title: U50,488H inhibits neutrophil accumulation and TNF-α induction induced by ischemia-reperfusion in rat heart.
abstract: The role of the κ-opioid receptor in inflammation is not well understood. The aim of this study was to investigate whether the κ-opioid receptor agonist U50,488H modulates neutrophil accumulation and TNF-α induction in an ischemia-reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia-reperfusion (MI/R) alone, MI/R+U50,488H, MI/R+U50,488H+Wortmannin, and MI/R+U50,488H+L-NAME. The results demonstrated that compared to MI/R, U50,488H reduced myocardial infarction area, myocardial myeloperoxidase (MPO) levels, serum creatinine kinase (CK) levels, and both serum and myocardial TNF-α production. Increases were seen in NOx levels in the myocardium subjected to MI/R injury. All demonstrated effects of U50,488H were abolished by Nor-BNI, a selective κ-opioid receptor antagonist; Wortmannin, a specific PI3K inhibitor; or L-NAME, a nitric oxide synthase (NOS) inhibitor. In summary, κ-opioid receptor stimulation with U50,488H produces both cardioprotective and anti-inflammatory effects. These effects may be associated with an increase in NO production and the inhibition of neutrophil accumulation and TNF-α induction via a PI3K sensitive pathway in myocardium subjected to MI/R.
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, and Department of Urology, Tangdu Hospital, Xi'an 710032, Shaanxi Province, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wu
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Wang
authors.forename: Shumiao
authors.initials: S
authors.lastname: Zhang
authors.forename: Alan David
authors.initials: AD
authors.lastname: Kaye
authors.forename: Luyu
authors.initials: L
authors.lastname: Huang
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009195:Peroxidase; D003402:Creatine Kinase