Role of leukocytes in acute myocardial infarction in anesthetized dogs: relationship to myocardial salvage by anti-inflammatory drugs.
The invasion of leukocytes into and around a myocardial infarct was studied in chloralose-anesthetized dogs subjected to 1-hr occlusion of the left anterior descending coronary artery and reperfused for periods up to 5 hr. Polymorphonuclear leukocytes adhering to the endothelium of blood vessels within the ischemic area are evident at the end of the occlusion period. During reperfusion, the leukocytes migrate into the myocardium and large groups of cells can be observed "streaming" toward the irreversibly damaged area after 5 hr reperfusion. Infarcted tissue produces 10 times more 12-hydroxyeicosatetraenoic acid (a metabolite attributed to the invading leukocytes) from arachidonic acid than adjacent "normal" areas of the ventricle. BW755C (10 mg/kg-1 i.v.), which inhibits both the lipoxygenase and cyclooxygenase pathways of arachidonic metabolism, attenuates leukocyte infiltration into the infarcted myocardium, prevents 12-hydroxyeicosatetraenoic acid formation and significantly reduces infarct size (P less than .005). BW755C also significantly diminishes the incidence of cardiac arrhythmias during infarction. In animals where circulating white cells are reduced 60% by treatment with hydroxyurea (20 mg/kg-1 i.v./day for 5 days), there is also a smaller infarct (P less than .01). Indomethacin (5 mg/kg-1 i.v.) and dexamethasone (0.2 mg/kg-1 i.v.), which do not affect leukocyte migration into the ischemic myocardium, do not reduce infarct size. It is proposed that migrating leukocytes contribute to the tissue injury accompanying myocardial ischemia, possibly by the release of proinflammatory mediators such as lipoxygenase products, free radicals (oxygen metabolites) and hydrolytic enzymes. Drugs which reduce the migration and/or activation of leukocytes may be useful in reducing infarct size.
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000758:Anesthesia; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use; D004285:Dogs; D006918:Hydroxyurea / Q000627:therapeutic use; D007213:Indomethacin / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011720:Pyrazoles / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D011720:Pyrazoles; D016718:Arachidonic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D003907:Dexamethasone; D006918:Hydroxyurea; D007213:Indomethacin