atorvastatin Lipitor
The protective role of atorvastatin on function, structure and ultrastructure in the aorta of dyslipidemic rabbits.

Aragoncillo P, Maeso R, Vazquez-Perez S, Navarro-Cid J, Ruilope LM, Diaz C, Hernandez G, Lahera V, Cachofeiro V.

Pathology Department, Unit II, Hospital Clinico San Carlos, Spain.

Responses to both an endothelium-dependent (acetylcholine 10(-9)-10(-5) mol/l) and an endothelium-independent vasodilator (sodium nitroprusside 10(-10)-10(-6) mol/l) were studied in aortic rings from rabbits fed or not with a diet containing 0.5% cholesterol plus 14% coconut oil for 14 weeks and treated or not with atorvastatin (2.5 mg/kg/day). Morphometric and ultrastructure analyses were also performed. Rabbits fed the dyslipidemic diet presented higher plasma cholesterol and triglyceride concentrations than controls (P < 0.05). This was associated with intima-media thickening and, consequently, aortic stenosis (29 +/- 3%) since vessel cross-sectional area did not change. Endothelial cells presented numerous alterations in dyslipidemic rabbits. Atorvastatin treatment only reduced plasma levels in dyslipidemic rabbits (P < 0.05), which were nevertheless higher than those of controls. In addition, it prevented the reduction in acetylcholine relaxation in hypercholesterolemic animals. Atorvastatin administration also enhanced the response to acetylcholine in rabbits fed a control diet. Likewise, atorvastatin treatment reduced lesion area and consequently increased aortic lumen in dyslipidemic rabbits but did not modify media thickening. It also prevented the majority of the ultrastructural changes observed in endothelial cells. In conclusion, chronic atorvastatin treatment exerts a protective role in vascular function, structure and ultrastructure even in the presence of high cholesterol and triglyceride plasma levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11147177&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Short- and long-term effects of atorvastatin, lovastatin and simvastatin on the cellular metabolism of cholesteryl esters and VLDL secretion in rat hepatocytes.

Isusi E, Aspichueta P, Liza M, Hernandez ML, Diaz C, Hernandez G, Martinez MJ, Ochoa B.

Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain.

The short- and long-term in vitro effects of the hydroxymethylglutaryl-CoA reductase inhibitor atorvastatin, compared with lovastatin and simvastatin on VLDL secretion, and on the formation and the neutral and acid lysosomal hydrolysis of cholesteryl esters was investigated in rat liver hepatocytes maintained in suspension (2 or 4 h) or cultured in monolayers (24 h). All statins time-dependently reduced [14C]oleate incorporation into cholesteryl esters, but when exogenous cholesterol was added only atorvastatin caused an immediate transient decrease in hepatocyte ACAT activity. Activity of the lysosomal, microsomal and cytosolic CEH isoforms was unaffected by the hepatocyte treatments. Statins reduced free and esterified cholesterol mass in hepatocyte microsomes after 2 h, and this was followed by a modest decline in VLDL cholesteryl esters, whilst secretion of VLDL apoB and triglycerides was unaltered. However, after 24 h of treatment, statins caused generalized 20-40% decreases in the secretion of VLDL apoB, cholesterol and triglycerides, with the reduction in apoB48 secretion being significantly superior to that caused in apoB100. The mean diameter of secreted VLDL was not modified by either duration or drug treatment. Additional studies with subcellular fractions demonstrated that statins have a direct selective effect on the enzymes governing the cholesterol-cholesteryl ester cycle, with the exception of the microsomal CEH. Atorvastatin, lovastatin and simvastatin inhibited ACAT activity in microsomes by 50% at doses of 250, 100 and 50 microM, respectively. The cytosolic CEH elicited a biphasic profile of activity with activations up to 100 microM statin and inhibitions above 250 microM, and the lysosomal CEH was only inhibited by atorvastatin at a dose of 100 microM or more. We conclude that a prolonged, but not a short, limited availability of hepatocyte cholesterol derived from the endogenous synthesis reduces VLDL secretion, and that reactivity of statins at the cellular level are more similar than reactivity at the subcellular level as regards the cholesterol-cholesteryl ester cycle.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11164417&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase.

Wassmann S, Laufs U, Baumer AT, Muller K, Konkol C, Sauer H, Bohm M, Nickenig G.

Medizinische Klinik und Poliklinik, Innere Medizin III, Universitatskliniken des Saarlandes, Homburg/Saar, Germany.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert pleiotropic effects on vascular cells independent of lowering plasma cholesterol. To elucidate the molecular mechanisms involved in these effects, we investigated the impact of statins on production of reactive oxygen species (ROS) in rat aortic vascular smooth muscle cells (VSMC). Exposure of VSMC to angiotensin II caused production of ROS via angiotensin AT1 receptor activation. Pretreatment with atorvastatin inhibited angiotensin II-induced ROS production. Atorvastatin decreased AT1 receptor mRNA levels in a time- and concentration-dependent manner and consistently reduced AT1 receptor density. L-Mevalonate but not hydroxy-cholesterol reversed the inhibitory effect of atorvastatin on AT1 receptor transcript levels. Inhibition of geranylgeranyl-transferase but not of farnesyl-transferase mimicked the effect of atorvastatin on AT1 receptor gene expression. Atorvastatin did not decrease AT1 receptor gene transcription but did reduce the half-life of the AT1 receptor mRNA. AT1 receptor activation by angiotensin II increased the expression of the GTPase rac1, enhanced rac1 GTP-binding activity, and increased the geranylgeranyl-dependent translocation of rac1 to the cell membrane. In contrast, statins inhibited rac1 activity and membrane translocation. Consequently, specific inhibition of rac1 with Clostridium sordellii lethal toxin blocked angiotensin II-induced production of free radicals. Finally, treatment of rats with atorvastatin caused down-regulation of aortic AT1 receptor mRNA expression and reduced aortic superoxide production in vivo. Cholesterol-independent down-regulation of AT1 receptor gene expression and inhibition of rac1, leading to decreased ROS production, demonstrates a novel regulatory mechanism of statins that may contribute to the beneficial effects of these drugs beyond lowering of plasma cholesterol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11179461&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
F 12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in New Zealand rabbits fed a casein-enriched diet.

Junquero D, Bruniquel F, N'Guyen X, Autin JM, Patoiseau JF, Degryse AD, Colpaert FC, Delhon A.

Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin-81106 Cedex, Castres, France. didier.junquero pierre-fabre.com

F 12511, a novel ACAT inhibitor, lowers plasma cholesterol levels in New Zealand rabbits fed a cholesterol-free casein-rich diet. In rabbits endogenous hypercholesterolemia pre-established for 8 weeks was used to compare treatments with F 12511 and atorvastatin for a further 8-week period, and to determine whether both agents act synergistically. F 12511 appears to be 3-4-fold more potent than atorvastatin in reducing total plasma cholesterol (active doses ranging from 0.16 to 2.5 and from 1.25 to 10 mg/kg per day, respectively) while the hypocholesterolemic efficacy of both compounds at 2.5 mg/kg per day amounted to 70 and 45%, respectively. A reduction by as much as 75% of esterified cholesterol in liver mediated by F 12511 could account for the decrease of plasma VLDL, LDL and apo B-100, whereas a reduction of the LDL production rate has been described as the main mechanism underlying the atorvastatin effect. F 12511 modified adrenal cholesterol balance only at the largest dose studied. In a further experiment the co-administration of threshold doses of F 12511 and atorvastatin (0.63 and 1.25 mg/kg per day, respectively) lowered plasma total cholesterol and apo B-100 containing lipoproteins to a greater extent and more rapidly than either agent alone. In the liver a decrease by atorvastatin in free cholesterol substrate for ACAT may amplify the effect of F 12511 on cholesteryl ester content leading to a diminution, in at least an additive manner, of the assembly and secretion of atherogenic lipoproteins in New Zealand rabbits which have developed an endogenous hypercholesterolemia. Thus, the combination of the ACAT inhibitor F 12511 with atorvastatin can represent a better approach than either agent alone to regulate lipoprotein metabolism in certain pathophysiological situations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11223434&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model.

