(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Arterial-Occlusive-Diseases

At sites of thrombosis and vascular injury, interactions occur among platelets, leucocytes and endothelial cells. Patients with peripheral arterial occlusive disease (PAOD) have been shown to have raised total serum cholesterol and serum triglycerides and increased sP-selectin levels when compared with controls. A total of 31 patients with PAOD and hypercholesterolaemia took part in this three-staged study. Soluble P-selectin (sP-selectin) levels were significantly lowered after 12 weeks of fluvastatin treatment (157.0 ng/ml versus 113.77 ng/ml, p = 0.01), whereas 12 weeks of placebo treatment had no statistically significant effect on sP-selectin levels (150.0 ng/ml versus 139.4 ng/ml). An unpaired t-test almost reached statistical significance (p = 0.051) when the levels by which sP-selectin fell after 12 weeks of active or placebo treatment were compared. The placebo group was then put onto long-term, active treatment and sP-selectin levels were significantly lowered by fluvastatin when compared to pre-treatment levels (150.0 ng/ml versus 110.0 ng/ml, p = 0.03). By lowering the levels of P-selectin, fluvastatin may not only attenuate atherosclerotic progression but may also decrease the platelet activation associated with PAOD.

Topics: Aged; Anticholesteremic Agents; Arterial Occlusive Diseases; Cholesterol; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hypercholesterolemia; Indoles; Lipoproteins, LDL; Male; Middle Aged; P-Selectin; Time Factors

Elevated blood cholesterol is a major risk factor for atherosclerosis. Recent studies show that lowering cholesterol reduces the risk of vascular disease, but the precise mechanisms for vascular improvement are not fully understood. Furthermore, it is not known whether the beneficial effects of cholesterol lowering extend to the skin microvasculature. In this unrandomized, open design study, we used iontophoresis and laser Doppler flowmetry to examine forearm skin perfusion in hypercholesterolaemic patients with PAOD before and after cholesterol-lowering therapy with fluvastatin. Endothelium-dependent and -independent vasodilatation were measured following skin iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. Before cholesterol-lowering, vascular responses to ACh and SNP were reduced significantly in patients compared with responses in control subjects (p < 0.001 and p < 0.05, ANOVA, respectively). Fluvastatin therapy (40 mg/day) for 24 weeks significantly reduced total cholesterol (7.3+/-0.3 to 6.0+/-0.2 mmol/l, p < 0.001) and LDL cholesterol (5.4+/-0.5 to 4.2+/-0.4 mmol/l, p < 0.01). Vasodilatation to SNP was significantly improved at week 24 (p < 0.05). In patients with hypercholesterolaemia and PAOD, cholesterol-lowering with statin therapy significantly improved endothelium-independent vascular responses to SNP in skin microvessels. The application of the non-invasive techniques of iontophoresis and laser Doppler flowmetry may provide useful markers for the assessment of microvascular function in this group of patients.

Topics: Acetylcholine; Anticholesteremic Agents; Arterial Occlusive Diseases; Cholesterol, LDL; Endothelium, Vascular; Fatty Acids, Monounsaturated; Female; Fluvastatin; Forearm; Humans; Hypercholesterolemia; Indoles; Iontophoresis; Laser-Doppler Flowmetry; Male; Middle Aged; Nitroprusside; Skin; Vasodilation

The present studies were undertaken to investigate the potential effect of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular neointimal formation and to explore the cellular mechanism of cross-talk of the AT1 receptor and statin in vascular smooth muscle cells (VSMCs).. Neointimal formation and the proliferation of VSMCs induced by cuff placement around the femoral artery were significantly inhibited by treatment with an ARB, valsartan, at a dose of 0.1 mg x kg(-1) x d(-1) and with fluvastatin at a dose of 1 mg x kg(-1) x d(-1), which did not influence mean arterial blood pressure or plasma cholesterol level, whereas valsartan or fluvastatin alone at these doses did not affect neointimal formation or the proliferation of VSMCs. Pretreatment with fluvastatin (approximately 5 micromol/L) for 24 hours significantly inhibited Ang II (1 micromol/L)-mediated DNA synthesis and c-fos promoter activity in cultured VSMCs. Moreover, pretreatment of VSMCs with fluvastatin significantly inhibited Ang II-mediated extracellular signal-regulated kinase (ERK) activation and tyrosine- and serine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. AT1 receptor-mediated recruitment of Rac-1 to Janus kinase (Jak) family/STATs was also inhibited by fluvastatin. Consistent with these in vitro results, phosphorylation of ERK, STAT1, and STAT3 was attenuated by the coadministration of valsartan and fluvastatin even at low doses in vivo.. These results suggest that the cholesterol-independent inhibition of AT1 receptor-mediated VSMC proliferation by statins may contribute to the beneficial effects of statins combined with an ARB on vascular diseases.

Topics: Angiotensin Receptor Antagonists; Animals; Arterial Occlusive Diseases; Cell Division; Cells, Cultured; DNA; DNA-Binding Proteins; Drug Synergism; Fatty Acids, Monounsaturated; Fluvastatin; Genes, fos; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Phosphorylation; Receptor, Angiotensin, Type 1; Signal Transduction; Tetrazoles; Valine; Valsartan

Topics: Anticholesteremic Agents; Arterial Occlusive Diseases; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Simvastatin; Thrombosis

Topics: Anticholesteremic Agents; Arterial Occlusive Diseases; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Simvastatin; Thrombosis

Topics: Anticholesteremic Agents; Arterial Occlusive Diseases; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Simvastatin; Thrombosis