We have previously demonstrated that long-term metformin treatment prevents the development of hyperinsulinemia and hypertension in fructose-hypertensive (FH) rats; however, the exact nature of its antihypertensive effects remains elusive. Since hyperinsulinemia has been proposed to be a strong stimulus for norepinephrine (NE) release, the present study examined the effects of long-term metformin treatment (500 mg/kg/d for 10 weeks) on the reactivity of superior mesenteric arteries to NE in FH rats. Metformin treatment prevented the development of hyperinsulinemia and hypertension in FH rats. Mesenteric arteries from FH rats exhibited an increased cross-sectional area ([CSA] 0.45 +/- 0.07 mm2 v 0.32 +/- 0.05 in controls, P < .05), which was prevented by long-term metformin treatment (0.34 +/- 0.04 mm2, p > .05 v untreated FH). Interestingly, mesenteric arteries from metformin-treated fructose and control rats exhibited a reduction in maximum responsiveness to NE both with and without the endothelium. These data suggest that metformin directly reduces catecholamine constrictor responses in resistance arteries of rats, which may contribute to its antihypertensive effects in rats.