Fructose feeding increases insulin resistance but not blood pressure in Sprague-Dawley rats

Fructose feeding has been widely reported to cause hypertension in rats, as assessed indirectly by tail cuff plethysmography. Because there are potentially significant drawbacks associated with plethysmography, we determined whether blood pressure changes could be detected by long-term monitoring with telemetry in age-matched male Sprague-Dawley rats fed either a normal or high-fructose diet for 8 weeks. Fasting plasma glucose (171+/-10 versus 120+/-10 mg/dL), plasma insulin (1.8+/-0.5 versus 0.7+/-0.1 microg/L), and plasma triglycerides (39+/-2 versus 30+/-2 mg/dL) were modestly but significantly elevated in fructose-fed animals. Using the hyperinsulinemic euglycemic clamp technique, the rate of glucose infusion necessary to maintain equivalent plasma glucose was significantly reduced in fructose-fed compared with control animals (22.9+/-3.6 versus 41.5+/-2.9 mg/kg per minute; P<0.05). However, mean arterial pressure (24-hour) did not change in the fructose-fed animals over the 8-week period (111+/-1 versus 114+/-2 mm Hg; week 0 versus 8), nor was it different from that in control animals (109+/-2 mm Hg). Conversely, systolic blood pressure measured by tail cuff plethysmography at the end of the 8-week period was significantly greater in fructose-fed versus control animals (162+/-5 versus 139+/-1 mm Hg; P<0.001). Together, these data demonstrate that long-term fructose feeding induces mild insulin resistance but does not elevate blood pressure. We propose that previous reports of fructose-induced hypertension reflect a heightened stress response by fructose-fed rats associated with restraint and tail cuff inflation.     

Decrease in renal medullary endothelial nitric oxide synthase of fructose-fed,salt-sensitive hypertensive rats

We investigated the expression of endothelial NO synthase (eNOS) in the kidneys of fructose-fed insulin-resistant rats (FFR) with a low- or high-sodium diet. Male Sprague-Dawley rats were fed a control (C) or high-fructose (40% fructose; F) diet, with each coming in low-sodium (0.024% NaCl; LS-C or LS-F) or high-sodium (3% NaCl; HS-C or HS-F) varieties, for 2 weeks. Half of the FFR were orally administered pioglitazone (10 mg. kg(-1). day(-1)), an insulin-sensitizing agent (LS-FP or HS-FP). The systolic blood pressure was significantly higher in the HS-F rats than in the LS-F rats or the HS-C rats (HS-F rats, 129+/-4 mm Hg, versus LS-F rats, 115+/-3 mm Hg, P<0.05; or versus HS-C rats, 116+/-5 mm Hg, P<0.05), which indicated the salt dependence of hypertension in FFR. The protein expression of eNOS in the renal medulla of FFR was significantly lower than that in control rats during a high sodium load. The administration of pioglitazone prevented the hypertension (HS-F rats, 129+/-4 mm Hg, versus HS-FP rats, 113+/-3 mm Hg, P<0.05) and the reduction of medullary eNOS protein expression in HS-F rats. There was no significant difference in eNOS expression in the renal cortex or aorta between FFR and control rats, regardless of sodium load. These results suggest that the decrease in renal medullary NO production by eNOS during a high sodium load may play a role in fructose-fed, salt-sensitive hypertension.     

Increased vascular endothelin-1 gene expression with unaltered nitric oxide synthase levels in fructose-induced hypertensive rats

The present study aimed to investigate whether altered expression levels of endothelin-1 (ET-1) and nitric oxide synthase (NOS) are related to the development of insulin-resistant hypertension. Male Sprague-Dawley rats were fed a fructose-rich diet for 5 weeks. Systolic blood pressure significantly increased in fructose-fed rats. While serum free fatty acid (FFA) and plasma nitrite/nitrate (NOx) levels did not significantly differ between the fructose-fed and control groups, plasma insulin and serum triglyceride (TG) concentrations significantly increased in the former. ET-1 mRNA expression in the aorta increased to 195% in fructose-fed rats. Neither the protein expression of constitutive NOS (cNOS) nor that of inducible NOS (iNOS) were significantly affected by fructose feeding. However, NOx levels in the aorta were significantly increased. These results indicate that an increased expression of vascular ET-1 may be causally related to the development of hypertension in fructose-fed rats. However, an altered role of the vascular nitric oxide (NO) pathway may not be primarily involved in the development of fructose-induced hypertension.     

