Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of -opioid receptor

Okubo, Shinji, Yujirou Tanabe, Kenji Takeda, Michihiko Kitayama, Seiyu Kanemitsu, Rakesh C. Kukreja, and Noboru Takekoshi. Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of -opioid receptor. Am J Physiol Heart Circ Physiol 287: H1786–H1791, 2004; 10.1152/ajpheart.01143.2003.—We examined whether ischemic preconditioning (IPC) attenuates ischemiareperfusion injury, in part, by decreasing apoptosis and whether the -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.