EFFECTS OF DOXAZOSIN ON ATHEROSCLEROSIS IN CHOLESTEROL-FED RABBITS

Doxazosin was administered to rabbits fed diets enriched in cholestero l and peanut oil for 7.5 or 12 weeks, in 2 separate experiments. Doxaz osin suppressed the accumulation of cholesterol and formation of ather osclerotic plaques in the aortas of treated rabbits and prevented a di et-induced increase in aortic collagen and wall mass. Doxazosin was mo re effective in the thoracic and abdominal segments of the aorta than in the aortic arch. Pharmacokinetic analysis indicated that treated ra bbits were exposed to concentrations of doxazosin, integrated over 24 h, which were consistent with the therapeutic range of doxazosin measu red in patients treated for hypertension. Doxazosin did not alter seru m levels of cholesterol or triglycerides, nor were there any consisten t effects on glucose, free fatty acid or ketone levels. Hypotheses of the mechanism of action of doxazosin are discussed, including the poss ible involvement of alpha1-adrenergic receptors in recruitment of smoo th muscle cells by subintimal macrophages and nonadrenergic mechanisms of inhibition of lipid infiltration.