title: Quaternary ammonium salt of U50488H, a new κ-opioid receptor agonist, protects rat heart against ischemia/reperfusion injury.
abstract: To keep U50488H from going through the blood-brain barrier, U50488H, a selective κ-opioid receptor agonist, was structurally transformed into its quaternary ammonium salt (Q-U50488H). The effect of Q-U50488H on ischemic/reperfused myocardium and its underlying mechanisms were also investigated. U50488H was transformed into Q-U50488H, which was identified with mass spectrometry. The existences of U50488H and Q-U50488H in serum and brain tissue fluid were determined by high performance liquid chromatography (HPLC). SD rats' hearts were subjected to 30min of ischemia followed by 120min of reperfusion in vivo. After reperfusion, myocardial enzymes and free radicals in serum, area of myocardial infarction, cardiomyocyte apoptosis and the expression of Kir6.2 in rats' myocardium were determined. Molecular weight and solubility of Q-U50488H were higher than those of U50488H. Result of HPLC showed that Q-U50488H existed in serum but not in brain tissue after Q-U50488H intravenous injection. However, U50488H was detected in both serum and brain tissue. Compared with the I/R group, treatment with Q-U50488H significantly attenuated the activity of LDH, CK, AST/GOT and content of MDA in serum, upregulated the activity of SOD, and increased the expression of myocardial Kir6.2. It also reduced myocardial infarct size and cardiomyocyte apoptosis induced by I/R. Moreover, pretreatment with Nor-BNI (a selective κ-opioid receptor antagonist), 5-HD and glibenclamide (KATP antagonists) abolished the effects of Q-U50488H. It is suggested Q-U50488H, a new compound of κ-opioid receptor agonist, which is not able to pass the blood-brain barrier, elicits a protective effect against myocardial ischemia/reperfusion injury. The cardioprotective effect of Q-U50488H is associated with the opening of KATP.
authors.affiliation: Department of Emergency, Xijing Hospital, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR China; Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR China.
authors.forename: Qianmei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR 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, Shaanxi Province, PR China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xing
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR China.
authors.forename: Shumiao
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR 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, Shaanxi Province, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR 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, Shaanxi Province, PR China.
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Emergency, Xijing Hospital, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR China. Electronic address: xjyyyw@fmmu.edu.cn.
authors.forename: Wen
authors.initials: W
authors.lastname: Yin
authors.affiliation: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi׳an 710032, Shaanxi Province, PR China. Electronic address: jmpei8@fmmu.edu.cn.
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 / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D000099161:Kcnj11 Channel
chemical_list: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D002316:Cardiotonic Agents; D008315:Malondialdehyde; D024661:Potassium Channels, Inwardly Rectifying; D000644:Quaternary Ammonium Compounds; D017473:Receptors, Opioid, kappa; D000099161:Kcnj11 Channel
keywords: Apoptosis; Ischemia/reperfusion (I/R) injury; K(ATP); Myocardial infarction; Quaternary ammonium of U50488H (PubChem CID: Q-U50488H); Quaternary ammonium of U50488H (Q-U50488H); κ-opioid receptor