Role of iron in postischemic microvascular injury
Smith, J.K.; Carden, D.L.; Grisham, M.B.; Granger, D.N.; Korthuis, R.J.
American Journal of Physiology 256(5 Pt 2): H1472-H1477
1989
ISSN/ISBN: 0002-9513 PMID: 2719141 Document Number: 331530
Iron-catalyzed formation of hydroxyl radicals has been postulated to occur during reperfusion of ischemic tissues. To assess the role of iron-catalyzed oxidant production in ischemia/reperfusion (I/R) injury to skeletal muscle, we examined the effects of deferoxamine (an iron chelator) and apotransferin (an iron-binding protein) on the increased vascular permeability produced by I/R in isolated, pump-perfused rat hindquarters. Solvent drag reflection coefficients (.sigma.) were measured in hindquarters subjected to 2 h of ischemia and 30 min of reperfusion with either no pretreatment, pretreatment with 50 mg/kg deferoxamine, 200 mg/kg apotransferrin, or iron-loaded deferoxamine (50 mg/kg). I/R alone was associated with an increase in vascular permeability as indicated by the significantly lower estimates of .sigma. obtained after I/R (0.68 .+-. 0.03) compared with those obtained in nonischemic preparations (0.82 .+-. 0.02). Pretreatment with deferoxamine or apotransferrin attenuated this permeability increase (.sigma. = 0.83 .+-. 0.03 and 0.86 .+-. 0.02, respectively), whereas pretreatment with iron-loaded deferoxamine afforded no protection (.sigma. = 0.71 .+-. 0.02). These findings are consistent with the hypothesis that iron-catalyzed oxidant production is important in the genesis of microvascular injury following I/R. Since the enzyme xanthine oxidase has been implicated as a major source of oxidants generated during reperfusion, we also measured tissue levels of xanthine oxidase and xanthine dehydrogenase in muscle samples obtained from the same hindquarters in which we measured permeability changes. In nonischemic skeletal muscle, xanthine oxidase activity averaged 3.6 .+-. 0.3 mU/g muscle (33 .+-. 4% of total xanthine dehydrogenase plus oxidase activity). When measured after 2 h of ischemia, xanthine oxidase activity was increased to 5.5 .+-. 0.3 mU/g (64 .+-. 3% of total xanthine dehydrogenase plus oxidase activity). These data indicate that I/R produces an increase in rat skeletal muscle xanthine oxidase activity and that pretreatment with deferroxamine or apotransferrin does not alter this increase in xanthine oxidase levels in postischemic skeletal muscle.