Chen Zuolei, Li Tianzuo, Zhang Bingxi
Department of Anesthesiology, Affiliated Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China.
J Surg Res. 2008 Apr;145(2):287-94. doi: 10.1016/j.jss.2007.07.020. Epub 2007 Aug 23.
Postconditioning is a novel strategy of attaining cardioprotection. Previous studies have suggested morphine mimics the effects of ischemic preconditioning. Whether it is also capable of producing postconditioning or not is still unclear. The purpose of this study was to determine (1) whether morphine postconditioning (MPostcond) would protect the heart against reperfusion injury and the subtype(s) of opioid receptors (OR) involved, (2) whether combining MPostcond with morphine preconditioning (MPC) would afford additive cardioprotection, and (3) to evaluate the role mitochondrial adenosine triphosphate-sensitive potassium (mito-K atp) channel played in MPostcond.
Isolated perfused rat hearts were subjected to 45 min of ischemia followed by 1 h of reperfusion. First, three morphine concentrations (0.3, 3.0 and 30 microM) were used to study the protective effect of MPostcond. Second, the effect of blockade of OR subtypes by three antagonists (nonselective OR antagonist naloxone, kappa-OR antagonist nor-binaltorphimine, and delta-OR antagonist naltrindole) on MPostcond was investigated. Third, the protective effects of MPC, MPostcond and the combining MPC with MPostcond on reperfusion injury were compared. Last, the effect of blockade of mito-K atp by 5-hydroxydecanoate on MPostcond was studied. MPostcond was induced by a 10-min perfusion of morphine in Krebs-Ringer's solution performed at the onset of reperfusion, and MPC was produced by a 20-min perfusion of morphine 10 min before ischemia. Infarct size (IS/AAR, as a percentage of the area at risk) was determined by 2,3,5-triphenyltetrazolium staining.
IS/AAR was significantly reduced after MPostcond from 58% +/- 8% (control) to 37% +/- 6% (morphine 3.0 microM, P < 0.01). This effect was abolished by coadministering naloxone (58% +/- 7%), nor-binaltorphimine (52% +/- 5%), but not naltrindole (34% +/- 5%). MPC and MPostcond had similar extent of protective effect on IS/AAR, and combining MPC with MPostcond did not afford further cardiprotection. 5-Hydroxydecanoate also abolished the cardioprotection of MPostcond. Unexpectedly, all three OR antagonists and 5-hydroxydecanoate themselves also afforded some extent of cardioprotection.
MPost confers cardioprotection via activating kappa-OR but not delta-OR and opening mito-K atp channels. MPost and MPC have no additive protection. kappa-OR and mito-K atp channel may play a dual role in protecting ischemia-reperfusion injury.
后适应是一种实现心脏保护的新策略。先前的研究表明吗啡可模拟缺血预处理的作用。它是否也能够产生后适应作用仍不清楚。本研究的目的是确定：（1）吗啡后适应（MPostcond）是否能保护心脏免受再灌注损伤以及所涉及的阿片受体（OR）亚型；（2）将MPostcond与吗啡预处理（MPC）联合使用是否能提供额外的心脏保护；（3）评估线粒体三磷酸腺苷敏感性钾（mito-KATP）通道在MPostcond中的作用。
将离体灌注的大鼠心脏进行45分钟缺血，随后1小时再灌注。首先，使用三种吗啡浓度（0.3、3.0和30微摩尔）研究MPostcond的保护作用。其次，研究三种拮抗剂（非选择性OR拮抗剂纳洛酮、κ-OR拮抗剂去甲二氢吗啡酮和δ-OR拮抗剂纳曲吲哚）对OR亚型的阻断对MPostcond的影响。第三，比较MPC、MPostcond以及MPC与MPostcond联合使用对再灌注损伤的保护作用。最后，研究5-羟基癸酸对mito-KATP的阻断对MPostcond的影响。MPostcond在再灌注开始时通过在Krebs-Ringer溶液中灌注10分钟吗啡诱导产生，MPC在缺血前10分钟通过灌注20分钟吗啡产生。梗死面积（IS/AAR，占危险区域面积的百分比）通过2,3,5-三苯基四氮唑染色确定。
MPostcond后IS/AAR显著降低，从58%±8%（对照组）降至37%±6%（吗啡3.0微摩尔，P<0.01）。同时给予纳洛酮（58%±7%）、去甲二氢吗啡酮（52%±5%）可消除这种作用，但给予纳曲吲哚（34%±5%）则不能。MPC和MPostcond对IS/AAR的保护程度相似，MPC与MPostcond联合使用并未提供进一步的心脏保护。5-羟基癸酸也消除了MPostcond的心脏保护作用。出乎意料的是，所有三种OR拮抗剂和5-羟基癸酸自身也提供了一定程度的心脏保护。
MPostcond通过激活κ-OR而非δ-OR并开放mito-KATP通道赋予心脏保护作用。MPostcond和MPC没有叠加保护作用。κ-OR和mito-KATP通道可能在保护缺血再灌注损伤中发挥双重作用。
