Effects of doxazosin on atherosclerosis in cholesterol-fed rabbits.
Doxazosin was administered to rabbits fed diets enriched in cholesterol and peanut oil for 7.5 or 12 weeks, in 2 separate experiments. Doxazosin suppressed the accumulation of cholesterol and formation of atherosclerotic plaques in the aortas of treated rabbits and prevented a diet-induced increase in aortic collagen and wall mass. Doxazosin was more effective in the thoracic and abdominal segments of the aorta than in the aortic arch. Pharmacokinetic analysis indicated that treated rabbits were exposed to concentrations of doxazosin, integrated over 24 h, which were consistent with the therapeutic range of doxazosin measured in patients treated for hypertension. Doxazosin did not alter serum levels of cholesterol or triglycerides, nor were there any consistent effects on glucose, free fatty acid or ketone levels. Hypotheses of the mechanism of action of doxazosin are discussed, including the possible involvement of alpha 1-adrenergic receptors in recruitment of smooth muscle cells by subintimal macrophages and nonadrenergic mechanisms of inhibition of lipid infiltration.
Central Research Division, Pfizer Inc, Groton, CT 06340.
A C
AC
Swindell
M N
MN
Krupp
T M
TM
Twomey
J A
JA
Reynolds
C O
CO
Chichester
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003094:Collagen / Q000378:metabolism; D017292:Doxazosin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004549:Elastin / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D011817:Rabbits
D002791:Cholesterol, Dietary; D003094:Collagen; D004549:Elastin; D002784:Cholesterol; D017292:Doxazosin