Endothelin-1 modulates angiotensin II in the development of hypertension in fructose-fed rats

Two of the most potent vasoconstrictors, endothelin-1 (ET-1) and angiotensin II (Ang II), are upregulated in fructose hypertensive rats. It is unknown whether an interrelationship exists between these peptides that may contribute to the development of fructose-induced hypertension. The objective of this study was to investigate the existence of an interaction between the endothelin and renin angiotensin systems that may play a role in the development of fructose-induced hypertension. High fructose feeding and treatment with either bosentan, a dual endothelin receptor antagonist, or with L-158,809, an angiotensin type 1 receptor antagonist, were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma Ang II, and vascular ET-1-immunoreactivity were determined following 6 weeks of high fructose feeding. Rats fed with a high fructose diet exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, hypertension, and elevated plasma Ang II. Treatment with either bosentan or L-158,809 significantly attenuated the rise in blood pressure with no effect on insulin levels or insulin sensitivity in fructose-fed rats. Bosentan treatment significantly reduced plasma Ang II levels, while L-158,809 treatment significantly increased vascular ET-1-immunoreactivity in fructose-fed rats. Thus, treatment with the endothelin receptor antagonist prevented the development of fructose-induced hypertension and decreased plasma Ang II levels. These data suggest that ET-1 contributes to the development of fructose-induced hypertension through modulation of Ang II levels.     

Bezafibrate, an anti-hypertriglyceridemic drug, attenuates vascular hyperresponsiveness and elevated blood pressure in fructose-induced hypertensive rats

A high fructose diet induces hypertension, hyperinsulinemia - insulin resistance, and hypertriglyceridemia (syndrome X). In this study, we investigated the role of an abnormal lipid profile in mediating fructose-induced hypertension. We hypothesized that bezafibrate, a lipid-lowering drug, would reduce elevated blood pressure and inhibit increased vascular reactivity in fructose-fed rats. Male rats were placed on four different diets: group 1 was fed standard chow (n = 6); group 2 was fed 60% fructose (n = 5); group 3 was fed fructose plus bezafibrate (30 mg x kg(-1) x day(-1); drinking water; n = 5); and group 4 was fed standard chow plus bezafibrate (n = 6). In addition, the direct effects of very low density lipoprotein (VLDL) on vascular reactivity were examined. Bezafibrate treatment lowered blood pressure, free fatty acids, and triglycerides in the fructose-fed group, suggesting that lipid abnormalities play a role in the elevation of blood pressure in the fructose-induced hypertensive rat. Aortae from fructose-fed rats were hyperresponsive to the calcium channel agonist Bay K 8644, which was normalized with bezafibrate treatment. Incubation of aortae in a VLDL medium resulted in increased responsiveness to Bay K 8644, lending further support to lipid abnormalities altering vascular reactivity. An altered lipid profile evidenced by elevated triglycerides and free fatty acids is causally related to the development of high blood pressure and increased vascular reactivity in the fructose-induced hypertensive rat.     

The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension

The metabolic syndrome is an important public health concern that predisposes individuals to the development of cardiovascular disease and/or Type 2 diabetes. The fructose-fed rat is an animal model of acquired systolic hypertension that displays numerous features of the metabolic syndrome. This animal model is used to study the relationship between insulin resistance/compensatory hyperinsulinemia and the development of hypertension. Several mechanisms have been proposed to mediate the link between insulin resistance and hypertension. In this review, we have addressed the role of sympathetic nervous system overactivation, increased production of vasoconstrictors, such as endothelin-1 and angiotensin II, and prostanoids in the development of hypertension in fructose-fed rats. The roles of nitric oxide, impaired endothelium-dependent relaxation and sex hormones in the pathogenesis of the fructose-fed induced hypertensive rats have also been highlighted. More recently, increased formation of reactive oxygen species and elevated levels of uric acid have been reported to contribute to fructose-induced hypertension.     

