Inhibitory effects of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl- 2H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (AA-2379) on lysosomal enzyme and arachidonic acid release from rat polymorphonuclear leukocytes and its mode of action.
AA-2379 (methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl- 2H-pyrazolo [3,4-d]pyrimidine-2-carboxylate) has antiinflammatory, analgesic, and antipyretic activities, and inhibits the type III allergic (Arthus) reaction. In the studies reported here, we investigated the effect of AA-2379 on rat polymorphonuclear leukocyte (PMN) functions to clarify the mechanism of the antiinflammatory and antiallergic actions of AA-2379. AA-2379 at 10(-4) M inhibited lysozomal enzyme release. AA-2379 inhibits formyl methionyl-leucyl-phenylalanine (fMLP)- and C5a-induced arachidonic acid release; their 50% inhibitory concentrations were 2.8 x 10(-5) and 3.8 x 10(-5) M, respectively. Because dibutyryl cAMP, a cAMP analogue, and 3-isobutyl-1-methylxanthine, a cAMP phosphodiesterase inhibitor, inhibited fMLP-induced arachidonic acid release, and AA-2379 inhibited cAMP phosphodiesterase and increased cAMP content in PMNs, it is likely that AA-2379 inhibited arachidonic acid release by increasing cAMP content in rat PMNs. Furthermore, from the studies of fMLP-induced arachidonic acid release in Ca free medium it is suggested that AA-2379 inhibits the process which depends on Ca concentration in the medium. These results suggest that the inhibitory effect of AA-2379 on inflammation and allergic reactions such as the Arthus reaction is partly exerted by inhibiting PMN functions such as arachidonic acid and lysozomal enzyme release.
Makino
H
H
Biology Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Saijo
T
T
Maki
Y
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009113:Muramidase / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015054:Zymosan / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D011743:Pyrimidines; C058395:AA 2379; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015054:Zymosan; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D009113:Muramidase; D005966:Glucuronidase