Attenuation of fructose-induced hypertension in rats by exercise training

This study was initiated to see if the insulin resistance, hyperinsulinemia, and hypertension that follow feeding normotensive Sprague-Dawley rats a fructose-rich diet could be prevented by letting rats run spontaneously in exercise wheel cages. Blood pressure in sedentary rats increased from (mean +/- SEM) 125 +/- 2 to 148 +/- 3 mm Hg in response to 2 weeks of a high fructose diet, and this increment was significantly (p less than 0.001) attenuated in exercising rats (from 121 +/- 1 to 131 +/- 2 mm Hg). In addition, mean (+/- SEM) plasma insulin concentration was lower in fructose-fed rats allowed to run spontaneously (44 +/- 2 vs 62 +/- 5 microU/ml; p less than 0.01). Finally, resistance to insulin-stimulated glucose uptake was assessed by determining the steady state plasma glucose response to a continuous glucose and exogenous insulin infusion during a period in which endogenous insulin secretion was suppressed. The results of these studies indicated that the mean (+/- SEM) steady state plasma glucose concentration was significantly lower in the exercise-trained rats (127 +/- 5 vs 168 +/- 6 mg/dl; p less than 0.001), despite the fact that the steady state plasma insulin levels were also lower in rats allowed to run spontaneously (75 +/- 4 vs 90 +/- 5 microU/ml; p less than 0.05). Thus, the ability of exercise-trained rats to stimulate glucose disposal was enhanced as compared with that of sedentary rats fed the same fructose-rich diet. These data demonstrate that the insulin resistance, hyperinsulinemia, and hypertension produced in normotensive rats by feeding them a high fructose diet can be attenuated if rats are allowed to run spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)     

Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance.

It has been hypothesized that insulin resistance and hyperinsulinemia contribute to the development of arterial hypertension. To further investigate this relationship, we compared arterial blood pressure in controls and women with polycystic ovary syndrome (PCO), an insulin-resistant state. Fourteen PCO women and 18 normal control women of similar age, body mass index, and race were studied. Plasma glucose and insulin levels were determined in an oral glucose tolerance test. The insulin sensitivity (SI) index was determined by the minimal model method. Systolic and diastolic blood pressure were measured by 24-h ambulatory monitoring. Left ventricular mass was assessed by echocardiography. The two groups had comparable fasting glucose levels, but the 2-h postload glucose was higher in PCO (8.0 +/- 0.5 vs. 5.6 +/- 0.3 mmol/L; P less than 0.001). Compared to controls, PCO women were significantly more insulin resistant by fasting insulin, 2-h insulin concentrations, and SI (28.3 +/- 6.7 vs. 68.3 +/- 10.0 min-1/nmol.mL; P less than 0.01). Average ambulatory systolic (121 +/- 2 vs. 118 +/- 2 mm Hg) and diastolic (76 +/- 2 vs. 73 +/- 2 mm Hg) blood pressures were similar for PCO and control women. No difference was found in left ventricular mass. Therefore, despite profound insulin resistance and hyperinsulinemia, women with PCO do not have increased arterial pressure or left ventricular mass.     

Subpressor dose of L-NAME unmasks hypertensive effect of chronic hyperinsulinemia

We previously found that chronic exogenous hyperinsulinemia without sugar supplementation does not elevate blood pressure. This may be partially explained by the ability of insulin to release nitric oxide and cause vasodilatation. To test this hypothesis, we studied 4 groups of rats: 9 rats (body weight, 213+/-14 g) treated with a gradual increase of a sustained-release subcutaneous insulin pellet; 9 rats (body weight, 213+/-9 g) treated with N:(G)-nitro-L-arginine methyl ester (L-NAME) in drinking water 50 mg/L; 19 rats (body weight, 217+/-11 g) treated with the combination of L-NAME and insulin; and 9 control rats (body weight, 218+/-11 g). Blood pressure was followed weekly for 6 weeks, and then rats were studied in metabolic cages. Weight gain was not different during the 6 weeks. Renal function did not differ between the 4 groups, but 24-hour urinary nitrite/nitrate excretion was lower (P<0.02) in L-NAME-treated and higher in insulin-treated rats. Plasma insulin doubled (P<0.002) in the insulin-treated rats, but there was no hypoglycemia and, by week 6, fructosamine levels were 2.1+/-0.2, 2.1+/-0.2, 2.3+/-0.1, and 2.3+/-0.2 mmol/L in control rats and rats treated with L-NAME, insulin, and L-NAME plus insulin, respectively. Systolic blood pressure, which did not differ at baseline, at week 3 was 122+/-17, 118+/-17, and 118+/-24 mm Hg in the control, L-NAME, and insulin groups and 136+/-14 mm Hg (P<0.03) in the combination group. At week 6, systolic blood pressure was 128+/-14, 127+/-15, and 118+/-13 mm Hg in the control, L-NAME, and insulin groups, respectively, and 150+/-14 mm Hg (P<0.0005) in the combination group. In a subsequent experiment, L-arginine 2 g/L abrogated the effects of L-NAME and insulin combination. In conclusion, chronic exogenous hyperinsulinemia does not affect blood pressure but may cause hypertension when endothelial function is compromised.     

Effects of the Chinese medicine Jiang-Tang-Ke-Li on insulin resistance in fructose-fed rats.

The aim of this study was to determine the effect of Jiang-Tang-Ke-Li (JTKL), a Chinese medicine used to treat diabetes mellitus, on insulin resistance and hypertension in fructose-fed rats (FFR). Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or a fructose-rich chow (FFR) for 6 weeks. For the last 2 weeks of the 6-week period of either diet, the rats were treated by gavage with gum arabic solution as a vehicle (control or FFR) or JTKL (3.24 g/kg/day; FFR+JT), and then an euglycemic hyperinsulinemic glucose clamp technique was performed to estimate insulin sensitivity. Systolic blood pressure was measured each week of the 6-week period. At the end of the glucose clamp, the soleus and extensor digitorum longus (EDL) muscles were dissected out for determination of the role of tumor necrosis factor (TNF)-alpha by an ELISA assay. Systolic blood pressures in the FFR groups were significantly higher than that in the control group, although there was no effect on systolic blood pressure for the last 2 weeks of treatment with JTKL. The average rate of glucose infusion during the glucose clamp, as an index of insulin sensitivity (M value), was significantly lower in the FFR than in the control rats, and treatment with JTKL for 2 weeks significantly increased the M value to that of control. TNF-alpha levels were significantly higher in the soleus and EDL muscles of the FFR (480+/-46 and 570+/-45 pg/g wet tissue in the soleus and EDL muscles, respectively) than in those of the control rats (177+/-34 and 206+/-33 pg/g wet tissue in the soleus and EDL muscles, respectively; p<0.01). Treatment with JTKL for 2 weeks significantly lowered TNF-alpha levels to the control levels (189+/-22 and 239+/-92 pg/g wet tissue in the soleus and EDL muscles, respectively). The results suggest that the Chinese medicine JTKL improves insulin resistance and modulates TNF-alpha in the soleus and EDL muscles in hypertensive and insulin-resistant fructose-fed rats.     

Androgens are necessary for the development of fructose-induced hypertension

Hyperinsulinemia and insulin resistance are closely associated with hypertension in humans and in animal models. Gender differences have been found in the development of hypertension in fructose-fed rats. The objectives of the present study were, first, to clarify whether androgens are required in the development of hyperinsulinemia, insulin resistance, and hypertension in fructose-fed rats, and second, to determine if cyclooxygenase-1 and cyclooxygenase-2 are also increased in the arteries of these rats. Male rats were gonadectomized or sham-operated and fed a 60% fructose diet beginning at age 7 weeks. Blood pressure was measured by a tail-cuff method, and an oral glucose tolerance test was performed to assess insulin sensitivity after 8 weeks of fructose feeding. Cyclooxygenase-1 and cyclooxygenase-2 mRNA expression was also assessed in the thoracic aortae and mesenteric arteries. Gonadectomy prevented hypertension from developing in the fructose-fed rats, but hyperinsulinemia and insulin resistance developed. There was an increase in cyclooxygenase-2 expression in the thoracic aortae and mesenteric arteries of the fructose-fed sham-operated rats while the expression of cyclooxygenase-1 remained unchanged. Gonadectomy prevented the mRNA overexpression of vascular cyclooxygenase-2 in the fructose-fed rats. These results suggest that the presence of androgens is necessary for the development of fructose-induced hypertension. Androgens apparently act as a link between hyperinsulinemia/insulin resistance and hypertension in fructose-hypertensive rats. Furthermore, an increase in the expression of cyclooxygenase-2 is implicated in the development of hypertension. The mechanisms involved require further study.     

