Hearse D J, Tosaki A
J Cardiovasc Pharmacol. 1987 Jun;9(6):641-50. doi: 10.1097/00005344-198706000-00002.
We have shown that the free radical spin trap DMPO (5,5-dimethyl-1-pyrroline-N-oxide) reduces reperfusion-induced arrhythmias in a dose-dependent manner in the isolated perfused rat heart subjected to 10 min regional ischemia and 3 min reperfusion. At its optimal concentration (1,000 mumol/L) DMPO, added to the perfusate 5 min prior to ischemia, reduced (p less than 0.05) the incidence of reperfusion-induced irreversible ventricular fibrillation from 83 (10 of 12) to 33% (4 of 12). When hearts were subjected to ischemia (10 min) and reperfusion, with DMPO (1,000 mumol/L) added to the perfusion fluid only 2 min before reperfusion, comparable protection was observed. To ascertain whether or not DMPO achieved an absolute reduction in vulnerability to arrhythmias irrespective of the duration of ischemia, hearts (12 for each group) were also subjected to 5, 10, 20, 30, or 40 min of ischemia; DMPO (1,000 mumol/L) was added to the perfusate either 5 min before ischemia or 2 min before reperfusion. In each instance a bell-shaped time-response profile was obtained. In the DMPO-free controls this gave a maximal vulnerability to arrhythmias after 10 min of ischemia. In the DMPO-treated hearts this curve was shifted to the right, with a peak vulnerability at 20 min. These results indicate that the primary action of DMPO is to exert a delaying effect which extends the duration of ischemia that can be tolerated before the heart becomes vulnerable to reperfusion-induced arrhythmias. However, this effect is achieved during the reperfusion period and not during the preceding period of ischemia. The precise mechanism by which this free radical spin trapping agent achieves this unusual effect remains to be resolved, but in studies with light-inactivated DMPO, this protective effect was lost, indicating that its ability to be oxidized, possibly by superoxide or hydroxyl radicals, may be critical to its mechanism of action.
我们已经表明，自由基自旋捕获剂DMPO（5,5-二甲基-1-吡咯啉-N-氧化物）在离体灌注的大鼠心脏中，对经历10分钟局部缺血和3分钟再灌注的情况，以剂量依赖方式减少再灌注诱导的心律失常。在其最佳浓度（1000μmol/L）下，在缺血前5分钟加入灌注液中的DMPO，将再灌注诱导的不可逆心室颤动发生率从83%（12只中的10只）降低至33%（12只中的4只）（p<0.05）。当心脏经历缺血（10分钟）和再灌注时，仅在再灌注前2分钟将DMPO（1000μmol/L）加入灌注液中，观察到了类似的保护作用。为了确定DMPO是否无论缺血持续时间如何都能绝对降低心律失常易感性，心脏（每组12只）还经历了5、10、20、30或40分钟的缺血；在缺血前5分钟或再灌注前2分钟将DMPO（1000μmol/L）加入灌注液中。在每种情况下都获得了钟形的时间反应曲线。在无DMPO的对照组中，缺血10分钟后心律失常易感性达到最大。在DMPO处理的心脏中，这条曲线向右移动，在20分钟时易感性峰值出现。这些结果表明，DMPO的主要作用是发挥延迟作用，延长心脏在变得易受再灌注诱导的心律失常影响之前所能耐受的缺血持续时间。然而，这种作用是在再灌注期间而非之前的缺血期间实现的。这种自由基自旋捕获剂实现这种异常作用的确切机制仍有待解决，但在对光灭活的DMPO的研究中，这种保护作用丧失了，表明其被超氧化物或羟基自由基氧化的能力可能对其作用机制至关重要。
