High doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase.

Wong PT.

Department of Pharmacology, Faculty of Medicine, National University of Singapore, MD2, 18 Medical Drive, Singapore 117597, Singapore.

This study aims to investigate whether or not long-term statin treatment causes upregulation of D1 and D2 receptor gene expression with concomitant increase in endothelial nitric oxide synthase (eNOS) expression in Sprague-Dawley rats. Serum triglyceride levels were dose dependently reduced in the simvastatin-treated rats reaching statistical significance at the highest dose (49% reduction), while pravastatin caused similar effects (52%) at the same dose. Cholesterol levels remained unchanged in both groups at all doses. Simvastatin, 10 or 30 mg kg(-1) day(-1), increased D1 and D2 receptor expressions in the prefrontal cortex. Similar upregulation was observed neither with simvastatin in the striatum nor with pravastatin in both brain regions. Simvastatin (10 mg kg(-1) day(-1)) also increased eNOS expression in the prefrontal cortex but not neuronal NOS or inducible NOS. D1 receptor activation by chloro-APB (5 microM) increased cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats by 88 and 285%, respectively. This effect was markedly attenuated by the selective D1 antagonist SCH-23390 (25 microM). D2 receptor activation by quinpirole (5 microM) had no effect on the basal cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin-treated rats, while the same concentration of quinpirole completely abolished the D1 receptor-mediated increase. These results suggest that lipophilic statins can alter dopaminergic functions in the prefrontal cortex possibly via a central mechanism. The possibility of a nitric oxide mechanism involving eNOS requires further investigation.

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The changes in the endothelial expression of cell adhesion molecules and iNOS in the vessel wall after the short-term administration of simvastatin in rabbit model of atherosclerosis.

Semecky V.

Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University Hradec Kralove, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic. nachti faf.cuni.cz

Cell adhesion molecules P-selectin, VCAM-1 and ICAM-1 play an important role in the pathogenesis of atherosclerosis. High levels of nitric oxide (NO) produced by inducible NO synthase (iNOS) have been associated with atherosclerotic processes. Simvastatin is an HMG-CoA reductase inhibitor responsible for many clinical benefits. The aim of this study was to detect and quantify changes in endothelial expression of P-selectin, VCAM-1, ICAM-1 and iNOS in the vessel wall after the shortterm administration of simvastatin in a rabbit model of atherosclerosis. Eighteen New Zealand White rabbits were randomly divided into three groups (n=6). In the cholesterol group, rabbits consumed an atherogenic diet (0.4% cholesterol) for eight weeks. In the simvastatin group, rabbits consumed an atherogenic diet for six weeks and then consumed an atherogenic diet supplemented with simvastatin (10 mg kg(-1)) for two weeks. Biochemical analysis showed that administration of simvastatin led to an almost two-fold lowering of the total serum cholesterol, VLDL, LDL and HDL, but not triglycerides, compared with the cholesterol-fed rabbits only. Stereological analysis of the immunohistochemical staining revealed that administration of simvastatin (10 mg kg(-1) daily) in an atherogenic diet decreased the endothelial expression of P-selectin, ICAM-1 and iNOS in both aortic arch and carotid artery compared with the cholesterol fed-rabbits only. We conclude that simvastatin has beneficial effects on endothelial function by decreasing expression of P-selectin, ICAM-1 and iNOS in endothelial cells in the very early stages of atherogenesis.

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Prognostic significance of simvastatin therapy in patients with ischemic heart failure who underwent percutaneous coronary intervention for acute myocardial infarction.

Kang JC.

The Heart Center of Chonnam National University Hospital, Chonnam National University Research Institute of Medical Science, Gwangju, Korea.

We prospectively followed 202 patients with ischemic heart failure who underwent percutaneous coronary intervention (PCI) for acute myocardial infarction (left ventricular [LV] ejection fraction <40%). Patients were divided into 2 groups: groups I (simvastatin group, n = 106, aged 60.8 +/- 10.3 years, men 71.7%) and II (non-simvastatin group, n = 96, aged 60.9 +/- 10.4 years, men 78.1%). During 1-year clinical follow-up, simvastatin therapy was associated with a significant reduction in mortality (1.9% vs 7.5%, p = 0.048), restenosis rate (25.7% vs 43.1%, p = 0.033), and repeat PCI rate (25.7% vs 43.1%, p = 0.033), and with significant improvement in LV ejection fraction (31% to 42% vs 32% to 39%, p = 0.042). The event-free survival rate was higher in group I than in group II (79.8% vs 57.0%, p = 0.001). In conclusion, simvastatin therapy improves LV systolic function and decreases mortality, restenosis, and repeat PCI rate in patients with ischemic heart failure who underwent PCI for acute myocardial infarction.

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Simvastatin inhibits MMP-9 secretion from human saphenous vein smooth muscle cells by inhibiting the RhoA/ROCK pathway and reducing MMP-9 mRNA levels.

Porter KE.

Institute for Cardiovascular Research, University of Leeds, Leeds, UK.

Increased matrix metalloproteinase-9 (MMP-9) expression is associated with intimal hyperplasia in saphenous vein (SV) bypass grafts. Recent evidence suggests that HMG-CoA reductase inhibitors (statins) can prevent the progression of vein graft failure. Here we investigated whether statins inhibited MMP-9 secretion from cultured human SV smooth muscle cells (SMC) and examined the underlying mechanisms. SV-SMC from different patients were exposed to phorbol ester (TPA) or PDGF-BB plus interleukin-1alpha (IL-1). MMP-9 secretion and mRNA expression were analyzed using gelatin zymography and RT-PCR, respectively. Specific signal transduction pathways were investigated by immunoblotting and pharmacological inhibition. Simvastatin reduced TPA- and PDGF/IL-1-induced MMP-9 secretion and mRNA levels, effects reversed by geranylgeranyl pyrophosphate and mimicked by inhibiting Rho geranylgeranylation or Rho-kinase (ROCK). MMP-9 secretion induced by PDGF/IL-1 was mediated via the ERK, p38 MAPK, and NFkappaB pathways, whereas that induced by TPA was mediated specifically via the ERK pathway. Simvastatin failed to inhibit activation of these signaling pathways. Moreover, simvastatin did not affect MMP-9 mRNA stability. Together these data suggest that simvastatin reduces MMP-9 secretion from human SV-SMC by inhibiting the RhoA/ROCK pathway and decreasing MMP-9 mRNA levels independently of effects on signaling pathways required for MMP-9 gene expression.

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Effect of simvastatin given alone and in combination with valsartan or enalapril on blood pressure and the structure of mesenteric resistance arteries and the basilar artery in the genetically hypertensive rat model.

Laverty R.

Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand. janet.ledingham stonebow.otago.ac.nz

1. The aims of the present study were to investigate, in the New Zealand genetically hypertensive (GH) rat model, the effects of treatment with simvastatin, alone or in combination with valsartan or enalapril, on blood pressure (BP) and structural remodelling of mesenteric resistance arteries (MRA) and of the basilar artery, an artery that plays a major role in the regulation of cerebral resistance. 2. Genetically hypertensive rats were treated with simvastatin at two dose levels (5 and 10 mg/kg per day) and simvastatin in combination with valsartan or enalapril (also 5 and 10 mg/kg per day) from the age of 7 to 12 weeks. Systolic BP and bodyweight were measured weekly. 3. At the end of the experiment, following fixation by perfusion, MRA and the basilar artery were excised and embedded in Technovit (a glycol methacrylate medium; Heraeus Kulzer, Werheim, Germany). Serial sections were cut and stereological techniques used to determine tunica media width and cross-sectional area (CSA), lumen diameter and the ratio of media width/lumen diameter. 4. Simvastatin monotherapy did not lower BP at either dose. In the high- and low-dose groups, the combination of simvastatin + enalapril lowered BP more than with enalapril alone; this was also true for the simvastatin + valsartan combination in the lower-dose group. 5. The MRA were hypotrophically remodelled by the 10 mg/kg per day dose of simvastatin; the 5 mg/kg per day dose caused hypotrophic remodelling with decreased media/lumen ratio. Valsartan and enalapril caused hypotrophic remodelling together with outward remodelling of the lumen in the 10 mg/kg per day valsartan group and, in all groups, a reduction in the media/lumen ratio, with the greatest effect observed in the high-dose groups. 6. The combination treatments of simvastatin + valsartan and simvastatin + enalapril did not have any consistent extra effect on MRA remodelling. 7. In the basilar artery, high-dose simvastatin had a hypotrophic effect on the media and both doses reduced the media/lumen ratio independently of any change in BP. 8. Simvastatin given in combination with valsartan produced a slight further reduction in medial CSA, media width and ratio. In combination with enalapril, there was little consistent additional effect. 9. Simvastatin monotherapy hypotrophically remodelled the media of the basilar artery in the GH rat model, even in the absence of changes in BP. A similar structural effect may explain, in part, the reduction in stroke seen in patients treated with statins.

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Effects of simvastatin on bone mineral density and remodeling parameters in postmenopausal osteopenic subjects: 1-year follow-up study.

Tuzun C.

Department of Physical Medicine and Rehabilitation, Faculty of Medicine, University of Celal Bayar, Manisa, Turkey.

Observational studies suggest that statin use may be associated with lower incidence of fracture. However, there are conflicting data for their effects on bone remodeling parameters and bone mineral density (BMD). In the present study, we aimed to investigate the effects of simvastatin on bone metabolism and BMD in subjects with hypercholesterolemia (>240 mg/dl). For this purpose, 32 postmenopausal osteopenic subjects who were given simvastatin treatment (20 mg/day) and not on osteoporosis treatment were included in the study. During the 1-year follow-up period, the total cholesterol level decreased from 262.1+/-30.9 to 202.2+/-30.1 mg/dl (p<0.0001). At a period as early as the 3rd month, levels of the anabolic markers, e.g., bone-specific alkaline phosphatase (BSAP) and osteocalcin (OCL), were found to be significantly increased (from 120.8+/-56.6 to 149.5+/-57.6 IU/l, p=0.008, and from 20.8+/-12.6 to 34.7+/-18.4 mug/l, p=0.015, respectively) while no significant change was observed in the resorptive marker of serum N-telopeptide of type I collagen (CTX). At the 6th and 12th month, BSAP and OCL were both found to be decreased below the pretreatment values. While a significant reduction was found in BSAP levels (from 120.8+/-56.6 to 55.9+/-18.8 IU/l, p<0.001), no significant change was observed in CTX levels after the 6-month treatment period. Parathyroid hormone showed a gradual profound increase during the follow-up period (from 62.7+/-41.5 to 108.4+/-51.7 pg/ml, p<0.001). No significant change was found in BMD levels at the spine, femoral neck, Ward's triangle, and trochanter at the end of the 1-year follow-up period. In conclusion, simvastatin treatment showed a short-lasting anabolic effect on bone metabolism. However, this effect was lost by prolongation of therapy. The decrease in both anabolic and resorptive markers at the 6th and 12th month suggests that simvastatin affects bone metabolism mostly in favor of inhibition of the bone turnover in a long-term observation period although this inhibitory effect was not reflected in BMD.

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