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.