Inhibition of low density lipoprotein oxidation in vitro by the 6- and 7-hydroxy-metabolites of doxazosin, an alpha 1-adrenergic antihypertensive agent.
Antioxidants may be of use in the prevention of coronary artery disease by inhibiting low density lipoprotein (LDL) oxidation, a process that is believed to play an important role in atherogenesis. Because the structures of the 6- and 7-hydroxy-metabolites of doxazosin, an alpha 1-adrenergic-blocking antihypertensive agent, suggest that they might have antioxidant properties, studies were performed to determine whether these metabolites inhibit LDL oxidation. Micromolar concentrations of 6- and 7-hydroxydoxazosin, but not doxazosin itself, inhibited Cu(2+)-mediated oxidative modification of LDL in a dose-dependent fashion, similar to that observed with the lipophilic antioxidant, probucol. LDL modified in the presence of these metabolites was not taken up and degraded by macrophages to the same extent as LDL oxidized in their absence. In contrast to probucol, the antioxidant effect was lost after reisolation of LDL incubated with the metabolites. Whereas probucol, like vitamin E, sequesters with LDL, 3H-labeled 6- and 7-hydroxydoxazosin did not comigrate with lipoproteins on FPLC, but were associated with albumin and occurred free in solution. Thus, these metabolites of doxazosin may exert their antioxidant effect in the aqueous milieu of the lipoprotein, similar to vitamin C, and may be useful for the prevention of atherosclerosis in hypertensive individuals.
Chait
A
A
Department of Medicine, University of Washington, Seattle 98195.
Gilmore
M
M
Kawamura
M
M
D058668:Adrenergic alpha-1 Receptor Antagonists; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002853:Chromatography, Liquid; D017292:Doxazosin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008315:Malondialdehyde / Q000097:blood; D009000:Monocytes / Q000378:metabolism; D010084:Oxidation-Reduction; D011341:Probucol / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances; D014461:Ultracentrifugation
D058668:Adrenergic alpha-1 Receptor Antagonists; D000959:Antihypertensive Agents; D000975:Antioxidants; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D017392:Thiobarbituric Acid Reactive Substances; C087263:6-hydroxydoxazosin; C087264:7-hydroxydoxazosin; D008315:Malondialdehyde; D017292:Doxazosin; D011341:Probucol