Effects of the Chinese medicine, TSJN on insulin resistance and hypertension in fructose-fed rats.

The aim of this study was to determine the effect of Tang-Shen-Jiao-Nang (TSJN), a Chinese medicine used to treat diabetes mellitus, on insulin resistance and hypertension in fructose-fed rats (FFR). Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or a fructose-rich chow (FFR) for 6 wk. For the last 2 or 4 wk of a 6-wk period of either diet, the rats were treated by gavage with gum arabic solution as a vehicle (control or FFR) or TSJN (800 mg/kg/d; FFR+TS), and then we performed the euglycemic hyperinsulinemic glucose clamp technique to estimate insulin sensitivity. Systolic blood pressure was measured weekly for 6 wk. At the end of the glucose clamp, the soleus muscle was dissected out for determination of muscle fiber composition by ATPase methods. Systolic blood pressure was elevated at 2 wk after the start of the fructose-rich chow feeding and persisted thereafter throughout the study. Systolic blood pressure during the glucose clamp in the FFR group was significantly higher than that in the control group. Although there was no effect on systolic blood pressure in rats treated with TSJN for the last 2 wk of their 6-wk diet, those treated with TSJN for the last 4 wk of their 6-wk diet had lower systolic blood pressure than did the rats in the FFR group. The average rate of glucose infusion during the glucose clamp, as a measure of insulin sensitivity (M value), was significantly lower in the FFR than in the controls (10.9 +/- 0.6 and 15.4 +/- 0.4, mg/kg/min, for FFR and controls, respectively; p< 0.01). Treatment with TSJN for 2 wk significantly improved the M value compared to that of the control level (15.1 +/- 0.5 mg/kg/min). The composite ratio of type I fibers in the soleus muscle was significantly decreased in the FFR compared to controls (75.0 +/- 1.7 and 81.7 +/- 1.5%, for FFR and controls, respectively; p< 0.01), and treatment with TSJN for 2 wk led to a recovery composite ratio of type I fiber to the same level as that of the control group (78.7 +/- 1.7% in FFR + TS). The M value was significantly correlated with the compositions of type I and type II fibers (for type I fibers, r= 0.45, p < 0.01, for type II fibers, r= -0.44, p< 0.05). These results suggest that the Chinese medicine TSJN may improve insulin resistance, lower the systolic blood pressure, and modulate muscle fiber composition in hypertensive and insulin-resistant fructose-fed rats.     

Somatostatin inhibition of fructose-induced hypertension

The role of insulin resistance and hyperinsulinemia in the etiology of fructose-induced hypertension was studied in male Sprague-Dawley rats. Rats consumed a fructose-enriched diet (containing 66% of total calories as fructose) for 11 days and were infused continuously during the last 7 days with either a somatostatin analogue or vehicle. At the end of this period, rats receiving the somatostatin analogue had a lower plasma insulin concentration (52 +/- 4 vs. 70 +/- 6 microunits/ml, p less than 0.01) and a lower blood pressure (133 +/- 2 vs. 150 +/- 2 mm Hg) than did the rats infused with the control solution. In addition, the increase in plasma triglyceride concentration in response to the fructose-enriched diet was significantly attenuated (p less than 0.001) in the rats infused with somatostatin. These data provide further support that the increase in blood pressure that occurs when normal rats are fed a high fructose diet is dependent on the ability of this intervention to cause insulin resistance and hyperinsulinemia.     

