Fructose-drinking Rats Research Articles

Impairment of Novel Object Recognition Memory and Brain Insulin Signaling in Fructose- but Not Glucose-Drinking Female Rats.

Excessive sugar intake has been related to cognitive alterations, but it remains unclear whether these effects are related exclusively to increased energy intake, and the molecular mechanisms involved are not fully understood. We supplemented Sprague-Dawley female rats with 10% w/v fructose in drinking water or with isocaloric glucose solution for 7months. Cognitive function was assessed through the Morris water maze (MWM) and the novel object recognition (NOR) tests. Plasma parameters and protein/mRNA expression in the frontal cortex and hippocampus were determined. Results showed that only fructose-supplemented rats displayed postprandial and fasting hypertriglyceridemia (1.4 and 1.9-fold, p < 0.05) and a significant reduction in the discrimination index in the NOR test, whereas the results of the MWM test showed no differences between groups. Fructose-drinking rats displayed an abnormal glucose tolerance test and impaired insulin signaling in the frontal cortex, as revealed by significant reductions in insulin receptor substrate-2 protein levels (0.77-fold, p < 0.05) and Akt phosphorylation (0.72-fold, p < 0.05), and increased insulin-degrading enzyme levels (1.86-fold, p < 0.001). Fructose supplementation reduced the expression of antioxidant enzymes and altered the amount of proteins involved in mitochondrial fusion/fission in the frontal cortex. In conclusion, cognitive deficits induced by chronic liquid fructose consumption are not exclusively related to increased caloric intake and are correlated with hypertriglyceridemia, impaired insulin signaling, increased oxidative stress and altered mitochondrial dynamics, especially in the frontal cortex.

Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats.

What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensinII/angiotensinII type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n=8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100gl-1 ). After 2weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8weeks (60minday-1 , 4days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and glycogen accumulation. Furthermore, exercise improved the response to the deleterious effects of HFr overload by normalizing the gluconeogenesis pathway and the protein levels of interleukin-6 and tumour necrosis factor-α. The HFr rats displayed increased hepatic ACE activity and protein expression and angiotensinII concentration, which were attenuated by exercise training. Exercise training restored the ACE2/angiotensin-(1-7)/Mas receptor axis. Exercise training may favour the counter-regulatory ACE2/angiotensin-(1-7)/Mas receptor axis over the classical RAS (ACE/angiotensin II/angiotensinII type 1 receptor axis), which could be responsible for the reduction of metabolic dysfunction and the prevention of non-alcoholic fatty liver disease.

FGF21 ameliorates the neurocontrol of blood pressure in the high fructose-drinking rats.

Fibroblast growth factor-21 (FGF21) is closely related to various metabolic and cardiovascular disorders. However, the direct targets and mechanisms linking FGF21 to blood pressure control and hypertension are still elusive. Here we demonstrated a novel regulatory function of FGF21 in the baroreflex afferent pathway (the nucleus tractus solitarii, NTS; nodose ganglion, NG). As the critical co-receptor of FGF21, β-klotho (klb) significantly expressed on the NTS and NG. Furthermore, we evaluated the beneficial effects of chronic intraperitoneal infusion of recombinant human FGF21 (rhFGF21) on the dysregulated systolic blood pressure, cardiac parameters, baroreflex sensitivity (BRS) and hyperinsulinemia in the high fructose-drinking (HFD) rats. The BRS up-regulation is associated with Akt-eNOS-NO signaling activation in the NTS and NG induced by acute intravenous rhFGF21 administration in HFD and control rats. Moreover, the expressions of FGF21 receptors were aberrantly down-regulated in HFD rats. In addition, the up-regulated peroxisome proliferator-activated receptor-γ and -α (PPAR-γ/-α) in the NTS and NG in HFD rats were markedly reversed by chronic rhFGF21 infusion. Our study extends the work of the FGF21 actions on the neurocontrol of blood pressure regulations through baroreflex afferent pathway in HFD rats.

