Protective effect of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on copper-induced hydroxyl radical generation in the rat heart.
The present study was examined the effect of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on Cu(II)-induced hydroxyl radical generation (OH) in the extracellular fluid of rat myocardium. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the myocardium. When Cu(II) was infused through the microdialysis probe, Cu(II) increased in OH formation trapped as 2,3-DHBA in the dialysate. When fluvastatin (100 microM) was administered to Cu(II) (50 microM)-pretreated animals, the levels of 2,3-DHBA at 300 min after administration of fluvastatin significantly decreased. In cumulative dose dependent experiments, three concentrations of Cu(II), 10, 25 and 50 microM, were infused through the microdialysis probe in the rat myocardium. A positive linear correlation between Cu(II) and the formation of 2,3-DHBA (R(2)=0.980) was observed. However, when corresponding experiments were performed with fluvastatin (100 microM) pretreated animals, the level of 2,3-DHBA decreased. These results suggest that blocking LDL oxidation by fluvastatin may attenuate Cu(II)-induced OH formation in the rat heart.
Obata
Toshio
T
Department of Analytical Chemistry, Ohu University, School of Pharmaceutical Sciences, Koriyama, Fukushima 963-8611, Japan. t-obata@pha.ohu-u.ac.jp
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003300:Copper / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000201:enzymology / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; 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 / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002316:Cardiotonic Agents; 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