Increasing Insulin Sensitivity Lowers Blood Pressure in the Fructose-Fed Rat

In the rat, simple carbohydrate feeding induces insulin resistance, and insulin resistance is associated with impaired endothelium dependent vasodilation. To determine if increasing insulin sensitivity corrects this defect of endothelial function, we evaluated the effects of an insulin-sensitizing agent, pioglitazone, on arterial pressure and in vitro vascular reactivity in three groups of Sprague Dawley rats: 1) control; 2) 60% fructose diet for 4 weeks; 3) 60% fructose diet plus pioglitazone (20 mg/kg daily, by oral gavage). Direct mean arterial pressure did not differ in Groups 1 (120 mm Hg ± 2) and 2 (121 ± 2) and was lower (P < .05) in Group 3 (112 ± 2). In vitro uptake of tritiated glucose by adipocytes in response to insulin was reduced (P < .05) by fructose and increased (P < .01) by pioglitazone. In strips of thoracic aorta, norepinephrine-induced vasoconstriction and nitroprusside induced vasodilation did not differ among groups. However, in response to graded dose of acetylcholine, vasodilation was reduced (P < .05) by fructose; this was normalized by pioglitazone. In all groups, N^G-nitro-l-arginine methyl ester (L-NAME) completely blocked acetylcholine-induced vasodilation. Thus, pioglitazone increased insulin sensitivity, lowered blood pressure, and normalized acetylcholine-induced vasodilation in insulin resistant, fructose-fed rats. Increasing insulin sensitivity may lower arterial pressure by augmenting endothelium dependent vasodilation.     

Visceral fat in hypertension: influence on insulin resistance and beta-cell function

Preferential visceral adipose tissue (VAT) deposition has been associated with the presence of insulin resistance in obese and diabetic subjects. The independent association of VAT accumulation with hypertension and its impact on insulin sensitivity and beta-cell function have not been assessed. We measured VAT and subcutaneous fat depots by multiscan MRI in 13 nondiabetic men with newly detected, untreated essential hypertension (blood pressure=151+/-2/94+/-2 mm Hg, age=47+/-2 years, body mass index [BMI]=28.4+/-0.7 kg x m(-2)) and 26 age-matched and BMI-matched normotensive men (blood pressure=123+/-1/69+/-2 mm Hg). Insulin secretion was measured by deconvolution of C-peptide data obtained during an oral glucose tolerance test, and dynamic indices of beta-cell function were calculated by mathematical modeling. For a similar fat mass in the scanned abdominal region (4.8+/-0.3 versus 3.9+/-0.3 kg, hypertensive subjects versus controls, P=0.06), hypertensive subjects had 60% more VAT than controls (1.6+/-0.2 versus 1.0+/-0.1 kg, P=0.003). Intrathoracic fat also was expanded in patients versus controls (45+/-5 versus 28+/-3 cm2, P=0.005). Insulin sensitivity was reduced (10.7+/-0.7 versus 12.9+/-0.4 mL x min(-1) x kg(ffm)(-1), P=0.006), and total insulin output was proportionally increased (64 [21] versus 45 [24] nmol x m(-2). h, median [interquartile range], P=0.01), but dynamic indices of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) were similar in the 2 groups. Abdominal VAT, insulin resistance, and blood pressure were quantitatively interrelated (rho's of 0.39 to 0.47, P<0.02 or less). In newly found, untreated men with essential hypertension, fat is preferentially accumulated intraabdominally and intrathoracically. Such visceral adiposity is quantitatively related to both height of blood pressure and severity of insulin resistance, but has no impact on the dynamics of beta-cell function.     

Effects of increased adrenomedullary activity and taurine in young patients with borderline hypertension

Recent studies showed that taurine, a sulphonic amino acid, could decrease blood pressure and increase sympathoadrenal tone in DoCA-salt-treated hypertensive rats. To determine whether taurine exerts its antihypertensive action in man in a similar fashion, we studied the effect of oral administration of taurine (6 g for 7 days) on blood pressure and plasma catecholamines in 19 young patients with borderline hypertension in a double-blind, placebo-controlled fashion. Systolic blood pressure in the 10 patients who were treated with taurine decreased by 9.0 +/- 2.9 mm Hg (mean +/- SE; p less than .05 by paired t test), compared with a 2.7 +/- 2.3 mm Hg decrease (NS) in the nine patients treated with placebo and diastolic blood pressure in the taurine-treated patients decreased by 4.1 +/- 1.7 mm Hg (p less than .05) compared with 1.2 +/- 3.0 mm Hg (NS) in the placebo-treated subjects. In the patients receiving taurine plasma epinephrine (E) decreased significantly, with a negligible decrease in plasma norepinephrine (NE). The effect of taurine on plasma catecholamines and the response of plasma E after the stimulation with glucagon was also studied in 12 borderline hypertensive and nine age-matched normotensive subjects. Basal plasma E was significantly higher in borderline hypertensive than in normal subjects, but basal plasma NE did not differ in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Trandolapril and endothelin antagonist LU-135252 in the treatment of the fructose-induced hypertensive,hyperinsulinemic, hypertriglyceridemic rat

