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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 lysozomal enzyme and arachidonic acid release from rat polymorphonuclear leukocytes and its mode of action

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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 2.8×10−5 and 3.8×10−5 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.

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References

  1. H. Makino, S. Kuzuna, T. Naka, T. Saijo and Y. Maki,Antiinflammatory, analgesic, and antipyretic activities of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2 H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (AA-2379), a novel nonacidic agent. Agents and Actions25, 385–393 (1988).

    PubMed  Google Scholar 

  2. H. Makino, T. Naka, T. Saijo and Y. Maki,The effect of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2 H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (AA-2379) on type III allergic (Arthus) reaction. Agents and Actions25, 326–335 (1988).

    PubMed  Google Scholar 

  3. C. G. Cochrane and J. Janoff,The Arthus reaction: A model of neutrophil and complement-mediated injury; In the inflammatory process. (Ed. B. W. Zwifach, L. Grant and R. T. Macluskey) pp. 85–162, Academic Press, New York 1974.

    Google Scholar 

  4. R. J. Smith, S. S. Iden and N. A. Rohloff,A model of Arthus pleurisy: Modulation by various pharmacologic and therapeutic agents. Clin. Immunol. and Immunopathol.26, 24–34 (1983).

    Google Scholar 

  5. N. J. Zvaifler,Etiology and pathogenesis of rheumatoid arthrits. InArthritis and Allied Conditions, 10th ed. (Ed. D. J. MacCarty) pp. 557–570, Lea & Febiger, Philadelphia 1985.

    Google Scholar 

  6. H. Makino, Y. Ashida, T. Saijo, H. Kuriki, S. Terao and Y. Maki,Role of leukotrienes in rat reversed passive Arthus pleurisy and the effect of AA-861, a 5-lipoxygenase inhibitor. Int. Archs Allergy apple. Immun.79, 38–44 (1986).

    Google Scholar 

  7. J. H. Humphrey,The mechanism of Arthus reactions. I. The role of polymorphonuclear leukocytes and other factors in reversed passive Arthus reactions in rabbits. Br. J. Exp. Pathol.36, 268–282 (1955).

    PubMed  Google Scholar 

  8. N. S. Ranadive and H. Z. Movat,Tissue injury and inflammation induced by immune complexes. InInflammation, immunity and hypersensitivity. 2nd ed. (Ed. Movat) pp. 409–443, Harper & Row, New York 1979.

    Google Scholar 

  9. H. Hayashi, M. Yoshinaga, M. Koono, H. Miyoshi and M. Matsumura,Endogeneous permeability factors and their inhibitors affecting vascular permeability in cutaneous Arthus reactions and thermal injury. Br. J. Exp. Pathol.45, 419–435 (1964).

    PubMed  Google Scholar 

  10. C. V. Wedmore and T. J. Williams,Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature289, 646–650 (1981).

    PubMed  Google Scholar 

  11. A. C. Issekutz,Vascular responses during acute neutrophilic inflammation. Their relationship to in vivo neutrophil emigration. Lab. Invest.45, 435–441 (1981).

    PubMed  Google Scholar 

  12. A. Naef, B. Damerau and H. U. Keller,Relationship between the transient cAMP increase, exocytosis from specific and azulophil granules and chemotaxis in neutrophil granulocytes. Agents and Actions14, 63–71 (1984).

    PubMed  Google Scholar 

  13. R. J. Smith and S. S. Iden,Pharmacological modulation of chemotactic factor-elicited release of granule-associated enzymes from human neutrophils. Effects of prostaglandins, nonsteroid antiinflammatory agents and corticosteroids. Biochem. Pharmacol.29, 2389–2395 (1980).

    PubMed  Google Scholar 

  14. F. Okajima and M. Ui,ADP-ribosylation of the specific membrane protein by islet-activating protein, pertussis toxin, associated with inhibition of a chemotactic peptide-induced arachidonate release in neutrophils. A possibly role of the toxin substrate in Ca 2+ -mobilizing biosignaling. J. Biol. Chem.259, 13863–13871 (1984).

    PubMed  Google Scholar 

  15. L. Simchowitz, L. C. Fischbein, I. Spilberg and J. P. Atkinson,Induction of a transient elevation in intracellular levels of adenosine-3',5'-cyclic monophosphate by chemotactic factors: an early event in human neutrophil activation. J. Immunol.124, 1482–1491 (1980).

    PubMed  Google Scholar 

  16. E. L. Becker, M. Sigman and J. M. Oliver,Superoxide production induced in rabbit polymorphonuclear leukocytes by synthetic chemotactic peptides and A23187. The nature of the receptor and the requirement for Ca 2+. Am. J. Pathol.95, 81–97 (1979).

