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DOI: 10.1055/s-0038-1661037
SQ 22536, an Adenylate-Cyclase Inhibitor, Prevents the Antiplatelet Effect of Dazoxiben, a Thromboxane-Synthetase Inhibitor
Publication History
Received 08 August 1983
Accepted 09 December 1983
Publication Date:
26 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/198401/lookinside/thumbnails/10-1055-s-0038-1661037-1.jpg)
Summary
This study shows that dazoxiben, a selective inhibitor of thromboxane A2-synthetase in human platelets, inhibited arachidonic acid-induced platelet aggregation in platelet-rich plasma samples from four out of 16 healthy volunteers. In these four “responder” samples, the anti-aggregating effect of dazoxiben was prevented by the compound SQ 22536, a 9-substituted adenine analogue, endowed with an inhibitory activity on adenylate-cyclase. The compound SQ 22536 also counteracted the antiaggregating effect of prostaglandin D2, a known activator of platelet adenylate-cyclase. When platelet thromboxane A2-syn- thetase was blocked by dazoxiben, a marked increase of prostaglandin D2 was concomitantly observed both in “responder” and “non responder” samples. The compound SQ 22536 blunted the increase in platelet cAMP caused by either dazoxiben and sodium arachidonate or prostaglandin D2. It is suggested that the antiaggregating effect of dazoxiben is mediated by newly synthesized prostaglandin D2. The latter acts by stimulating adenylate-cyclase and increasing cAMP levels. The compound SQ 22536 prevents both phenomena. In “non responder” samples some factors - still to be defined - might counteract similarly to the compound SQ 22536 the antiaggregating activity of PGD2.
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References
- 1 Tyler HM, Saxton CA P D, Parry MJ. Administration to man of UK- 37, 248-01, a selective inhibitor of thromboxane synthetase. Lancet 1981; 1: 629-632
- 2 Bertelé V, Cerletti C, Schieppati A, Di Minno G, de Gaetano G. Inhibition of thromboxane synthetase does not necessarily prevent platelet aggregation. Lancet 1981; 1: 1057-1058
- 3 Grimm LJ, Knapp DR, Senator D, Halushka PV. Inhibition of platelet thromboxane synthesis by 7-(1-imidazolyl) heptanoic acid: Dissociation from inhibition of aggregation. Thromb Res 1981; 24: 307-317
- 4 Heptinstall S, Bevan J, Cockbill SR, Hanley SP, Parry MJ. Effects of a selective inhibitor of thromboxane synthetase on human blood platelet behaviour. Thromb Res 1980; 20: 219-230
- 5 Smith JB, Araki H, Lefer AM. Thromboxane A2, prostacyclin and aspirin: Effects on vascular tone and platelet aggregation. Circulation 1980; 62 (suppl) (Suppl. 05) 19-25
- 6 de Gaetano G, Bertelé V, Cerletti C, Di Minno G. Prostaglandin effects on platelets. In: Prostaglandins in Clinical Medicine. Cardiovascular and Thrombotic Disorders Wu KK, Rossi EC. (eds) Year Book Medical Publ; Chicago: 1982. pp 49-74
- 7 Di Minno G, Bertelé V, Bianchi L, Barbieri B, Cerletti C, Dejana E, de Gaetano G, Silver MJ. Effects of an epoxymethano stable analogue of prostaglandin endoperoxides (U-46619) on human platelets. Thromb Haemostas 1981; 45: 103-106
- 8 Smith JB, Silver MJ, Ingerman CM, Kocsis JJ. Prostaglandin D2 inhibits the aggregation of human platelets. Thromb Res 1974; 5: 291-299
- 9 Nishizawa EE, Miller WL, Gorman R, Bundy GL, Svensson J, Hamberg M. Prostaglandin D2 as a potential antithrombotic agent. Prostaglandins 1975; 9: 109-121
- 10 Mills DC B, Macfarlane DE. Stimulation of human platelet adenylate cyclase by prostaglandin D2 . Thromb Res 1974; 5: 401-412
- 11 Di Minno G, Silver MJ, de Gaetano G. Prostaglandins as inhibitors of human platelet aggregation. Br J Haematol 1979; 43: 637-647
- 12 Ingerman-Wojenski C, Silver MJ, Smith JB, Macarak E. Bovine endothelial cells in culture produce thromboxane as well as prosta-cylin. J Clin Invest 1981; 67: 1292-1296
- 13 Sors H, Pradelles P, Dray F, Rigaud M, Maclouf J, Bernard P. Analytical methods for thromboxane B2 measurement and validation of radioimmunoassay by gas liquid chromatography-mass spectrometry. Prostaglandins 1978; 16: 277-290
- 14 Steer ML, MacIntyre DE, Levine L, Salzman EW. Is prostacyclin a physiologically important circulating anti-platelet agent. Nature 1980; 283: 194-195
- 15 Barbieri B, Balconi G, Dejana E, Donati MB. Evidence that vascular endothelial cells can induce the retraction of fibrin clots. Proc Soc Exp Biol Med 1981; 168: 204-207
- 16 Dejana E, Balconi G, De Castellamau C, Barbieri B, Vergara-Dauden M, de Gaetano G. Prostacyclin production by human endothelial and bovine smooth muscle cells in culture. Effect of repeated stimulation with arachidonic acid, thrombin and ionophore A23187 Biochim Biophys Acta 1983; 750: 261-267
- 17 Smith JB. Effect of thromboxane synthetase inhibitors on platelet function: Enhancement by inhibition of phosphodiesterase. Thromb Res 1982; 28: 477-485
- 18 Heptinstall S, Bients N, Cockbill SR, Hanley SP, Peacock I. Different effects of thromboxane synthetase inhibitors on platelets from different individuals. Lancet 1982; 2: 1156
- 19 Haslam RJ, Davidson MM, Desjardins JV. Inhibition of adenylate cyclase by adenosine analogues in preparations of broken and intact human platelets. Biochem J 1978; 176: 83-95
- 20 Harris DN, Asaad MM, Phillips MB, Goldenberg HJ, Antonaccio MJ. Inhibition of adenylate cyclases in human blood platelets by 9-substituted adenine derivatives. J Cyclic Nucleotide Res 1979; 5: 125-134
- 21 Salzman EW. Interrelation of prostaglandin endoperoxide (prostaglandin G2) and cyclic 3’, 5’-adenosine monophosphate in human blood platelets. Biochim Biophys Acta 1977; 499: 48-60
- 22 Defreyn G, Deckmyn H, Vermylen J. A thromboxane synthetase inhibitor reorients endoperoxide metabolism in whole blood towards prostacyclin and prostaglandin E2 . Thromb Res 1982; 26: 389-400
- 23 Watanabe T, Narumiya SShimizu, Hayaishi O. Characterization of the biosynthetic pathway of Prostaglandin D2 in human platelet-rich plasma. J Biol Chem 1982; 257: 847-853