Pravastatin attenuates cardiovascular inflammatory and proliferative changes in a rat model of chronic inhibition of nitric oxide synthesis by its cholesterol-lowering independent actions

Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3- methylglutaryl (HMG)-CoA reductase inhibitors such as pravastatin may be th rough their cholesterol-lowering independent effects on the blood vessels. We have recently reported that chronic inhibition of nitric oxide (NO) synt hesis with N-G-nitro-L-arginine methyl ester(L-NAME) increases systolic blo od pressure and induces coronary vascular inflammatory changes in rats. We designed this study to investigate whether treatment with pravastatin atten uates such proarteriosclerotic changes through their cholesterol-lowering i ndependent effects, Several groups of Wistar-Kyoto rats were studied: the c ontrol group, L group received L-NAME in their drinking water (100 mg/kg pe r day) and L + Px group received L-NAME plus pravastatin (50, 100 or 250 mg /kg per day). We observed marked increases in monocyte infiltration into th e coronary arteries, proliferative cell nuclear antigen positive cells, and monocyte chemoattractant protein-1 (MCP-1) expression in the heart on day 3 after L-NAME administration began. Treatment with pravastatin did not aff ect serum cholesterol levels or systolic blood pressure but did reduce the L-NAME induced inflammatory and proliferative changes. Pravastatin also att enuated the MCP-1 gene expression induced by L NAME. In summary, pravastati n inhibited the inflammatory and proliferative changes in the coronary vess els through their cholesterol-independent effects in this model, which may provide an insight into the mechanisms of antiinflammatory or anti-arterios clerotic actions of pravastatin.