HMG CoA Reductase Inhibitors In Vivo Effects on Carotid Intimal Thickening in Normocholesterolemic Rabbits

The in vivo activity of different 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (vastatins) on neointimal formation induced by insertion of a flexible collar around one carotid artery of normocholesterolemic rabbits was investigated. The contralateral carotid artery served as a sham control. Pravastatin, lovastatin, simvastatin, and fluvastatin were given mixed with food at daily doses of 20 ing/kg body wt for 2 weeks starting on the day of collar placement. The treatment with vastatins did not modify rabbit plasma cholesterol concentrations. The neointimal formation was assessed by measuring the cross-sectional thickness of intimal and medial tissues of fixed arteries with light microscopy. Fourteen days after collar placement, intimal hyperplasia (mostly cellular) was pronounced in treated carotid arteries. The intimal/medial (I/M) tissue ratio was 12-fold higher in treated arteries than in arteries without the collar (0.36±0.04 versus 0.03±0.02). Animals treated with lovastatin (R=12), simvastatin (n=12), and fluvastatin (R=12) showed significantly less neointimal formation; I/M tissue ratios were 0.24±0.03, 0.20±0.03, and 0.17±0.03, respectively. The inhibition elicited by pravastatin (n=12, 032 ±0.03) did not reach statistical significance. or-Actin antibody immunofluorescence analysis of serial sections revealed that cells present in the hyperplastic intima were mostly myocytes. Rates of intimal myocyte proliferation were also measured by incorporation of 5-bromo-2'-deoxyuridine, a thymidin