Effects of aerobic exercise of different intensities in the liver of metabolic syndrome animals

Abstract Introduction: Metabolic syndrome (MS) corresponds to a sum of alteration in which, glucose intolerance is characterized as one of the most important. Among these are included: insulin resistance, type 2 diabetes mellitus, hypertension, obesity, dyslipidemia, endothelial dysfunction and others Nonalcoholic steatohepatitis (NASH) is also currently cited as a risk factor for MS Studies have demonstrated a strong correlation between physical inactivity and MS. The aim of this paper was to evaluate the effects of aerobic exercise training of different intensities on the liver of metabolic syndrome rats. Methods: 20 male Wistar rats were used and divided into four groups (n=5): control (C) sedentary MS (MS), walking MS (WMS) and running MS (RMS). Fructose-drinking rats received D-fructose (100 g/l). MS Training rats were assigned to a treadmill training protocol at low and moderate intensity during 1 h/day, 5 days/week for 8 weeks. At the end of the experiment, the livers were collected and submitted to a histological technique (HE). The images were captured and morphometric and stereological analysis of the hepatic tissue were performed. Results: It was verified that MS promoted a hypertrophy of the hepatocytes, a significant increase in the density volume of the hepatocytes, of the Kupffer cells, and hepatic sinusoids, and that, in both intensities (Running and Walking) the exercise training has mitigated the alterations. Conclusions: The data suggest, as nonpharmacological treatment, the walking (low intensity) is the most eficient, able to reverse the alterations caused by metabolic syndrome, the results being approximate to those of control group.

Fructose-induced metabolic syndrome decreases protein expression and activity of intestinal P-glycoprotein

ObjectvesMetabolic syndrome (MetS) is a health disorder that increases the risk for cardiovascular complications such as heart disease and type 2 diabetes. Some drugs used in patients with MetS are substrates of intestinal P-glycoprotein (P-gp), one of the most important efflux pumps that limit the absorption of xenobiotics. Thus, their bioavailability could be affected by changes in this transporter. Because one of the major causes of MetS in humans is excessive sugar intake, the aim of this study was to evaluate the effect of a fructose-rich diet on intestinal P-gp activity and protein expression in male Sprague-Dawley rats. MethodsFructose-drinking animals received standard chow and 15% (w/v) fructose in the drinking water over 8 wk; control rats were fed on standard chow and tap water. ResultsIleal protein expression of P-gp was 50% lower in fructose-drinking rats than in control animals. This reduction was confirmed by immunofluorescence microscopy. These results correlated well with the decrease of about 50% in the transport rate of the substrate rhodamine 123 in everted intestinal sacs. Finally, an increase of 62% in the intestinal absorption of digoxin, a P-gp substrate used as therapeutic drug, was observed in vivo, in fructose-drinking animals. ConclusionThe present study demonstrated that MetS-like conditions generated by enhanced fructose intake in rats decreased the protein expression and activity of ileal P-gp, thus increasing the bioavailability of P-gp substrates.

Metabolic, hemodynamic and structural adjustments to low intensity exercise training in a metabolic syndrome model

BackgroundThe increase in fructose consumption is paralleled by a higher incidence of metabolic syndrome, and consequently, cardiovascular disease mortality. We examined the effects of 8 weeks of low intensity exercise training (LET) on metabolic, hemodynamic, ventricular and vascular morphological changes induced by fructose drinking in male rats.MethodsMale Wistar rats were divided into (n = 8 each) control (C), sedentary fructose (F) and ET fructose (FT) groups. Fructose-drinking rats received D-fructose (100 g/l). FT rats were assigned to a treadmill training protocol at low intensity (30% of maximal running speed) during 1 h/day, 5 days/week for 8 weeks. Measurements of triglyceride concentrations, white adipose tissue (WAT) and glycemia were carried out together with insulin tolerance test to evaluate metabolic profile. Arterial pressure (AP) signals were directly recorded. Baroreflex sensitivity (BS) was evaluated by the tachycardic and bradycardic responses. Right atria, left ventricle (LV) and ascending aorta were prepared to morphoquantitative analysis.ResultsLET reduced WAT (−37.7%), triglyceride levels (−33%), systolic AP (−6%), heart weight/body weight (−20.5%), LV (−36%) and aortic (−76%) collagen fibers, aortic intima-media thickness and circumferential wall tension in FT when compared to F rats. Additionally, FT group presented improve of BS, numerical density of atrial natriuretic peptide granules (+42%) and LV capillaries (+25%), as well as the number of elastic lamellae in aorta compared with F group.ConclusionsOur data suggest that LET, a widely recommended practice, seems to be particularly effective for preventing metabolic, hemodynamic and morphological disorders triggered by MS.

