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    Please use this identifier to cite or link to this item: http://ir.cnu.edu.tw/handle/310902800/30960


    標題: Phosphodiesterase inhibitor KMUP-3 displays cardioprotection via protein kinase G and increases cardiac output via G-protein-coupled receptor agonist activity and Ca2+ sensitization
    作者: Liu, Chung-Pin
    Yeh, Jwu-Lai
    Liou, Shu-Fen
    Wu, Bin-Nan
    Chen, Ing-Jun
    貢獻者: Yuans Gen Hosp, Dept Internal Med
    Kaohsiung Med Univ, Sch Med, Dept Pharmacol
    Chia Nan Univ Pharm & Sci, Dept Pharm
    Pingtung Christian Hosp, Dept Med & Educ
    關鍵字: Ca2+ entry
    Cardiac output
    Cardioprotection
    PKG
    G-protein-coupled receptor
    cgmp
    日期: 2016-02
    上傳時間: 2018-01-18 11:38:45 (UTC+8)
    出版者: Elsevier Taiwan
    摘要: KMUP-3 (7-{2-[4-(4-nitrobenzene) piperazinyl]ethyl}-1, 3-dimethylxanthine) displays cardioprotection and increases cardiac output, and is suggested to increase cardiac performance and improve myocardial infarction. To determine whether KMUP-3 improves outcomes in hypoperfused myocardium by inducing Ca2+ sensitization to oppose protein kinase (PK) G-mediated Ca2+ blockade, we measured left ventricular systolic blood pressure, maximal rates of pressure development, mean arterial pressure and heart rate in rats, and measured contractility and expression of PKs/RhoA/Rho kinase (ROCK) II in beating guinea pig left atria. Hemodynamic changes induced by KMUP-3 (0.5-3.0 mg/kg, intravenously) were inhibited by Y27632 [(R)-(+)-trans-4-1-aminoethyl)-N-(4-Pyridyl) cyclohexane carboxamide] and ketanserin (1 mg/kg, intravenously). In electrically stimulated left guinea pig atria, positive inotropy induced by KMUP-3 (0.1-100 mu M) was inhibited by the endothelial NO synthase (eNOS) inhibitors N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole, cyclic AMP antagonist SQ22536 [9-(terahydro-2-furanyl)-9H-purin-6-amine], soluble guanylyl cyclase (sGC) antagonist ODQ (1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one), RhoA inhibitor C3 exoenzyme, beta-blocker propranolol, 5-hydroxytryptamine 2A antagonist ketanserin, ROCK inhibitor Y27632 and KMUP1 (7-{2-[4-(2-chlorobenzene) piperazinyl]ethyl}-1, 3-dimethylxanthine) at 10 mu M. Western blotting assays indicated that KMUP-3 (0.1-10 mu M) increased PKA, RhoA/ROCKII, and PKC translocation and CIP-17 (an endogenous 17-kDa inhibitory protein) activation. In spontaneous right atria, KMUP-3 induced negative chronotropy that was blunted by 7-nitroindazole and atropine. In neonatal myocytes, L-NAME inhibited KMUP-3-induced eNOS phosphorylation and RhoA/ROCK activation. In H9c2 cells, Y-27632 (50 mu M) and PKG antagonist KT5823 [2,3,9,10,11,12-hexahydro-10R- methoxy-2,9-dimethyl-1-oxo-9S, 12R-epoxy-1H-diindolo(1,2,3-fg: 3',2',1'-kl) pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid, methyl ester] (3 mu M) reversed KMUP-3 (1-100 mu M)-induced Ca2+-entry blockade. GPCR agonist activity of KMUP-3 appeared opposed to KMUP-1, and increased cardiac output via Ca2+ sensitization, and displayed cardioprotection via cyclic GMP/PKG-mediated myocardial preconditioning in animal studies. Copyright (C) 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC.
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