DN 9693: A Phosphodiesterase Inhibitor with a Platelet Membrane Effect

Summary

We have examined the in vitro effects of DN 9693 (piperidinylimidazo-quinazolinone) on various aspects of platelet reactivity. Our results are consistent with its known function as a phosphodiesterase inhibitor in that it increased platelet cyclic AMP, particularly in conjunction with an adenylate cyclase stimulator, and exerted a profound inhibitory effect on platelet aggregation responses to a variety of agonists. DN 9693 also inhibited ristocetin-induced platelet agglutination (RIPA). We therefore examined its effect on ristocetin co-factor assays and on the binding of a monoclonal antibody (McAb) to platelet membrane glycoprotein lb (GPIb). The drug inhibited the binding of the monoclonal antibody in a dose-dependent manner. This suggests an effect of the drug on the platelet surface membrane with reduced expression of GPIb. Our results indicate that in addition to its anticipated inhibitory effect on platelet aggregation, DN 9693 may also inhibit platelet adhesion.

Keywords

DN 9693 - Phosphodiesterase inhibitor - Platelet membrane glycoprotein Ib

• References

• 1 Sakuma K, Ashida S. Anti-platelet effect of DN 9693, a new water soluble compound: a cyclic AMP dependent phenomenon. Thromb Haemostas 1985; 54: 134 (Abstr)
• 2 O’Brien JR, Etherington MD, Salmon GP. DN 9693, a phosphodiesterase inhibitor, compard with prostaglandin El and prostacyclin in four platelet function tests. Thromb Res 1988; 50: 237-241
• 3 Jackson CA, Greaves M, Boulton AJ M, Ward JD, Preston FE. Near-normal glycaemic control does not correct abnormal platelet reactivity in diabetes mellitus. Clin Sci 1984; 67: 551-555
• 4 Greaves M, Preston FE. The laboratory investigation of acquired and congenital platelet disorders. In: Blood Coagulation and Haemostasis; a Practical Guide. Third Edition. Thompson JM. (ed) Churchill Livingstone; Edinburgh: 1985. p 56-135
• 5 Feinman RD, Lubowsky J, Charo IF, Zabinski MP. The lumiag- gregometer: a new instrument for simultaneous measurement of secretion and aggregation by platelets. J Lab Clin Med 1977; 90 (01) 125-129
• 6 Best LC, McGuire MB, Jones PB, Holland TK, Martin TJ, Preston FE, Segal DS, Russell RG G. Mode of action of dipyridamole on human platelets. Thromb Res 1979; 16 3-4 367-379
• 7 Evans RJ, Austen DC G. Assay of Ristocetin co-factor using fixed platelets and a platelet counting technique. Br J Haematol 1977; 37: 289-294
• 8 Brinkhous KM, Graham JE, Cooper HA, Allain JP, Wagner RH. Assay of von Willebrand factor in von Willebrand’s disease and haemophilia: use of a macroscopic platelet aggregation test. Thromb Res 1975; 6 (03) 267-272
• 9 Johnston GI, Heptinstall S, Robins RA, Price MR. The expression of glycoproteins on single blood platelets from healthy individuals and from patients with congenital bleeding disorders. Biochem Biophys Res Commun 1984; 123 (03) 1091-1098
• 10 Hawiger J, Steer ML, Salzman EW. Intracellular regulatory processes in platelets. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 2nd Edition. Colman RW, Hirsh J, Marder VJ, Salzman EW. (eds) J. B. Lippincott Co.; Philadelphia: 1987. pp 710-725
• 11 Zavoico GB, Feinstein MB. Cytoplasmic Ca⁺⁺in platelets is controlled by cyclic AMP: antagonism between stimulators and inhibitors of adenylate cyclase. Biochem Biophys Res Commun 1984; 120 (02) 579-585
• 12 Kirby EP. Factor VIII associated platelet aggregation. Thromb Haemostas 1977; 38: 1054-1072
• 13 Coller BS. Inhibition of von Willebrand factor dependent platelet function by increased cyclic AMP and its prevention by cytoskeleton disrupting agents. Blood 1981; 57: 846-855
• 14 Fox JE B. Platelet cytoskeleton. In: Thrombosis and Haemostasis. Verstraete M, Vermylen J, Lijnen R, Arnout J. (eds) Leuven University Press; Leuven: 1987. pp 175-225