[Tumor necrosis factor in myocardial ischemia and reperfusion].
The role of tumor necrosis factor (TNF-alpha) was investigated 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 necrosis, myocardial myeloperoxidase activity (MPO; investigated as an index of leukocyte adhesion and accumulation), serum creatinphosphokinase (CPK) activity and serum and macrophage TNF-alpha were studied. Ischemia and reperfusion produced a marked myocardial injury, with enhancement of serum CPK levels and myocardial MPO activity in the area at risk and in the necrotic area. Furthermore, serum TNF-alpha was undetectable during the occlusion period, but increased significantly after release of the coronary artery. At the end of reperfusion, macrophage TNF-alpha was also enhanced. A passive immunization with a hyperimmune serum containing antibodies against murine TNF-alpha or administration of an inhibitor of TNF-alpha synthesis, such as cloricromene, significantly lowered myocardial necrosis, reduced the increase in serum CPK and decreased MPO activity in the area at risk and in the necrotic area. Finally, the administration of the specific anti-TNF-alpha antibodies neutralized the serum levels of TNF-alpha and the injection of cloricromene reduced both serum and macrophage TNF-alpha. These data are consistent with an involvement of TNF-alpha in myocardial ischemia-reperfusion injury and suggest that drugs capable of reducing TNF-alpha might represent a novel therapeutic approach to the treatment of myocardial reperfusion injury.
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Istituto di Farmacologia, Università degli Studi, Messina.
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AP
D000818:Animals; D000918:Antibody Specificity; D002866:Chromonar / Q000031:analogs & derivatives / Q000627:therapeutic use; D003402:Creatine Kinase / Q000097:blood / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D007116:Immunization, Passive; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000097:blood* / Q000209:etiology; D015428:Myocardial Reperfusion Injury / Q000097:blood* / Q000209:etiology; D009195:Peroxidase / Q000097:blood / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000276:immunology
D014409:Tumor Necrosis Factor-alpha; C025945:cloricromen; D009195:Peroxidase; D003402:Creatine Kinase; D002866:Chromonar