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Progress in Clinical Neurosciences: The ‘Antiplatelet’ Agents and the Role of the Endothelium

Published online by Cambridge University Press:  02 December 2014

Farrah J. Mateen  and
Ashfaq Shuaib
Farrah J. Mateen
Affiliation:
The College of Medicine, University of Saskatchewan, Saskatoon, SK
Ashfaq Shuaib
Affiliation:
Division of Neurology, University of Alberta, Edmonton, AB, Canada
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Abstract

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The antiplatelet drugs, commonly used in the prevention and treatment of cerebrovascular disease, possess a number of effects that are independent of direct antiplatelet actions. Beneficial and detrimental effects both occur. The endothelium is an important mediator of these non-antiplatelet effects. We performed a literature search to locate articles related to acetylsalicylic acid (aspirin), clopidogrel, ticlopidine, and dipyridamole and the interactions of these medications with the endothelium. The role of each of the above medications is explored in relation to vasodilation, inflammation, oxidation, platelet-leukocyte interactions, and thrombogenic tendency via platelet-vessel wall interactions.

Résumé:

RÉSUMÉ:

Agents antiplaquettaires et rôle de l'endothélium. Les antiplaquettaires utilisés couramment dans la prévention et le traitement de la maladie cérébrovasculaire ont certains effets qui sont indépendants de l'activité antiplaquettaire directe. Certains sont bénéfiques, d'autres sont néfastes. L'endothélium est un médiateur important de ces effets non antiplaquettaires. Nous avons fouillé la littérature pour trouver des articles sur l'acide acétylsalicylique, le clopidogrel, la ticlopidine et le dipyridamole et leurs interactions avec l'endothélium. Nous examinons le rôle de chacun de ces médicaments dans la vasodilatation, l'inflammation, l'oxydation, les interactions plaquettes-leucocytes et la thrombogénicité via les interactions plaquettes-paroi vasculaire.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 34 , Issue 3 , August 2007 , pp. 270 - 279
Copyright
Copyright © The Canadian Journal of Neurological 2007

References

1. Vallance, P, Collier, J, Bhagat, K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet. 1997;349:1391–2.CrossRefGoogle ScholarPubMed
2. Vane, JR, Änggård, EE, Botting, RM. Regulatory functions of the vascular endothelium. N Engl J Med. 1990;323:27–36.Google ScholarPubMed
3. Husain, S, Andrews, NP, Mulcahy, D, Panza, JA, Quyyumi, AA. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation. 1998;97:716–20.CrossRefGoogle ScholarPubMed
4. Bhagat, K, Vallance, P. Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. Circulation. 1997;96:3042–7.CrossRefGoogle ScholarPubMed
5. Landmesser, U, Hornig, B, Drexler, H. Endothelial function: a critical determinant in atherosclerosis? Circulation. 2004;109 Suppl II:II-27–33.CrossRefGoogle ScholarPubMed
6. Williams, SB, Goldfine, AB, Timimi, FK, Ting, HH, Roddy, M, Simonson, DC, et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation. 1998;97:1695–1701.CrossRefGoogle ScholarPubMed
7. Noon, JP, Walker, BR, Malcolm, FH, Webb, DJ. Impairment of forearm vasodilatation to acetylcholine in hypercholesterolemia is reversed by aspirin. Cardiovasc Res. 1998;38:480–4.CrossRefGoogle ScholarPubMed
8. Hingorani, AD, Cross, J, Kharbanda, RK, Mullen, MJ, Bhagat, K, Taylor, M, et al. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation. 2000;102:994–9.CrossRefGoogle ScholarPubMed
