Remote postconditioning - Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors
Remote postconditioning - Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors
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DOI：
10.1007/s00395-005-0539-2
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发表时间：
2005-09-01
影响因子：
9.5
通讯作者：
Vinten-Johansen, J
中科院分区：
文献类型：
--
作者：
Kerendi, F;Kin, H;Vinten-Johansen, J
目的在冠状动脉再流早期应用一系列短暂的冠状动脉再灌注和再闭塞（“后处理”）减轻再灌注损伤。然而，尚不清楚在心肌再灌注开始时对远端器官进行短暂缺血-再灌注（即“远程后处理”，远程PostC）是否会减少再灌注心肌的梗死面积。在体内麻醉大鼠模型的心肌梗死诱导的冠状动脉闭塞和再灌注，这项研究测试的假设，远程postC诱导的一个单一的5分钟发作的肾动脉（RA）闭塞和再灌注应用之前立即冠状动脉再灌注保护心肌再灌注损伤的机制，涉及内源性腺苷受体激活。方法采用结扎大鼠左冠状动脉30 min，再灌注3 h的方法，观察大鼠冠状动脉结扎后再灌注的变化。将大鼠随机分为六组之一：1）对照组：LCAO和仅再灌注，无其他干预; 2）远程PostC组：LCAO 24分钟后，RA闭塞5分钟，并在冠状动脉再灌注前1分钟释放; 3）永久性RA闭塞：LCAO 24分钟后，RA永久性闭塞，持续至再灌注结束; 4）延迟远程PostC组：LCAO 26分钟后，RA闭塞5分钟，其释放延迟至冠状动脉再灌注后1分钟; 5）CON + SPT：LCAO和再灌注的大鼠在冠状动脉再灌注前5分钟接受10 mg/kg IV的非选择性腺苷受体拮抗剂8-磺苯基茶碱[SPT];和6）Remote PostC + SPT：LCAO 24分钟后，在冠状动脉再灌注前5分钟给予10 mg/kg SPT，闭塞RA 5分钟，并在冠状动脉再灌注前1分钟释放RA。结果与对照组（49 +/-4%，p = 0.003）相比，Remote PostC组（25 +/- 4%）的心肌梗死面积（坏死百分比/风险面积，平均值+/- SEM）减少了50%，与血浆CK活性降低一致（44 +/- 5 vs. 67 +/- 6 U/ml，p = 0.023）。相反，与对照组相比，LCAO和再灌注前永久性RA闭塞未能减少心肌梗死面积（47 +/- 5%）。延迟RA闭塞的释放（延迟Remote PostC）消除了Remote PostC观察到的心肌梗死减少（48 +/- 6%）。单用SPT对梗死面积无影响（CON + SPT组为47 +/- 4%，CON组为49 +/- 4%）;然而，Remote PostC+SPT消除了Remote PostC组的心肌梗死面积缩小（Remote PostC + SPT组为50 +/- 3%，Remote PostC组为25 +/- 4%）。结论：在冠状动脉再灌注开始前即刻应用远程肾脏后处理提供了可能在冠状动脉再灌注的最初几分钟内发挥的有效的心肌梗死面积减小。这种器官间的远程后处理现象可能部分由缺血-再灌注肾释放腺苷和随后激活腺苷受体介导。
Objectives A series of brief coronary artery reperfusions and reocclusions applied during the early minutes of coronary artery reflow ("postconditioning") attenuates reperfusion injury. However, it is not known whether brief ischemia-reperfusion applied to a distant organ at the onset of myocardial reperfusion (i.e. "remote postconditioning", remote PostC) reduces infarct size in the reperfused myocardium. In an in vivo anesthetized rat model of myocardial infarction induced by coronary artery occlusion and reperfusion, this study tested the hypothesis that remote postC induced by a single 5 minute episode of renal artery (RA) occlusion and reperfusion applied immediately before the onset of coronary artery reperfusion protects the myocardium from reperfusion injury by mechanisms involving endogenous adenosine receptor activation. Methods All rats were subjected to a total of 30 minutes of left coronary artery occlusion (LCAO) and 3 hours of reperfusion. The rats were randomized to one of six groups: 1) Control: LCAO and reperfusion only with no other intervention; 2) Remote PostC: after 24 minutes of LCAO the RA was occluded for 5 minutes and released 1 min before coronary artery reperfusion; 3) Permanent RA occlusion: the RA was permanently occluded after 24 minutes LCAO continuing to the end of reperfusion; 4) Delayed Remote PostC: after 26 minutes LCAO the RA was occluded for 5 minutes, and its release was delayed until 1 min after coronary artery reperfusion; 5) CON + SPT: rats with LCAO and reperfusion received 10 mg/kg IV of the non-selective adenosine receptor antagonist 8-sulfophenyl theophylline [SPT] administered 5 minutes before coronary artery reperfusion; and 6) Remote PostC + SPT: after 24 minutes of LCAO the RA was occluded for 5 minutes and released 1 minute before coronary artery reperfusion in the presence of 10 mg/kg SPT given 5 min before coronary artery reperfusion. Results Myocardial infarct size (percentage necrosis/area at risk, mean +/- SEM) was reduced by 50% in Remote PostC (25 +/- 4%) compared to Control (49 +/- 4%, p = 0.003), consistent with a reduction in plasma CK activity (44 +/- 5 vs. 67 +/- 6 U/ml, p = 0.023). In contrast, permanent RA occlusion before LCAO and reperfusion failed to reduce myocardial infarct size (47 +/- 5%) vs Control. Delaying the release of the RA occlusion (delayed Remote PostC) abrogated the myocardial infarct reduction observed with Remote PostC (48 +/- 6%). SPT alone had no effect on infarct size (47 +/- 4% in CON + SPT vs. 49 +/- 4% in CON); however, Remote PostC+SPT abrogated the myocardial infarct size reduction in Remote PostC (50 +/- 3% in Remote PostC + SPT vs. 25 +/- 4% in Remote PostC). Conclusions Remote renal postconditioning applied immediately before the onset of coronary artery reperfusion provides potent myocardial infarct size reduction likely exerted during the first minutes of coronary artery reperfusion. This inter-organ remote postconditioning phenomenon is likely mediated in part by release of adenosine by the ischemic-reperfused kidney and subsequent activation of adenosine receptors.