Probucol and other antioxidants prevent the inhibition of endothelium-dependent relaxation by low density lipoproteins.
Hypercholesterolaemia and atherosclerosis impair responses to endothelium-derived nitric oxide (EDRF) in human and animal coronary arteries, a dysfunction that correlates with elevated low density lipoproteins (LDL). Previous studies show that native LDL immediately and reversibly inhibit acetylcholine-evoked EDRF responses in rabbit aortic ring precontracted with noradrenaline or serotonin whereas Cu(2+)-oxidised LDL (oxLDL) inhibit relaxations after 30 min with a potency that varies with the donor. We now show that antioxidants, probucol (10 microM) and ascorbic acid (100 microM) in vitro, prevent the inhibition by native LDL, indicating that this effect involves free radicals. As expected, the antioxidants had no influence on the inhibition by oxLDL. Superoxide dismutase appeared to have no effect on the inhibition by native or oxLDL. The oral administration of probucol to selected volunteers also prevented the inhibition of relaxation by their native LDL. These preparations showed a diminished susceptibility to oxidation and their oxLDL caused a markedly reduced and always reversible inhibition of relaxation compared to the potent and sometimes irreversible inhibition prior to administration of the drug. We conclude that antioxidants such as probucol reduce the formation of free radicals and the oxidative modification of LDL that lead to the impairment of EDRF responses and may prevent this same dysfunction in hypercholesterolaemia and atherosclerosis.
Plane
F
F
Department of Pharmacology, Royal Free Hospital School of Medicine, London, UK.
Jacobs
M
M
McManus
D
D
Bruckdorfer
K R
KR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants; D001011:Aorta; D001205:Ascorbic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005609:Free Radicals; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011341:Probucol / Q000494:pharmacology*; D011817:Rabbits; D013482:Superoxide Dismutase / Q000494:pharmacology
D000975:Antioxidants; D005609:Free Radicals; D008077:Lipoproteins, LDL; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D000109:Acetylcholine; D011341:Probucol; D001205:Ascorbic Acid