Edaravone reduces myocardial infarct size and improves cardiac function and remodelling in rabbits.
1. In the present study, we investigated the effect of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), a free radical scavenger, on myocardial infarct (MI) size and cardiac function in an in vivo model of MI in rabbits. We further investigated the contribution of hydroxyl radicals, superoxide and nitric oxide (NO) to its effects. 2. Anaesthetized open-chest Japanese white male rabbits were subjected to 30 min coronary occlusion and 48 h reperfusion. The control group (n = 10) was injected with saline 10 min before reperfusion. The edaravone group (n = 10) was injected with a bolus of 3 mg/kg edaravone 10 min before reperfusion. The edaravone + N(G)-nitro-L-arginine methyl ester (L-NAME) group (n = 5) was given 10 mg/kg, i.v., L-NAME 10 min before the administration of 3 mg/kg edaravone. The L-NAME group (n = 5) was given 10 mg/kg, i.v., L-NAME 20 min before reperfusion. Infarct size was measured using the triphenyl tetrazolium chloride method and is expressed as a percentage of area at risk. Cardiac function was assessed by echocardiography 14 days after infarction. 3. In another series of experiments, rabbits were subjected to 30 min coronary occlusion and 30 min reperfusion and myocardial interstitial 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA levels, indicators of hydroxyl radical, were measured using a microdialysis technique. 4. Infarct size in the edaravone group was significantly reduced compared with that in the control group (27.4 +/- 6.8 vs 43.4 +/- 6.8%, respectively; P < 0.05). The edaravone-induced reduction of infarct size was abolished by pretreatment with L-NAME. Myocardial interstitial levels of 2,3-DHBA and 2,5-DHBA increased 20 and 30 min after ischaemia and peaked at 10 min reperfusion in the control group. Edaravone significantly inhibited the increase in 2,3-DHBA and 2,5-DHBA levels seen during reperfusion. Dihydroethidium staining showing in situ detection of superoxide was less intense in ischaemic myocardium in the edaravone-treated group compared with the control group. Edaravone improved cardiac function and left ventricular remodelling 14 days after infarction. 5. In conclusion, edaravone significantly reduces MI size and improves cardiac function and LV remodelling by decreasing hydroxyl radicals and superoxide in the myocardium and increasing the production of NO during reperfusion in rabbits.
Onogi
Hirohito
H
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Minatoguchi
Shinya
S
Chen
Xue-Hai
XH
Bao
Narentuoya
N
Kobayashi
Hiroyuki
H
Misao
Yu
Y
Yasuda
Shinji
S
Yamaki
Takahiko
T
Maruyama
Rumi
R
Uno
Yoshihiro
Y
Arai
Masazumi
M
Takemura
Genzou
G
Fujiwara
Hisayoshi
H
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D000077553:Edaravone; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D005841:Gentisates / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects*; D062385:Hydroxybenzoates / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D005841:Gentisates; D062385:Hydroxybenzoates; D013481:Superoxides; C009135:2,3-dihydroxybenzoic acid; D000077553:Edaravone; D000983:Antipyrine; D019331:NG-Nitroarginine Methyl Ester; C010925:2,5-dihydroxybenzoic acid