BACKGROUND: In view of the demonstrated interaction between endothelin and the renin-angiotensin system, the antihypertensive effect of combined therapy with an endothelin antagonist LU-135252 and the angiotensin converting enzyme inhibitor trandolapril, was studied in fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic male Sprague-Dawley rats. METHODS: Forty animals were fed a fructose-enriched diet (Tekled, Harlan) for 5 weeks, as follows: group A, fructose only; group B, trandolapril 0.1 mg/kg/day added during the last 2 weeks; group C, LU-135252 100 mg/kg/day added during the last 2 weeks; group D, both trandolapril and LU-135252 added the last 2 weeks. Systolic blood pressure (BP) was measured weekly in conscious rats by the indirect tail-cuff method. Blood samples from a retro-orbital sinus puncture were taken at the beginning of the experiment and after 3 and 5 weeks and examined for insulin and triglyceride concentrations. RESULTS: Systolic BP decreased in group B (trandolapril) from 148.8 +/- 9.8 at 3 weeks to 138.3 +/- 8.7 mm Hg after 5 weeks; in group C (endothelin antagonist) from 155.1 +/- 5.5 to 142.5 +/- 10.6 mm Hg; and in group D (combination) from 154.6 +/- 10.9 to 121.2 +/- 8.9 mm Hg. Triglyceride levels decreased only in the combined trandolapril/endothelin antagonist group from 167.6 +/- 55.3 in the third week to 134.9 +/- 53.7 mg/dL after 5 weeks. Insulin levels decreased only on combination therapy from 7.4 +/- 3.6 to 5.3 +/- 3.8 ng/mL during the same period. The BP decrease was additive compared with the respective individual substances. CONCLUSIONS: The trandolapril/endothelin antagonist combination appears to offer a rational antihypertensive combination that is superior to that of either drug alone. This finding applies to the specific rat model studied in which BP, insulin, and triglycerides were increased by fructose diet.     

High-fructose diet decreases catalase mRNA levels in rat tissues

Insulin resistance and hyperinsulinemia have recently been identified as independent determinants of several risk factors for cardiovascular disease. The generation of reactive oxygen species (ROS) may play an important role as a final common mediator by which glucose and insulin resistance might contribute to development of cardiovascular disease and hypertension. The aim of the present study was to evaluate changes on mRNA expression of antioxidant enzymes [catalase, Cu-Zn superoxide dismutase (Cu-ZnSOD), MnSOD], blood pressure and metabolic parameters in insulin resistance that follow feeding normotensive Wistar rats a high-fructose-enriched diet. In our investigation 26 normal male Wistar rats were fed a high-fructose diet for 2 weeks (no.=14) or normal chow to serve as a control group (no.=12). In vivo insulin resistance was verified in a subgroup of control and fructose-fed rats by the euglycemic hyperinsulinemic clamp technique at 2 different insulin infusion rates, 29 (submaximal stimulation) and 290 (maximal stimulation) pmol/kg/min respectively. The glucose infusion rate (GIR) was not significantly different in the two groups during the submaximal infusion of insulin (1.4 +/- 0.8 mmol/kg/min in fructose-fed rats vs 1.6 +/- 0.7 mmol/kg/min in control rats, NS) while in fructose-fed rats it was significantly lower (-29.8%) than in control rats during maximal infusion of insulin (2.6 +/- 0.3 mmol/kg/min vs 3.7 +/- 0.3 mmol/kg/min, p<0.05). Fructose feeding markedly reduced the expression of catalase mRNA and Cu-ZnSOD mRNA in the liver, catalase mRNA in the heart (p<0.05). A tendency of fructose feeding to reduce the expression of antioxidant enzymes in skeletal muscle and adipose tissue was also observed (NS). Fructose feeding also increased plasma uric acid (119.9 +/- 30.4 vs 42.1 +/- 10 pmol/l, p<0.05) and systemic blood pressure (128 +/- 4 vs 109 +/- 5 mmHg, p<0.05) respect to control animals. No significant changes were observed in plasma levels of glycemia and tryglycerides. Our study suggests that in non-hyperglycemic, fructose-fed insulin-resistant rats the expression of catalase is inhibited in liver and heart. This condition might lead to higher susceptibility to oxidative stress in insulin resistance. However, an adaptive cellular response to maintain the effectiveness of intracellular signaling pathways mediated by insulin-activated hydrogen peroxide generating systems may also be hypothesized.     

Glucose tolerance and insulin action in rats with renovascular hypertension

To test whether hypertension can cause hyperinsulinemia or insulin resistance, we performed intravenous glucose tolerance tests at 1 month and euglycemic clamps at 3 months after induction of two-kidney, one clip renovascular hypertension in rats. At 1 month, systolic pressure was higher in 21 clipped than in 12 control animals (161 +/- 5 mm Hg, range 134-187 mm Hg versus 119 +/- 3 mm Hg, range 108-146 mm Hg; p less than 0.001). Glucose tolerance, assessed as the glucose fractional disappearance rate between 3 and 11 minutes after the glucose injection, was similar in the clipped and sham groups (0.059 +/- 0.002 versus 0.056 +/- 0.002 min-1, respectively; p greater than 0.4). The total area under the insulin curve during glucose tolerance tests was also similar in the clipped and sham groups (926 +/- 95 versus 869 +/- 126 microunits/ml x min; p greater than 0.4). There was no significant relation between systolic blood pressure and insulin area during glucose tolerance tests in the clipped group, but there was a positive rectilinear relation in the control group (r = 0.66; p = 0.01). Fourteen animals had euglycemic clamps 2 months after glucose tolerance tests. At that time, systolic pressure (direct femoral measurement) was higher in the seven clipped animals (189 +/- 13 mm Hg versus 122 +/- 5 mm Hg in controls; p less than 0.001). Insulin infusions of 1 and 4 milliunits/min/kg body wt effected similar plasma insulin levels in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Afferent arteriolar reactivity to angiotensin II is enhanced during the early phase of angiotensin II hypertension

Increased renal microvascular reactivity may contribute to the blunted pressure natriuretic response and increase in blood pressure during the development of angiotensin II hypertension. The current studies were performed to determine renal microvascular reactivity during the early phases of angiotensin II-infused hypertension. Male-Sprague Dawley rats received angiotensin II (60 ng/min) or vehicle via an osmotic minipump. Normotensive and angiotensin II hypertensive rats were studied 1 and 2 weeks after implantation of the minipump. Systolic blood pressure averaged 117 +/- 4 mm Hg (n = 31) before pump implantation. Angiotensin II infusion increased systolic blood pressure to 149 +/- 3 and 187 +/- 5 mm Hg on infusion days 6 and 12, respectively. Renal microvascular responses to angiotensin II and norepinephrine at renal perfusion pressures of 100 and 150 mm Hg were observed using the in vitro juxtamedullary nephron preparation. Afferent arteriolar diameters of 1-week normotensive animals averaged 22 +/- 1 microm and after 2 weeks of vehicle infusion averaged 21 +/- 1 microm at a perfusion pressure of 100 mm Hg. In animals infused with angiotensin II for 1 or 2 weeks, diameters of the afferent arterioles perfused at a pressure of 100 mm Hg were 20% and 9% smaller, respectively. Additionally, 1- and 2-week hypertensive animals had an enhanced responsiveness of the renal microvasculature to angiotensin II. At a perfusion pressure of 100 mm Hg, angiotensin II (10 nmol/L) decreased afferent arteriolar diameter by 26 +/- 5% and 22 +/- 3% in the 1- and 2-week angiotensin II hypertensive rats, respectively. In 1- and 2-week normotensive animals, angiotensin II (10 nmol/L) decreased afferent arteriolar diameter by 18 +/- 2% and 15 +/- 2%, respectively, at a perfusion pressure of 100 mm Hg. In contrast, the afferent arteriolar response to norepinephrine was not altered in angiotensin II hypertensive rats. These data demonstrate an elevated renal microvascular resistance and enhanced vascular reactivity that is selective for angiotensin II in the early phases of hypertension development after infusion of angiotensin II. Thus, an alteration in renal microvascular function contributes to the blunted pressure natriuretic response and progressive development of hypertension.     

