Fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, resists hydroxyl radical generation in the rat myocardium.
The aim of this study was to determine whether fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist Cu (II)-induced hydroxyl radical generation (*OH) in the extracellular fluid of rat myocardium. Rats were anaesthetized and sodium salicylate in Ringer's solution (0.5 nmol microL(-1) min(-1)) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA) in the myocardium. When Cu (II) (0, 10, 25 or 50 microM) was administered to 1 mM tyramine-pretreated rats, a marked elevation in the levels of 2,3-DHBA was found, indicating a positive linear correlation between Cu (II) and the increase in *OH formation trapped as 2,3-DHBA in the dialysate (r2 = 0.977). In the presence of fluvastatin (100 microM), a marked decrease in the levels of 2,3-DHBA was found. Corresponding experiments performed with iron (II) (0, 10, 25 or 50 microM), showed a marked elevation in the levels of 2,3-DHBA, indicating a positive linear correlation between iron (II) and the increase in *OH formation trapped as 2,3-DHBA in the dialysate (r2 = 0.986). However, in the presence of fluvastatin (100 microM) a small decrease in the level of 2,3-DHBA was found. The results show that iron (II) against LDL oxidation may be insensitive compared with Cu (II). Cu (II)-induced *OH formation may be reduced by inhibiting LDL with fluvastatin.
Obata
T
T
Department of Pharmacology, Oita Medical University, Japan. tobata@oita-med.ac.jp
Ebihara
A
A
Yamanaka
Y
Y
D000818:Animals; D003300:Copper / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D006321:Heart / Q000187:drug effects; D062385:Hydroxybenzoates / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014439:Tyramine / Q000494:pharmacology
D005229:Fatty Acids, Monounsaturated; D062385:Hydroxybenzoates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D017665:Hydroxyl Radical; D000077340:Fluvastatin; C009135:2,3-dihydroxybenzoic acid; D003300:Copper; D014439:Tyramine