Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of delta-opioid receptor.
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.
Okubo
Shinji
S
Dept. of Cardiology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan. shinkubo@kanazawa-med.ac.jp
Tanabe
Yujirou
Y
Takeda
Kenji
K
Kitayama
Michihiko
M
Kanemitsu
Seiyu
S
Kukreja
Rakesh C
RC
Takekoshi
Noboru
N
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D011817:Rabbits; D017465:Receptors, Opioid, delta / Q000378:metabolism*
D000701:Analgesics, Opioid; D017465:Receptors, Opioid, delta; D009020:Morphine