Effect of anti-oxidant treatment and cholesterol lowering on resting arterial tone, metabolic vasodilation and endothelial function in the human forearm: A randomized, placebo-controlled study

1. The aim of the present study was to determine whether anti-oxidant thera py with vitamin E and/or cholesterol-lowering therapy with simvastatin woul d augment resting forearm blood flow (FBF) and metabolic vasodilation in re sponse to exercise and improve endothelial function in young patients with hypercholesterolaemia. 2. Endothelium-dependent and -independent, nitric oxide (NO)-mediated vasod ilation have been shown to be impaired in young, otherwise healthy subjects with hypercholesterolaemia. Recent experimental and clinical studies sugge st that vascular function may be improved with anti-oxidant or cholesterol- lowering therapy, although these treatments may be synergistic. 3. We compared FBF at rest, in response to isotonic exercise, the endotheli um-dependent vasodilator acetylcholine (ACh), the endothelium-independent v asodilator sodium nitroprusside (SNP) and the NO synthase inhibitor N-G-mon omethyl-L-arginine (L-NMMA) in 26 young, otherwise healthy volunteers (mean (+/- SD) age 29 +/-7 years; 14 female, 12 male) with hypercholesterolaemia , before and after 6 months treatment with vitamin E, simvastatin and/or pl acebo. Treatment was randomized, double-blinded in a 2 x 2 factorial design . Forearm blood flow was measured using venous occlusion plethysmography. 4. Vitamin E therapy increased plasma alpha -tocopherol from 39.5 +/-9.6 to 75.7 +/- 33.8 mu mol/L (P < 0.001). Simvastatin reduced total cholesterol from 6.9 +/-1.7 to 4.9 +/-0.8 mmol/L and low- density lipoprotein (LDL) fro m 4.8 +/-1.7 to 3.0 +/-0.7 mmol/L (both P < 0.001), although total and LDL- cholesterol also decreased slightly in the placebo group. Vitamin E increas ed resting FBF from 2.1 +/-0.3 to 2.4 +/-0.3 mL/100 mL per min (P = 0.04) a nd decreased resting forearm vascular resistance from 42.1 +/-4.2 to 36.1 /-3.4 units (P = 0.01), but the reduction in resting FBF with L-NMMA was no t affected. Vasodilation in response to isotonic exercise, ACh and SNP was similar before and after treatment in the placebo, vitamin E, simvastatin a nd in the combined vitamin E-simvastatin groups. N-G-Monomethyl-L-arginine infusion reduced resting FBF and functional hyperaemia in response to exerc ise and these responses were not altered by treatment. 5. These data suggest that while vitamin E therapy augments resting FBF and reduces forearm vascular resistance in young hypercholesterolaemic subject s, these effects may not be via NO-dependent pathways. Metabolic vasodilati on and responses to the NO-mediated vasodilators ACh and SNP were not favou rably affected by anti-oxidant or cholesterol-lowering therapy, either alon e or in combination.