Neonatal chemical sympathectomy attenuates fructose-induced hypertriglyceridemia and hypertension in rats

Experiments were performed to determine the pathogenic contribution of the peripheral sympathetic nervous system to fructose-induced hypertriglyceridemia, hyperinsulinemia and hypertension in rats. Neonatal chemical sympathectomy was performed in neonatal Sprague-Dawley rats (1-week old) by administration of guanethidine (50 microg/g, i.p.) 5 times per week for consecutive 3 weeks and nerve-intact rats were served as controls. Both groups of rats were fed a fructose-enriched diet for 9 weeks. The systolic blood pressure (SBP) and body weight were measured weekly and arterial blood samples were taken weekly for determinations of plasma insulin, glucose and triglyceride levels. The results showed that fructose feeding for one week significantly increased SBP in intact rats and sympathectomized rats (116+/-1 to 119+/-1 mmHg and 116+/-1 to 120+/-1 mmHg, respectively). SBP further increased thereafter in both groups. However, the increased SBP levels were significantly higher in intact group than in sympathectomized group after 5 weeks of fructose feeding. Fructose feeding for one week concurrently produced hypertriglyceridemia that preceded the appearance of hyperinsulinemia in both groups. The elevated plasma triglyceride levels were significantly lower in sympathectomized rats than in intact rats after 3 weeks of fructose feeding, whereas the elevated plasma insulin concentrations were not different between groups throughout fructose feeding period. Plasma glucose concentrations of both groups were comparable and remained unchanged throughout the study. These data indicate that neonatal chemical sympathectomy attenuated, but did not prevent, fructose-induced elevations in blood pressure and plasma triglyceride levels, suggesting a partial dependency of fructose-induced hypertriglyceridemia and hypertension on the integrity of the peripheral sympathetic nervous system (SNS) in rats.     

Female rats are protected against fructose-induced changes in metabolism and blood pressure

The objective of this study was to determine whether the effects of a fructose diet, which causes hyperinsulinemia, insulin resistance, and hypertension in male rats, are dependent on sex. Blood pressure was measured via the tail-cuff method, and oral glucose tolerance tests were performed to assess insulin sensitivity. Blood pressure in female rats did not differ between fructose-fed and control rats at any time point (126 +/- 5 and 125 +/- 3 mmHg at week 9 for fructose-fed and control rats, respectively) nor was there a difference in any metabolic parameter measured. Furthermore, the vascular insulin resistance that is present in male fructose-fed rats was not observed. After ovariectomy, fructose caused a significant change in systolic blood pressure from baseline compared with fructose-fed ovary-intact rats (change of 21 +/- 5 vs. -2 +/- 4 mmHg). The results demonstrate that females do not develop hypertension or hyperinsulinemia upon fructose feeding except after ovariectomy, suggesting that female sex hormones may confer protection against the effects of a fructose diet.     

Endothelial dysfunction in insulin-resistant rats is associated with oxidative stress and COX pathway dysregulation

Because insulin resistance is inevitably associated with cardiovascular complications, there is a need to further investigate the potential involvement of oxidative stress and the cyclo-oxygenase (COX) pathway in the vascular modifications associated to this pathological context. Endothelial function was evaluated in control and fructose-fed rats (FFR) by i) in vitro study of endothelium-dependent and -independent relaxations of aortic rings, and ii) in vivo telemetric evaluation of pressor response to norepinephrine. After 9 weeks of diet, FFR displayed hypertriglyceridemia, hyperinsulinemia and exaggerated response to glucose overload. Aortic rings from control rats and FFR exhibited comparable endothelium-dependent relaxations to Ach. In the presence of indomethacin, relaxations were significantly reduced. FFR showed exaggerated pressor responses to norepinephrine that were abolished with indomethacin. Urinary nitrites/nitrates, 8-isoprostanes and thromboxane B2 excretion levels were markedly enhanced in FFR, whereas the plasma levels of 6-keto prostaglandin F1alpha were unchanged. In conclusion, fructose overload in rats induced hypertriglyceridemia and insulin resistance associated with an enhanced oxidative stress. This was associated with COX pathway dysregulation which could be one of the contributors to subsequent vascular dysfunction. Consequently, reduction of oxidative stress and regulation of the COX pathway could represent new potential therapeutic strategies to limit vascular dysfunction and subsequent cardiovascular complications associated with insulin resistance.     

Pregnancy-associated increase in rat systemic arteries endothelial nitric oxide production diminishes vasoconstrictor but does not enhance vasodilator responses

Late pregnancy in rats is characterized by a decrease in arterial pressure and in isolated arterial vessels response to vasoconstrictors. In uterine arteries the pregnancy-associated attenuation of the response to vasoconstrictors has been attributed to an increase in basal and agonist-induced endothelial NO production. However, the role of NO in pregnancy-associated changes of systemic arteries reactivity to vasoactive agents remains to be fully elucidated. We examined whether pregnancy influences the reactivity of systemic arteries to vasodilator or vasoconstrictor agents through NO-dependent mechanisms. Thoracic aortic rings and mesenteric arterial bed of late pregnant rats showed refractoriness to phenylephrine-induced vasoconstriction that was abolished by NO synthase inhibition. The potency of L-NNA to enhance tension of aortic rings preconstricted with phenylephrine (10–20% of their maximal response) was significantly lower in preparations from pregnant animals. In phenylephrine-contracted aortas and mesenteric bed, the effects of the endothelium-dependent vasodilators acetylcholine, A23187 and bradykinin, were not influenced by pregnancy. Similarly, pregnancy did not affect the vasodilator responses of adenosine, isoproterenol, capsaicin, nitroprusside, forskolin, and Hoe234 in the mesenteric bed. NO synthase activity measured by determining the conversion of L−[³H]-arginine to L−[³H]-citrulline in aorta and mesenteric arteries homogenates was not altered by pregnancy. These findings show that endothelial-dependent and -independent vasodilators action as well as NO synthase activity in systemic arteries is uninfluenced by pregnancy, whereas pregnancy-associated hyporeactivity of systemic arteries to vasoconstrictors is related to an enhanced endothelial NO production either spontaneous or elicited directly or indirectly by vasoconstrictor agents. This interpretation implies that the enhanced NO production observed in systemic arteries during late pregnancy involves cellular pathways other than the ones involved in the response to endothelium-dependent vasodilators such as acetylcholine.     

Gonadectomy prevents endothelial dysfunction in fructose-fed male rats, a factor contributing to the development of hypertension

Insulin resistance has been shown to be associated with increased blood pressure (BP). The sex hormones estrogen and testosterone have opposing effects in the development of increased BP. Since testosterone has been implicated in increased BP following insulin resistance, we have tried to dissect out the effects of insulin resistance on endothelium-dependent vasorelaxation in the presence and absence of testosterone. Both gonadectomized and sham-operated male Wistar rats fed with a high-fructose diet developed insulin resistance, but BP increased only in the sham-operated rats. Reintroduction of testosterone in vivo restored the increase in BP, thereby abolishing the protective effects of gonadectomy. Fructose feeding did not affect plasma testosterone levels. Insulin resistance induced endothelial dysfunction in the mesenteric arteries of sham-operated rats, which was prevented by gonadectomy, thus suggesting a key role for testosterone in the pathogenesis of secondary vascular complications. Subsequent to blocking the actions of endothelium-dependent hyperpolarizing factor (EDHF), relaxation to acetylcholine (ACh) was lower in sham-operated fructose-fed rats compared with other groups, suggesting the involvement of nitric oxide (NO) in vasorelaxation. Inhibition of NO synthesis nearly abolished the ACh-evoked relaxation in both fructose-fed groups, thus suggesting a testosterone-independent impairment of EDHF-mediated relaxation. The improvement in endothelial function following gonadectomy could be ascribed to a NO component, although plasma nitrite and nitrate levels were unchanged. In summary, testosterone is essential in vivo for the development of endothelial dysfunction and hypertension secondary to insulin resistance, suggesting a facilitatory role for testosterone in increasing BP in fructose-fed male rats.     

Chronic ouabain treatment increases the contribution of nitric oxide to endothelium-dependent relaxation

The aim of this study was to analyze the contribution of nitric oxide, prostacyclin and endothelium-dependent hyperpolarizing factor to endothelium-dependent vasodilation induced by acetylcholine in rat aorta from control and ouabain-induced hypertensive rats. Preincubation with the nitric oxide synthase inhibitor N-omega-nitro-l-arginine methyl esther (L-NAME) inhibited the vasodilator response to acetylcholine in segments from both groups but to a greater extent in segments from ouabain-treated rats. Basal and acetylcholine-induced nitric oxide release were higher in segments from ouabain-treated rats. Preincubation with the prostacyclin synthesis inhibitor tranylcypromine or with the cyclooxygenase inhibitor indomethacin inhibited the vasodilator response to acetylcholine in aortic segments from both groups. The Ca²⁺-dependent potassium channel blocker charybdotoxin inhibited the vasodilator response to acetylcholine only in segments from control rats. These results indicate that hypertension induced by chronic ouabain treatment is accompanied by increased endothelial nitric oxide participation and impaired endothelium-dependent hyperpolarizing factor contribution in acetylcholine-induced relaxation. These effects might explain the lack of effect of ouabain treatment on acetylcholine responses in rat aorta.     

Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of very low density lipoprotein (VLDL) in the insulin resistant state. Fructose feeding for a 2-week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance was documented using the euglycemic-hyperinsulinemic clamp technique. In vivo Triton WR-1339 studies showed evidence of VLDL-apoB overproduction in the fructose-fed hamster. Fructose feeding induced a significant increase in cellular synthesis and secretion of total triglyceride (TG) as well as VLDL-TG by primary hamster hepatocytes. Increased TG secretion was accompanied by a 4.6-fold increase in VLDL-apoB secretion. Enhanced stability of nascent apoB in fructose-fed hepatocytes was evident in intact cells as well as in a permeabilized cell system. Analysis of newly formed lipoprotein particles in hepatic microsomes revealed significant differences in the pattern and density of lipoproteins, with hepatocytes derived from fructose-fed hamsters having higher levels of luminal lipoproteins at a density of VLDL versus controls. Immunoblot analysis of the intracellular mass of microsomal triglyceride transfer protein, a key enzyme involved in VLDL assembly, showed a striking 2.1-fold elevation in hepatocytes derived from fructose-fed versus control hamsters. Direct incubation of hamster hepatocytes with various concentrations of fructose failed to show any direct stimulation of its intracellular stability or extracellular secretion, further supporting the notion that the apoB overproduction in the fructose-fed hamster may be related to the fructose-induced insulin resistance in this animal model. In summary, hepatic VLDL-apoB overproduction in fructose-fed hamsters appears to result from increased intracellular stability of nascent apoB and an enhanced expression of MTP, which act to facilitate the assembly and secretion of apoB-containing lipoprotein particles.     

Potential role of kinins in the effects of taurine in high-fructose-fed rats

The present work investigates the involvement of kinins in the effects of taurine in fructose-fed hypertensive rats. The effects of taurine on blood pressure, plasma glucose, insulin, and the insulin sensitivity index were determined. Angiotensin-converting enzyme (ACE) activity and nitrite content in plasma, plasma and tissue kallikrein activity, and taurine content were also investigated. The blood pressure changes in response to the coadministration of inhibitors of the synthesis of nitric oxide (NO), prostaglandins (PGs), or a kinin receptor blocker along with taurine was also evaluated. Fructose-fed rats had higher blood pressure and elevated plasma levels of glucose and insulin. Kallikrein activity, taurine, and nitrite contents were significantly lower in fructose-fed rats as compared with controls. The increases in systolic blood pressure, hyperglycemia, and hyperinsulinemia were controlled by taurine administration in fructose-fed rats. ACE activity was lower, while nitrite and taurine content and kallikrein activity were higher, in taurine-supplemented rats as compared with fructose-fed rats. A significant increase in blood pressure was observed in rats cotreated with the inhibitors Hoe 140 (a kinin receptor blocker), L-NAME (a NO synthase inhibitor), or indomethacin (a PG synthesis inhibitor) with taurine for 1 week as compared with taurine-treated fructose-fed rats. This suggests that the antihypertensive effect of taurine in fructose-fed rats was blocked by the inhibitors. Augmented kallikrein activity and, hence, increased kinin availability may be implicated in the effects of taurine in fructose-fed hypertensive rats.     

Differential Effect of Amylin on Endothelial-Dependent Vasodilation in Mesenteric Arteries from Control and Insulin Resistant Rats

Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, amylin has long been related to IR. However the role of amylin in the vascular dysfunction associated to IR is not well addressed. Therefore, the aim of the study was to assess the effect of acute treatment with amylin on endothelium-dependent vasodilation of isolated mesenteric arteries from control (CR) and insulin resistant (IRR) rats and to evaluate the possible mechanisms involved. Five week-old male Wistar rats received 20% D-fructose dissolved in drinking water for 8 weeks and were compared with age-matched CR. Plasmatic levels of glucose, insulin and amylin were measured. Mesenteric microvessels were dissected and mounted in wire myographs to evaluate endothelium-dependent vasodilation to acetylcholine. IRR displayed a significant increase in plasmatic levels of glucose, insulin and amylin and reduced endothelium-dependent relaxation when compared to CR. Acute treatment of mesenteric arteries with r-amylin (40 pM) deteriorated endothelium-dependent responses in CR. Amylin-induced reduction of endothelial responses was unaffected by the H₂O₂ scavenger, catalase, but was prevented by the extracellular superoxide scavenger, superoxide dismutase (SOD) or the NADPH oxidase inhibitor (VAS2870). By opposite, amylin failed to further inhibit the impaired relaxation in mesenteric arteries of IRR. SOD, or VAS2870, but not catalase, ameliorated the impairment of endothelium-dependent relaxation in IRR. At concentrations present in insulin resistance conditions, amylin impairs endothelium-dependent vasodilation in mircrovessels from rats with preserved vascular function and low levels of endogenous amylin. In IRR with established endothelial dysfunction and elevated levels of amylin, additional exposure to this peptide has no effect on endothelial vasodilation. Increased superoxide generation through NADPH oxidase activity may be a common link involved in the endothelial dysfunction associated to insulin resistance and to amylin exposure in CR.     

Testosterone-dependent increase in blood pressure is mediated by elevated Cyp4A expression in fructose-fed rats

Endothelial dysfunction and increased blood pressure following insulin resistance play an important role in the development of secondary cardiovascular complications. The presence of testosterone is essential for the development of endothelial dysfunction and increased blood pressure. Testosterone regulates the synthesis of vasoconstrictor eicosanoids such as 20-hydroxyeicosatetranoic acid (20-HETE). In a series of studies, we examined: (1) the role of the androgen receptor in elevating blood pressure and (2) the effects of Cyp4A-catalyzed 20-HETE synthesis on vascular reactivity and blood pressure in fructose-fed rats. In the first study, intact and castrated male rats were made insulin resistant by feeding fructose for 9?weeks following which their superior mesenteric arteries (SMA) were isolated and examined for changes in endothelium-dependent relaxation in the presence and absence of 1-aminobenzotriazole (ABT) and N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), which are inhibitors of 20-HETE synthesis. In another study, male rats were treated with either ABT or the androgen receptor blocker, flutamide, following which changes in insulin sensitivity, blood pressure, and vascular Cyp4A expression were measured. In the final study, HET0016, which is a more selective inhibitor of 20-HETE synthesis, was used to confirm our earlier findings. Treatment with HET0016 or ABT prevented or ameliorated the increase in blood pressure. Gonadectomy or flutamide prevented the increase in both the Cyp4A and blood pressure. Furthermore, both ABT and DDMS improved relaxation only in the intact fructose-fed rats. Taken together our results suggest that in the presence of testosterone, the Cyp4A/20-HETE system plays a key role in elevating the blood pressure secondary to insulin resistance.     

Selective alpha1-adrenoceptor blockade prevents fructose-induced hypertension

The purpose of this study was to investigate the effect of chronic treatment with prazosin, a selective α₁-adrenoceptor antagonist, on the development of hypertension in fructose-fed rats (FFR). High-fructose feeding and treatment with prazosin (1 mg/kg/day via drinking water) were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma norepinephrine (NE), uric acid, and angiotensin II (Ang II) were determined following 9 weeks of treatment. FFR exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension, as well as elevations in plasma NE and Ang II levels. Treatment with prazosin prevented the rise in blood pressure without affecting insulin levels, insulin sensitivity, uric acid, or Ang II levels, while normalizing plasma NE levels in FFR. These data suggest that over-activation of the sympathetic nervous system, specifically α₁-adrenoceptors, contributes to the development of fructose-induced hypertension, however, this over-activation does not appear to an initial, precipitating event in FFR.     