9. Visseren, F, Bouter, K, Bouwman, J, Erkelens, D, Diepersloot, R. Procoagulant activity of endothelial cells after infection with respiratory viruses. Eur J Clin Invest. 1996;26:A8 (abstr.)Google Scholar
10. Valtonen, V, Kuikka, A, Syrjanen, J. Thrombo-embolic complications in bacteraemic infections. Eur Heart J. 1993;14 Suppl K:20–3.Google ScholarPubMed
11. Furchgott, RF, Zawadzki, JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–6.CrossRefGoogle ScholarPubMed
12. Drexler, H, Hayoz, D, Munzel, T, Hornig, B, Just, H, Brunner, HR, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol. 1992;69:1596–601.CrossRefGoogle ScholarPubMed
13. Weiss, HJ, Aledort, LM. Impaired platelet-connective-tissue reaction in man after aspirin ingestion. Lancet. 1967;2:295–7.Google ScholarPubMed
14. Awtry, EH, Loscalzo, J. Aspirin. Circulation. 2000;101:1206–18.CrossRefGoogle ScholarPubMed
15. Hankey, GJ, Eikelboom, JW. Antiplatelet drugs. Med J Aust. 2003;178, 568–74.CrossRefGoogle ScholarPubMed
16. Müller, TH. Inhibition of thrombus formation by low-dose acetylsalicylic acid, dipyridamole, and their combination in a model of platelet-vessel wall interaction. Neurology. 2001;57 Suppl 2:S8–S11.CrossRefGoogle Scholar
17. Catella-Lawson, F. Vascular biology of thrombosis platelet-vessel wall interactions and aspirin effects. Neurology. 2001;57 Suppl 2:S5–S7.CrossRefGoogle ScholarPubMed
18. Fitzgerald, DJ, Roy, L, Catella, F, FitzGerald, GA. Platelet activation in unstable coronary disease. N Engl J Med. 1986;315:983–9.CrossRefGoogle ScholarPubMed
19. Torsney, E, Mayr, U, Zou, Y, Thompson, WD, Hu, Y, Xu, Q. Thrombosis and neointima formation in vein grafts are inhibited by locally applied aspirin through endothelial protection. Circ Res. 2004;94:1466–73.CrossRefGoogle ScholarPubMed
20. Henn, V, Slupsky, JR, Gräfe, M, Anagnostopoulos, I, Förster, R, Müller-Berghaus, G, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998;391:591–4.CrossRefGoogle ScholarPubMed
21. Nannizzi-Alaimo, L, Alves, VL, Phillips, DR. Inhibitory effects of glycoprotein IIb/Iiz antagonists and aspirin on the release of soluble CD40 ligand during platelet stimulation. Circulation. 2003;107:1123–8.CrossRefGoogle Scholar
22. Mach, F, Schönbeck, U, Sukhova, GK, Bourcier, T, Bonnefoy, JY, Pober, JS, et al. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-Cd40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA. 1997;94:1931–6.CrossRefGoogle ScholarPubMed
23. Schonbeck, U, Varo, N, Libby, P, Buring, J, Ridker, PM. Soluble CD40L and cardiovascular risk in women. Circulation. 2001;104:2266–8.CrossRefGoogle ScholarPubMed
24. Schönbeck, U, Libby, . CD40 signaling and plaque instability. Circ Res. 2001;89:1092–1103.CrossRefGoogle ScholarPubMed
25. Aguejouf, O, Belougne-Malfatti, E, Doutremepuich, F, Belon, P, Doutremepuich, C. Thromboembolic complications several days after a single dose administration of aspirin. Thromb Res. 1998;89:12–7.CrossRefGoogle ScholarPubMed
26. Nishimura, H, Naritomi, H, Iwamoto, Y, Tachibana, H, Sugita, M. In vivo evaluation of antiplatelet agents in gerbil model of carotid artery thrombosis. Stroke. 1996;27:1099–104.CrossRefGoogle ScholarPubMed
27. Eldor, A, Vlodavsky, I, Fuks, Z, Muller, TH, Eisert, WG. Different effects of aspirin, dipyridamole and UD-CG 115 on platelet activation in a model of vascular injury: studies with extracellular matrix covered with endothelial cells. Thromb Haemost. 1986;56:333–9.Google Scholar
28. Aguejouf, O, Malfatti, E, Belon, P, Doutremepuich, C. Time related neutralization of two doses acetyl salicylic acid. Thromb Res. 2000;100:317–23.CrossRefGoogle ScholarPubMed
