Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits:: role of δ-opioid receptor
Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits:: role of δ-opioid receptor
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DOI：
10.1152/ajpheart.01143.2003
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发表时间：
2004-10-01
影响因子：
4.8
通讯作者：
Takekoshi, N
中科院分区：
文献类型：
--
作者：
Okubo, S;Tanabe, Y;Takekoshi, N
我们研究了缺血预处理（IPC）是否在一定程度上通过减少细胞凋亡来减轻缺血再灌注损伤，以及delta-阿片受体（DOR）是否在细胞凋亡的调节中起关键作用。兔冠状动脉闭塞30 min，再灌注180 min。缺血10 min再灌注4个周期后，在CAO前诱导IPC。术前15 min给予吗啡（0.3 mg/kg iv）。纳洛酮（Nal; 10 mg/kg iv）和纳曲多（Nti; 10 mg/kg iv），分别是非选择性和选择性DOR拮抗剂，在吗啡或IPC前10分钟给予。梗死面积（%危险面积）从对照组的46 +/- 3.8降低到IPC组的11.6 +/- 1.0和吗啡组的19.5 +/- 3.8（平均值+/- SE；与对照组相比P < 0.001）。Nal阻断了IPC和吗啡的保护作用，梗死面积分别增加到38.6 +/- 7.2和44.5 +/- 1.8。同样，Nti阻断IPC和吗啡诱导的保护。与对照组（12.4 +/- 1.6,P < 0.001）相比，IPC组（3.6 +/- 1.9）和吗啡组（5.2 +/- 1.2）的凋亡细胞百分比（末端脱氧核苷酸转移酶介导的dUTP镍端标记法）有所下降。Nti预处理使IPC组凋亡细胞增加11.2 +/- 2.2%，吗啡组凋亡细胞增加12.1 +/- 0.8%。Nal未能阻断IPC组细胞凋亡的抑制（IPC组细胞百分比：5.7 +/- 1.3 vs. 3.6 +/- 1.9; P < 0.05）。核小体DNA阶梯图也证实了这些结果。我们得出结论，IPC减少致死性损伤，部分原因是通过减少缺血再灌注后的细胞凋亡，DOR的激活可能在IPC或吗啡诱导的心肌保护中起关键作用。
We examined whether ischemic preconditioning (IPC) attenuates ischemia-reperfusion injury, in part, by decreasing apoptosis and whether the delta-opioid receptor (DOR) plays a pivotal role in the regulation of apoptosis. Rabbits were subjected to 30-min coronary artery occlusion (CAO) and 180 min of reperfusion. IPC was elicited with four cycles of 5-min ischemia and 10-min reperfusion before CAO. Morphine (0.3 mg/kg iv) was given 15 min before CAO. Naloxone (Nal; 10 mg/kg iv) and naltrindole (Nti; 10 mg/kg iv), the respective nonselective and selective DOR antagonists were given 10 min before either morphine or IPC. Infarct size (%risk area) was reduced from 46 +/- 3.8 in control to 11.6 +/- 1.0 in IPC and 19.5 +/- 3.8 in the morphine group (means +/- SE; P < 0.001 vs. control). Nal blocked the protective effects of IPC and morphine, as shown by the increase in infarct size to 38.6 +/- 7.2 and 44.5 +/- 1.8, respectively. Similarly, Nti blocked IPC and morphine-induced protection. The percentage of apoptotic cells ( revealed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay) decreased in IPC (3.6 +/- 1.9) and morphine groups (5.2 +/- 1.2) compared with control group (12.4 +/- 1.6; P < 0.001). Nti pretreatment increased apoptotic cells 11.2 +/- 2.2% in IPC and 12.1 +/- 0.8% in morphine groups. Nal failed to block inhibition of apoptosis in the IPC group (% of cells: 5.7 +/- 1.3 vs. 3.6 +/- 1.9 in IPC alone; P > 0.05). These results were also confirmed by nucleosomal DNA laddering pattern. We conclude that IPC reduces lethal injury, in part, by decreasing apoptosis after ischemia-reperfusion and activation of the DOR may play a crucial role in IPC or morphine-induced myocardial protection.