Angelica keiskeiExtract Improves Insulin Resistance and Hypertriglyceridemia in Rats Fed a High-Fructose Drink

Angelica keiskei is a traditional herb peculiar to Japan and abundantly contains vitamins, dietary fiber and such polyphenols as chalcone. We investigated in the present study the effect of A. keiskei on insulin resistance and hypertriglyceridemia in fructose-drinking rats as a model for the metabolic syndrome. Male Wistar rats were given a 15% fructose solution as drinking water for 11 weeks. Fructose significantly increased the levels of serum insulin and triglyceride (TG) compared with the control level. Treatment with an ethanol extract of A. keiskei (AE) significantly reduced the levels of blood glucose (-16.5%), serum insulin (-47.3%), HOMA-R (-56.4%) and TG (-24.2%). A hepatic gene analysis showed that fructose reduced the expression of the genes related to fatty acid β-oxidation and high-density lipoprotein (HDL) production. Treatment with AE enhanced the expression of the acyl-CoA oxidase 1 (ACO1), medium-chain acyl-CoA dehydrogenase (MCAD), ATP-binding membrane cassette transporter A1 (ABCA1) and apolipoprotein A1 (Apo-A1) genes. These results suggest that AE improved the insulin resistance and hypertriglyceridemia of the fructose-drinking rats.

Candesartan Cilexetil Improves Angiotensin II Type 2 Receptor–Mediated Neurite Outgrowth via the PI3K-Akt Pathway in Fructose-Induced Insulin-Resistant Rats

We have shown previously that stimulation of the angiotensin II type 2 receptor (AT2R) results in nerve facilitation. In this study, we determined the capacity of candesartan to correct expression patterns characteristic of neuropathy and AT2R-mediated neurite outgrowth in the fructose-induced insulin-resistant rat, which is one of the human hyperinsulinemia models. Wistar rats received a 15% (w/v) fructose solution in their drinking water for 4 weeks (fructose-drinking rats [FDRs]), with or without candesartan (5 mg/kg/day). We evaluated physiological and behavioral parameters and performed immunohistochemical studies. We found that the FDR developed insulin resistance and downregulated both AT2R neuronal function and phosphorylated Akt expression in dorsal root ganglia (DRG) neurons. Candesartan improved neurite outgrowth in the FDR, which was associated with the restoration of AT2R and phosphorylated Akt expression. Furthermore, downregulation of phosphoinositide 3-kinase (PI3K) inhibited AT2R-mediated neurite outgrowth in control DRG cells. PI3K activation increased AT2R-mediated neurite outgrowth and phosphorylated Akt expression in FDR DRG cells. These results suggest that the decrease of AT2R-mediated neurite outgrowth in FDRs is likely to be the result of decreased PI3K-dependent Akt activation. Candesartan improved AT2R neuronal function and Akt phosphorylation, which were associated with sensory nerve defects and insulin sensitivity in the FDR.

Hyperinsulinemia induces hypertension associated with neurogenic vascular dysfunction resulting from abnormal perivascular innervations in rat mesenteric resistance arteries

We previously reported that chronic hyperinsulinemia and insulin resistance induced by fructose-drinking loading elicited hypertension associated with abnormal neuronal regulation of vascular tone in an in vivo study using pithed rats. Therefore, to further clarify the detailed mechanisms of perivascular nervous system malfunction induced by chronic hyperinsulinemia, we investigated the neurogenic vascular responses and distribution of perivascular nerves using mesenteric vascular beds isolated from fructose-loaded rats with hyperinsulinemia. Male Wistar rats (6 weeks old) received 15% fructose solution as drinking fluid for 10 weeks (fructose-drinking rats, FDR), which resulted in significant increases in plasma levels of insulin, the glucose-insulin index, blood norepinephrine (NE) levels and systolic blood pressure, but not blood glucose levels, when compared with normal water-drinking rats (control rats). In perfused mesenteric vascular beds of FDR, enhanced adrenergic nerve-mediated vasoconstriction with no effect on NE-induced vasoconstriction and decreased calcitonin gene-related peptide (CGRP)-containing nerve-mediated vasodilation with no effect on CGRP-induced vasodilation were observed. Immunohistochemistry studies showed increased density of neuropeptide Y immunopositive adrenergic fibers and reduced density of CGRP immunopositive fibers in mesenteric arteries of FDR. Furthermore, FDR showed decreased CGRP content in dorsal root ganglia. These findings suggest that dysfunction of the neuronal vascular control system resulting from abnormal innervation of mesenteric perivascular nerves induced by the hyperinsulinemic state is responsible for the development of hypertension in FDR.