29. Bhagat, K, Collier, J, Vallance, P. Endothelial “stunning” following a brief exposure to endotoxin: a mechanism to link infection to infarction? Cardiovasc Res. 1996;32:822–9.Google ScholarPubMed
30. Kharbanda, RK, Walton, B, Allen, M, Klein, N, Hingorani, AD, MacAllister, RJ, et al. Prevention of inflammation-induced endothelial dysfunction: a new vasculo-protective action of aspirin. Circulation. 2002;105:2600–4.CrossRefGoogle Scholar
31. Radomski, MW, Palmer, RM, Moncada, S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol. 1987;92:639–46.CrossRefGoogle ScholarPubMed
32. Capone, ML, Tacconelli, S, Sciulli, MG, Grana, M, Ricciotti, E, Minuz, P. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and the low-dose aspirin in healthy subjects. Circulation. 2004;109:1468–71.CrossRefGoogle ScholarPubMed
33. Dinarello, CA. Proinflammatory cytokines. Chest. 2000;118:503–8.CrossRefGoogle ScholarPubMed
34. Liu, Y, Pelekanakis, K, Woolkalis, MJ. Thromin and tumor necrosis factor alpha synergistically stimulate tissue factor expression in human endothelial cells: regulation through c-Fos and c-Jun. J Biol Chem. 2004; 279:3512–7.Google Scholar
35. Levine, B, Kalman, J, Mayer, L, Fillit, HM, Packer, M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Eng J Med. 1990;323:236–41.CrossRefGoogle ScholarPubMed
36. Weber, C, Erl, W, Pietsch, A, Weber, PC. Aspirin inhibits nuclear factor-kappa B mobilization and monocyte adhesion in stimulated human endothelial cells. Circulation. 1995; 91:1914–7.CrossRefGoogle ScholarPubMed
37. Ridker, PM, Rifai, N, Stampfer, MJ, Hennekens, CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000; 101:1767–72.CrossRefGoogle ScholarPubMed
38. Biasucci, LM, Liuzzo, G, Fantuzzi, Galigiuri G, Rebuzzi, AG, Ginnetti, F, et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation. 1999;99:2079–84.CrossRefGoogle ScholarPubMed
39. Lopez-Farre, A, Caramelo, C, Esteban, A, Alberola, ML, Millás, I, Montón, M, et al. Myocardial ischemia/myocardial infarction: effects of aspirin on platelet-neutrophil interactions: role of nitric oxide and endothelin-1. Circulation. 1995;91;2080–8.CrossRefGoogle Scholar
40. Li, N, Wallén, NH, Hjemdahl, P. Evidence for prothrombotic effects of exercise and limited protection by aspirin. Circulation. 1999;100:1374–9.CrossRefGoogle ScholarPubMed
41. Evangelista, V, Manarini, S, Sideri, R, Rotondo, S, Martelli, N, Piccoli, A, et al. Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule. Blood. 1999;93:876–85.CrossRefGoogle ScholarPubMed
42. Ott, I, Neumann, FJ, Gawaz, M, Schmitt, M, Schomig, A. Coronary heart disease/myocardial infarction/bypass grafts/endothelial function: increased neutrophil-platelet adhesion in patients with unstable angina. Circulation. 1996;94:1239–46.CrossRefGoogle Scholar
43. Asako, H, Kubes, P, Wallace, J, Wolf, RE, Granger, DN. Modulation of leukocyte adhesion in rat mesenteric venules by aspirin and salicylate. Gastroenterology. 1992;103:146–52.CrossRefGoogle ScholarPubMed
44. Kubes, P, Suzuki, M, Granger, DN. Nitric oxide: an endogenous modulator of leukocyte adhnesion. Proc Natl Acad Sci U S A. 1991;88:4651–5.CrossRefGoogle Scholar
45. Li, N, Hu, H, Hjemdahl, P. Aspirin treatment does not attenuate platelet or leukocyte ativation as monitored by whole blood flow cytometry. Thromb Res. 2003;111,165–70.CrossRefGoogle Scholar
46. Michelson, AD, Barnard, MR, Krueger, LA, Valeri, CR, Furman, MI. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human cute myocardial infarction. Circulation. 2001;104:1533–7.CrossRefGoogle Scholar
