Dual effects of the antioxidant agents probucol and carvedilol on proliferative and fatty lesions in hypercholesterolemic rabbits

The in vivo direct antiatherogenic activity of the antioxidant probucol (20 0 mg/kg per day) or the beta-blocker with antioxidant properties carvedilol (10 and 20 mg/kg per day) was tested in the same animal in two different t ypes of atherosclerotic lesion (proliferative and fatty lesions) induced in cholesterol-fed rabbits (1%). Drugs were given daily mixed with standard d iet for 8 weeks; body weight and plasma lipid profile were not different am ong groups throughout the study. Aortic fatty lesions were induced by chole sterol feeding (n = 25 in each group) and their extent expressed as % of ao rta inner surface covered by plaques was significantly reduced by both drug s (28.2 +/- 9.6%, P < 0.05, 19.9 +/- 6.2%, P < 0.01 for low- and high-dose carvedilol, respectively; 22.3 +/- 7.6%, P < 0.01 for probucol, versus 41.6 +/- 10.7% in control rabbits). Proliferative lesions were obtained by posi tioning a hollow silastic collar around one carotid artery 6 weeks after di etary and drug treatments started (n = 5 in each group). The neointimal for mation, mostly composed by myocytes, was determined by measuring cross-sect ional thickness ratio of intimal (I) and medial (M) tissue of fixed arterie s. In untreated animals, collared arteries resulted in a significant neoint imal cell accumulation compared to the sham (1.10 +/- 0.14 versus 0.02 +/- 0.01) without change in medial thickness. I/M ratio was reduced by about 50 % in animals treated with probucol (0.51 +/- 0.1) and carvedilol (0.66 +/- 0.21 and 0.52 +/- 0.1 in the low- and high-dose group, respectively). Total plasma TEARS were more than 50% lower in both probucol- and high-dose carv edilol-treated rabbits. Results show that pharmacological pretreatment with antioxidants directly inhibits early atherogenic processes, representing a potentially useful approach in the prevention of atherosclerosis. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.