title: κ-Opioid Receptor Stimulation Improves Endothelial Function via Akt-stimulated NO Production in Hyperlipidemic Rats.
abstract: This study was designed to investigate the effect of U50,488H (a selective κ-opioid receptor agonist) on endothelial function impaired by hyperlipidemia and to determine the role of Akt-stimulated NO production in it. Hyperlipidemic model was established by feeding rats with a high-fat diet for 14 weeks. U50,488H and nor-BNI (a selective κ-opioid receptor antagonist) were administered intraperitoneally. In vitro, the involvement of the PI3K/Akt/eNOS pathway in the effect of U50,488H was studied using cultured endothelial cells subjected to artificial hyperlipidemia. Serum total cholesterol and low-density lipoprotein cholesterol concentrations dramatically increased after high-fat diet feeding. Administration of U50,488H significantly alleviated endothelial ultrastructural destruction and endothelium-dependent vasorelaxation impairment caused by hyperlipidemia. U50,488H also increased Akt/eNOS phosphorylation and serum/medium NO level both in vivo and in vitro. U50,488H increased eNOS activity and suppressed iNOS activity in vivo. The effects of U50,488H were abolished in vitro by siRNAs targeting κ-opioid receptor and Akt or PI3K/Akt/eNOS inhibitors. All effects of U50,488H were blocked by nor-BNI. These results demonstrate that κ-opioid receptor stimulation normalizes endothelial ultrastructure and function under hyperlipidemic condition. Its mechanism is related to the preservation of eNOS phosphorylation through activation of the PI3K/Akt signaling pathway and downregulation of iNOS expression/activity.
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Tian
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xu-Yang
authors.initials: XY
authors.lastname: Zheng
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Shu-Miao
authors.initials: SM
authors.lastname: Zhang
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Na
authors.initials: N
authors.lastname: Feng
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Guo
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yue-Min
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an 710032, China.
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 / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D017473:Receptors, Opioid, kappa; D009569:Nitric Oxide; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D019001:Nitric Oxide Synthase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt