Polyethylene glycol-superoxide dismutase prevents endotoxin-induced cardiac dysfunction.
BACKGROUND
Sepsis produces significant mitochondrial and contractile dysfunction in the heart, but the role of superoxide-derived free radicals in the genesis of these abnormalities is not completely understood.


OBJECTIVE
The study was designed to test the hypothesis that superoxide scavenger administration prevents endotoxin-induced cardiac mitochondrial and contractile dysfunction.


METHODS
Four groups of rats were studied, and animals were injected with either saline, endotoxin, endotoxin plus polyethylene glycol-adsorbed-superoxide dismutase (PEG-SOD; a free-radical scavenger), or PEG-SOD alone. Animals were killed 48 h after injections. We then measured cardiac mitochondrial generation of reactive oxygen species (ROS), formation of free-radical reaction products (protein carbonyls, lipid aldehydes, nitrotyrosine), mitochondrial function, and cardiac contractile function.


RESULTS
Endotoxin elicited increases in cardiac mitochondrial ROS formation (p < 0.001), increases in cardiac levels of free-radical reaction products, reductions in mitochondrial ATP generation (p < 0.001), and decrements in cardiac pressure-generating capacity (p < 0.01). Administration of PEG-SOD blocked formation of free-radical reaction products, prevented mitochondrial dysfunction, and preserved cardiac contractility. For example, mitochondrial ATP generation was 923 +/- 50, 392 +/- 32, 753 +/- 25, and 763 +/- 36 nmol/min/mg, respectively, for control, endotoxin, endotoxin + PEG-SOD, and PEG-SOD groups (p < 0.001). In addition, cardiac systolic pressure generation at a diastolic pressure of 15 mm Hg averaged 110 +/- 11, 66 +/- 7, 129 +/- 10 and 124 +/- 5 mm Hg, respectively, for control, endotoxin, endotoxin + PEG-SOD, and PEG-SOD groups (p < 0.01).


CONCLUSIONS
These data indicate that superoxide-derived oxidants play a critical role in the development of cardiac mitochondrial and contractile dysfunction in endotoxin-induced sepsis.
Supinski
Gerald S
GS
Pulmonary and Critical Care Division, Department of Medicine, Medical College of Georgia, Augusta, GA 30912, USA. gsupinski@mail.mcg.edu
Callahan
Leigh A
LA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins; D004926:Escherichia coli; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D006861:Hydrogen Peroxide / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D004731:Endotoxins; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; C044101:endotoxin, Escherichia coli; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase