Blood Pressure In Fructose-fed Rats Research Articles

The effects of phentolamine on fructose-fed rats

Metabolic syndrome (MS) is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. MS is associated with obesity, increased blood pressure, hyperlipidemia, and hyperglycemia. This study was designed to investigate the pharmacological profile of phentolamine, a nonselective α adrenergic receptor antagonist, in the prevention of increased blood pressure in fructose-fed rats. Phentolamine prevented the fructose-induced increase in systolic blood pressure without affecting insulin sensitivity and major metabolic parameters. The levels of plasma noradrenaline and angiotensin II, 2 proposed contributors to the development of fructose-induced elevated blood pressure, were examined. Neither noradrenaline nor angiotensin II levels were affected by phentolamine treatment. Since overproduction of nitric oxide has been shown to lead to an elevation in peroxynitrite, the role of oxidative stress, a proposed mechanism of fructose-induced elevated blood pressure and insulin resistance, was examined by measuring plasma levels of total nitrate/nitrite. Plasma nitrate/nitrite was significantly elevated in all fructose-fed animals, regardless of treatment with phentolamine. Another proposed contributor toward fructose-induced MS is an elevation in uric acid levels. In this experiment, plasma levels of uric acid were found to be increased by dietary fructose and were unaffected by phentolamine treatment.

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 9weeks 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.

Functional interaction of AT1 and AT2 receptors in fructose-induced insulin resistance and hypertension in rats

The present study was performed to evaluate the potential role and functional interaction of angiotensin II AT1 and AT2 receptors (AT1R and AT2R) in the regulation of blood pressure and glucose homeostasis in fructose-induced insulin-resistant, hypertensive rats. Male Sprague-Dawley rats on fructose-enriched or regular diets for 4 weeks were subjected to 2-step euglycemic euinsulinemic (EEI) and euglycemic hyperinsulinemic (EHI) clamp studies with [3- 3H]glucose infusion. After a 40-minute basal period, selective AT1R and AT2R antagonists, losartan (LOS, 10 mg/kg IV bolus) and PD123319 (PD, 50 μg/kg/min), alone or in combination were separately given to control and fructose-fed groups in the 2 clamp periods. The results showed that during the EEI period, LOS significantly reduced the elevated blood pressure in fructose-fed rats, whereas PD further increased fructose-induced high blood pressure. Coadministration of LOS and PD did not alter the elevated blood pressure in fructose-fed rats. Administration of LOS and/or PD failed to change the blood pressure in control rats. During the EHI period, blockade of both AT1R and AT2R eliminated the insulin-induced blood pressure elevation in control and fructose-fed rats. Hepatic glucose production (HGP) did not alter among groups in the basal and EEI periods. Insulin infusion (EHI period) markedly suppressed HGP in control rats, but this suppressive effect was significantly attenuated in fructose-fed rats. LOS administration further reduced the insulin-induced suppression of HGP in fructose-fed rats. The whole-body glucose uptakes (rates of glucose disappearance, R d) during the basal and EEI periods were similar among groups. During the EHI period, R d was markedly increased in all groups and the magnitude of increase was significantly greater in control rats than in fructose-fed rats except those with LOS treatment. LOS treatment also redirected R d in favor of glycolysis in fructose rats, but not in control rats, during the EEI and EHI periods. The effects of LOS on glycolysis during the 2 clamp periods and on HGP during the EHI period were reversed when PD was concomitantly administered, but PD alone did not alter glucose metabolism throughout the experiment in fructose-fed rats. Administration of LOS and/or PD did not change the glucose metabolism in control rats. Our data suggest that AT2R can counterbalance the AT1R-mediated effects on blood pressure and glucose metabolism in fructose-induced insulin-resistant, hypertensive rats. Furthermore, AT1R- and AT2R-mediated effects on blood pressure are disassociated with their actions on glucose metabolism in this hypertensive model.

