Fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, scavenges free radicals and inhibits lipid peroxidation in rat liver microsomes

Yamamoto, Akira; Hoshi, Katsuji; Ichihara, Kazuo

doi:10.1016/s0014-2999(98)00692-x

Cited by 83 publications

(52 citation statements)

References 33 publications

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“…Firstly, in a cell-free system with hypoxanthine-xanthine oxidase generated superoxide measured by lucigenin-derived chemiluminescence, the clinically relevant concentration of pravastatin had no scavenging effect (data not shown). This result is consistent with a previous study 43 demonstrating superoxide-scavenging by fluvastatin but not pravastatin at low concentrations, but contrasts with another study in which pravastatin exhibited a superoxide-scavenging effect at very high concentrations. 44 Our second approach involved combining PEG-SOD (at maximal superoxide scavenging concentrations) with the clinically relevant concentration of pravastatin in the small arteries.…”

Section: Mechanism Of Pravastatin's Effects On Responses In Small Vessupporting

confidence: 90%

Acute Modulation of Vasoconstrictor Responses by Pravastatin in Small Vessels

Ghaffari

Ball

Kennedy

et al. 2011

Circ J

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Background:Statins have been shown to inhibit conduit vessel constrictor responses via the endothelial nitric oxide (NO) pathway. Clinical studies have implicated an effect in microvascular resistance vessels; however, direct effects of therapeutically relevant statin concentrations have not been examined. We examined the effect of acute pravastatin pretreatment on vasoconstrictor responsiveness of isolated rat mesenteric small vessels. Methods and Results:Pravastatin (112 nmol/L) pretreatment for 60 min reduced both the potency and maximal constrictor responses to phenylephrine, thromboxane (U46619) and serotonin in small vessels. This effect was abolished by endothelial denudation, NO synthase (NOS) inhibition with N-ω-nitro-L-arginine methyl ester (L-NAME 300 μmol/L) and Akt inhibition (Akt1/2 kinase inhibitor 500 nmol/L), confirming an endothelium-dependent mechanism and implicating a NO-mediated effect via the Akt pathway. Maximal superoxide scavenging with polyethylene glycolsuperoxide dismutase (PEG-SOD), 150 U/ml did not influence phenylephrine constrictor responses but potentiated pravastatin's effect, suggesting that the statin did not increase NO bioavailability merely via an antioxidant mechanism. In contrast, pravastatin did not affect endothelin-1 (ET-1) constrictor responses. However, after pre-incubation with a selective endothelin-B (ETB) receptor antagonist (BQ788 3 μmol/L) pravastatin inhibited ET-1 constriction, suggesting that its effect is via the same mechanistic pathway as the ETB receptor. Conclusions:In small vessels, pravastatin inhibits constrictor responses by increasing endothelial NO bioavailability via the Akt pathway. Furthermore, ETB receptor blockade unmasks this effect in ET-1 constrictor responses. (Circ J 2011; 75: 1506 - 1514

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Section: Mechanism Of Pravastatin's Effects On Responses In Small Vessupporting

confidence: 90%

Acute Modulation of Vasoconstrictor Responses by Pravastatin in Small Vessels

Ghaffari

Ball

Kennedy

et al. 2011

Circ J

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“…27 Nevertheless, the PWV levels of these patients did not decrease during the 12-month treatment period. The serum LDL and CRP levels did not decrease significantly in the nonstatin group.…”

Section: Discussionmentioning

confidence: 77%

“…Vascular superoxide production promotes the development and progression of atherosclerosis through endothelial dysfunction, 25 which is inhibited by the antioxidant effects of statins. 26 Recent in vivo 27,28 and in vitro 29,30 studies have shown that fluvastatin has more potent antioxidative effects than other statins, including pravastatin, simvastatin, cerivastatin, and atorvastatin, although simvastatin also has some antioxidant effect. 31 Thus, the powerful antioxidant properties of fluvastatin may have contributed to the reduction in PWV.…”

