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DOI: 10.1160/TH10-07-0439
Shear-dependent suppression of platelet thrombus formation by phosphodiesterase 3 inhibition requires low levels of concomitant Gs-coupled receptor stimulation
Publication History
Received:
10 July 2010
Accepted after major revision:
25 November 2010
Publication Date:
27 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201103/lookinside/thumbnails/10-1160-th10-07-0439-1.jpg)
Summary
Phosphodiesterase (PDE)3 inhibitors exert potent antiplatelet effects through maintaining elevated intracellular cyclic adenosine monophosphate levels, but do not prolong bleeding time. To resolve this discrepancy, we hypothesised that PDE3 inhibitors effectively suppress shear-induced platelet thrombus formation initiated by the interaction of the platelet receptor GPIb/V/IX with its ligand, von Willebrand factor (VWF), since arterial thrombosis is more dependent on shear stress as compared with haemostatic plug formation. To test the hypothesis, we compared the in vitro effects of K-134 (a PDE3 inhibitor), tirofiban (a GPIIb/IIIa inhibitor) and acetylsalicylic acid (ASA) on ristocetin-induced platelet aggregation and platelet thrombus formation on VWF or collagen surfaces under flow conditions. K-134 inhibited GPIIb/IIIa-dependent platelet aggregation to the same extent as tirofiban and more potently than ASA. Likewise, K-134 and tirofiban effectively inhibited stable platelet thrombus formation (platelet firm adhesion and subsequent aggregation) on the VWF or collagen surface under high shear, but ASA only inhibited aggregation. Notably, inhibition by K-134 became evident only when a low concentration of PGE1 was present. These inhibitors did not block shear-induced initial platelet contact with VWF via GPIb/V/IX. In contrast, under low shear, the inhibitory effects of K-134 on platelet aggregation on the collagen surface were lower than tirofiban or ASA. The observed shear-dependent suppression of platelet thrombus formation by PDE3 inhibitor in the presence of low levels of adenylate cyclase stimulator may contribute to high therapeutic benefit with low risk of bleeding.
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References
- 1 Feijge MA, Ansink K, Vanschoonbeek K. et al. Control of platelet activation by cyclic AMP turnover and cyclic nucleotide phosphodiesterase type-3. Biochem Pharmacol 2004; 67: 1559-1567.
- 2 Norgren L, Hiatt WR, Dormandy JA. et al. TASC II Working Group.. Inter-Society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007; 45 Suppl S S5-67.
- 3 Kim JS, Lee KS, Kim YI. et al. A randomized crossover comparative study of aspirin, cilostazol and clopidogrel in normal controls: analysis with quantitative bleeding time and platelet aggregation test. J Clin Neurosci 2004; 11: 600-602.
- 4 Wilhite DB, Comerota AJ, Schmieder FA. et al. Managing PAD with multiple platelet inhibitors: the effect of combination therapy on bleeding time. J Vasc Surg 2003; 38: 710-713.
- 5 Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects). J Vasc Surg 2008; 47: 330-336.
- 6 Gotoh F, Tohgi H, Hirai S. et al. Cilostazol stroke prevention study: a placebo-controlled double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis 2000; 9: 147-157.
- 7 Savage B, Saldívar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84: 289-297.
- 8 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998; 94: 657-666.
- 9 Kasirer-Friede A, Cozzi MR, Mazzucato M. et al. Signaling through GPIb/IX/V activates alpha IIb beta 3 independently of other receptors. Blood 2004; 103: 3403-3411.
- 10 Nieswandt B, Brakebusch C, Bergmeier W. et al. Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. EMBO J 2001; 20: 2120-2130.
- 11 Jackson SP, Nesbitt WS, Westein E. Dynamics of platelet thrombus formation. J Thromb Haemost 2009; 7 (Suppl. 01) 17-20.
- 12 Akiyama H, Kudo S, Shimizu T. The metabolism of a new antithrombotic and vasodilating agent, cilostazol, in rat, dog and man. Arzneimittelforschung 1985; 35: 1133-1140.
