Serum from hypercholesterolemic patients treated with atorvastatin or simvastatin inhibits cultured human smooth muscle cell proliferation.
We evaluated the pharmacological activity of whole-blood serum from atorvastatin- vs. simvastatin- (both 40 mg/day) treated hypercholesterolemic patients (n=10) on cultured smooth muscle cell (SMC) proliferation and cholesterol biosynthesis, as related to lipid-lowering effect. Patients received either single or 2-weeks repeated doses of both simvastatin and atorvastatin, following a randomised, double-blind, cross-over design. Blood samples were collected before drug administration and at the scheduled intervals after administration, and the obtained serum was separated by centrifugation, sterilized and frozen until assayed. Cultured SMC were supplemented with medium plus 15% of separate serum sampled from the patients, and grown for 72 h. Proliferation was assayed by a Coulter Counter, while cholesterol biosynthesis was measured by the incorporation of 14C-acetate into cholesterol, under the same experimental conditions. Atorvastatin was more active vs. simvastatin in reducing total- (-28.3% vs. -20.7%; p=0.045) and LDL-cholesterol (-39.8% vs. -30.1%; p=0.011) after a 2-weeks regimen. Serum from atorvastatin-treated patients inhibited SMC proliferation vs.t=0 after both single (AUC -21.6%) and repeated (AUC -26.9%) doses, while serum from simvastatin-treated patients inhibited SMC proliferation only after repeated doses (AUC -24.5%). Interestingly, in the same experimental conditions, the serum concentrations of both statins (and of their active metabolites) were constantly below the detection limits, as shown from the lack of inhibition of cholesterol biosynthesis. The absence of any significant association between the lipid-lowering effects and the inhibition of SMC proliferation, together with no detectable active statin in the serum, suggests that these effects are elicited through independent mechanisms.
Arnaboldi
Lorenzo
L
Department of Pharmacological Sciences, University of Milan, via Balzaretti, 9, 20133 Milan, Italy. lorenzo.arnaboldi@unimi.it <lorenzo.arnaboldi@unimi.it>
Guzzetta
Massimiliano
M
Pazzucconi
Franco
F
Radaelli
Giovanni
G
Paoletti
Rodolfo
R
Sirtori
Cesare R
CR
Corsini
Alberto
A
D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005263:Femoral Artery / Q000166:cytology; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D011758:Pyrroles / Q000627:therapeutic use*; D044967:Serum; D019821:Simvastatin / Q000627:therapeutic use*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin