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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

A Xanthine-Based Epithelium-Dependent Airway Relaxant KMUP-3 (7-[2-[4-(4-Nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) Increases Respiratory Performance and Protects against Tumor Necrosis Factor--Induced Tracheal Contraction, Involving Nitric Oxide Release and Expression of cGMP and Protein Kinase G

Institute of Medicine (R.-J.L.), Department and Graduate Institute of Pharmacology (B.-N.W., Y.-C.L., L.-M.A., I.-J.C.), and Departments of Pediatrics (Z.-K.D.), Cardiovascular Surgery (Y.-T.L.), and Anesthesiology (C.-S.T.), College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

KMUP-3 (7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) was investigated in guinea pig tracheal smooth muscle. Intratracheal instillation of tumor necrosis factor (TNF)- (0.01 mg/kg/300 µl) induced bronchoconstriction, increases of lung resistance, and decreases of dynamic lung compliance. Instillation of KMUP-3 (0.5-2.0 mg/kg) reversed this situation. In isolated trachea precontracted with carbachol, KMUP-3 (10-100 µM)-caused relaxations were attenuated by epithelium removal and by pretreatments with an inhibitor of K⁺ channel, tetraethylammonium (10 mM); K_ATP channel, glibenclamide (1 µM); voltage-dependent K⁺ channel, 4-aminopyridine (100 µM); Ca²⁺-dependent K⁺ channel, charybdotoxin (0.1 µM) or apamin (1 µM); soluble guanylate cyclase (sGC), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1one (ODQ, 1 µM); nitric-oxide (NO) synthase, N-nitro-L-arginine methyl ester (L-NAME, 100 µM); and adenylate cyclase, SQ 22536 [9-(terahydro-2-furanyl)-9H-purin-6-amine] (100 µM). KMUP-3 (0.01-100 µM) induced increases of cGMP and cAMP in primary culture of tracheal smooth muscle cells (TSMCs). The increase in cGMP by KMUP-3 was reduced by ODQ and L-NAME; the increase in cAMP was reduced by SQ 22536. Western blot analysis indicated that KMUP-3 (1 µM) induced expression of protein kinase A (PKA)_ri and protein kinase G (PKG)_{1 1} in TSMCs.SQ 22536 inhibited KMUP-3-induced expression of (PKA)_ri.On the contrary, ODQ inhibited KMUP-3-induced expression of PKG_{1 1} In epithelium-intact trachea, KMUP-3 increased the NO release. Activation of sGC, NO release, and inhibition of phosphodiesterases in TSMCs by KMUP-3 may result in increases of intracellular cGMP and cAMP, which subsequently activate PKG and PKA, efflux of K⁺ ion, and associated reduction in Ca²⁺ influx in vitro, indicating the action mechanism to protect against TNF--induced airway dysfunction in vivo.

Address correspondence to: Dr. Ing-Jun Chen, Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan. E-mail: ingjun{at}kmu.edu.tw

This article has been cited by other articles:

				B.-N. Wu, C.-W. Chen, S.-F. Liou, J.-L. Yeh, H.-H. Chung, and I.-J. Chen Inhibition of Proinflammatory Tumor Necrosis Factor-{alpha}-Induced Inducible Nitric-Oxide Synthase by Xanthine-Based 7-[2-[4-(2-Chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) and 7-[2-[4-(4-Nitrobenzene)piperazinyl]ethyl]-1, 3-dimethylxanthine (KMUP-3) in Rat Trachea: The Involvement of Soluble Guanylate Cyclase and Protein Kinase G Mol. Pharmacol., September 1, 2006; 70(3): 977 - 985. [Abstract] [Full Text] [PDF]