Kumagai K, Nakashima H, Saku K.

School of Internal Medicine, Department of Cardiology, Fukuoka University Hospital, 7-45-1, Nanakuma, Jonan, Fukuoka 814-0180, Japan. kxk fukuoka-u.ac.jp

OBJECTIVE: It has been recently reported that AF is associated with tissue inflammation. Statins reduce C-reactive protein (CRP) levels. However, the effect of statin on atrial fibrillation (AF) is unclear. The purpose of the present study was to evaluate the effect of statin on AF in a canine sterile pericarditis model. METHODS: Sterile pericarditis was created in 20 dogs randomly assigned to two groups: a control group (10 dogs) and an atorvastatin treatment group (10 dogs). Atorvastatin was administered orally (2 mg/kg/day) beginning 1 week before the operation until the end of the study. Before and 2 days after the operation, CRP levels, the duration of induced AF, the atrial effective refractory period (AERP), and intra-atrial conduction time were determined. RESULTS: Before the operation, there were no significant differences in any of the parameters between the two groups. On the second postoperative day, the atorvastatin group had a lower CRP level (7.6+/-0.5 versus 11.7+/-1.3 mg/dl, P<0.0001), a shorter AF duration (177+/-57 versus 534+/-189 s, P<0.0001), a longer AERP (138+/-6 versus 130+/-6 ms, P<0.01), and a shorter intra-atrial conduction time (46+/-3 versus 51+/-5 ms, P<0.01) than the control group. CONCLUSIONS: Atorvastatin can prevent maintenance of AF by inhibiting inflammation in the canine sterile pericarditis model. Atorvastatin may thus be a novel therapeutic agent for AF.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15023557&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Effect of atorvastatin on endothelium-dependent constrictor factors in dyslipidemic rabbits.

Maeso R, Aragoncillo P, Navarro-Cid J, Ruilope LM, Diaz C, Hernandez G, Lahera V, Cachofeiro V.

Department of Physiology, School of Medicine, Universidad Complutense, Madrid 28040, Spain.

Relaxations to acetylcholine and contractions to acetylcholine in the presence of the nitric oxide (NO) synthesis inhibitor (L-N(G)-nitroarginine methyl ester, L-NAME) were studied in aortic rings from rabbits fed either a control or a diet containing 0.5% cholesterol+14% coconut oil for 14 weeks and treated or not with atorvastatin (2.5 mg kg(-1) day(-1)). Rings were incubated with the endothelin (ET(A)) receptor antagonist BQ123, and/or the thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist ifetroban. In rabbits, high cholesterol and triglyceride plasma levels were associated with intimal thickening and blunted acetylcholine-relaxation as compared with controls. By contrast, acetylcholine+L-NAME response was higher. Incubation with either ifetroban or BQ123 increased acetylcholine-relaxation in both diet groups and it reduced the constrictor response only in dyslipidemic rabbits. Removal of endothelium reduced acetylcholine+L-NAME contraction in dyslipidemic rabbits, although increased it in control animals. Atorvastatin treatment reduced plasma lipid levels and lesion size in dyslipidemic animals. Likewise, it prevented acetylcholine-relaxation reduction. In addition, atorvastatin reduced constrictor response in dyslipidemic rabbits but only in rings with endothelium. Incubation with either ifetroban or BQ123 did not further modify these responses in atorvastatin-treated animals in any group. These data suggest that ET and TXA(2) availabilities seem to participate in the endothelial dysfunction associated with dyslipidemia. Atorvastatin treatment reduces intimal thickening and improves endothelial dysfunction in rabbits. This effect seems to be a consequence of its ability to act on ET and TXA(2) systems.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11282220&dopt=Abstract atorvastatin Lipitor