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1 Effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin and simvastatin, on the myocardial level of coenzyme Qi0, and on mitochrondrial respiration were examined in dogs.2 Either vehicle (control), pravastatin (4 mg kg-'day-), or simvastatin (2 mg kg-'day-') was administered orally for 3 weeks. First, the myocardial tissue level of coenzyme Qio was determined in the 3 groups. Second, ischaemia was induced by ligating the left anterior descending coronary artery (LAD) in anaesthetized open chest dogs, pretreated with the inhibitors. After 30 min of ischaemia, nonischaemic and ischaemic myocardium were removed from the left circumflex and LAD regions, respectively, and immediately used for isolation of mitochondria. The mitochondrial respiration was determined by polarography, with glutamate and succinate used as substrates. 3 Simvastatin significantly decreased the myocardial level of coenzyme Qio, but pravastatin did not. 4 Ischaemia decreased the mitochondrial respiratory control index (RCI) in both groups. Significant differences in RCI between nonischaemic and ischaemic myocardium were observed in the control and simvastatin-treated groups. 5Only in the simvastatin-treated group did ischaemia significantly decrease the ADP/O ratio, determined with succinate. 6 The present results indicate that simvastatin but not pravastatin may cause worsening of the myocardial mitochondrial respiration during ischaemia, probably because of reduction of the myocardial coenzyme Qio level.

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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