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.

Abstract

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.

• Authors: H Makino, T Saijo, Y Maki
• Journal: Agents and actions (Agents Actions) Vol. 28 Issue 3-4 Pg. 248-55 (Nov 1989) ISSN: 0065-4299 [Print] Switzerland
• PMID: 2556899 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Arachidonic Acids
• Pyrimidines
• AA 2379
• Arachidonic Acid
• N-Formylmethionine Leucyl-Phenylalanine
• Zymosan
• Cyclic AMP
• 3',5'-Cyclic-AMP Phosphodiesterases
• Muramidase
• Glucuronidase

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arachidonic Acid
• Arachidonic Acids (metabolism)
• Cyclic AMP (metabolism)
• Glucuronidase (metabolism)
• Lysosomes (drug effects, enzymology)
• Male
• Muramidase (metabolism)
• N-Formylmethionine Leucyl-Phenylalanine (pharmacology)
• Neutrophils (drug effects, enzymology, metabolism)
• Pyrimidines (pharmacology)
• Rats
• Rats, Inbred Strains
• Zymosan (pharmacology)