RECURRENT ISCHEMIA IN THE CANINE HEART CAUSES RECURRENT BURSTS OF FREE-RADICAL PRODUCTION THAT HAVE A CUMULATIVE EFFECT ON CONTRACTILE FUNCTION - A PATHOPHYSIOLOGICAL BASIS FOR CHRONIC MYOCARDIAL STUNNING
RECURRENT ISCHEMIA IN THE CANINE HEART CAUSES RECURRENT BURSTS OF FREE-RADICAL PRODUCTION THAT HAVE A CUMULATIVE EFFECT ON CONTRACTILE FUNCTION - A PATHOPHYSIOLOGICAL BASIS FOR CHRONIC MYOCARDIAL STUNNING
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DOI：
10.1172/jci118093
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发表时间：
1995-08-01
影响因子：
15.9
通讯作者：
MCCAY, PB
中科院分区：
文献类型：
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作者：
BOLLI, R;ZUGHAIB, M;MCCAY, PB
开胸犬117例患者行10次5 min冠脉闭塞（O），再灌注（R）10 min，在每次R后9 min测定收缩期增厚分数，发现第一个O-R周期引起的收缩期增厚分数减少最大，在随后的4个周期中仅略有增加，在最后5个周期中无进一步减少（组IV），表明缺血的前几次发作预处理心肌对最后五次发作引起的顿抑。然而，当测量最后4小时R间期期间壁增厚的总赤字时，得到了不同的结果。在1次和3次5分钟O（分别为V组和VI组）后，总缺陷相似，表明第一次缺血发作确实对接下来的两次发作进行了预处理;然而，在10次O（IV组）后，总缺陷相似，是3次后的2.5倍，表明前3次发作未能对接下来的7次进行预处理。因此，在第4次和第10次O之间的某个时间点，预处理效果丧失，反复缺血发作开始产生累积效应。用Cu-苯基N-叔丁基硝酮（PEN）进行的自由基测量表明，在第1、5和10次R（Vm组）后立即产生自由基。在再流的最初5分钟内，第5次再流后PEN加合物的总累积释放量比第1次再流后少58%（P < 0.05），但第1次再流与第10次再流之间无显著差异。当在整个10个O-R周期中给药时，OH清除剂巯基丙酰甘氨酸显着增强功能的恢复（组I），并显着抑制自由基的形成（组VII）。然而，如果在前五个月后停药，巯基丙酰甘氨酸的有益作用完全或大部分丧失。（第二组）或8个（III组）O-R周期，这意味着（a）与最后五个或甚至两个周期相关的氧化应激足以引起严重的缺血后功能障碍，和（B）由反复缺血发作引起的累积损伤由反复氧化应激介导。本研究为氧自由基在反复缺血后心肌顿抑的发病机制中发挥重要作用提供了直接的体内证据，并暗示。作为一个主要的罪犯。总之，数据表明，反复短暂缺血发作导致反复发作的氧自由基介导的损伤，对收缩力有累积作用，这种情况可能导致长期甚至慢性心肌顿抑。
Open-chest dogs (total number used, 117) underwent 10 5-min coronary occlusions (O) interspersed with 10 min of reperfusion (R), When systolic thickening fraction was measured 9 min after each R, the first O-R cycle was found to cause the largest decrement, with only a slight additional loss during the next four cycles and no further loss during the last five cycles (group IV), suggesting that the first few episodes of ischemia preconditioned the myocardium against the stunning induced by the last five episodes. However, different results were obtained when the total deficit of wall thickening during the final 4-h R interval was measured. The total deficit was similar after one and three 5-min O (groups V and VI, respectively), indicating that the first ischemic episode did precondition against the next two episodes; however, it was similar to 2.5-fold greater after 10 O (group IV) than after 3, indicating that the first 3 episodes failed to precondition against the next 7. Thus, at some point between the 4th and 10th O, the preconditioning effect was lost and recurrent ischemic episodes started to have a cumulative effect. Measurements of free radicals with cu-phenyl N-tert-butyl nitrone (PEN) demonstrated a burst of free radical generation immediately after the Ist, 5th, and 10th R (group Vm). The total cumulative release of PEN adducts during the initial 5 min of reflow was 58% less after the 5th R than after the Ist (P < 0.05) but did not differ significantly between the Ist and 10th R. When administered throughout the 10 O-R cycles, the . OH scavenger mercaptopropionyl glycine significantly enhanced the recovery of function (group I) and markedly suppressed the formation of free radicals (group VII). However, the beneficial effects of mercaptopropionyl glycine were completely, or largely, lost if the drug was discontinued after the first five (group II) or eight (group III) O-R cycles, respectively, implying that (a) the oxidative stress associated with the last five, or even two, cycles was sufficient to cause severe postischemic dysfunction, and (b) the cumulative injury caused by repetitive ischemic episodes is mediated by recurrent oxidative stress. This study provides direct in vivo evidence that oxygen radicals play an important role in the pathogenesis of myocardial stunning after repetitive ischemia, and implicates . OH as a primary culprit. Taken together, the data indicate that recurrent brief ischemic episodes result in recurrent bouts of oxyradical-mediated injury that have a cumulative effect on contractility, a situation that could lead to protracted or even chronic myocardial stunning.