Protective effects of IRFI-016, a new antioxidant agent, in myocardial damage, following coronary artery occlusion and reperfusion in the rat.
The new free radical scavenger IRFI-016 [2(2,3-dihydro-5-acetoxy 4,6,7-trimethyl-benzofuranyl) acetic acid] was assessed in a rat model of myocardial injury induced by 1 h of left coronary artery occlusion followed by 30 min of reperfusion. Myocardial ischaemia plus reperfusion (MI/R) produced severe cardiac necrosis, neutrophil infiltration in the jeopardized tissue, increased serum creatine kinase (CK) and ST segment of the electrocardiogram (ECG), lowered the pressure rate index (PRI), increased serum levels of tumour necrosis factor (TNF-alpha) and caused a decrease in the survival rate. Administration of IRFI-016 (100 and 200 mg/kg i.p.) 30 min before occlusion resulted in a significant protective effect in post-ischaemic reperfusion. Compared with untreated rats, IRFI-016, in particular the dose of 200 mg/kg, caused a reduction of the necrotic zone whether the necrotic area was expressed as a percentage of the area at risk (55 +/- 4% in the MI/R vehicle group and 24 +/- 2.5% in the MI/R treated group; p < 0.001) or as a percentage of the total left ventricle (23 +/- 3.4% in the MI/R vehicle group and 8 +/- 2.1% in the MI/R treated group; p < 0.005), reduced the myeloperoxidase activity, an index of neutrophil infiltration in the necrotic area (from 4.8 +/- 0.8 to 1.6 +/- 0.4 U/g tissue; p < 0.005), reduced the serum levels of TNF-alpha (from 216 +/- 13 to 45 +/- 7 U/ml; p < 0.001), blunted the rise of the ST segment of the ECG (from 0.47 +/- 0.13 mV in the vehicle group to 0.3 +/- 0.18 mV in the treated group; p < 0.001), reduced the loss of CK (from 220 +/- 15 to 88 +/- 13 IU/ml of blood; p < 0.001) and improved the depressed PRI (from 56 +/- 4% to 78 +/- 3% mm Hg/beats/min; p < 0.005). Finally, IRFI-016 significantly enhanced the survival rate evaluated at the end of the experiment. The results strongly indicate that IRFI-016 is a promising drug for cardiac ischaemia and reperfusion.
Campo
G M
GM
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Squadrito
F
F
Ioculano
M
M
Altavilla
D
D
Zingarelli
B
B
Pollicino
A M
AM
Rizzo
A
A
Calapai
G
G
Calandra
S
S
Scuri
R
R
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D016166:Free Radical Scavengers; D006321:Heart / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives*
D000975:Antioxidants; D001572:Benzofurans; D016166:Free Radical Scavengers; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; D009195:Peroxidase; D003402:Creatine Kinase; C071049:Raxofelast