Effect of pioglitazone on altered expression of Aβ metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance

Accumulation of β-amyloid (Aβ) peptide in the brain is a major hallmark of Alzheimer's disease. An optimal brain insulin level promotes Aβ clearance, which may play protective roles against Alzheimer's disease. In this study we examined the role of dietary conditions leading to insulin resistance on amyloidosis in fructose-drinking rats. Further investigations tested pioglitazone, an insulin sensitizer, intervention on the altered amyloidosis in this rodent model of insulin resistance. Six-week-old male Wistar rats were fed a standard commercial diet and water without (control) or with 10% fructose for 16 weeks. The animals were randomly divided into 4 groups (n = 10): non-treated and water-drinking rats (control group); pioglitazone treated and water-drinking (control treatment group); non-treated and fructose-drinking rats (fructose group) and pioglitazone-treated and fructose-drinking rats (fructose treatment group). Pioglitazone was given at the dose of 10 mg/kg d by gavage for the last 12 weeks of the 16-week period. We found that diet-induced insulin resistance induced Aβ overproduction with altered expression of Aβ metabolism-associated molecules, which corresponded with increased β-secretase-1 (BACE1), γ-secretase (PS-1) activities and decreased insulin degrading enzyme (IDE) activities, but not neprilysin in the cortex and hippocampus. Additionally, pioglitazone treatment prevented all these observed abnormalities. This study indicates that insulin resistance induced by fructose-drinking affects the expression of Aβ metabolism-associated molecules that are responsible for Aβ deposition and pioglitazone treatment negatively modulate amyloidogenesis.

Ameliorative effect of Eucommia ulmoides Oliv. leaves extract (ELE) on insulin resistance and abnormal perivascular innervation in fructose-drinking rats

Aim of the study Eucommia ulmoides Oliv. leaf is a traditional Chinese medicine that exhibits an anti-diabetic action. This study was designed to investigate whether long-term administration of Eucommia ulmoides Oliv. leaves extract (ELE) ameliorates pre-diabetic state of insulin resistance and abnormal perivascular innervation in the hyperinsulinemic state. Materials and methods ELE at doses of 500 and 1000 mg/kg was administered orally once daily for 4 weeks in fructose-drinking rats (FDRs). Plasma levels of insulin, blood glucose levels, and perivascular innervation were assessed using biochemical and immunohistochemical methods. Results FDR showed significant increase in plasma levels of insulin, an index for insulin resistance (Homeostasis Model Assessment ratio—HOMA-IR) and systolic blood pressure (SBP), but not blood glucose levels, as compared with control rats. Immunohistochemical study showed significantly greater density of tyrosine hydroxylase (TH)-like immunoreactivity (LI)-containing nerves and significantly lower density of calcitonin gene-related peptide (CGRP)-LI-containing nerves in mesenteric arteries of FDR than those in control. A 4-week treatment with ELE (500 and 1000 mg/kg, p.o.) significantly decreased plasma levels of insulin and HOMA-IR without affecting blood glucose levels and significantly lowered SBP in FDR. ELE treatment in FDR resulted in significant increase in CGRP-LI never fiber density and significant decrease in TH-LI never fiber density in mesenteric arteries of FDR. Conclusions These results suggest that long-term ELE treatment effectively prevents insulin resistance development and ameliorates abnormal perivascular innervation in FDR.

Effect of pioglitazone on insulin resistance in fructose-drinking rats correlates with AGEs/RAGE inhibition and block of NAPDH oxidase and NF kappa B activation

Insulin resistance, which may influence Alzheimer's disease, is associated with an increase in circulating advanced glycosylation end products (AGEs) and the increased expression of the receptor for AGEs (RAGE). Inhibition of AGE/RAGE system has been shown to attenuate neuronal damage. Specific ligands for peroxisome proliferator-activated receptor γ (PPARγ), which have proven effective in the animal models of Alzheimer's disease and other neuroinflammatory diseases, have been shown to decrease RAGE expression. Here we investigated the effect of PPARγ agonist, pioglitazone, on cognition function and AGE/RAGE system in a rodent model of insulin resistance, the fructose-drinking rats. Six-week-old male Wistar rats were fed a standard commercial diet and water without (control) or with 10% fructose for 16 weeks. The animals were randomly divided into 4 groups ( n = 10): non-treated and water-drinking rats (control group); pioglitazone-treated and water-drinking (control treatment group); non-treated and fructose-drinking rats (fructose group) and pioglitazone-treated and fructose-drinking rats (fructose treatment group). Pioglitazone was given at the dose of 10 mg/kg d by gavage for the last 12 weeks of the 16-week period. The results showed that pioglitazone treatment reduced the escape latency in Morris water maze test, decreased AGE/RAGE expression in the cerebral cortex of fructose-drinking rats. Furthermore, we found that the expression of p47phox component of NAPDH oxidase, phosphorylated nuclear factor NF-κB p65, tumor necrosis factor alpha and interleukin-1 beta was significantly increased in the cerebral cortex of fructose-drinking rats ( P < 0.001). These effects were reversed by pioglitazone treatment ( P < 0.01 or 0.001). Taken together, these findings suggest that the activation of AGEs–RAGE system contribute to the brain damage of insulin resistance. Pioglitazone administration can improve cognition function probably related to its effect of decreasing the activation of AGEs–RAGE system, which correlates with block of NAPDH oxidase and NF-κB activation in this rodent model of insulin resistance.

