atorvastatin Lipitor
HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species.

Wassmann S, Laufs U, Baumer AT, Muller K, Ahlbory K, Linz W, Itter G, Rosen R, Bohm M, Nickenig G.

Medizinische Klinik und Poliklinik, Innere Medizin III, Universitatsklinken des Saarlandes, Hamburg/Saar, Germany.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) significantly reduce cardiovascular mortality associated with hypercholesterolemia. There is evidence that statins exert beneficial effects in part through direct effects on vascular cells independent of lowering plasma cholesterol. We characterized the effect of a 30-day treatment with atorvastatin in normocholesterolemic, spontaneously hypertensive rats (SHR). Systolic blood pressure was significantly decreased in atorvastatin-treated rats (184+/-5 versus 204+/-6 mm Hg for control). Statin therapy improved endothelial dysfunction, as assessed by carbachol-induced vasorelaxation in aortic segments, and profoundly reduced angiotensin II-induced vasoconstriction. Angiotensin type 1 (AT(1)) receptor, endothelial cell NO synthase (ecNOS), and p22phox mRNA expression were determined with quantitative reverse transcription-polymerase chain reaction. Atorvastatin treatment downregulated aortic AT(1) receptor mRNA expression to 44+/-12% of control and reduced mRNA expression of the essential NAD(P)H oxidase subunit p22phox to 63+/-7% of control. Aortic AT(1) receptor protein expression was consistently decreased. Vascular production of reactive oxygen species was reduced to 62+/-12% of control in statin-treated SHR, as measured with lucigenin chemiluminescence assays. Accordingly, treatment of SHR with the AT(1) receptor antagonist fonsartan improved endothelial dysfunction and reduced vascular free-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138+/-7% of control) and an enhanced ecNOS activity in the vessel wall (209+/-46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound improvement of endothelial dysfunction mediated by a reduction of free radical release in the vasculature. The underlying mechanism could in part be based on the statin-induced downregulation of AT(1) receptor expression and decreased expression of the NAD(P)H oxidase subunit p22phox, because AT(1) receptor activation plays a pivotal role for the induction of this redox system in the vessel wall.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11408394&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Prolonged inhibition of cholesterol synthesis by atorvastatin inhibits apo B-100 and triglyceride secretion from HepG2 cells.

Funatsu T, Suzuki K, Goto M, Arai Y, Kakuta H, Tanaka H, Yasuda S, Ida M, Nishijima S, Miyata K.

Pharmacology Laboratory, Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba-shi, Ibaraki 3058585, Japan. funatsu yamanouchi.co.jp

Atorvastatin is a new HMG-CoA reductase inhibitor that strongly lowers plasma cholesterol and triglyceride (TG) levels in humans and animals. Since previous data indicated that atorvastatin has prolonged inhibition of hepatic cholesterol synthesis, we tested whether this longer duration of inhibitory effect on cholesterol synthesis decreased hepatic lipoprotein secretion in vitro. We used the HepG2 hepatoma cell line to: (1) determine the time required until levels of secreted apo B-100 and TG declined significantly, (2) examine the relation to the mass of cellular cholesteryl ester (CE) and (3) test microsomal triglyceride transfer protein (MTP) activity which leads to decreased apo B-100 production. Although atorvastatin significantly inhibited cholesterol synthesis in HepG2 cells regardless of treatment duration (1, 14 or 24 h), it did not inhibit TG synthesis. Apo B-100 and TG secretion were unchanged after 1-h atorvastatin treatment, but declined significantly after 24-h treatment. Atorvastatin treatment also reduced cellular CE mass, exhibiting both time- and dose-dependency. Mevalonolactone, a product of HMG-CoA reductase, attenuated the inhibitory effects of atorvastatin. Atorvastatin strongly reduced mRNA levels of MTP, whereas it did not inhibit MTP activity as measured by TG transfer assay between liposomes. Simvastatin also induced treatment- and time-dependent reductions in apo B-100, whereas the MTP inhibitor BMS-201038 exhibited no time dependency, instead inhibiting this variable even on 1-h treatment. These results indicate that reduced apo B-100 secretion caused by atorvastatin is a secondary result owing to decreased lipid availability, and that atorvastatin's efficacy depends on the duration of cholesterol synthesis inhibition in the liver.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11427209&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Effect of atorvastatin on low-density lipoprotein subtypes in patients with different forms of hyperlipoproteinemia and control subjects.

