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

Abstract

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.

Survivin mediates the anti-apoptotic effect of δ-opioid receptor stimulation in cardiomyocytes

“…This finding is in agreement with those of Okubo et al who reported a ␦-opioid receptor-mediated effect against myocardial apoptosis in a rabbit model of ischemia-reperfusion injury (Okubo et al, 2004).…”

Ischemic but not mechanical preconditioning attenuates ischemia/reperfusion induced myocardial apoptosis in anaesthetized rabbits: The role of Bcl-2 family proteins and ERK1/2

“…Both DNA fragmentation and infarct size were significantly decreased after prolonged ischemia and reperfusion in the preconditioned rat and rabbit heart in vivo [14,33,34]. Moreover, a direct correlation between myocardial infarct size and internucleosomal DNA fragmentation was reported [33].…”

Cellular localization and adaptive changes of the cardiac delta opioid receptor system in an experimental model of heart failure in rats

“…Activation of cardiac G-protein coupled delta opioid receptors (DOR) induces an intracellular kinase pathway in which activation of mitochondrial ATP-sensitive K + -channels seem to play an important role [8][9][10]. In addition, DOR activation triggers different mechanisms at multiple levels to stabilize homeostasis, to increase pro-survival signaling and antioxidative capacity, and to stimulate the growth of neonatal rat ventricular myocytes [11][12][13].…”