Prevention of postischemic cardiac injury by the orally active iron chelator 1,2-dimethyl-3-hydroxy-4-pyridone (L1) and the antioxidant (+)-cyanidanol-3.
In this study, we investigated the role of oxygen-derived free radicals and iron in mediating myocardial injury during ischemia and reperfusion. Iron is of special interest because it may enhance tissue injury during ischemia and reperfusion by catalyzing the formation of highly reactive hydroxyl radicals (by modified Haber-Weiss or Fenton reactions). Rat hearts, perfused by the Langendorff method, were subjected to global ischemia (15 minutes at 37 degrees C) and reperfusion. The effects of two iron chelators, 1,2-dimethyl-3-hydroxy-4-pyridone (L1) and 5-hydroxy-2-hydroxymethyl-4-pyrone (kojic acid), and one antioxidant, (+)-cyanidanol-3, on contractile function, coronary flow, lactate dehydrogenase release, and lactate production were studied. The combination of these iron chelators is of special importance because L1 is known to prevent lipid peroxidation, induced by ADP/Fe3+ and NADPH in microsomes, in contrast to kojic acid. We found significant protection of contractile function (apex displacement) during reperfusion with 50 microM L1 and 20 microM (+)-cyanidanol-3 (p less than 0.01, n = 6), whereas no protection was found with 50 microM kojic acid (n = 6). Measurements of lactate dehydrogenase release during reperfusion showed a protective pattern similar to that found for heart contractile function, although 50 microM kojic acid also showed a significantly lower lactate dehydrogenase release during the first 10 minutes of reperfusion. No differences in coronary resistance or lactate release were found between the various groups. Our findings indicate that iron and oxygen-derived free radicals are important in the pathogenesis of postischemic reperfusion injury probably because of the formation of hydroxyl radicals.(ABSTRACT TRUNCATED AT 250 WORDS)
van der Kraaij
A M
AM
Department of Biochemistry, Erasmus University Rotterdam, The Netherlands.
van Eijk
H G
HG
Koster
J F
JF
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D003326:Coronary Circulation / Q000187:drug effects; D000077543:Deferiprone; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D000975:Antioxidants; D007502:Iron Chelating Agents; D007773:Lactates; D011728:Pyridones; D011753:Pyrones; D000077543:Deferiprone; D019344:Lactic Acid; C011890:kojic acid; D002392:Catechin; D007770:L-Lactate Dehydrogenase