Section: Discussionmentioning

confidence: 99%

Long-term effects of statins on arterial pressure and stiffness of hypertensives

et al. 2004

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Although lowering blood pressure (BP) reduces aortic stiffness, achieving the recommended BP goal can be difficult. Recent studies have shown that short-term use of statins can reduce BP significantly. To determine the long-term effects of statins on BP and aortic stiffness, a single-blind randomized prospective study was performed on 85 hyperlipidaemic hypertensive patients whose BP was insufficiently controlled by antihypertensive therapy. Every 3 months, aortic stiffness was assessed by measuring pulse wave velocity (PWV). Patients were randomly allocated to groups treated with pravastatin, simvastatin, fluvastatin, or a nonstatin antihyperlipidaemic drug. No significant differences in patient characteristics, kinds of antihypertensive drugs, BP, ankle brachial index, PWV, or serum lipid, creatinine, or C-reactive protein levels were found between the four groups at the start of the study. During the 12-month treatment period, PWV did not change in the pravastatin group or nonstatin group, but it was transiently reduced in the simvastatin group and significantly decreased in the fluvastatin group, even though the doses of the statins used in this study were lower than the usually prescribed dose. All four antihyperlipidaemic drugs significantly decreased serum cholesterol levels without affecting BP, ankle brachial index, or serum triglyceride levels. The Creactive protein serum levels decreased significantly in the three statin groups but not in the nonstatin group. These results suggest that long-term use of fluvastatin by hyperlipidaemic hypertensive patients is associated with a significant reduction in aortic stiffness without any effect on BP.

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“…There are several reports that fluvastatin suppresses lipid peroxidation by scavenging active oxygen species such as hydroxyl radicals and the superoxide anions of rat liver microsomes in vivo and in vitro. 18,19) Pravastatin did not show a chemical scavenging action, such as hydroxyl radicals and superoxide anions. It is assumed that these phenomena originate in its chemical structure.…”

Section: Discussionmentioning

confidence: 92%

Antioxidative Potential of Fluvastatin <i>via</i> the Inhibition of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase Activity

Bandoh

Sato

Mitani

et al. 2003

Biological & Pharmaceutical Bulletin

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Oxidative stress plays a critical role in the pathogenesis of atherosclerosis.1-3) Elevated oxidative stress and superoxide anion generation could promote the conversion of low density lipoprotein (LDL) to atherogenic oxidized LDL (ox-LDL), contributing to atherosclerosis. There is increasing evidence that the oxidative modification of LDL contributes to the formation of foam cells in the artery wall. 4) Concerning the modification of LDL, neutrophils rapidly take up ox-LDL and generate superoxide anions, which may cause superoxide mediated lipid peroxidation in vivo.5) The superoxide anions of human monocytes participate in both the oxidation of LDL and its conversion to a cytotoxin. 6)We had reported that fluvastatin, a strong inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the late limiting enzyme of cholesterol biosynthesis, suppresses atherosclerotic progression, mediated through its inhibitory effect on endothelial dysfunction, lipid peroxidation, and macrophage deposition, unrelated to its strong hypocholesterolemic action.7) Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important and major source of superoxide anions in neutrophils. 8)Thus, the aim of this study was to determine the direct effect of fluvastatin on the NADPH oxidase activity in neutrophils using phorbor 12-myristate 13-acetate (PMA) as a stimulant to clarify the strong anti-atherosclerotic effect without serum lipid reduction. PMA activates protein kinase C (PKC) directly, and PKC activity is primarily cytosolic in unstimulated neutrophils, but becomes firmly associated with the membrane fraction after PMA treatment.9) The effects of fluvastatin on NADPH oxidase activity were also compared with those of another HMG-CoA reductase inhibitor, pravastatin, which is known as a highly hepatocyte-selective agent in inhibiting cholesterol synthesis. Preparation of Neutrophils Neutrophils were obtained from 6-week-old male Wistar rats 16 h after an intraperitoneal injection of 2% casein solution at a dosage of 1/10 the body weight, as described by Morimoto et al. 11) After 16 h, migrated neutrophils were collected by an intraperitoneal injection of 50 ml calcium-free 0.9% NaCl solution containing 10 mM phosphate buffer (pH 7.4), 6 mM KCl, and 1 mM MgCl 2 (Krebs-Ringer phosphate buffer solution, KRP). The neutrophils were washed 3 times with KRP solution by cen- Key words fluvastatin; nicotinamide adenine dinucleotide phosphate oxidase; antioxidant; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor 10) MATERIALS AND METHODS Chemicals

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Fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, scavenges free radicals and inhibits lipid peroxidation in rat liver microsomes

Cited by 83 publications

References 33 publications

Acute Modulation of Vasoconstrictor Responses by Pravastatin in Small Vessels

Acute Modulation of Vasoconstrictor Responses by Pravastatin in Small Vessels

Long-term effects of statins on arterial pressure and stiffness of hypertensives

Antioxidative Potential of Fluvastatin <i>via</i> the Inhibition of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase Activity

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