ANTIOXIDANT VITAMINS, LIPOPROTEIN OXIDATION & VASOMOTION IN HYPERCHOLESTEROLEMIA

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Animals and humans with hypercholesterolemia have been shown to exhibit impaired endothelium-dependent vasodilation. In vitro studies suggest that oxidatively modified low density lipoprotein (LDL) can impair specific signal transduction pathways that link endothelial cell surface receptor activation to stimulation of nitric oxide production. Recently, antioxidant vitamins have been shown to protect human LDL from oxidative modification. We measured forearm blood flow and oxidative susceptibility of low density lipoproteins in 19 hypercholesterolemic patients and in 14 normal subjects. Vascular responsiveness was determined by infusions of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside. Oxidative susceptibility of LDL isolated from the plasma of study participants was measured by an in vitro assay. Hypercholesterolemic patients then received daily antioxidant vitamin supplementation (beta carotene 30 mg, vitamin C 1000 mg, vitamin E 800 IU) for one month, with repeat measurement of forearm blood flow responsiveness to the same agonists, and repeat measure of LDL oxidative susceptibility. We found that the maximum forearm flow response to acetylcholine was impaired in patients compared with normal subjects, with similar maximum flow responses to sodium nitroprusside. After one month of antioxidant vitamins the time to onset of LDL oxidation was prolonged by 71plus/minus7% and the maximum rate of oxidation decreased by 26plus/minus25% compared to baseline measurements. However, the maximum forearm blood flow response of hypercholesterolemic patients to acetylcholine on vitamins remained unchanged compared to baseline measurements. Thus, hypercholesterolemic patients have impaired forearm endothelium-dependent vasodilator function. Although one month of antioxidant vitamin supplements to hypercholesterolemic patients reduced the susceptibility of their LDL to oxidation, the impairment in endothelial function remained unaltered. The use of non-vitamin antioxidants or concomitant reduction in LDL levels may be required to show a beneficial effect on endothelial vaso-dilator function and hypercholesterolemic patients.