This study was conducted to investigate whether altered vascular responsiveness to vasoactive compounds contributes to the development of hypertension in diet-induced hyperinsulinemic rats. Male Sprague-Dawley rats were randomly assigned to receive high fructose, high sucrose, or standard rat chow for 13-18wk. Blood pressure was monitored by indirect (tail-cuff) measurements at regular intervals during the diet treatment. Vascular responses to various vasoactive agents were studied both in vivo and in vitro. Blood pressure response, as assessed by direct (intra-arterial) measurement, to graded dose infusions of norepinephrine or angiotensin II or bolus infusion of acetylcholine were determined. In vitro vascular responses of the tail arteries to exogenous norepinephrine were also studied. The fructose- and the sucrose-fed rats had significantly higher blood pressure than controls. Serum insulin levels were also significantly higher in fructose- and sucrose-fed rats than in controls. The blood pressure responses to graded infusions of norepinephrine were significantly less in the fructose-fed rats than in controls. The blood pressure responses to angiotensin II and acetylcholine infusion were not significantly different among the three groups of rats. In vitro studies of vascular reactivity in the tail arteries revealed than the concentration of norepinephrine that produced half-maximal contraction (NE EC₅₀) was significantly higher in the fructose group than control. Thus, impaired vascular responses to exogenous norepinephrine were observed in fructose-fed rats both in vivo and in vitro. This may be due to an adaptation to increased sympathetic nervous activity, or may be a compensatory response to other structural or functional changes that produce hypertension in this model. (Hypertens Res 1997; 20: 17-21)