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Am J Physiol Heart Circ Physiol 287: H1786-H1791, 2004. First published July 1, 2004; doi:10.1152/ajpheart.01143.2003
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Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of {delta}-opioid receptor

Shinji Okubo,1 Yujirou Tanabe,1 Kenji Takeda,1 Michihiko Kitayama,1 Seiyu Kanemitsu,1 Rakesh C. Kukreja,2 and Noboru Takekoshi1

1Department of Cardiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; and 2Division of Cardiology, Department of Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298

Submitted 4 December 2003 ; accepted in final form 1 June 2004

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.

reperfusion injury


Address for reprint requests and other correspondence: S. Okubo, Dept. of Cardiology, Kanazawa Medical Univ., 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan (E-mail: shinkubo{at}kanazawa-med.ac.jp)




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