F. Plane et al., PROBUCOL AND OTHER ANTIOXIDANTS PREVENT THE INHIBITION OF ENDOTHELIUM-DEPENDENT RELAXATION BY LOW-DENSITY LIPOPROTEINS, Atherosclerosis, 103(1), 1993, pp. 73-79
Hypercholesterolaemia and atherosclerosis impair responses to endothel
ium-derived nitric oxide (EDRF) in human and animal coronary arteries,
a dysfunction that correlates with elevated low denisty lipoproteins
(LDL). Previous studies show that native LDL immediately and reversibl
y inhibit acetylcholine-evoked EDRF responses in rabbit aortic ring pr
econtracted with noradrenaline or serotonin whereas Cu2+-oxidised LDL
(oxLDL) inhibit relaxations after 30 min with a potency that varies wi
th the donor. We now show that antioxidants, probucol (10 muM) and asc
orbic acid (100 muM) in vitro, prevent the inhibition by native LDL, i
ndicating that this effect involves free radicals. As expected, the an
tioxidants had no influence on the inhibition by oxLDL. Superoxide dis
mutase appeared to have no effect on the inhibition by native or oxLDL
. The oral administration of probucol to selected volunteers also prev
ented the inhibition of relaxation by their native LDL. These preparat
ions showed a diminished susceptibility to oxidation and their oxLDL c
aused a markedly reduced and always reversible inhibition of relaxatio
n compared to the potent and sometimes irreversible inhibition prior t
o administration of the drug. We conclude that antioxidants such as pr
obucol reduce the formation of free radicals and the oxidative modific
ation of LDL that lead to the impairment of EDRF responses and may pre
vent this same dysfunction in hypercholesterolaemia and atherosclerosi
s.