Doxazosin treatment and peroxidation of low-density lipoprotein among male hypertensive subjects: in vitro and ex vivo studies.
Doxazosin is an antihypertensive drug that gives rise to 6- and 7-hydroxydoxazosin during hepatic metabolism. The structures of the hydroxymetabolites suggest that they may possess antioxidative properties. The aim of the present study was to examine whether doxazosin and 6- and 7-hydroxydoxazosin were able to scavenge free radicals and whether these compounds might protect low-density lipoprotein (LDL) against in vitro and ex vivo oxidation. Both 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 microM 6- and 7-hydroxydoxazosin significantly reduced human mononuclear cell-mediated oxidation of LDL, measured as the formation of lipid peroxides and the relative electrophoretic mobility of LDL (to 10 and 6% of the control, respectively). Furthermore, formation of conjugated dienes in LDL during Cu2+-induced oxidation was significantly reduced in the presence of 5 microM 6- and 7-hydroxydoxazosin (to 28% of tmax [time to maximum] of control). However, treatment of hypertensive patients with increasing doses of doxazosin (from 1 to 8 mg/day) for 8 weeks altered neither Cu2+-catalyzed, 2,2'azobis-(2-amidinopropane hydrochloride)-initiated, nor cell-mediated oxidation of patient LDL ex vivo. Furthermore, the total antioxidative 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 weeks did not affect ex vivo oxidation of LDL.
Brude
I R
IR
Institute for Nutrition Research, University of Oslo, Norway.
Drevon
C A
CA
Viken
K
K
Arnstad
J E
JE
Valnes
K N
KN
Nenseter
M S
MS
D000328:Adult; D000368:Aged; D000578:Amidines / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000378:metabolism / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology; D015764:Bepridil / Q000031:analogs & derivatives; D001713:Biphenyl Compounds; D003300:Copper / Q000378:metabolism; D017292:Doxazosin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016877:Oxidants / Q000494:pharmacology; D010851:Picrates
D000578:Amidines; D000959:Antihypertensive Agents; D000975:Antioxidants; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D008077:Lipoproteins, LDL; D016877:Oxidants; D010851:Picrates; C087263:6-hydroxydoxazosin; C087264:7-hydroxydoxazosin; C046728:2,2'-azobis(2-amidinopropane); D015764:Bepridil; D003300:Copper; C004931:1,1-diphenyl-2-picrylhydrazyl; D017292:Doxazosin