Differential effects of sodium tungstate and vanadyl sulfate on vascular responsiveness to vasoactive agents and insulin sensitivity in fructose-fed rats

High fructose feeding induces insulin resistance, impaired glucose tolerance, and hypertension in rats and mimics most of the features of the metabolic syndrome X. The effects of a 6-week treatment with the transition metals administered in drinking water, vanadium (VOSO4.5H2O, 0.75 mg/mL) or tungsten (Na2O4W, 2 g/mL), were investigated on the reactivity to norepinephrine (NEPI) or acetylcholine (ACh) of thoracic aorta rings isolated from fructose (60%) or standard chow fed rats. Maximal effect (Emax) and pD2 (-log EC50) values were determined in each case in the presence or absence of endothelium, while the degree of insulin resistance was determined using the euglycemic hyper insulinemic glucose clamp technique. Aortic segments isolated from 6-week fructose-fed animals were characterized by NEPI hyperresponsiveness (increase in Emax) and endothelium-dependent NEPI supersensitivity (increase in pD2) without any change in the reactivity to ACh. Vanadium or tungsten administered in fructose-fed animals prevented both hypertension and NEPI hyperresponsiveness, while vanadium, but not tungsten, reduced NEPI supersensitivity. Vanadium, but not tungsten, increased the relaxing activity of ACh, both in control and fructose-fed animals. Insulin resistance associated with high fructose feeding was reversed by vanadium but not by tungsten treatment. The differential effects of the two transition metals on vascular responsiveness to NEPI or ACh may be explained by their differential effects on insulin sensitivity.     

Infusion of beta-endorphin improves insulin resistance in fructose-fed rats.

In an attempt to probe the effect of beta-endorphin on insulin resistance, we used Wistar rats that were fed fructose-rich chow to induce insulin resistance. Insulin action on glucose disposal rate (GDR) was measured using the hyperinsulinemic euglycemic clamp technique, in which glucose (variable), insulin (40 mU/kg/min), and beta-endorphin (6 ng/kg/min) or vehicle were initiated simultaneously and continued for 120 min. A marked reduction in insulin-stimulated GDR was observed in fructose-fed rats compared to normal control rats. Infusion of beta-endorphin reversed the value of GDR, which was inhibited by naloxone and naloxonazine each at doses sufficient to block opioid mu-receptors. Opioid mu-receptors may therefore be activated by beta-endorphin to improve insulin resistance. Next, soleus muscle was isolated to investigate the effect of beta-endorphin on insulin signals. Insulin resistance in rats induced by excess fructose was associated with the impaired insulin receptor (IR), tyrosine autophosphorylation, and insulin receptor substrate (IRS)-1 protein content in addition to the significant decrease in IRS-1 tyrosine phosphorylation in soleus muscle. This impaired glucose transportation was also due to signaling defects that included an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation. However, IR protein levels were not markedly changed in rats with insulin resistance. beta-endorphin infusion reversed the fructose-induced decrement in the insulin-signaling cascade with increased GDR. Apart from IR protein levels, infusion of beta-endorphin reversed the decrease in protein expression for the IRS-1, p85 regulatory subunit of PI3-kinase, and Akt serine phosphorylation in soleus muscle in fructose-fed rats. The decrease in insulin-stimulated protein expression of glucose transporter subtype 4 (GLUT 4) in fructose-fed rats returned to near-normal levels after beta-endorphin infusion. Infusion of beta-endorphin may improve insulin resistance by modulating the insulin-signaling pathway to reverse insulin responsiveness.     

Effects of fructose loading in streptozotocin-diabetic and nondiabetic rats.

The present study compares the cardiovascular consequences of a 6-week fructose feeding in nondiabetic and streptozotocin-diabetic rats. Myocardial performance of these animals was determined using the isolated perfused working heart preparation. Systolic blood pressure, pulse rate, ventricular weight/body weight ratio, and plasma levels of glucose, insulin, triglycerides, and cholesterol were measured. In nondiabetic rats, fructose drinking caused significant increases in blood pressure, pulse rate, and plasma concentrations of insulin and triglycerides. Streptozotocin-diabetic animals exhibited significantly less body weight growth, slower pulse rate, higher plasma levels of cholesterol and triglycerides, ventricular enlargement, and functional impairment of the myocardium. The fructose-loaded diabetic rats had larger increases in plasma cholesterol and triglycerides than did control fructose-fed rats, but the fructose-induced increases in blood pressure and pulse rate were attenuated significantly. However, plasma levels of glucose and insulin and the degree of ventricular enlargement and myocardial dysfunction were not significantly different from those of control diabetic rats. These results show that fructose loading for 6 weeks can cause increases in blood pressure, pulse rate, and plasma lipids in both nondiabetic and diabetic rats. However, fructose ingestion does not significantly alter glycemic control or affect the development of myocardial dysfunction in streptozotocin-diabetic rats.