Iron-mediated radical reactions upon reperfusion contribute to myocardial "stunning"

Abstract

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.

Evidence of cytosolic iron release during post‐ischaemic reperfusion of isolated rat hearts Influence on spin‐trapping experiments with DMPO

“…This molecule chelates 'free' iron to form a chemically inert complex and thus can inhibit the catalytic properties of this metal [2 I]. Desferrioxamine has recently been shown to be cardioprotective when administered to dogs at the time of post-ischaemic reperfusion [22]. This observation supports the concept that iron-catalysed radical reactions occurring in the initial seconds of reperfusion may play a major role in reperfusion injury.…”

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

“…33,38,39 At the time of this writing, at least 22 full-length articles have been published that have examined the effect of antioxidants on myocardial stunning after a 15-minute coronary occlusion; all of these articles (except those that used superoxide dismutase alone [40][41][42] or catalase alone 40 ) have reported a protective effect of antioxidants against stunning. 37 Furthermore, generation of ROS in stunned myocardium has been demonstrated directly by both spin trapping 9,39,[43][44][45][46][47] and aromatic hydroxylation 48 techniques, and attenuation of ROS generation has repeatedly been shown to result in attenuation of contractile dysfunction. 9,39,43,45,46 A role of ROS in the genesis of myocardial stunning can now be regarded as a proven hypothesis.…”

“…37 Furthermore, generation of ROS in stunned myocardium has been demonstrated directly by both spin trapping 9,39,[43][44][45][46][47] and aromatic hydroxylation 48 techniques, and attenuation of ROS generation has repeatedly been shown to result in attenuation of contractile dysfunction. 9,39,43,45,46 A role of ROS in the genesis of myocardial stunning can now be regarded as a proven hypothesis. Nevertheless, it remains unclear whether ROS play a role in all settings of stunning.…”

“…For example, in the setting of a 15-minute coronary occlusion in the dog, antioxidant therapies are equally effective in alleviating myocardial stunning irrespective of whether they are begun before ischemia or just prior to reperfusion; however, antioxidant therapies begun 1 minute after reperfusion are ineffective, indicating that the ROS important in causing myocardial stunning are those produced immediately after reflow. 43,46 Thus, myocardial stunning can be viewed in part as a form of ROS-mediated "reperfusion injury." 27,43 This concept may have significant therapeutic implications because it suggests that antioxidant therapies begun after the onset of ischemia could still be effective in preventing postischemic dysfunction; however, a delay in the implementation of such therapies until after reperfusion would result in loss of efficacy.…”

Cardiac Effects of ST‐6, a Novel Cyclohexane Dicarboximide Derivative

“…To mimic clinical application, we have subjected the hearts to the delayed treatment with these compounds. That is, rat hearts were subjected to 20-min hypoxia induced by the perfusion buffer equilibrated with a gas mixture of 95% N 2 and 5% CO 2 with replacement of 11 mM glucose by 11 mM Tris-HCl, pH 7.4, and then to 45-min reoxygenation with a gas mixture of 95% O 2 and 5% CO 2 …”