Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits.
Studies in vitro reveal that fluvastatin, an HMG-CoA reductase inhibitor, has a strong DPPH radical scavenging activity and achieves concentration-dependent inhibition of copper- and cell-induced oxidation of low-density lipoprotein (LDL). To further examine the anti-oxidative activity of fluvastatin in vivo, we elucidated the effects of chronic treatment with fluvastatin at a dose insufficient to reduce plasma cholesterol levels (2 mg/kg per day) on vasomotion and vascular oxidative stress in thoracic aortas of 0.5% cholesterol-fed rabbits. After 12 weeks of dietary treatment, aortic segments from rabbits fed cholesterol alone showed impaired endothelium-dependent relaxation responses to acetylcholine and A23187 compared to normal chow-fed rabbits in association with a significant increase in plasma total cholesterol levels. In contrast, although plasma total cholesterol levels were not different from those in control cholesterol-fed rabbits, aortic segments from fluvastatin-treated rabbits showed normal relaxation. Compared with rabbits fed cholesterol alone, fluvastatin treatment decreased susceptibility of LDL to ex vivo copper-induced oxidation, reduced vascular superoxide generation, and atheromatous plaque formation. In conclusion, the potent anti-oxidative properties of fluvastatin in addition to its cholesterol-lowering activity appear to contribute to its anti-atherosclerotic effect in vivo.
Rikitake
Y
Y
The First Department of Internal Medicine, Kobe University School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan.
Kawashima
S
S
Takeshita
S
S
Yamashita
T
T
Azumi
H
H
Yasuhara
M
M
Nishi
H
H
Inoue
N
N
Yokoyama
M
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology* / Q000517:prevention & control*; D015764:Bepridil / Q000031:analogs & derivatives*; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D002791:Cholesterol, Dietary; D003300:Copper / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005609:Free Radicals; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007477:Ions / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000096:biosynthesis; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D010851:Picrates; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D001713:Biphenyl Compounds; D002791:Cholesterol, Dietary; D005229:Fatty Acids, Monounsaturated; D016166:Free Radical Scavengers; D005609:Free Radicals; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007477:Ions; D008055:Lipids; D008077:Lipoproteins, LDL; D010851:Picrates; C099252:oxidized low density lipoprotein; D013481:Superoxides; D000077340:Fluvastatin; D015764:Bepridil; D003300:Copper; C004931:1,1-diphenyl-2-picrylhydrazyl