The Inhibitory Action of LDL and Oxidized on Relaxations Evoked by Endothelium-Derived Nitric Oxide: The Influence of Antioxidants

Abstract

Hypercholesterolemia and atherosclerosis has been found to impair the vasodilation mediated by the release of endothelium-derived nitric oxide in human and animal arteries. We have previously found that native low-density lipoproteins (LDL) from healthy human donors inhibit acetylcholine (ACh) evoked relaxations in intact rabbit aortic rings precontracted with noradrenaline of serotonin in vitro Cu²⁺-oxidized LDLinhibits relaxations after preincubation for 30 min and the potency and reversibility of the inhibition depends on the donor (Jacobs et aL, 1990; Plane, F., et aL, 1992). Thus, native LDL from donors whose lipoproteins oxidize rapidly (fast oxidizers) inhibit potently and sometimes irreversibly whereas those which oxidize slowly (slow oxidizers) inhibit less potently and reversibly (Plane F., et al., 1992). We now show that antioxidants influence these effects. native LDL (2 mg protein/ml) caused a reduction in sensitively to ACh which was prevented by the addition of 10 uM probucol or 100 uM ascorbic acid, whereas, superoxide dismutase (20 U/ml) had no effect. This indicates that native LDL inhibit via a process involving free radicals but not superoxide. As expected, the antioxidants had no effect in vitro in the inhibition by oxidized LDL. Oxidized LDL prepared from the lipoproteins of selected volunteers (fast oxidizers), exhibited reduced and reversible inhibition of relaxation compared with the potent and irreversible inhibition prior to administration of the drug, resembling that of the slow oxidizers. We include that antioxidants such as probucol attenuate the inhibition of endothelium-dependent relaxation by LDL and may prevent the impairment resulting from hypercholesterolemia and atherosclerosis.