RAPID REVERSAL OF ENDOTHELIAL DYSFUNCTION IN HYPERCHOLESTEROLEMIC RABBITS TREATED WITH SIMVASTATIN AND PRAVASTATIN

1. The main objective of the present study was to verify the speed wit h which two 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors , simvastatin and pravastatin, could revert endothelial cell dysfuncti on in hypercholesterolaemic rabbits. An attempt was also made to corre late the plasma cholesterol level and the tissue cholesterol and malon dialdehyde (MDA) contents of the aortae with the endothelium-dependent relaxation on the assumption that any endothelial dysfunction could b e rapidly and partially reversed, even in the presence of relatively h igh serum cholesterol levels. 2. Ninety-one male New Zealand white rab bits were randomly assigned to hypercholesterolaemic (control), simvas tatin 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 administere d 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 histolo gical examination as well as for the measurement of cholesterol and MD A contents and for endothelium-dependent relaxation studies. 3. The re sults showed that significant improvement in endothelium-dependent rel axation was obtained only with pravastatin and only with 4 or 6 days o f administration. In these cases, the cholesterol and MDA contents of the vessel wall were reduced, although no significant changes were obs erved in plasma total cholesterol. Higher doses of the drugs did not a lter these results. 4. We conclude that pravastatin enhances endotheli um-dependent relaxation when administered to cholesterol-fed rabbits, probably via an anti-oxidant action. This effect, which was observed t o start on the 4th day of drug administration, may represent a new the rapeutic approach for the treatment of acute coronary syndromes in hyp ercholesterolaemic patients.