THE EFFECTS OF PROBUCOL ON THE PROGRESSION OF ATHEROSCLEROSIS IN MATURE WATANABE HERITABLE HYPERLIPEMIC RABBITS

1 Probucol was administered to mature Watanabe heritable hyperlipidaemic (WHHL) rabbits (almost-equal-to 9 months old). Groups of WHHL rabbits were randomly selected and treated as follows: Group 1 killed at 9 months (n = 9); Group II placed on sham-treated diet at 9 months and followed for 6 months (n = 8); Group III placed on probucol at 9 months and followed for 6 months (n = 8). Probucol was administered by mixing 1% wt/wt drug with standard laboratory diet. 2 Plasma concentrations of probucol increased to 93 +/- 11-mu-g ml-1 in Group III during the initial 2 weeks and increased further to 149 +/- 24-mu-g ml-1 at the end of the treatment period. 3 Plasma concentrations of total cholesterol, unesterified cholesterol and phospholipids were significantly reduced overall by probucol, while triglycerides were not affected. 4 No statistically significant differences were observed in the presence of oxidized products in low density lipoproteins (LDL) isolated from plasma of controls compared to probucol-treated rabbits. However, LDL from probucol-treated animals was resistant to oxidation in the presence of Cu2+ (3-mu-M). 5 Group I had aortic atherosclerosis covering 70 +/- 5% of intimal area of thoracic aortae, that increased to 91 +/- 3% in Group II. This was associated with cholesterol contents of aortae increasing from 1.4 +/- 0.2-mu-g mg-1 in Group I to 2.7 +/- 0.3-mu-g mg-1 in Group II. Probucol administration did not produce a statistically significant reduction of atherosclerotic lesion area (78 +/- 7%). However, probucol treatment reduced cholesterol content to 1.9 +/- 0.3-mu-g mg-1 (P < 0.01). Collagen content of aortae was not affected by probucol treatment. 6 Thus, while probucol did not promote regression, the drug did retard the continued deposition of cholesterol esters into atherosclerotic lesions of mature WHHL rabbits.