Vander Heide R S, Sobotka P A, Ganote C E
J Mol Cell Cardiol. 1987 Jun;19(6):615-25. doi: 10.1016/s0022-2828(87)80367-x.
The oxygen paradox refers to the abrupt release of cytoplasmic enzymes and severe cellular disruption that occurs following reoxygenation of anoxic perfused hearts. In this study, the ability of a series of oxygen-derived free radical inhibitors and scavenging agents to protect isolated perfused rat hearts from the oxygen-induced enzyme release following 30 or 60 mins of anoxic perfusion (oxygen paradox) and cumene hydroperoxide-induced injury was evaluated. Malondialdehyde (MDA) release, an indicator of lipid peroxidation, and creatine kinase (CK) release, an indicator of cellular injury, were monitored. We evaluated five agents previously reported to scavenge or inhibit the formation of oxygen free radicals. The putative hydroxyl radical scavengers dimethylthiourea (DMTU) and mannitol; catalase, an agent protective against peroxide injury; allopurinol, an inhibitor of xanthine oxidase; and albumin, a non-specific protein control, were evaluated. Coronary flow rates and myocardial temperature were continuously monitored to ensure uniform perfusion conditions. The MDA assay was carefully monitored by constructing standard curves on each experimental day. Addition of 20 microM cumene hydroperoxide to oxygenated perfused hearts caused peroxidative cell injury as evidenced by significant MDA and CK release in the coronary effluent. DMTU and catalase provided near complete protection from cumene hydroperoxide-induced cell injury but did not reduce CK release from hearts subjected to either the mild (30-min) or the severe (60-min) oxygen paradox (reoxygenation-induced injury). Allopurinol caused a significant reduction in MDA release but not CK release from oxygen paradox-injured hearts. Allopurinol and albumin had no significant effect on MDA release from cumene-hydroperoxide-injured hearts. Catalase (300 U/ml) caused a mild but not statistically significant reduction in MDA release from cumene hydroperoxide injury but did not provide protection from the oxygen paradox at either injury level. Mannitol (120 mM), in contrast to DMTU, was ineffective in reducing cumene-induced injury but showed a significant protective effect against oxygen paradox-induced damage. It is concluded that the ability of mannitol to reduce reoxygenation-induced CK release in the oxygen paradox may be due to its osmotic activity and consequent ability to prevent cellular swelling rather than its activity as an oxygen-free radical scavenger.
氧悖论是指在对缺氧灌注的心脏进行再氧合后，细胞质酶突然释放以及细胞严重受损的现象。在本研究中，评估了一系列氧衍生自由基抑制剂和清除剂对离体灌注大鼠心脏的保护能力，这些心脏在经历30或60分钟缺氧灌注（氧悖论）以及异丙苯过氧化氢诱导的损伤后，免受氧诱导的酶释放的影响。监测了丙二醛（MDA）释放（脂质过氧化的指标）和肌酸激酶（CK）释放（细胞损伤的指标）。我们评估了先前报道的五种清除或抑制氧自由基形成的试剂。推测的羟自由基清除剂二甲基硫脲（DMTU）和甘露醇；过氧化氢酶，一种预防过氧化物损伤的试剂；别嘌呤醇，一种黄嘌呤氧化酶抑制剂；以及白蛋白，一种非特异性蛋白质对照。持续监测冠状动脉血流量和心肌温度，以确保灌注条件均匀。在每个实验日通过构建标准曲线仔细监测MDA测定。向氧合灌注的心脏中添加20微摩尔异丙苯过氧化氢会导致过氧化细胞损伤，冠状动脉流出物中显著的MDA和CK释放证明了这一点。DMTU和过氧化氢酶几乎完全保护心脏免受异丙苯过氧化氢诱导的细胞损伤，但并未降低经历轻度（30分钟）或重度（60分钟）氧悖论（再氧合诱导的损伤）的心脏的CK释放。别嘌呤醇使氧悖论损伤心脏的MDA释放显著降低，但未降低CK释放。别嘌呤醇和白蛋白对异丙苯过氧化氢损伤心脏的MDA释放没有显著影响。过氧化氢酶（300单位/毫升）使异丙苯过氧化氢损伤的心脏的MDA释放略有降低，但无统计学意义，并且在任何一种损伤水平下都不能保护心脏免受氧悖论的影响。与DMTU相反，甘露醇（120毫摩尔）在减少异丙苯诱导的损伤方面无效，但对氧悖论诱导的损伤显示出显著的保护作用。得出的结论是，甘露醇在氧悖论中减少再氧合诱导的CK释放的能力可能归因于其渗透活性以及随之而来的防止细胞肿胀的能力，而不是其作为氧自由基清除剂的活性。
