Effects of doxazosin, an alpha 1-adrenergic inhibitor, on plasma lipid and lipoprotein levels, low density lipoprotein metabolism and cholesterol absorption in cynomolgus monkeys.
The mechanism(s) by which doxazosin, an alpha 1 inhibitor, regulates plasma low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) levels were investigated in 'normocholesterolemic' (average total cholesterol (TC) of 218 mg/dl) and 'hypercholesterolemic' (average TC of 350 mg/dl) cynomolgus monkeys. Twelve weeks of doxazosin treatment (1 mg/kg per day) significantly reduced plasma TC and LDL-C levels in both groups while high density lipoprotein cholesterol and apolipoprotein A-I concentrations rose. Despite these changes in plasma lipids, LDL and HDL lipid composition was not affected by doxazosin. The reduction in LDL-C and apo B in the doxazosin-treated 'hypercholesterolemic' group was associated with a significant increase in both receptor-dependent and -independent LDL apo B fractional catabolic rates. Similar associations were noted in the 'normocholesterolemic' group. LDL apo B production or transport rate was not affected by doxazosin. Cholesterol absorption was also significantly reduced by doxazosin which may also contribute to lowering plasma LDL-C levels. These studies suggest that doxazosin treatment can produce beneficial changes in the plasma lipid profile over a wide rage of plasma cholesterol levels by up-regulating LDL fractional clearance.
Stucchi
A F
AF
Department of Clinical Sciences, University of Massachusetts-Lowell 01854.
Vespa
D B
DB
Terpstra
A H
AH
Nicolosi
R J
RJ
D000042:Absorption; D000818:Animals; D016632:Apolipoprotein A-I / Q000032:analysis; D001055:Apolipoproteins B / Q000032:analysis; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D017292:Doxazosin / Q000494:pharmacology*; D006031:Glycosylation; D006937:Hypercholesterolemia / Q000097:blood; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D011973:Receptors, LDL / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D017292:Doxazosin