Geiss HC, Otto C, Schwandt P, Parhofer KG.

Department of Internal Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany.

Atorvastatin is a potent hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor that decreases low-density lipoprotein (LDL) cholesterol and triglyceride concentrations, but little is known about its effects on LDL subtype distribution in different types of hyperlipoproteinemia. Thus, we evaluated the influence of atorvastatin (10 mg/d, 4 weeks) on lipid concentrations and LDL subtype distribution in patients with hypercholesterolemia (n = 9; LDL cholesterol, 227 +/- 30 mg/dL; triglycerides, 137 +/- 56 mg/dL), patients with type 2 diabetes and dyslipoproteinemia (n = 11; LDL cholesterol, 163 +/- 34 mg/dL; triglycerides, 260 +/- 147 mg/dL), and controls (n = 10; LDL cholesterol, 116 +/- 20 mg/dL; triglycerides, 130 +/- 47 mg/dL). Cholesterol concentration was determined in 7 LDL subfractions isolated by density gradient ultracentrifugation before and during atorvastatin treatment. Atorvastatin decreased LDL cholesterol (-36%, -28%, and -41%, all P <.01) and triglyceride (-4%, NS; -2%, NS; -24%, P <.05) concentrations but had little effect on high-density lipoprotein (HDL) cholesterol (-1%, NS; +10%, P <.05; +6%, NS) in hypercholesterolemic, diabetic, and control subjects, respectively. In all 3 groups, a significant reduction in cholesterol in each LDL subfraction was observed. Large-buoyant (LDL-1, LDL-2) and intermediate-dense (LDL-3, LDL-4) LDL were reduced more than small-dense (LDL-5 through LDL-7) LDL in hypercholesterolemic (-45%, -35%, and -32%, P <.05) and control subjects (-48%, -44%, and -25%, P <.05), but in diabetic patients cholesterol reduction was uniform in all LDL subtypes (-32%, -27%, and -29%, P =.45). Thus, atorvastatin decreases cholesterol concentration in all LDL subfractions in hypercholesterolemic, diabetic, and control subjects. However, the relative reduction of individual LDL subtypes differed between these groups. This finding suggests that the effect of atorvastatin on LDL subtype distribution depends on the type of underlying hyperlipoproteinemia. Copyright 2001 by W.B. Saunders Company

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11474489&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Atorvastatin improves endothelial function in renal-transplant recipients.

Asberg A, Hartmann A, Fjeldsa E, Holdaas H.

Laboratory for Renal Physiology, Section of Nephrology, Medical Department, The National Hospital, N-0027 Oslo, Norway.

BACKGROUND: Hyperlipidaemia and endothelial dysfunction are common features in cyclosporin A (CsA)-treated renal transplant recipients. Endothelial dysfunction may contribute to the risk of premature atherosclerosis and cardiovascular death in these patients. A beneficial effect of statin therapy beyond cholesterol lowering may be an improvement of endothelial function. The present study was designed to assess the effect of atorvastatin on serum lipids and endothelial function in CsA treated renal transplant recipients. METHODS: This pilot study was an open trial of 4 weeks atorvastatin (10 mg per day) treatment in renal transplant recipients (n=22). All patients received a CsA- and prednisolone-based immunosuppressive regimen. Endothelial function was assessed in the forearm skin microvasculature by acetylcholine stimulation and laser Doppler flowmetry, before and after atorvastatin treatment. Serum lipids, plasma endothelin-1 (ET-1), nitric oxide (NO), and von Willebrand factor (vWF) were also measured. RESULTS: Both total and LDL cholesterol were significantly reduced by 26.8 +/- 8.4 and 41.5 +/- 11.0% respectively, after 4 weeks of treatment. Endothelial function was significantly improved during atorvastatin treatment, area under the flux versus time curve (AUC)(ACh) was 538 +/- 362 AU x min before and 682 +/- 276 AU x min after treatment (P=0.042). Plasma NO levels also showed a borderline significant increase from 49 +/- 30 to 57 +/- 37 micromol/l during the treatment period (P=0.051), though plasma ET-1 (0.37+/-0.08 vs 0.37+/-0.12 fmol/ml) and vW (196+/-57 vs 197+/-37%) were unchanged. CONCLUSION: Atorvastatin lowered serum cholesterol significantly and improved endothelial function in renal transplant recipients after 4 weeks of treatment. Plasma NO levels were increased during atorvastatin treatment, indicating a possible endothelial protective effect through an "endothelial-NO pathway".

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11522880&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study.

Athyros VG, Elisaf M, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, Milionis HJ, Mikhailidis DP; GREACE Study Collaborative Group.

Atherosclerosis Unit, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece. athyros med.auth.gr

BACKGROUND: Little is known about the effect of dyslipidemia on serum uric acid (SUA) levels, and less is known about the effect of statin treatment on them. The GREek Atorvastatin and Coronary-heart-disease Evaluation study suggested that a mean atorvastatin dose of 24 mg/d achieves the National Cholesterol Educational Program treatment goals and significantly reduces morbidity and mortality in patients with coronary heart disease (CHD) in comparison to the usual care. Here, we report the time course of SUA levels in usual-care patients undertreated for their dyslipidemia (12% were administered statins) in comparison to structured-care patients treated with atorvastatin in the vast majority (98%). METHODS: Mean on-study SUA levels (up to 48 months) were compared with those at baseline by using analyses of variance to assess differences over time within and between treatment groups. Cox multivariate analysis was used to investigate whether changes in SUA levels during the study were clinically relevant. RESULTS: All patients had normal renal function at baseline; serum creatinine (SCr) levels less than 1.3 mg/dL (<115 micromol/L) and moderately elevated SUA levels (mean, 7.1 +/- 0.9 [SD] mg/dL [425 +/- 52 micromol/L]; upper normal limit, 7.0 mg/dL [415 micromol/L]). Usual-care patients (n = 800) showed an increase in SUA levels by 3.3% ( P < 0.0001). Structured-care patients (n = 800) had an 8.2% reduction in SUA levels ( P < 0.0001). In all patients not administered diuretics (n = 1,407), SUA level changes showed a positive correlation with changes in SCr levels ( r = 0.82; P < 0.0001) and an inverse correlation with estimated glomerular filtration rate ( r = -0.77; P < 0.0001). After adjustment for 19 predictors of all CHD-related events, Cox multivariate analysis involving backward stepwise logistic regression showed a hazard ratio (HR) of 0.89 (95% confidence interval [CI], 0.78 to 0.96; P = 0.03) with every 0.5-mg (30-micromol/L) reduction in SUA level, an HR of 0.76 (95% CI, 0.62 to 0.89; P = 0.001) with every 1-mg (60-micromol/L) reduction, an HR of 1.14 (95% CI, 1.03 to 1.27; P = 0.02) with every 0.5-mg increase, and an HR of 1.29 (95% CI, 1.17 to 1.43; P = 0.001) with every 1-mg increase in SUA levels. CONCLUSION: Data suggest that SUA level is an independent predictor of CHD recurrent events. Atorvastatin treatment significantly reduces SUA levels in patients with CHD, thus offsetting an additional factor associated with CHD risk.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15042535&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Simvastatin and atorvastatin enhance hypotensive effect of diltiazem in rats.

Marumo H, Satoh K, Yamamoto A, Kaneta S, Ichihara K.

Department of Pharmacology, Hokkaido College of Pharmacy, 7-1 Katsuraoka, Otaru 047-0264, Japan.

Effects of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin, on diltiazem-induced hypotension were examined in anaesthetized rats and compared to that of pravastatin. Vehicle, 2 mg/kg/day simvastatin, 2 mg/kg/day atorvastatin, or 4 mg/kg/day pravastatin was administered orally for 4 days. Diltiazem at 3 mg/kg was given orally 2 hours after the final administration of the inhibitors. Arterial blood pressure was measured via a cannula introduced into the left carotid artery, and heart rate was counted from the pulse pressure. In all groups, diltiazem significantly decreased the mean arterial blood pressure without any changes in heart rate. Pretreatment with simvastatin and atorvastatin significantly enhanced the hypotensive effect of diltiazem, while that with pravastatin did not. Heart rate was not modified by pretreatment with the inhibitors. The results indicate that concomitant use of diltiazem with simvastatin or atorvastatin enhances diltiazem-induced hypotension, probably by competitive inhibition of diltiazem metabolism with simvastatin and atorvastatin metabolisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11676178&dopt=Abstract atorvastatin Lipitor