PROTECTIVE ACTION OF IRON-CHELATING AGENTS (CATECHOL, MIMOSINE, DEFEROXAMINE, AND KOJIC ACID) AGAINST ISCHEMIA-REPERFUSION INJURY OF ISOLATED NEONATAL RABBIT HEARTS

Iron is suggested to play an important role in free radical generation during ischemia reperfusion. In the present study, the protective action of 4 iron-chelating agents, with different iron affinities, against reperfusion injury was examined in Langendorff-perfused hearts of neonatal rabbits. The chelators and their iron-binding constants (log K(m)) were as follows: catechol (43), mimosine (36), deferoxamine (31) and kojic acid (27). Following cardiac arrest, the hearts were subjected to global ischemia for 45 min at 37-degrees-C, and then reperfused with modified Krebs-Henseleit solution for 30 min. In control, the left ventricular developed pressures (LVDP) after 30 min reperfusion recovered to 50.5 +/- 3.0% (mean +/- SEM; n = 5) of the preischemic level. In the hearts treated with catechol (30 muM), mimosine (30 muM) or deferoxamine (30 muM), the LVDP recovery was significantly improved up to 84.9 +/- 1.3, 88.2 +/- 2.9 or 87.4 +/- 1.5%, respectively (p < 0.01 vs. control). Creatine phosphokinase (CPK) leakage during the initial 5 min of reperfusion was significantly decreased to about half of control in the hearts treated with catechol, mimosine, or deferoxamine. However, the treatment with kojic acid (30 muM) showed no improvement in the LVDP recovery and CPK leakage. Free radical generation was measured with an electron spin resonance using a spin-trapping agent, 5,5-dimethyl-pyroline-N-oxide (DMPO). The treatment with catechol, mimosine, or deferoxamine reduced the maximum intensity of DMPO-OH signal to about one third of control. However, the maximum intensity in the hearts treated with kojic acid showed a similar level to control. These results suggest that iron chelators have a protective effect on myocardial injury induced by ischemia reperfusion through inhibition of iron-catalyzed radical formation, and that the potentiality of iron chelators for myocardial protection is related to their iron affinity.