SUMMARY To determine if hypertension could be produced in normal rats by feeding them a fructose-enriched diet, Sprague-Dawley rats were fed either normal chow or a diet containing 66% fructose as a percentage of total calories for approximately 2 weeks. At the end of this period systolic blood pressure had increased from 124 ± 2 to 145 ± 2 (SEM) mm Hg in the fructose-fed rats, whereas no change occurred in the control group. In addition, hyperinsulinemia and hypertriglyceridemia were associated with hypertension in fructose-fed rats. The addition of clonidine to the drinking water inhibited fructose-induced hypertension, but not the increase in plasma insulin or triglyceride concentration seen in fructose-fed rats. Thus, the metabolic changes associated with fructose-induced hypertension are unlikely to be secondary to an increase in sympathetic activity. Whether or not this is also true of the hypertension remains to be clarified. IT has been apparent for some time that increases in dietary carbohydrate intake can raise blood pressure in experimental animals. '• 2 In particular, the ability of sucrose feeding to accentuate the magnitude of the blood pressure elevation already present in spontaneously hypertensive rats has been documented. 3 " 3 Since sucrose feeding stimulates sympathetic nervous system activity, 6 it has been suggested that sucroseinduced increases in sympathetic activity may elevate blood pressure in susceptible animals.4 Indirect support for this hypothesis was provided by the observation that rats with sucrose-induced hypertension had faster heart rates and larger hypotensive responses to a-adrenergic blockade with phentolamine than did their normotensive controls.7 This point of view has recently received added support from the demonstration that hypertension produced by sucrose feeding is associated with evidence of increased catecholamine Received March 13, 1987; accepted June 21, 1987. secretion. 5 However, the physiological effects of sucrose are not limited to an increase in sympathetic activity, and rats fed a high sucrose diet also become insulin-resistant and hyperinsulinemic.8 ' 9 Since several recent observations have documented an association between hyperinsulinemia and hypertension in humans, 10 " 12 it seemed important to see if a similar phenomenon could be found in carbohydrate-induced hypertension in rats. Thus, the current study was initiated to address this issue, and we have taken a somewhat different approach than has been conventionally used in an effort to broaden the nature of inquiry. First, we used normal Sprague-Dawley rats, not animals with spontaneous hypertension, to see if high carbohydrate diets can induce hypertension in rats with no apparent genetic propensity to become hypertensive. Second, we used fructose, not sucrose, as the source of dietary carbohydrate. Fructose feeding can also cause insulin resistance and hyperinsulinemia in normal rats.'14 If fructose also produces hypertension, it would suggest that the insulin resistance and hyperinsu...

SUMMARY This study was initiated to see if the insulin resistance, hyperinsulinemia, and hypertension that follow feeding nonnotensive 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 < 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 /xU/ml; p < 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 < 0.001), despite tbe fact that the steady state plasma insulin levels were also lower in rats allowed to run spontaneously (75 ± 4 vs 90 ± 5 ftU/ml; p < 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 hi nonnotensive rats by feeding them a high fructose diet can be attenuated if rats are allowed to run spontaneously. I N a previous report we found that hypertension can be produced by feeding a high fructose diet to normal rats.1 Fructose-fed rats also develop resistance to insulin-stimulated glucose uptake and hyperinsulinemia, 1 -3 phenomena that have recently been identified as occurring in patients with hypertension.4 -7 Based on these findings, we raised the possibility that the changes in insulin action and concentration noted in fructose-fed rats with hypertension may play a role in the pathogenesis of the elevated blood pressure seen in this situation. In this context, we have previously demonstrated that insulin-stimulated glucose uptake is enhanced in exercise-trained rats 8 and that the hyperinsulinemia associated with feeding rats a high fructose diet is attenuated if rats are allowed to run spontaneously. 9Thus, in the present report, we tested the hypothesis that insulin resistance and hyperinsulinemia are involved in the development of hypertension in fructose-fed rats by comparing the effects of fructoserich diets on both insulin metabolism and blood pressure in sedentary rats with those seen in rats allowed to exercise spontaneously in running wheels. Materials and Methods General ProtocolMale Sprague-Dawley rats (Harlan, Indianapolis, IN, USA) were used for all experiments. The rats were approximately 6 weeks old and weighed approximately 150 g when the study was started. Prior to any manipulation of diet or level of ...

The role of insulin resistance and byperinsulinemia 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 /iunits/ml, /><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<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. and the hyperinsulinemia appears to be associated with resistance to insulin-stimulated glucose uptake.5 ' 6 Sprague-Dawley rats become insulin resistant, hyperinsulinemic, and hypertrigryceridemic when fed a fructose-enriched diet, 7 -8 and the fact that this dietary manipulation also leads to an increase in blood pressure 8 lends further support to the possibility that insulin resistance and hyperinsulinemia may play a role in the genesis of high blood pressure. Furthermore, we have shown that exercise training of rats, which enhances insulin sensitivity 9 and reduces fructose-induced hyperinsulinemia, 10 also attenuates the increase in blood pressure seen in fructose-fed rats. 11The present experiments were initiated to further study the relation between insulin-resistance, hyperinsulinemia, and hypertension in fructosefed rats and were based on the use of somatostatin Received September 1, 1988; accepted February 14, 1989. to suppress insulin secretion by /3 cells in pancreatic islets. We reasoned that the infusion of somatostatin would suppress the hyperinsulinemia that normally results when rats are fed a fructoseenriched diet, 7 -8 -10 ' 11 and if elevated plasma insulin concentrations play a role in fructose-induced hypertension, this intervention would also ameliorate the rise in blood pressure that occurs when rats eat a high fructose diet. The results indicated that this prediction was borne out, providing further support for the view that insulin plays a role in the regulation of blood pressure in rats with fructose-induced hypertension. Materials and Methods General ProtocolMale Sprague-Dawley rats (Simonsen Laboratories, Gilroy, California), initially weighing 160-180 g, were used for all experiments. Before dietary manipulation, all rats were fed standard rat chow (Wayne Lab Blox, Allied Mills, Chicago, Illinois) containing 60% vegetable starch, 11% fat, and 29% protein and were maintained on a 12-hour light/dark (6:00 AM-6:00 PM) cycle. In addition, rats were acclimated to the procedure of blood pressure measure...

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