    PubMed  Google Scholar 

  17. I. M. Goldstein, D. Roos, H. B. Kaplan and G. Weissmann,Complement and immunoglobulins stimulate superoxide production by human leukocytes independently of phagocytosis. J. Clin. Invest.56, 1155–1163 (1975).

    PubMed  Google Scholar 

  18. K. Takamori, T. Yamashita,Biochemical properties of polymorphonuclear neutrophils from venous blood and peritoneal exudates of rabbit. Infect. Immun.29, 395–400 (1980).

    PubMed  Google Scholar 

  19. M. Watanabe, R. Negishi, I. Imada, M. Nishikawa and H. Morimoto,Ubiquinone and related compounds. XXVIII. Effect of the metabolites of α-tocopherol, phylloquinone and ubiquinone on the stability of rat-liver lysozomal membrane. Chem. Pharm. Bull.22, 183–188 (1974).

    PubMed  Google Scholar 

  20. H. Makino, T. Saijo, Y. Ashida, H. Kuriki and Y. Maki,Mechanism of action of an antiallergic agent, amlexanox (AA-673), in inhibiting histamine release from mast cells. Acceleration of cAMP generation and inhibition of phosphodiesterase. Int. Arch. Allergy appl. Immun.82, 66–71 (1987).

    Google Scholar 

  21. W. J. Thompson, M. M. Appleman,Multiple cyclic nucleotide phosphodiesterase activities from rat brain. Biochemistry10, 311–316 (1971).

    PubMed  Google Scholar 

  22. Y.-H. Chang and I. G. Otterness,Effects of pharmacologic agents on the reversed passive Arthus reaction in the rat. Eur. J. Pharmacol.69, 155–164 (1981).

    PubMed  Google Scholar 

  23. C. E. Walsh, B. M. Waite, M. J. Thomas and L. R. DeChatelet,Release and metabolism of arachidonic acid in human neutrophils. J. Biol. Chem.256, 7228–7234 (1981).

    PubMed  Google Scholar 

  24. W. F. Stenson and C. W. Parker,Metabolism of arachidonic acid in ionophore-stimulated neutrophils. Esterification of a hydroxylated metabolite into phospholipids. J. Clin. Invest.64, 1457–1464 (1979).

    PubMed  Google Scholar 

  25. M. M. Billah, R. W. Bryant and M. I. Siegel,Lipoxygenase products of arachidonic acid modulate biosynthesis of plateletactivating factor (1-O-alkyl-2-acethyl-sn-glycero-3-phosphocholine) by human neutrophils via phospholipase A 2. J. Biol. Chem.260, 6899–6906 (1985).

    PubMed  Google Scholar 

  26. C. S. Ramesha and W. C. Pickett,Platelet-activating factor and leukotriene biosynthesis is inhibited in polymorphonuclear leukocytes depleted of arachidonic acid. J. Biol. Chem.261, 7592–7595 (1986).

    PubMed  Google Scholar 

  27. D. Aked, S. J. Foster, A. Howarth, M. E. McCormick and H. C. Potts,The inflammatory response of rabbit skin to topical arachidonic acid and its pharmacological modulation. Br. J. Pharmac.89, 431–438 (1986).

    Google Scholar 

  28. A. Ueno, K. Tanaka, M. Katori, M. Hayashi and Y. Arai,Species difference in increased vascular permeability by synthetic leukotriene C 4 and D 4. Prostaglandins21, 637–648 (1981).

    PubMed  Google Scholar 

  29. K. F. Swingle and M. J. Reiter,Inhibition of Paf-acetherinduced edema of the rat's paw. Agents and Actions18, 359–365 (1986).

    PubMed  Google Scholar 

  30. T. J. Williams and P. J. Jose,Mediation of increased vascular permeability after complement activation, Histamineindependent action of rabbit C5a. J. Exp. Med.153, 136–153 (1981).

    PubMed  Google Scholar 

  31. O. N. Fernandez, P. M. Henson, A. Otani and T. E. Hugli,Chemotactic response to human C3a and C5a anaphylatoxins. I. Evaluation of C3a and C5a leukotaxis in vitro and under stimulated in vivo conditions. J. Immunol.120, 109–115 (1978).

    PubMed  Google Scholar 

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  1. Biology Laboratories, Central Research Division, Takeda Chemical Industries, Ltd., 17-85 Jusohonmachi 2-chome, Yodogawa-ku, 532, Osaka, Japan

    H. Makino,  T. Saijo & Y. Maki

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Makino, H., Saijo, T. & Maki, Y. 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 lysozomal enzyme and arachidonic acid release from rat polymorphonuclear leukocytes and its mode of action. Agents and Actions 28, 248–255 (1989). https://doi.org/10.1007/BF01967411

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