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Inhibition of Proinflammatory Tumor Necrosis Factor-α-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
- Source :
- Molecular Pharmacology. 70:977-985
- Publication Year :
- 2006
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2006.
-
Abstract
- In the study of anti-proinflammation by 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), exposure of rat tracheal smooth muscle cells (TSMCs) to tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, increased the expression of inducible nitric-oxide synthase (iNOS) and NO production and decreased the expression of soluble guanylate cyclase alpha1 (sGCalpha1), soluble guanylate cyclase beta1 (sGCbeta1), protein kinase G (PKG), and the release of cGMP in TSMCs. The cell-permeable cGMP analog 8-Br-cGMP, xanthine-based KMUP-1 and KMUP-3, and the phosphodiesterase 5 inhibitor zaprinast all inhibited TNF-alpha-induced increases of iNOS expression and NO levels and reversed TNF-alpha-induced decreases of sGCalpha1, sGCbeta1, and PKG expression. These results imply that cGMP enhancers could have anti-proinflammatory potential in TSMCs. TNF-alpha also increased protein kinase A (PKA) expression and cAMP levels, cyclooxygenase-2 (COX-2) expression, and activated productions of prostaglandin (PG) E2 and 6-keto-PGF1alpha (stable PGI2 metabolite). Dexamethasone and N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398; a selective COX-2 inhibitor) attenuated TNF-alpha-induced expression of COX-2 and activated productions PGE2 and PGI2. However, KMUP-1 and KMUP-3 did not affect COX-2 activities and did not further enhance cAMP levels in the presence of TNF-alpha. It is suggested that TNF-alpha-induced increases of PKA expression and cAMP levels are mediated by releasing PGE2 and PGI2, the activation products of COX-2. In conclusion, xanthine-based KMUP-1 and KMUP-3 inhibit TNF-alpha-induced expression of iNOS in TSMCs, involving the sGC/cGMP/PKG expression pathway but without the involvement of COX-2.
- Subjects :
- Male
medicine.medical_specialty
GUCY1B3
medicine.drug_mechanism_of_action
Myocytes, Smooth Muscle
Nitric Oxide Synthase Type II
Cyclic AMP-Dependent Protein Kinase Type II
Pharmacology
Nitric Oxide
Models, Biological
chemistry.chemical_compound
Piperidines
Internal medicine
Cyclic GMP-Dependent Protein Kinases
medicine
Animals
Rats, Wistar
Protein kinase A
Cells, Cultured
Nitrites
Inflammation
Nitrates
biology
Tumor Necrosis Factor-alpha
GUCY1A3
KMUP-1
Cyclic AMP-Dependent Protein Kinases
Rats
Trachea
Nitric oxide synthase
Endocrinology
Solubility
chemistry
Cyclooxygenase 2
Guanylate Cyclase
Xanthines
Prostaglandins
biology.protein
Molecular Medicine
Nucleotides, Cyclic
Zaprinast
cGMP-dependent protein kinase
Phosphodiesterase 5 inhibitor
Subjects
Details
- ISSN :
- 15210111 and 0026895X
- Volume :
- 70
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmacology
- Accession number :
- edsair.doi.dedup.....890b802a9fb15c612f5b6ff9eb194d6a