Iron-mediated radical reactions upon reperfusion contribute to myocardial "stunning".
Recent evidence suggests that postischemic myocardial dysfunction ("stunning") is mediated by iron-catalyzed free radical reactions, but the exact time window during which the critical iron-mediated damage develops remains unknown. Furthermore, the evidence that iron promotes free radical reactions in vivo is indirect. Thus open-chest dogs undergoing a 15-min coronary occlusion and 4 h of reperfusion were given one of the following intracoronary infusions: desferrioxamine (DF) beginning 2 min before reperfusion (group I), DF beginning 1 min after reperfusion (group II), iron-loaded DF in dosage identical to group I (group III), or vehicle (controls, group IV). Recovery of contractile function was substantially greater in group I than in controls, whereas in groups II and III it was indistinguishable from controls. To determine whether the protection afforded by DF was due to inhibition of free radical reactions, myocardial production of free radicals was directly assessed by intracoronary infusion of the spin trap alpha-phenyl N-tert-butyl nitrone (PBN). In controls (group VI), radical adducts of PBN were released in the coronary venous blood after reperfusion. DF given as in group I (group V) markedly suppressed myocardial production of PBN adducts. These results strongly suggest that a substantial portion of the damage responsible for myocardial stunning is caused by iron-catalyzed free radical reactions that develop in the initial seconds of reperfusion and can be prevented by administration of iron chelators started just before reflow. Furthermore, the results demonstrate that attenuation of postischemic dysfunction by DF is associated with attenuation of free radical reactions in vivo, thereby providing direct evidence for a pathogenetic role of iron-catalyzed free radical reactions in myocardial stunning in the intact animal.
Bolli
R
R
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
Patel
B S
BS
Jeroudi
M O
MO
Li
X Y
XY
Triana
J F
JF
Lai
E K
EK
McCay
P B
PB
D000818:Animals; D003326:Coronary Circulation; D003497:Cyclic N-Oxides; D003676:Deferoxamine / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005609:Free Radicals; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D007501:Iron / Q000502:physiology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009589:Nitrogen Oxides; D010100:Oxygen / Q000378:metabolism / Q000502:physiology*; D013113:Spin Labels
D003497:Cyclic N-Oxides; D005609:Free Radicals; D009589:Nitrogen Oxides; D013113:Spin Labels; C029217:phenyl-N-tert-butylnitrone; D007501:Iron; D003676:Deferoxamine; D010100:Oxygen