Nafazatrom-induced salvage of ischemic myocardium in anesthetized dogs is mediated through inhibition of neutrophil function.
The effects of nafazatrom on leukocyte function in vitro and in vivo were related to its ability to salvage ischemic myocardium in an occlusion-reperfusion model of myocardial injury in the anesthetized dog. Nafazatrom (0.4-75 microM) produced dose-related inhibition in vitro of neutrophil aggregation, superoxide anion generation, arachidonic acid metabolism, and, to a lesser extent, the release of beta-glucuronidase. In contrast, nafazatrom (0.4-37.5 microM) did not substantially influence platelet aggregation or the platelet metabolism of arachidonic acid. In vivo nafazatrom (10 mg/kg, po) reduced infarct size from 58 +/- 3% of the risk area (mean +/- SEM, n = 9) in control dogs to 23 +/- 2% of the risk area (n = 9, P less than 0.01). Nafazatrom also reduced the incidence of accompanying arrhythmias. Nafazatrom-induced myocardial salvage was not associated with any hemodynamic changes; moreover, it was independent of platelets, since thrombocytopenia did not prevent nafazatrom from exerting a protective effect. Measurements of the neutrophil-specific myeloperoxidase enzyme in ischemic myocardium indicate that the smaller infarct size in dogs treated with nafazatrom is accompanied by diminished leukocyte infiltration. Thus, the ability of nafazatrom to inhibit neutrophil function in vitro and cell infiltration in vivo may underly its myocardial-protective effects.
Bednar
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M
Smith
B
B
Pinto
A
A
Mullane
K M
KM
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002449:Cell Aggregation / Q000187:drug effects; D003327:Coronary Disease / Q000188:drug therapy* / Q000473:pathology; D004285:Dogs; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D005966:Glucuronidase / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D011720:Pyrazoles / Q000627:therapeutic use*; D047069:Pyrazolones; D013481:Superoxides / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D047069:Pyrazolones; D013481:Superoxides; D016718:Arachidonic Acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D005966:Glucuronidase; C018845:nafazatrom