Rapid reversal of endothelial dysfunction in hypercholesterolaemic rabbits treated with simvastatin and pravastatin.

Abstract

1. The main objective of the present study was to verify the speed with which two 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, simvastatin and pravastatin, could revert endothelial cell dysfunction in hypercholesterolaemic rabbits. An attempt was also made to correlate the plasma cholesterol level and the tissue cholesterol and malondialdehyde (MDA) contents of the aortae with the endothelium-dependent relaxation on the assumption that any endothelial dysfunction could be rapidly and partially reversed, even in the presence of relatively high serum cholesterol levels. 2. Ninety-one male New Zealand white rabbits were randomly assigned to hypercholesterolaemic (control), simvastatin or pravastatin groups. All rabbits were fed a diet supplemented with cholesterol (0.5%) and coconut oil (2%) for 8 weeks. Simvastatin (10 and 20 mg/day) and pravastatin (15 and 30 mg/day) were administered 6, 4 and 2 days before the end of the experiment. At the end of the 8th week, animals were killed and the aortae were removed for histological examination as well as for the measurement of cholesterol and MDA contents and for endothelium-dependent relaxation studies. 3. The results showed that significant improvement in endothelium-dependent relaxation was obtained only with pravastatin and only with 4 or 6 days of administration. In these cases, the cholesterol and MDA contents of the vessel wall were reduced, although no significant changes were observed in plasma total cholesterol. Higher doses of the drugs did not alter these results. 4. We conclude that pravastatin enhances endothelium-dependent relaxation when administered to cholesterol-fed rabbits, probably via an anti-oxidant action. This effect, which was observed to start on the 4th day of drug administration, may represent a new therapeutic approach for the treatment of acute coronary syndromes in hypercholesterolaemic patients.