- 13 Minami N, Suzuki Y, Yamamoto M. et al. Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo. Life Sci 1997; 61: PL383-389.
- 14 Sudo T, Tachibana K, Toga K. et al. Potent effects of novel antiplatelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity. Biochem Pharmacol 2000; 59: 347-356.
- 15 Koga Y, Kihara Y, Okada M. et al. 2(1H)-quinolinone derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and anti-hyperplastic activities. Bioorg Med Chem Lett. 1998; 8: 1471-1476.
- 16 Nishiya T, Kainoh M, Murata M. et al. Reconstitution of adhesive properties of human platelets in liposomes carrying both recombinant glycoproteins Ia/IIa and Ibα under flow conditions: specific synergy of receptor-ligand interactions. Blood 2002; 100: 136-142.
- 17 Shenkman B, Savion N, Dardik R. et al. Testing of platelet deposition on polysty-rene surface under flow conditions by the cone and plate(let) analyzer: role of platelet activation, fibrinogen and von Willebrand factor. Thromb Res 2000; 99: 353-361.
- 18 Mazzucato M, Cozzi MR, Pradella P. et al. Distinct roles of ADP receptors in von Willebrand factor-mediated platelet signaling and activation under high flow. Blood 2004; 104: 3221-3227.
- 19 Tschopp TB, Baumgartner HR. Platelet adhesion and mural platelet thrombus formation on aortic subendothelium of rats, rabbits, and guinea pigs correlate negatively with the vascular PGI2 production. J Lab Clin Med 1981; 98: 402-411.
- 20 Sun B, Le SN, Lin S. et al. New mechanism of action for cilostazol: interplay between adenosine and cilostazol in inhibiting platelet activation. J Cardiovasc Pharmacol 2002; 40: 577-585.
- 21 Bodnar RJ, Xi X, Li Z. et al. Regulation of glycoprotein Ib-IX-von Willebrand factor interaction by cAMP-dependent protein kinase-mediated phosphorylation at Ser 166 of glycoprotein Ib(beta). J Biol Chem 2002; 277: 47080-47087.
- 22 Mazzucato M, Pradella P, Cozzi MR. et al. Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ibalpha mechanoreceptor. Blood 2002; 100: 2793-2800.
- 23 Yap CL, Hughan SC, Cranmer SL. et al. Synergistic adhesive interactions and signaling mechanisms operating between platelet glycoprotein Ib/IX and integrin alpha IIbbeta 3. J Biol Chem 2000; 275: 41377-41388.
- 24 Ichinohe T, Takayama H, Ezumi Y. et al. Cyclic AMP-insensitive activation of c-Src and Syk protein-tyrosine kinases through platelet membrane glycoprotein VI. J Biol Chem 1995; 270: 28029-28036.
- 25 Ryningen A, Jensen BO, Holmsen H. Role of autocrine stimulation on the effects of cyclic AMP on protein and lipid phosphorylation in collagen-activated and thrombin-activated platelets. Eur J Biochem 1999; 260: 87-96.
- 26 Liu J, Pestina TI, Berndt MC. et al. The roles of ADP and TXA2 in botrocetin/ VWF-induced aggregation of washed platelets. J Thromb Haemost 2004; 2: 2213-2222.
- 27 Pasini FL, Capecchi PL, Perri TD. Adenosine and chronic ischemia of the lower limbs. Vasc Med 2000; 5: 243-250.
- 28 Mubagwa K, Flameng W. Adenosine, adenosine receptors and myocardial protection: an updated overview. Cardiovasc Res 2001; 52: 25-39.
- 29 Sinzinger H, Silberbauer K, Horsch AK. et al. Decreased sensitivity of human platelets to PGI2 during long-term intraarterial prostacyclin infusion in patients with peripheral vascular disease--a rebound phenomenon?. Prostaglandins 1981; 21: 49-51.