Morita K, Ihnken K, Buckberg G D, Sherman M P, Young H H
Department of Cardiothoracic Surgery, University of California, Los Angeles School of Medicine 90095-1741, USA.
J Thorac Cardiovasc Surg. 1995 Oct;110(4 Pt 2):1190-9. doi: 10.1016/s0022-5223(95)70005-6.
This study tests the hypothesis that an iron chelator, deferoxamine, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass by its action on the iron-catalyzed Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets were placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level. In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenously just before reoxygenation and by a bolus injection (5 mg/kg) into the cardiopulmonary bypass circuit; nine others were not treated (no therapy). Myocardial function after cardiopulmonary bypass was evaluated form end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde in postcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (conjugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus control), and produced severe post-bypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypass control). Deferoxamine avoided conjugated diene production and creatine kinase release and retained normal antioxidant reserve, and functional recovery was complete (95% +/- 11%, p < 0.05 versus no treatment). These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgical advantage.
铁螯合剂去铁胺可通过作用于铁催化的哈伯-维伊斯途径，减少体外循环后氧介导的心肌损伤并避免心肌功能障碍。21只2至3周龄的未成熟仔猪接受了120分钟的体外循环，5只仔猪作为未进行体外循环的生化对照。5只仔猪在无低氧血症的情况下接受体外循环（体外循环对照组）。另外16只仔猪在体外循环60分钟期间通过将氧分压降至约25 mmHg而出现低氧血症，随后在氧分压约400 mmHg下再给氧60分钟。在低氧血症期间通过增加体外循环流量和血细胞比容水平来维持氧输送。7只仔猪在再给氧前静脉注射去铁胺（总剂量50 mg/kg），并通过大剂量注射（5 mg/kg）注入体外循环回路；另外9只未接受治疗（未治疗组）。通过收缩末期弹性（导管）和斯塔林曲线分析评估体外循环后的心肌功能。评估心肌共轭二烯生成和肌酸激酶泄漏作为损伤的生化标志物，并通过测量在氧化剂叔丁基过氧化氢中孵育的体外循环后心肌中的丙二醛来确定抗氧化储备能力。无低氧血症的体外循环未引起氧化损伤或功能损害。相反，再给氧（未治疗）会提高心肌共轭二烯水平和肌酸激酶生成（共轭二烯：3.5±0.7吸光度233 nm/分钟/100 g，肌酸激酶：8.5±1.5 U/分钟/100 g；与体外循环对照组相比，p<0.05），降低抗氧化储备能力（丙二醛：在4 mmol/L叔丁基过氧化氢时为1115±60 nmol/g蛋白质；与对照组相比，p<0.05），并导致严重的体外循环后功能障碍（收缩末期弹性仅恢复39%±7%，与体外循环对照组相比，p<0.05）。去铁胺可避免共轭二烯生成和肌酸激酶释放，并保持正常的抗氧化储备，且功能恢复完全（95%±11%，与未治疗组相比，p<0.05）。这些发现表明，铁催化的氧化剂可能导致再给氧损伤，并意味着去铁胺可用于手术获益。
