Phosphodiesterase inhibitor KMUP-3 displays cardioprotection via protein kinase G and increases cardiac output via G-protein-coupled receptor agonist activity and Ca²⁺ sensitization

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• 作者：Chung-Pin Liu^a ; Jwu-Lai Yeh^b ; Shu-Fen Liou^c ; Bin-Nan Wu^b ; Ing-Jun Chen^b ; ^d ; ^{ingjun@kmu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ca2+ entry ; Cardiac output ; Cardioprotection ; PKG ; G-protein-coupled receptor
• 刊名：The Kaohsiung Journal of Medical Sciences
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：32
• 期：2
• 页码：55-67
• 全文大小：2081 K

文摘

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 (0.1–100μM) 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, β-blocker propranolol, 5-hydroxytryptamine 2A antagonist ketanserin, ROCK inhibitor Y27632 and KMUP-1 (7-{2-[4-(2-chlorobenzene) piperazinyl]ethyl}-1, 3-dimethylxanthine) at 10μM. Western blotting assays indicated that KMUP-3 (0.1–10μM) 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 (50μM) 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] (3μM) reversed KMUP-3 (1–100μM)-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.