Doxazosin treatment and peroxidation of low-density lipoprotein among malehypertensive subjects: In vitro and ex vivo studies

Doxazosin is an antihypertensive drug that gives rise to 6- and 7-hydroxydo xazosin during hepatic metabolism. The structures of the hydroxymetabolites suggest that they may possess antioxidative properties. The aim of the pre sent study was to examine whether doxazosin and 6- and 7-hydroxydoxazosin w ere able to scavenge free radicals and whether these compounds might protec t low-density lipoprotein (LDL) against in vitro and ex vivo oxidation. Bot h 6- and 7-hydroxydoxazosin showed radical scavenging capacity as assessed by measuring scavenging of 1,1-diphenyl-2-picrylhydrazyl radicals. In vitro incubation with 10 mu M 6- and 7-hydroxydoxazosin significantly reduced hu man mononuclear cell-mediated oxidation of LDL, measured as the formation o f lipid peroxides and the relative electrophoretic mobility of LDL (to 10 a nd 6% of thr control, respectively). Furthermore, formation of conjugated d ienes in LDL during Cu2+-induced oxidation was significantly reduced in the presence of 5 mu M 6- and 7-hydroxydoxazosin (to 28% of t(max) [time to ma ximum] of control). However, treatment of hypertensive patients with increa sing doses of doxazosin (from 1 to 8 mg/day) for 8 weeks altered neither Cu 2+-catalyzed, 2,2' azobis-(2-amidinopropane hydrochloride)-initiated, nor c ell-mediated oxidation of patient LDL ex vivo. Furthermore, the total antio xidative capacity of plasma was unaffected by treatment. In conclusion, the present study shows that 6- and 7-hydroxydoxazosin have radical scavenging properties and protect LDL against in vitro oxidation. However, treatment of hypertensive male subjects with increasing doses of doxazosin for 8 week s did not affect ex vivo oxidation of LDL. BIOCHEM PHARMACOL 58;1:183-191, 1999. (C) 1999 Elsevier Science Inc.