Lesnefsky E J, Repine J E, Horwitz L D
Division of Cardiology, University of Colorado Health Sciences Center, Denver.
J Pharmacol Exp Ther. 1990 Jun;253(3):1103-9.
To test whether iron-catalyzed processes contribute to myocardial necrosis during ischemia and reperfusion, we administered the iron chelator, deferoxamine, to chloralose-anesthetized dogs subjected to 90 min of left anterior descending artery occlusion followed by 360 min of reperfusion. Deferoxamine blocks iron-catalyzed hydroxyl radical formation in vitro. Groups of dogs received either pretreatment with deferoxamine or iron-loaded deferoxamine (15 mg/kg over 30 min preocclusion and 2.5 mg/kg/hr during the first 120 min of reperfusion), equal volumes of saline or deferoxamine treatment during reperfusion (15 mg/kg over 30 min beginning at 75 min of occlusion followed by 2.5 mg/kg/hr during the remainder of the first 120 min of reperfusion). Infarct size as a percentage of area at risk was reduced (P less than .05) by deferoxamine pretreatment (29.8 +/- 4.8%, n = 7, +/- S.E.) compared to saline control (46.8 +/- 4.7%, n = 8), deferoxamine reperfusion (50.5 +/- 6.7%, n = 8) or iron-loaded deferoxamine (60.2 +/- 8.6%, n = 3)-treated dogs. Deferoxamine pretreatment also decreased (P less than .05) the release of oxidized glutathione into the coronary sinus during early reperfusion compared to the other groups. There were no differences between groups in area at risk, risk zone blood flow during ischemia or in heart rate-blood pressure product. Deferoxamine did not decrease hydrogen peroxide concentration, neutrophil superoxide anion production or neutrophil adherence in vitro. We conclude that iron-mediated processes, possibly including iron-catalyzed hydroxyl radical formation, contribute to myocardial necrosis during regional ischemia and reperfusion.
为了检测铁催化过程是否导致缺血和再灌注期间的心肌坏死，我们将铁螯合剂去铁胺给予用氯醛糖麻醉的犬，使其左前降支动脉闭塞90分钟，随后再灌注360分钟。去铁胺在体外可阻断铁催化的羟自由基形成。犬分为几组，分别接受去铁胺预处理或载铁去铁胺（闭塞前30分钟给予15mg/kg，再灌注的最初120分钟期间给予2.5mg/kg/小时），等体积的生理盐水或再灌注期间给予去铁胺治疗（闭塞75分钟开始的30分钟内给予15mg/kg，再灌注的最初120分钟剩余时间给予2.5mg/kg/小时）。与生理盐水对照组（46.8±4.7%，n=8）、去铁胺再灌注组（50.5±6.7%，n=8）或载铁去铁胺治疗组（60.2±8.6%，n=3）相比，去铁胺预处理使梗死面积占危险区域面积的百分比降低（P<0.05）（29.8±4.8%，n=7，±标准误）。与其他组相比，去铁胺预处理还使再灌注早期氧化型谷胱甘肽向冠状窦的释放减少（P<0.05）。各组之间在危险区域面积、缺血期间危险区域血流量或心率-血压乘积方面无差异。去铁胺在体外并未降低过氧化氢浓度、中性粒细胞超氧阴离子产生或中性粒细胞黏附。我们得出结论，铁介导的过程，可能包括铁催化的羟自由基形成，在局部缺血和再灌注期间导致心肌坏死。
