| 16234412 |
Lin RJ, Wu BN, Lo YC, An LM, Dai ZK, Lin YT, Tang CS, Chen IJ: 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-alpha-induced tracheal contraction, involving nitric oxide release and expression of cGMP and protein kinase G. J Pharmacol Exp Ther. 2006 Feb;316(2):709-17. Epub 2005 Oct 18.
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)-alpha (0.01 mg/kg/300 microl) 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 microM)-caused relaxations were attenuated by epithelium removal and by pretreatments with an inhibitor of K (+) channel, tetraethylammonium (10 mm); K (ATP) channel, glibenclamide (1 microM); voltage-dependent K (+) channel, 4-aminopyridine (100 microM); Ca (2+)-dependent K (+) channel, charybdotoxin (0.1 microM) or apamin (1 microM); soluble guanylate cyclase (sGC), 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1one (ODQ, 1 microM); nitric-oxide (NO) synthase, N (omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM); and adenylate cyclase, SQ 22536 [9-(terahydro-2-furanyl)-9H-purin-6-amine] (100 microM). KMUP-3 (0.01-100 microM) 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 microM) induced expression of protein kinase A (PKA)(ri) and protein kinase G (PKG)(1alpha 1beta) in TSMCs.SQ 22536 inhibited KMUP-3-induced expression of (PKA)(ri). On the contrary, ODQ inhibited KMUP-3-induced expression of PKG (1alpha 1beta) 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 Ca (2+) influx in vitro, indicating the action mechanism to protect against TNF-alpha-induced airway dysfunction in vivo. |
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