The effects of probucol on the progression of atherosclerosis in mature Watanabe heritable hyperlipidaemic rabbits

Probucol was administered to mature Watanabe heritable hyperlipidaemic (WHHL) rabbits (≅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. Plasma concentrations of probucol increased to 93 ± 11 μg ml⁻¹ in Group III during the initial 2 weeks and increased further to 149 ± 24 μg ml⁻¹ at the end of the treatment period. Plasma concentrations of total cholesterol, unesterified cholesterol and phospholipids were significantly reduced overall by probucol, while triglycerides were not affected. 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 μm). 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 μg mg⁻¹ in Group I to 2.7 ± 0.3 μg 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 μg mg⁻¹ (P < 0.01). Collagen content of aortae was not affected by probucol treatment. Thus, while probucol did not promote regression, the drug did retard the continued deposition of cholesterol esters into atherosclerotic lesions of mature WHHL rabbits. 1991 British Pharmacological Society