Royal Jelly Ameliorates Insulin Resistance in Fructose-Drinking Rats

Royal jelly (RJ) is known to contain excellent nutrition and a variety of biological activities. The present study was designed to investigate the effects of RJ on insulin resistance (hyperinsulinemia) in fructose-drinking rats (FDR; insulin resistance animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin and triglyceride, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), and systolic blood pressure, but not blood glucose levels, when compared with control rats. RJ (100, 300 mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma levels of insulin and triglyceride, HOMA-R, without affecting blood glucose or total cholesterol levels and tended to lower systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, RJ treatment resulted in a significant reduction in sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS) and tended to increase the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with those in untreated FDR. However, RJ treatment did not significantly affect norepinephrine-induced vasoconstriction or CGRP-induced vasodilation. These results suggest that RJ could be an effective functional food to prevent insulin resistance associated with the development of hypertension.

Effect of Propolis on Insulin Resistance in Fructose-drinking Rats

Propolis, a honeybee product, contains a variety of biologically active substances. The present study was designed to investigate the effects of propolis on insulin resistance induced by fructose-drinking rats (FDR; type 2 diabetic animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), body weight, and systolic blood pressure but not blood glucose levels, when compared with control rats. Brazilian propolis extract (100 and 300 mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma level of insulin, HOMA-R, and body weight, increased plasma triglyceride levels without affecting blood glucose and total cholesterol levels, and tended to decrease systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, propolis treatment resulted in a significant reduction of sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS; 8 Hz) and tended to increase the calcitonin gene-related peptide (CGRP) nerve-mediated vasodilator response to PNS, compared with those in untreated FDR. However, propolis treatment did not significantly affect norepinephrine-induced vasoconstriction and CGRP-induced vasodilation. These results suggest that propolis could be an effective functional food to prevent the development of insulin resistance.

Chronic Hyperinsulinemia Enhances Adrenergic Vasoconstriction and Decreases Calcitonin Gene-Related Peptide-Containing Nerve-Mediated Vasodilation in Pithed Rats

The present study investigated the influence of chronic hyperinsulinemia on vascular responsiveness induced by adrenergic nerves and calcitonin gene-related peptide-containing (CGRPergic) nerves in pithed rats with insulin resistance. Male Wistar rats (6 weeks old) received 15% fructose solution in drinking fluid for 10 weeks (fructose-drinking rats: FDR), which resulted in significant increases in plasma levels of insulin, total cholesterol and triglyceride, and systolic blood pressure, as compared with control rats. Pithed FDR showed greater adrenergic nerve-mediated pressor response to spinal cord stimulation (SCS) at the lower thoracic vertebra (Th 9-12) and pressor response to exogenous noradrenaline than control rats. In pithed FDR with blood pressure artificially increased by continuous infusion of methoxamine and blockade of autonomic ganglia by hexamethonium, CGRPergic nerve-mediated depressor responses to SCS were significantly smaller than those in control rats, but depressor responses to other vasodilators such as acetylcholine, CGRP and sodium nitroprusside were similar to those in control rats. These results suggest that chronic hyperinsulinemia in FDR facilitates adrenergic nerve-mediated vasoconstriction, which is associated with attenuated CGRPergic nerve-mediated vasodilation.

Effect of an insulin sensitizer, pioglitazone, on hypertension in fructose-drinking rats.

To determine whether insulin resistance is responsible for the development of hypertension, we examined whether blood pressure changes in an insulin-resistant animal that was given a fructose solution as their drinking water. Wistar Kyoto rats that drank a 10% fructose solution for 10 weeks showed significant increases not only in plasma triglyceride and insulin levels but also in systolic blood pressure. The decrease in blood glucose in response to the intraperitoneal injection of insulin (0.2-1.0 U/kg) was slight in these fructose-drinking rats. To confirm whether insulin resistance contributes to the observed hypertension, we examined the effect of pioglitazone, an insulin sensitizer, on blood pressure in rats given a 10% fructose solution. When pioglitazone was administered to the rats at a dose of 10 mg/kg/day for 4 weeks from 12 weeks of age, plasma triglyceride and insulin levels and systolic blood pressure decreased, and blood glucose reduction in response to insulin was normalized. These results suggest that insulin resistance is responsible for the development of hypertension in fructose-drinking rats.