Langleben D, Fox R B, Jones R C, Reid L M
Division of Cardiology, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Québec.
Clin Invest Med. 1989 Aug;12(4):235-40.
Ischemia, followed by reperfusion and restoration of oxygen to tissues, generates hydrogen peroxide which in turn generates injurious free radicals, particularly hydroxyl. Chronic hypoxia may also result in liberation of free radicals. In rats, chronic hypoxia causes pulmonary hypertension, associated with structural remodelling of pulmonary arteries, polycythemia, and vasoconstriction. We studied in rats the effects of dimethylthiourea (DMTU), a hydroxyl and hydrogen peroxide scavenger, on acute hypoxic vasoconstriction, and on the arterial structure and development of polycythemia after chronic hypoxia (FIO2 0.10 for 10 days, daily DMTU). DMTU did not affect acute vasoconstriction nor polycythemia. It significantly reduced muscularization of alveolar wall and alveolar duct arteries, medial thickening of alveolar wall and preacinar arteries, and right ventricular hypertrophy, suggesting reduction of pulmonary hypertension. However, DMTU caused marked growth retardation in both control and hypoxic rats, an effect not previously described. In other rats a similar degree of growth retardation due to reduced food intake failed to prevent the effects of hypoxia, suggesting that DMTU's effect is not through this mechanism. The results of this study support but do not confirm the hypothesis that free radicals may have a role in the pathogenesis of the arterial structural changes in the microcirculation contributing to chronic hypoxic pulmonary hypertension. However, in view of DMTU's effects on growth, definitive testing of the hypothesis will not be possible until other, less toxic, chronic hydroxyl scavengers become available.
局部缺血后，再灌注并恢复组织的氧供应，会产生过氧化氢，而过氧化氢又会产生具有损伤性的自由基，尤其是羟基自由基。慢性缺氧也可能导致自由基的释放。在大鼠中，慢性缺氧会导致肺动脉高压，伴有肺动脉结构重塑、红细胞增多症和血管收缩。我们在大鼠中研究了羟基和过氧化氢清除剂二甲硫脲（DMTU）对急性低氧性血管收缩以及慢性缺氧（吸入氧分数为0.10，持续10天，每日给予DMTU）后动脉结构和红细胞增多症发展的影响。DMTU对急性血管收缩和红细胞增多症均无影响。它能显著减轻肺泡壁和肺泡管动脉的肌化、肺泡壁和腺泡前动脉的中膜增厚以及右心室肥大，提示肺动脉高压有所减轻。然而，DMTU导致对照大鼠和缺氧大鼠均出现明显的生长迟缓，这一效应此前未被描述。在其他大鼠中，因食物摄入量减少导致的类似程度的生长迟缓并不能预防缺氧的影响，这表明DMTU的作用并非通过这一机制。本研究结果支持但未证实自由基可能在导致慢性低氧性肺动脉高压的微循环动脉结构变化的发病机制中起作用这一假说。然而，鉴于DMTU对生长的影响，在有其他毒性较小的慢性羟基清除剂可用之前，无法对该假说进行确定性测试。
