1101
–1106, 2001[Abstract/Free Full Text]
Nakagawa T, Tuttle KR, Short RA, Johnson RJ: Hypothesis: Fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome.
Nat Clin Pract Nephrol 1
: 80
–86, 2005[CrossRef][Medline]
Bray GA, Nielsen SJ, Popkin BM: Consumption of high-fructose corn syrup in beverages may play a role in the epidermic of obesity.
Am J Clin Nutr 79
: 537
–543, 2004[Abstract/Free Full Text]
Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ, Willett WC, Hu FB: Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women.
JAMA 292
: 927
–934, 2004[Abstract/Free Full Text]
Beck-Nielsen H, Pedersen O, Lindskov HO: Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects.
Am J Clin Nutr 33
: 273
–278, 1980[Abstract/Free Full Text]
Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L: Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men.
Diabetes 54
: 1907
–1913, 2005[Abstract/Free Full Text]
Le KA, Faeh D, Stettler R, Ith M, Kreis R, Vermathen P, Boesch C, Ravussin E, Tappy L: A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans.
Am J Clin Nutr 84
: 1374
–1379, 2006[Abstract/Free Full Text]
Sharabi Y, Oron-Herman M, Kamari Y, Avni I, Peleg E, Shabtay Z, Grossman E, Shamiss A: Effect of PPAR-gamma agonist on adiponectin levels in the metabolic syndrome: Lessons from the high fructose fed rat model.
Am J Hypertens 20
: 206
–210, 2007[CrossRef][Medline]
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 179
: 43
–49, 2005[CrossRef][Medline]
Grundy SM: Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance.
Clin Cornerstone 8[Suppl 1]
: S21
–S27, 2006
Avramoglu RK, Basciano H, Adeli K: Lipid and lipoprotein dysregulation in insulin resistant states.
Clin Chim Acta 368
: 1
–19, 2006[CrossRef][Medline]
Sousa T, Fernandes E, Nunes C, Laranjinha J, Carvalho F, Pinho D, Morato M, Albino-Teixeira A: Scavenging of nitric oxide by an antagonist of adenosine receptors.
J Pharm Pharmacol 57
: 399
–404, 2005[CrossRef][Medline]
Frishman WH, Burris JF, Mroczek WJ, Weir MR, Alemayehu D, Simon JS, Chen SY, Bryzinski BS: First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension.
J Clin Pharmacol 35
: 182
–188, 1995[Abstract]
Widimsky J, Cifkova R: The heart in hypertension and arrhythmias.
Herz 15
: 49
–53, 1990[Medline]
Bloomfield RL, Wilson DJ, Buckalew VM Jr: The incidence of diuretic-induced hypokalemia in two distinct settings.
J Clin Hypertens 2
: 331
–338, 1986[Medline]
Hollifield JW, Slaton PE: Thiazide diuretics, hypokalemia and cardiac arrhythmias.
Acta Med Scand Suppl 647
: 67
–73, 1981[Medline]
Helderman JH, Elahi D, Andersen DK, Raizes GS, Tobin JD, Shocken D, Andres R: Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium.
Diabetes 32
: 106
–111, 1983[Abstract]
Norbiato G, Bevilacqua M, Meroni R, Raggi U, Dagani R, Scorza D, Frigeni G, Vago T: Effects of potassium supplementation on insulin binding and insulin action in human obesity: Protein-modified fast and refeeding.
Eur J Clin Invest 14
: 414
–419, 1984[Medline]
Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH: K+ is an endothelium-derived hyperpolarizing factor in rat arteries.
Nature 396
: 269
–272, 1998[CrossRef][Medline]
Sudhir K, Kurtz TW, Yock PG, Connolly AJ, Morris RC: Potassium preserves endothelial function and enhances aortic compliance in Dahl rats.
Hypertension 22
: 315
–322, 1993[Abstract/Free Full Text]
Yang BC, Li DY, Weng Y, Lynch J, Wingo CS, Mehta JL: Increased superoxide anion generation and altered vasoreactivity in rabbits on low-potassium diet.
Am J Physiol 274
: 1955
–1961, 1998
Nakagawa T, Sato W, Glushakova O, Heinig M, Clarke T, Campbell-Thompson M, Yuzawa Y, Atkinson MA, Johnson RJ, Croker B: Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy.
J Am Soc Nephrol 18
: 539
–550, 2007[Abstract/Free Full Text]
Iwaki K, Yonetani Y: Decreased renal excretion of uric acid following diuretic administration in rats.
Jpn J Pharmacol 34
: 389
–396, 1984[Medline]
Zoccali C, Maio R, Mallamaci F, Sesti G, Perticone F: Uric acid and endothelial dysfunction in essential hypertension.
J Am Soc Nephrol 17
: 1466
–1471, 2006[Abstract/Free Full Text]
Sanchez-Lozada LG, Tapia E, Avila-Casado C, Soto V, Franco M, Santamaria J, Nakagawa T, Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J: Mild hyperuricemia induces glomerular hypertension in normal rats.
Am J Physiol Renal Physiol 283
: F1105
–F1110, 2002[Abstract/Free Full Text]
Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M: Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?
Hypertension 41
: 1183
–1190, 2003[Abstract/Free Full Text]
Havel PJ: Dietary fructose: Implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism.
Nutr Rev 63
: 133
–157, 2005[CrossRef][Medline]
Blakely SR, Hallfrisch J, Reiser S, Prather ES: Long-term effects of moderate fructose feeding on glucose tolerance parameters in rats.
J Nutr 111
: 307
–314, 1981[Abstract/Free Full Text]
Sanchez-Lozada LG, Lopez-Molina R, Soto V, Tapia E, Avila-Casado C, Bautista R, Nakagawa T, Franco M, Johnson RJ: Low fructose caloric intake concomitant to hyperuricemia induces hyperinsulinemia and renal structural damage in rats [Abstract].
J Am Soc Nephrol 2007
. The authors will present this study as poster in the ASN meeting 2007 and they are doing more experiments to complete the study.
Kelley DE, Goodpaster BH, Storlien L: Muscle triglyceride and insulin resistance.
Annu Rev Nutr 22
: 325
–346, 2002[CrossRef][Medline]
Chung SS, Ho EC, Lam KS, Chung SK: Contribution of polyol pathway to diabetes-induced oxidative stress.
J Am Soc Nephrol 14[Suppl]
: S233
–S236, 2003[Abstract/Free Full Text]
Webb RL, Navarrete AE, Davis S: Effects of valsartan and hydrochlorothiazide alone and in combination on blood pressure and heart rate in conscious-telemetered spontaneously hypertensive rats (SHR).
Am J Hypertens 11
: 59
–65, 1998[CrossRef][Medline]
Kobayashi H, Sano T, Tarazi RC, Fouad-Tarazi FM: Effects of antihypertensive drugs on heart and resistance vessels.
Cardiovasc Res 24
: 137
–143, 1990[Abstract/Free Full Text]
Straczkowski M, Stepien A, Kowalska I, Kinalska I: Comparison of simple indices of insulin sensitivity using the euglycemic hyperinsulinemic clamp technique.
Med Sci Monit 10
: CR480
–CR484, 2004[Medline]
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Abstract
Introduction
