This study was designed to test the hypothesis that fluvastatin preserves endothelium-dependent and nitric oxide (NO)-independent relaxations in arterial preparations from rabbits fed a high-cholesterol diet in the absence of any cholesterol-lowering action. Rabbits were fed a 0.5% high-cholesterol diet for 12 weeks and then fed the high-cholesterol diet with/without fluvastatin 2 mg/kg/d for an additional 8 weeks. Plasma total and LDL-cholesterol concentrations were not affected by fluvastatin treatment. Endothelium-dependent and NO-mediated relaxation elicited by acetylcholine and A23187 in both the thoracic aorta and femoral artery was impaired in the high-cholesterol group but not in the fluvastatin-treated group. Endothelium-independent relaxation elicited by sodium nitroprusside was similar among the 3 groups. Preincubation of thoracic aortas from each of the 3 groups with Nomega-nitro-L-arginine methyl ester (L-NAME) and indomethacin completely abolished the relaxant response to acetylcholine. In contrast, the maximal response to acetylcholine (1 microM) in femoral artery was only partially reversed in the presence of L-NAME and indomethacin. Fluvastatin treatment preserved the acetylcholine-induced L-NAME and indomethacin-resistant relaxation impaired in the femoral artery from the high-cholesterol diet group. These results suggest that fluvastatin treatment preserves endothelium-dependent, NO-independent function as well as NO-dependent function in absence of its lipid lowering-action.