Attenuation of atherosclerosis in a modified strain of hypercholesterolemic Watanabe rabbits with use of a probucol analogue (MDL 29,311) that does not lower serum cholesterol.

Abstract

Probucol is a drug that lowers plasma cholesterol in both humans and animals. In low density lipoprotein (LDL) receptor-deficient Watanabe rabbits, probucol reduces the progression of atherosclerosis. This effect may be attributed to the antioxidant and/or the cholesterol-lowering properties of the drug. In the present report we studied the antiatherogenic effect of a probucol analogue (MDL 29,311) that possesses antioxidant activity but that does not lower cholesterol. Modified Watanabe rabbits (11-12 weeks of age) produced by crossing British Brown and Japanese Watanabe rabbits were fed normal chow (n = 8), chow containing 1% probucol (n = 9), or chow containing 0.1% (n = 9), 0.5% (n = 8), or 1% (n = 6) probucol analogue. After 70 days serum cholesterol levels and the percent area of sudanophilic lesions in the thoracic region of aortas were determined. Total serum cholesterol was significantly lowered (p less than 0.05) in the probucol group (560 +/- 54 mg/dl) compared with that of controls receiving no drug (731 +/- 67 mg/dl) but was not lowered in the analogue groups (722-802 mg/dl). The lesioned area (mean% +/- SEM) in the probucol group (16 +/- 3) was significantly lower (p less than 0.01) than in the controls (52 +/- 8). There were 43 +/- 7%, 33 +/- 8%, and 35 +/- 5% of lesions for the 0.1%, 0.5%, and 1% analogue groups, respectively. After combining the data for the 0.5% and 1% analogue groups, the value (34%) was lower than that of the controls and almost reached significance (p = 0.066). The mean serum drug concentration in the 1% probucol group was 58 +/- 4 micrograms/ml compared with 13 +/- 2, 44 +/- 8, and 74 +/- 8 micrograms/ml for the 0.1%, 0.5%, and 1% analogue groups, respectively. Thus, the decreased effectiveness of the probucol analogue in preventing atherosclerosis could not be explained by a lack of bioavailability. LDLs isolated from rabbits treated with the drug were resistant to Cu(2+)-induced lipid peroxidation, as determined by thiobarbituric acid-reactive substances. The resistance within the analogue groups was dependent on the number of antioxidant molecules per LDL particle. However, there was no significant difference in atherosclerotic lesions between these two groups, suggesting, although not definitively, that the maximal antiatherogenic effect had been reached. Our data suggest that the antioxidant activity of this class of compounds may play an important role in reducing atherosclerosis, but not in reducing cholesterol levels, and that hypocholesterolemic and possibly other activities of probucol might further enhance its antiatherogenic activity.