title: Irsogladine, an anti-ulcer drug, suppresses superoxide production by inhibiting phosphodiesterase type 4 in human neutrophils.
abstract: Neutrophil superoxide production is implicated in the pathogenesis of gastric mucosal damage induced by various ulcerative agents and Helicobacter pylori infection. We investigated here the effects of an anti-ulcer drug irsogladine [2, 4-diamino-6-(2, 5-dichlorophenyl)-s-triazine maleate] on cAMP formation in isolated human neutrophils. The cAMP level in human neutrophils was elevated by a phosphodiesterase (PDE) type 4 selective inhibitor rolipram, but not by any inhibitors of PDE1, PDE2 and PDE3. Irsogladine also increased cAMP formation in a concentration-dependent manner in neutrophils. A non-selective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) alone significantly increased cAMP level, whereas irsogladine was unable to further increase cAMP level in the presence of IBMX. Irsogladine inhibited concentration-dependently the superoxide (O(2)(-)) production induced by various stimuli including formyl-methionyl-leucyl-phenylalanine, opsonized zymosan, guanosine 5'-[gamma-thio] triphosphate, A23187 and phorbol 12-myristate 13-acetate. These effects of irsogladine were mimicked by rolipram, IBMX and dibutyryl cAMP. The inhibitory effects of irsogladine and rolipram on the O(2)(-) production were reversed by a protein kinase A inhibitor H-89. These results indicate that irsogladine inhibits the superoxide production in human neutrophils by the increase of cAMP content by PDE 4 inhibition, which in turn contributing to the anti-ulcer effects of irsogladine on gastric mucosal lesions associated with oxidative stress.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan. t.kyoi@po.nippon-shinyaku.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kyoi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Noda
authors.forename: Michiko
authors.initials: M
authors.lastname: Oka
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Ukai
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000328:Adult; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000503:physiopathology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007546:Isoquinolines / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D020889:Rolipram / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000897:Anti-Ulcer Agents; D007527:Isoenzymes; D007546:Isoquinolines; D013449:Sulfonamides; D014227:Triazines; D013481:Superoxides; D003994:Bucladesine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C041836:irsogladine; D015056:1-Methyl-3-isobutylxanthine