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 mg/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 (n = 12), simvastatin (n = 12), and fluvastatin (n = 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, 0.32 +/- 0.03) did not reach statistical significance. alpha-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 thymidine analogue, into replicating DNA. Immunofluorescence analysis showed that 5-bromo-2'-deoxyuridine was actively incorporated into intimal myocytes after ++reinsertion of the collar, with a labeling index (percent of labeled myocytes) of 2.15 after 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Soma
M R
MR
Institute of Pharmacological Sciences, University of Milan, Italy.
Donetti
E
E
Parolini
C
C
Mazzini
G
G
Ferrari
C
C
Fumagalli
R
R
Paoletti
R
R
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D002784:Cholesterol / Q000097:blood*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D017035:Pravastatin / Q000494:pharmacology*; D011817:Rabbits; D012016:Reference Values; D019821:Simvastatin
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin