The effect of cloricromene, a coumarine derivative, on leukocyte accumulation, myocardial necrosis and TNF-alpha production in myocardial ischaemia-reperfusion injury.
The effects of cloricromene, a coumarine derivative, were studied in an anaesthetized rat model of coronary artery ligation (60 min) followed by reperfusion (60 min; MI/R). Sham operated rats were used as controls (Sham MI/R). Myocardial ischaemia-reperfusion injury produced a marked myocardial injury (necrotic area/area-at-risk = 68 +/- 4%; necrotic area/total area = 48 +/- 3%) high serum creatinphosphokinase activity (Sham MI/R = 29 +/- 8 U/ml; MI/R = 205 +/- 11 U/ml) and elevated myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation), in the area-at-risk (6.3 +/- 0.2 U x 10(-3)/g tissue) and in necrotic area (6.5 +/- 0.5 U x 10(-3)/g tissue). Furthermore, serum TNF-alpha was undetectable during the occlusion period, but upon the release of the coronary artery significantly increased. At the end of reperfusion, macrophage TNF-alpha was also enhanced. The administration of cloricromene (2 mg/kg, 5 minutes after the onset of reperfusion) significantly reduced myocardial injury (necrotic area/area-at-risk 30 +/- 1.3%; necrotic area/total area = 25 +/- 1.5) blunted the increase in serum creatinphosphokinase activity (92 +/- 5 U/ml) and lowered myeloperoxidase activity in area-at-risk (2.5 +/- 0.2 U x 10(-3)/g tissue) and in necrotic area (2.2 +/- 0.3 U x 10(-3)/g tissue) and decreased the serum and macrophage levels of TNF-alpha. These data indicate that cloricromene exerts beneficial effects on myocardial ischaemia/reperfusion injury. Finally, since we measured increased serum levels of TNF-alpha that were blunted by the cloricromene treatment, our data are consistent with an involvement of TNF-alpha in the reperfusion injury induced by myocardial ischaemia.
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
F
F
Squadrito
D
D
Altavilla
B
B
Zingarelli
M
M
Ioculano
G
G
Calapai
G M
GM
Campo
A
A
Miceli
M
M
Prosdocimi
A P
AP
Caputi
D000704:Analysis of Variance; D000818:Animals; D002866:Chromonar / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003402:Creatine Kinase / Q000097:blood; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009336:Necrosis / Q000517:prevention & control; D009195:Peroxidase / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects*
D014409:Tumor Necrosis Factor-alpha; C025945:cloricromen; D009195:Peroxidase; D003402:Creatine Kinase; D002866:Chromonar