Lovastatin prevents the impairment of endothelium dependent relaxation and inhibits accumulation of cholesterol in the aorta in experimental atherosclerosis in rabbits

Abstract

The aim was to determine the effect of the HMG CoA reductase inhibitor, lovastatin, on the loss of endothelium dependent relaxation and the accumulation of cholesterol in the aorta produced by feeding a diet enriched with cholesterol. The study was conducted in two stages. In stage 1, New Zealand white rabbits were randomised into four groups. Group 1 (n = 15) was fed standard rabbit diet for 6 weeks. Groups 2 (n = 15), 3 (n = 12), and 4 (n = 12) were fed standard rabbit diet supplemented with 2% cholesterol for 2 weeks followed by standard rabbit diet only for the next 4 weeks. In addition, lovastatin (4 mg.kg-1.d-1) was given for the entire 6 weeks in group 3 and for the first 2 weeks only in group 4. In stage 2 a second group of animals was fed a diet supplemented with 0.5% cholesterol for 2 weeks in order to match the serum cholesterol levels in groups 3 and 4 of stage 1. Aortic tissue was removed for measurement of cholesterol content, endothelium dependent relaxation (to acetylcholine), contractile responses (to noradrenaline), relaxant responses (to sodium nitrite), and sudan staining. Serum was obtained for measurement of cholesterol and triglyceride concentrations. In stage 1, at the end of 2 weeks, the serum cholesterol was significantly lower in groups 3 and 4 than in group 2. At 6 weeks, endothelium dependent relaxation to acetylcholine (-6.0 log mol.litre-1) was impaired in group 2 compared to the other groups: group 1 78.5(SEM 5.0); group 2 43.5(7.8)%; group 3 79.4(4.6)%; group 4 84.7(3.4)%. The relaxant response to sodium nitrite was not impaired in group 2. Further, the aortic tissue cholesterol concentration in group 2 was significantly greater than that in group 1, at 355(65) v 105(10) nmol.mg-1 protein. In groups 3 and 4, the aortic cholesterol concentrations were significantly lower than those in group 2, at 74(4) and 94(17) nmol.mg-1 protein respectively. In stage 2, the serum cholesterol values were matched to those in groups 3 and 4 of stage 1. In these animals, after a further 4 weeks the aortic cholesterol was significantly greater than in group 3. Lovastatin attenuates the accumulation of cholesterol and preserves endothelium dependent relaxation in this model of experimental atherosclerosis. It is likely that the latter is a secondary phenomenon.