Early administration of fluvastatin, but not at the onset of ischemia or reperfusion, attenuates myocardial ischemia-reperfusion injury through the nitric oxide pathway rather than its antioxidant property.
BACKGROUND
Three-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are known to attenuate myocardial ischemia-reperfusion (IR) injury. Fluvastatin (FV) has a potent free radical scavenging action, but it is unclear whether the timing of FV administration could affect its cardioprotective effect or if the antioxidant property of FV might attenuate IR injury.


RESULTS
IR was induced in rats by left coronary artery occlusion for 30 min followed by 24-h reperfusion. The rats were divided into 4 groups: oral FV group (10 mg/kg per day for 2 weeks before ischemia); iv, FV group (10 mg/kg) before ischemia; iv, FV group (10 mg/kg) before reperfusion; and control group. Oxidative stress was evaluated by myocardial 8-hydroxydeoxyguanosine (8-OHdG) content. The area at risk did not different among the 4 groups. Pretreatment with FV for 2 weeks significantly reduced the infarct size by 28% as compared with the control group, but FV administered just before ischemia or reperfusion did not. Myocardial 8-OHdG content was not affected by FV. The infarct-sparing effect of FV was completely abolished by N(omega)-nitro-l-arginine methyl ester or wortmannin.


CONCLUSIONS
The present results indicate that pretreatment with FV, but not just before ischemia or reperfusion, attenuates IR injury primarily through the nitric oxide pathway, not through its antioxidant property.
Matsuki
Akira
A
Second Department of Internal Medicine, Faculty of Medicine, University of Toyama, Sugitani, Toyama, Japan.
Igawa
Akihiko
A
Nozawa
Takashi
T
Nakadate
Teruo
T
Igarashi
Norio
N
Nonomura
Makoto
M
Inoue
Hiroshi
H
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage* / Q000494:pharmacology; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008055:Lipids; D009569:Nitric Oxide; D000077340:Fluvastatin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine