Identification of hydrogen peroxide and hydroxyl radicals as mediators of leukocyte-induced myocardial dysfunction. Limitation of infarct size with neutrophil inhibition and depletion.
Neutrophil infiltration of the myocardium is an important component of such diverse disease entities as myocarditis, ischemia, and ischemia-reperfusion injury. We have hypothesized that activated neutrophils are capable of disrupting myocardial function via an oxygen free-radical mechanism. Human neutrophils activated with phorbol myristate acetate disrupted calcium transport by canine cardiac sarcoplasmic reticulum, and this process was inhibited by a combination of superoxide dismutase and catalase. In addition, the activated neutrophil system was also inhibited by the combination of cyclooxygenase inhibitors (ibuprofen and indomethacin) and catalase and accelerated by MK-447. These results incriminate both hydrogen peroxide and the hydroxyl radical as mediators of neutrophil-induced myocardial dysfunction. A test of this hypothesis in vivo was performed by neutrophil-depleting dogs with anti-canine leukocyte antisera prior to coronary artery ligation. Following 6 hr of reperfusion, there was a 43% reduction in infarct size compared to non-immune-sera-injected animals. We conclude that oxygen free radicals generated by neutrophils are capable of inducing significant myocardial injury and play an important role in the pathophysiology of ischemia reperfusion injury.
Hess
M L
ML
Rowe
G T
GT
Caplan
M
M
Romson
J L
JL
Lucchesi
B
B
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D004285:Dogs; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D006878:Hydroxides / Q000378:metabolism* / Q000494:pharmacology; D017665:Hydroxyl Radical; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D005609:Free Radicals; D006878:Hydroxides; D002084:Butylated Hydroxytoluene; D017665:Hydroxyl Radical; D008353:Mannitol; C013753:2-aminomethyl-4-t-butyl-6-iodophenol; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D000251:Adenosine Triphosphatases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D007052:Ibuprofen; D007213:Indomethacin