title: Myocardial apoptosis and infarction after ischemia/reperfusion are attenuated by kappa-opioid receptor agonist.
abstract: OBJECTIVE
  It remains unclear whether U50488H (a selective kappa-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 kappa-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 kappa-opioid receptor may mediate a role in U50488H-induced myocardial protection.
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Shaanxi Province, PR China.
authors.forename: Fan
authors.initials: F
authors.lastname: Rong
authors.forename: Zhang
authors.initials: Z
authors.lastname: Peng
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Ye
authors.forename: Quan-Yu
authors.initials: QY
authors.lastname: Zhang
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shu-Miao
authors.initials: SM
authors.lastname: Zhang
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Guo
authors.forename: Bi
authors.initials: B
authors.lastname: Hui
authors.forename: Yue-Min
authors.initials: YM
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Liang
authors.forename: Chun-Hu
authors.initials: CH
authors.lastname: Gu
authors.forename: Chen
authors.initials: C
authors.lastname: Tao
authors.forename: Qin
authors.initials: Q
authors.lastname: Cui
authors.forename: Shi-Qiang
authors.initials: SQ
authors.lastname: Yu
authors.forename: Ding-Hua
authors.initials: DH
authors.lastname: Yi
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Pei
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D053453:Caspase 9 / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D008297:Male; D046529:Microscopy, Electron, Transmission; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D009292:Narcotic Antagonists; D019253:Proto-Oncogene Proteins c-bcl-2; D017473:Receptors, Opioid, kappa; D051028:bcl-2-Associated X Protein; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D053148:Caspase 3; D053453:Caspase 9