Nitric oxide does not participate in the metabolic effects of exogenous bradykinin in fructose-fed rats

The study was carried out to demonstrate the effects of bradykinin (BK) on hypertension, hyperinsulinemia, and hypertriglyceridemia in fructose-fed rats, and to determine whether these actions are mediated through nitric-oxide (NO) formation. Eighteen rats, rendered hypertensive, hyperinsulinemic, and hypertriglyceridemic by a fructose-enriched diet, were studied. BK (0.2 mg/day) was infused intravenously using osmotic pumps attached by a catheter to the jugular vein of 12 rats for 12 days. BK was administered either alone (n = 6) or with concomitant inhibition of NO synthase (n = 6). Six untreated rats served as control. Measurements of systolic blood pressure (indirect method) and levels of insulin and triglyceride in serum were taken every second day. BK infused chronically, induced a marked fall in all parameters as early as the second day of infusion: in blood pressure from 152+/-7 to 126+/-12 mmHg, in insulin from 8.7+/-2.9 to 4.6+/-5.4 pg/mL, and in triglyceride from 308+/-94 to 76+/-19 mg/dL. No such reduction was seen in untreated animals. When BK was administered concurrently with NO synthase inhibitor, blood pressure rose significantly, reaching very high values at the end of treatment. However, the reduction in insulin and triglyceride levels induced by BK was not affected. The capacity of BK to enhance reduction in hyperinsulinemia and hypertriglyceridemia in the fructose-fed rats is not mediated by NO formation. Whether this action of BK is related to a direct effect of this peptide remains to be determined.     

Heart rate variability and baroreflex function in AT2 receptor-disrupted mice

We adapted telemetry and sequence analysis employed in humans to mice and measured heart rate variability and the spontaneous baroreflex sensitivity in angiotensin II type 2 (AT2) receptor-deleted (AT2 -/-) and wild-type (AT2 +/+) mice with either deoxycorticosterone acetate (DOCA)-salt hypertension or N(omega)-nitro-L-arginine methylester hydrochloride (L-NAME) hypertension. Mean arterial pressure leveled during the day at 101+/-1 mm Hg and during the night at 109+/-1 mm Hg in AT2 receptor-deleted mice, compared with 98+/-2 mm Hg (day) and 104+/-2 mm Hg (night) in wild-type mice. Mean arterial pressure increased in AT2 receptor-deleted mice with L-NAME to 114+/-1 mm Hg (day) and 121+/-1 mm Hg (night), compared with 105+/-2 mm Hg (day) and 111+/-2 mm Hg (night), respectively. DOCA-salt also increased day and night blood pressures in AT2 receptor-deleted mice to a greater degree than in wild-type mice. Heart rate variability in the time and frequency domain was not different between AT2 receptor-deleted mice and AT2 receptor-deleted mice at baseline. Systolic blood pressure variability in the low frequency band was lower in AT2 receptor-deleted mice (0.6+/-0.1 ms2 versus 3.9+/-1.3 ms2) than in wild-type mice. Baroreceptor-heart rate reflex sensitivity was significantly increased in AT2 receptor-deleted mice compared with wild-type mice (3.4+/-0.6 versus 2.1+/-0.5 ms/mm Hg). These differences remained after DOCA-salt and L-NAME treatments. We conclude that activation of the AT2 receptor impairs arterial baroreceptor reflex function, probably by a central action. These data support the existence of an inhibitory central effect of the AT2 receptor on baroreflex function.     

Oral taurine supplementation prevents fructose-induced hypertension in rats

Taurine is known to have antihypertensive and lipid-lowering effects in some experimental models and patients. On the other hand, intracellular free calcium and magnesium play important roles in regulating the tonus of blood vessels and insulin sensitivity. We examined the effect of oral taurine supplementation on blood pressure, serum metabolic parameters, and platelet cytosolic free calcium ([Ca²⁺]_i) and magnesium ([Mg²⁺]_i) concentration in fructose-fed Sprague-Dawley rats. Systolic blood pressure and platelet [Ca²⁺]_i were significantly higher in rats fed a 60% fructose diet. Oral taurine supplementation (1% in drinking water) completely prevented the elevation of blood pressure and an increase in platelet [Ca²⁺]_i, but exacerbated hyperinsulinemia, hypertriglyceridemia, and a decrease in platelet [Mg²⁺]_i. In conclusion, taurine may ameliorate fructose-induced hypertension in rats by preventing an increase in intracellular free calcium concentration. The blood pressure-lowering effect of taurine appeared to be independent from its effect on glucose and lipid metabolism in this model.