Atsuko Yamamoto

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

We investigated the effect of fluvastatin sodium (fluvastatin) and pravastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, on the formation of thiobarbituric acid reactive substances both in vivo and in vitro in rat liver microsomes and on active oxygen species. Oral administration of fluvastatin at low doses (3.13 and 6.25 mg/kg) inhibited the formation of thiobarbituric acid reactive substances in rat liver microsomes, but high doses (12.5 and 25 mg/kg) did not change the formation of thiobarbituric acid reactive substances. Fluvastatin at any dose used had no effect on the content of cytochrome P-450 and the activity of NADPH-cytochrome P-450 reductase. In in vitro experiments, concentrations of fluvastatin ranging from 1 x 10(-6) - 1 x 10(-4) M markedly inhibited NADPH-dependent lipid peroxidation in liver microsomes, but pravastatin weakly inhibited lipid peroxidation. The order of magnitude of inhibition of each drug on in vitro lipid peroxidation was butylated hydroxytoluene > probucol > or = fluvastatin > pravastatin. Moreover, fluvastatin chemically scavenged active oxygen species such as hydroxyl radicals and superoxide anion generated by the Fenton reaction and by the xanthine-xanthine oxidase system, respectively, but pravastatin showed no scavenging of superoxide anion. These results indicate that the suppression of in vivo and in vitro lipid peroxidation in liver microsomes may be, at least in part, due to the scavenging by fluvastatin of free radicals.

Antioxidative effect of fluvastatin, an inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, on peroxidation of phospholipid liposomes

The antioxidative effect of fluvastatin sodium (fluvastatin), a 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, on lipid peroxidation of phosphatidylcholine (PC) liposomes was investigated in various peroxidizing systems. Fluvastatin markedly inhibited the formation of thiobarbituric acid reactive substances in iron (II)‐supported peroxidation of liposomes (IC50 = 1.2 × 10−5 M). The order of magnitude of inhibition of each drug on the peroxidation was: butylated hydroxytoluene > fluvastatin ≥ probucol ≥ pravastatin. Moreover, concentrations of fluvastatin ranging from 1 × 10−6 to 1 × 10−4 M inhibited peroxyl radical‐mediated peroxidation of liposomes induced by water‐soluble and lipid‐soluble radical generators, 2,2‐azobis (2‐amidinopropane) dihydro‐chloride and 2,2‐azobis (2,4‐dimethylvaleronitrile), respectively. However, pravastatin showed no effect against peroxyl radical‐mediated peroxidation. These results indicate that fluvastatin acted non‐enzymatically as an effective inhibitor against lipid peroxidation of PC liposomes and that the antioxidative effects of fluvastatin may be due to the scavenging action of fluvastatin on liposomal lipid peroxidation induced by peroxyl radicals generated in the aqueous and lipid phases.

Excitatory amino acid release in the locus coeruleus during naloxone-precipitated morphine withdrawal in adjuvant arthritic rats.

Abstract.Objective and Design: Excitatory amino acid levels in the locus coeruleus (LC) and the behavioral signs during naloxone-precipitated withdrawal in arthritic rats treated with chronic morphine were investigated by in vivo microdialysis.¶Methods: Increases in glutamate (Glu) and aspartate (Asp) were noted after naloxone (48 nmol/5 μl, LC)-precipitated withdrawal from normal and adjuvant arthritic rats which had been intracerebroventricularly infused for 3 days with morphine (26 nmol/1 μl/h).¶Results: The increases in Glu and Asp levels on morphine withdrawal in normal rats were attenuated following naloxone challenge in the morphine-dependent arthritic rats. Moreover, behavioral signs during morphine withdrawal were detected following the naloxone challenge in both the morphine-dependent normal and adjuvant arthritic rats, but not in the saline-infused controls.¶Conclusions: These results show that the attenuation of Glu and Asp release from the LC in the adjuvant arthritic rats might explain the anti-inflammatory and analgesic effects of μ-opioids in adjuvant arthritic rats.¶

Inhibition of cholesterol synthesis ex vivo and in vivo by fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase

The inhibitory effect of fluvastatin sodium (fluvastatin), a new type of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A inhibitor, on de novo cholesterol synthesis was investigated and compared with that of pravastatin. Fluvastatin at a concentration of 12.5 mg/kg inhibited sterol synthesis ex vivo from [14C]acetate in rat liver and ileum by 97–99% with respect to the control, while the inhibition in kidney was 55%. The inhibition by fluvastatin in the liver and ileum persisted for approximately 9 h after administration. Significant differences between fluvastatin also had an inhibitory effect on cholesterol synthesis in vivo in various tissues of rats given [14C]acetate intraperitoneally. Sterol synthesis in the liver, ileum and kidney was inhibited by over 95% 3 h after administration of 6.25 mg/kg of fluvastatin. Significant differences between fluvastatin and pravastatin were found in the liver and ileum. Fluvastatin was more potent than pravastatin in inhibiting both ex vivo and in vivo sterol synthesis in the ileum (but not in kidney) and liver.

Radical Scavenging Properties of Novel Benzopyran Derivatives, TA248 and TA276, and Effects of the Compounds on Ischemic/Reperfused Myocardium in Dogs

Characteristics of novel benzopyran derivatives, TA248 and TA276, and their effects on myocardial contraction in ischemic/reperfused hearts in dogs were examined. TA248 and TA276 inhibited NADPH-dependent lipid peroxidation induced by Fe(3+) in the rat brain homogenate. Both compounds reduced *O(2-) produced by xanthine-xanthine oxidase system in a dose-dependent manner. TA276 scavenged.OH generated by Fenton reaction in a dose-dependent manner. TA248 also inhibited the.OH production, but the effect was neither complete nor dose dependent. Myocardial contraction was assessed as segment shortening of the left ventricular wall in pentobarbital-anesthetized open-chest dogs. The segment shortening was decreased by the left anterior descending coronary artery ligation (ischemia) and returned by release of the ligated artery (reperfusion). The segment shortening did not recover fully during reperfusion. Either TA248 or TA276 injected 10 min before ischemia improved the recovery of myocardial contraction during reperfusion. Both compounds preserved the level of ATP in the 60-min reperfused myocardium. However, the level of lipid peroxides was not changed by TA248 and TA276. TA248 and TA276 may protect myocardium against ischemic/reperfusion insult, partly because of their free radical scavenging activity, but no significant change in myocardial lipid peroxide level was observed.

Effects of BIBR-277, an Angiotensin-II Type-1 Receptor Antagonist, on Ischemic Myocardial Stunning in Dogs

BIBR-277, an angiotensin-II type-1 receptor antagonist, improved the recovery of contractile function of the stunned myocardium. Enalapril also lessened the contractile dysfunction during reperfusion in the stunned myocardium. These drugs may act to reduce ischemic damage by removing the systemic and coronary vasoconstrictive effects of angiotensin II.