Myocardial Apoptosis and Infarction after Ischemia/Reperfusion Are Attenuated by κ-Opioid Receptor Agonist

Rong, Fan; Peng, Zhang; Ming-Xiang, Ye; Zhang, Quan-Yu; Zhao, Yin; Zhang, Shu-Miao; Guo, Hai-Tao; Bi, Hui; Wang, Yue-Min; Liang, Cheng; Gu, Chun-Hu; Tao, Chen; Cui, Qin; Yu, Shi-Qiang; Yi, Ding-Hua; Pei, Jian-Ming

doi:10.1016/j.arcmed.2009.04.009

« Previous Next »Archives of Medical Research
Volume 40, Issue 4 , Pages 227-234, May 2009

Myocardial Apoptosis and Infarction after Ischemia/Reperfusion Are Attenuated by κ-Opioid Receptor Agonist

Fan Rong
- Department of Physiology, National Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
- These authors contributed equally to this work.
Zhang Peng
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
- These authors contributed equally to this work.
Ye Ming-Xiang
- Department of Oral Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
- These authors contributed equally to this work.
Quan-Yu Zhang
- Department of Physiology, National Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Yin Zhao
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Shu-Miao Zhang
- Department of Physiology, National Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Hai-Tao Guo
- Department of Physiology, National Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Hui Bi
- Department of Physiology, National Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Yue-Min Wang
- Department of Physiology, National Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Cheng Liang
- Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Chun-Hu Gu
- Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Chen Tao
- Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Qin Cui
- Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Shi-Qiang Yu
- Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Ding-Hua Yi
- Department of Cardiac Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
Jian-Ming Pei
- Department of Physiology, National Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China
- Address reprint requests to: Jian-Ming Pei, Department of Physiology, Fourth Military Medical University, Xi'an 710032, China

Received 18 September 2008; accepted 11 February 2009.

(ARCMED-D-08-00422)

Background and Aims

It remains unclear whether U50488H (a selective κ-opioid receptor agonist) produces anti-apoptotic effect during ischemia and reperfusion (I/R). Therefore, the effect of U50488H on myocardial apoptosis was investigated in the present study.

Methods

Rats were subjected to 45min coronary artery occlusion and 180min of reperfusion. U50488H (1.5mg/kg IV) was given prior to occlusion. Nor-Binaltorphimine (nor-BNI) (2mg/kg IV), a selective κ-opioid receptor antagonist, was given 10min prior to U50488H. Cardiac apoptosis was evaluated by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) assay and in situ identification of nuclear DNA fragmentation.

Results

The ultrastructure injury of myocardium, myocardial infarct size, and plasma CK and LDH were reduced significantly with administration of U50488H before I/R, whereas the effects of U50488H were abolished by nor-BNI. DNA fragments were visualized by agarose electrophoresis, and clear DNA ladder formation was observed in myocardial tissue from hearts subjected to I/R. Administration of U50488H before ischemia exerted a significant anti-apoptotic effect as evidenced by markedly weaker DNA ladder formation. TUNEL staining showed U50488H treatment before I/R significantly reduced the percentage of apoptotic cells, which was blocked by 5-HD, a mitochondrial k_ATP channel blocker. In accordance, U50488H treatment significantly inhibited I/R-induced elevated activities of caspase-3 and caspase-9. U50488H also produced an increase in Bcl-2 and a decrease in Bax protein expression in the I/R heart, and the anti-apoptotic effects of U50488H were all blocked by nor-BNI.

Conclusions

U50488H reduces myocardial necrosis and apoptosis after I/R and activation of κ-opioid receptor may mediate a role in U50488H-induced myocardial protection.

Key Words: Ischemia/reperfusion, κ-Opioid receptor, U50488H, Apoptosis