Carnosine, the anti-ageing, anti-oxidant dipeptide, may react with protein carbonyl groups

Carnosine (β-alanyl- l-histidine) is a physiological dipeptide which can delay ageing and rejuvenate senescent cultured human fibroblasts. Carnosine's anti-oxidant, free radical- and metal ion-scavenging activities cannot adequately explain these effects. Previous studies showed that carnosine reacts with small carbonyl compounds (aldehydes and ketones) and protects macromolecules against their cross-linking actions. Ageing is associated with accumulation of carbonyl groups on proteins. We consider here whether carnosine reacts with protein carbonyl groups. Our evidence indicates that carnosine can react non-enzymically with protein carbonyl groups, a process termed ‘carnosinylation’. We propose that similar reactions could occur in cultured fibroblasts and in vivo. A preliminary experiment suggesting that carnosine is effective in vivo is presented; it suppressed diabetes-associated increase in blood pressure in fructose-fed rats, an observation consistent with carnosine's anti-glycating actions. We speculate that: (i) carnosine's apparent anti-ageing actions result, partly, from its ability to react with carbonyl groups on glycated/oxidised proteins and other molecules; (ii) this reaction, termed ‘carnosinylation,’ inhibits cross-linking of glycoxidised proteins to normal macromolecules; and (iii) carnosinylation could affect the fate of glycoxidised polypeptides.

Effects of cilnidipine on muscle fiber composition, capillary density and muscle blood flow in fructose-fed rats.

The aim of this study was to examine the roles of muscle fiber composition, capillary density and muscle blood flow in insulin resistance (IR) and the effect of cilnidipine, a calcium channel blocker in fructose-fed rats (FFR). Six-week-old male Sprague-Dawley rats were fed either normal rat chow or fructose-rich chow for 6 weeks. For the last 2 weeks, the rats were treated by gavage with a vehicle (Control and FFR groups) or with cilnidipine (FFR+Cil group). Blood pressure (BP) and insulin sensitivity were assessed in the sixth week. Muscle fiber composition, capillary density and blood flow in the soleus muscle were evaluated. BP of FFR was significantly higher than that of the controls. Cilnidipine significantly lowered BP in FFR. Insulin sensitivity was significantly lower in FFR than in the controls. Cilnidipine significantly improved IR in FFR. The composite ratio of type I fibers in the soleus muscle was significantly lower in FFR than in the controls, but that of type II fibers was significantly higher in FFR. Treatment with cilnidipine resulted in recovery of this ratio to that of the controls. Insulin sensitivity was found to be significantly correlated with the composite ratio of either type I fibers or type II fibers. There were no intergroup differences in capillary density. Muscle blood flow in the FFR+Cil group was higher than that in the Control or FFR groups. These results suggest that muscle fiber composition is linked to IR and that cilnidipine may improve IR in FFR either by modulating muscle fiber composition or by increasing muscle blood flow.

Fructose feeding in rats is not associated with sodium retention

Chronic fructose treatment in rats repeatedly has been shown to elevate blood pressure associated with insulin resistance and hyperinsulinemia. Activation of the sympathetic nervous system and the renin-angiotensin system, vascular hypertrophy, and sodium retention by the kidney tubules have been proposed to be some of the mechanisms by which insulin elevates blood pressure. The precise mechanism by which hypertension develops in fructose fed rats is still not known. The purpose of the current study was twofold. The first objective was to assess the effect of a fructose-enriched diet on urinary sodium excretion. The second objective was to investigate any changes in plasma volume and extracellular volume in fructose-fed rats. In both experiments, male Sprague-Dawley rats were divided into equal groups. Rats in the control group were fed Purina Laboratory Chow, whereas those in the experimental group were fed a 60% fructose diet. There was a significant elevation in the blood pressure of fructose-fed rats at the end of the second week of treatment, and it remained elevated for the remainder of the dietary intervention. In the first experiment, there was no significant difference in sodium, potassium or urine excretion throughout the 6 weeks of dietary treatment. At the end of this study, the serum insulin levels of fructose-fed rats were significantly greater than the levels in the control group. In the second experiment, which was a 4-week study, there was no significant difference in hematocrit, plasma volume, or extracellular fluid volume between control and fructose-fed animals at 2 or 4 weeks of dietary treatment. The results of these two in vivo studies are the first to document that elevation of blood pressure in fructose-fed rats does not occur directly via sodium retention or an increase in fluid volume.