Cardiac reperfusion damage prevented by a nitroxide free radical.
Experimental evidence is presented that directly links ischemia/reperfusion injury to the formation of oxygen-derived free radicals. 2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO)--a stable nitroxide radical that disproportionates superoxide radicals and oxidizes reduced metal ions required for OH. formation--was tested for its ability to prevent reperfusion damage in the isolated rat heart subjected to regional ischemia. Severe reperfusion arrhythmia--ventricular fibrillation and ventricular tachycardia--were prominent in control hearts, and their duration was significantly reduced by the presence of 0.4 or 1 mM TEMPO. TEMPO also repressed both postischemic release of lactate dehydrogenase and OH. formation. TEMPO slowed the heart rate, but compensatory pacing did not alter the dramatic effect of the nitroxide on reperfusion arrhythmia. TEMPO was partially protective when introduced at the end of ischemia but had no effect when added 1 min into reperfusion. It was concluded that both reperfusion arrhythmia and cell damage were directly related to oxidative damage incurred during the critical first minute of reperfusion. TEMPO strongly protected against reperfusion injury by preventing the formation of OH. and not by decreasing heart rate or by direct suppression of arrhythmia.
Gelvan
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D
Department of Biology, University of California, San Diego, La Jolla 92093.
Saltman
P
P
Powell
S R
SR
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015415:Biomarkers; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D005609:Free Radicals; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D006878:Hydroxides / Q000032:analysis; D017665:Hydroxyl Radical; D066298:In Vitro Techniques; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D015415:Biomarkers; D003497:Cyclic N-Oxides; D005609:Free Radicals; D006878:Hydroxides; D017665:Hydroxyl Radical; D007770:L-Lactate Dehydrogenase; C003959:TEMPO