47. Furman, MI, Barnard, MR, Krueger, LA, Fox, ML, Shilale, EA, Lessard, DM, et al. Circulating monocyte-platelet aggregates are an early markder of acute myocardial infarction. J Am Coll Cardiol. 2001;38:1002–6.CrossRefGoogle ScholarPubMed
48. Mickelson, JK, Ali, MN, Kleiman, NS, Lakkis, NM, Chow, TW, Hughes, BJ, et al. Chimeric 7E3 Fab (ReoPro) decreases detectable CD11b on neutrophils from patients undergoing coronary angioplasty. J Am Coll Cardiol. 1999;33:97–106.CrossRefGoogle ScholarPubMed
49. Serebruany, VL, Malinin, AI, Ziai, W, Pokov, AN, Bhatt, DL, Alberts, MJ, et al. Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in patients after recent ischemic stroke. Stroke 2005; 36:2289–92.CrossRefGoogle ScholarPubMed
50. Lancelot, E, Callebert, J, Revaud, M, Boulu, RG, Plotkine, M. Detection of hydroxyl radicals in rat striatum during transient focal cerebral ischemia: possible impolication in tissue damage. Neurosci Lett. 1995;85–8.CrossRefGoogle ScholarPubMed
51. Kuhn, W, Muller, T, Buttner, T, Gerlach, M. Aspirin as a free radical scavenger: consequences for therapy of cerebrovascular ischemia. Stroke. 1995;26:1959–60.Google ScholarPubMed
52. Kukreja, RC, Kontos, HA, Hess, ML, Ellis, EF. PGH synthase and lipoxygenase generate superoxide in the presence of NADH or NADPH. Circ Res. 1986;59:612–9.CrossRefGoogle ScholarPubMed
53. Armstead, WM, Mirro, R, Busija, DW, Leffler, CW. Postischemic generation of superoxide anion by newborn pig brain. Am J Physiol. 1998;255:H401–3.Google Scholar
54. Sagone, AL, Husney, RM. Oxidation of salicylates by stimulated granulocytes: evidence that these drugs act as free radical scavengers in biological systems. J Immunol. 1987;138:2177–83.CrossRefGoogle ScholarPubMed
55. Witztum, JL. The oxidation hypothesis of atherosclerosis. Lancet. 1994;344:793–5.CrossRefGoogle ScholarPubMed
56. Steer, KA, Wallace, TM, Bolton, CH, Hartog, M. Aspirin protects low density lipoprotein from oxidative modification. Heart. 1997;77:333–7.CrossRefGoogle ScholarPubMed
57. Eisele, G, Schwedhelm, E, Schieffer, B, Tsikas, D, Böger, RH. Acetylsalicylic acid inhibits monocyte adhesion to endothelial cells by an antioxidative mechanism. J Cardiovasc Pharmacol. 2004;43:514–21.CrossRefGoogle ScholarPubMed
58. Barbato, JE, Tzeng, E. Nitric oxide and arterial disease. J Vasc Surg. 2004;40:187–93.CrossRefGoogle ScholarPubMed
59. Madajka, M, Korda, M, White, J, Malinski, T. Effect of aspirin on constitutive nitric oxide synthase and the biovailability of NO. Thromb Res. 2003;110:317–21.CrossRefGoogle ScholarPubMed
60. Taubert, D, Berkels, R, Grosser, N, Schroder, H, Grundemann, D, Schomig, E. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol. 2004;143:159–65.CrossRefGoogle ScholarPubMed
61. Ferroni, P, Basili, S, Falco, A, Davì, G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost. 2004;2:1282–91.CrossRefGoogle ScholarPubMed
62. Dupin, JP, Gryglewski, RJ, Gravier, D, Hou, G, Casadebaig, F, Swies, J, et al. Synthesis and thrombolytic activity of new thienopyrimidinone derivatives. J Physiol Pharmacol. 2002;53:625–34.Google ScholarPubMed
63. Quinn, MJ, Fitzgerald, DJ. Ticlopidine and clopidogrel. Circulation. 1999;100:1667–72.CrossRefGoogle ScholarPubMed
64. CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin I patients at risk of ischaemic events (CAPRIE). Lancet. 1996;100:1667–72.Google Scholar
65. Gachet, C, Stierle, A, Cazenave, JP, Ohlmann, P, Lanza, F, Bouloux, C, et al. The thienopyridine PCR 4099 selectively inhibits ADP-induced platelet aggregation and fibrinogen binding without modifying the membrane glycoprotein IIb/IIIa complex in rat and in man. Biochem Pharmacol. 1990;40:229.CrossRefGoogle ScholarPubMed
66. Gryglewski, RJ, Korbut, R, Âwi’s, J, Kostka-Tràbka, E, Bierof, K, Robak, J. Thrombolytic action of ticlopidine: possible mechanisms. Eur J Pharmacol. 1996;308:61–7.CrossRefGoogle ScholarPubMed
67. Harker, LA. Therapeutic inhibition of platelet function in stroke. Cerebrovasc Dis. 1998;8 Suppl 5:8–18.CrossRefGoogle ScholarPubMed
68. Bhatt, DL, Hirsch, AT, Ringleb, PA, Hacke, W, Topol, EJ. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. Am Heart J. 2000;140:67–73.CrossRefGoogle ScholarPubMed
69. Müller, I, Seyfarth, M, Rüdiger, S, Wolf, B, Pogatsa-Murray, G, Schömig, A, et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart. 2001; 85:92–3.CrossRefGoogle ScholarPubMed
70. Arrebola, MM, De La Cruz, JP, Villalobos, MA, Pinacho, A, Guerrero, A, Sánchez de la Cuesta, F. In vitro effects of clopidogrel on the platelet-subendothelium interaction, platelet thromboxane and endothelial prostacyclin production, and nitric oxide synthesis. J Cardiovasc Pharmacol. 2004;43:74–82.CrossRefGoogle ScholarPubMed
71. Gryglewski, RJ, Uracz, W, Âwi’s, J. Unusual effects of aspirin on ticlopidine induced thrombolysis. Thorax. 2000;55 Suppl2 : S17-9.CrossRefGoogle ScholarPubMed
72. de Lorgeril, M, Bordet, JC, Salen, P, Durbin, S, Defreyn, G, Delaye, J, et al. Ticlopidine increases nitric oxide generation in heart-transplant recipients: a possible novel property of ticlopidine. J Cardiovasc Pharmacol. 1998;32:225–30.CrossRefGoogle ScholarPubMed
73. Yao, S, Ober, JC, Ferguson, JJ, Maffrand, J, Anderson, HV, Buja, M, et al. Clopidogrel is more effective than aspirin as adjuvant treatment to prevent reocclusion after thrombolysis. Am J Physiol. 1994;267:H488–93.Google ScholarPubMed
74. Savi, P, Bernat, A, Dumas, A, Aït-Chek, L, Herbert, J. Effect of aspirin and clopidogrel on platelet-dependent tissue factor expression in endothelial cells. Thromb Res. 1994;73:117–24.CrossRefGoogle ScholarPubMed
75. Kleiman, NS. Platelets, the cardiologist, and coronary artery disease: moving beyond aggregation. J Am Coll Cardiol. 2004;43:1989–91.CrossRefGoogle ScholarPubMed
76. Yao, S, Ober, JC, NcNatt, J, Benedict, CR, Rosolowsky, M, Anderson, HV, et al. ADP plays an important role in mediating platelet aggregation and cyclic flow variations in vivo in stenosed and endothelium-injured canine coronary arteries. Circ Res. 1992;70:39–48.CrossRefGoogle ScholarPubMed
77. Anderson, HV, McNatt, J, Clubb, FJ, Herman, M, Maffrand, J, DeClerck, F, et al. Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries. Circulation. 2001;104:2331–7.CrossRefGoogle ScholarPubMed
78. Kornowski, R, Mintz, GS, Kent, KM, Pitchard, AD, Satler, LF, Buchar, TA, et al. Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia. Circulation. 1997;95:1366–9.CrossRefGoogle ScholarPubMed
79. Mudra, H, Regar, E, Klauss, V, Werner, F, Henneke, KH, Sbarouni, E, et al. Serial follow-up after optimized ultrasound-guided deployment of Palmaz-Shatz stents: in stent neointimal proliferation without significant reference segment response. Circulation. 1997;95:363–70.CrossRefGoogle Scholar
80. Yao, S, McNatt, J, Kexin, C, Vernon, H, Maffrand, J, Buja, LM, et al. Endothelial function/myocardial ischemia/infarction: combined ADP and thromboxane A2 antagonism prevents cyclic flow variations in stenosed nad endothelium-injured arteries in nonhuman primates. Circulation. 1993;88:2888–93.CrossRefGoogle Scholar
81. Folts, JD, Rowe, GG. Epinephrine potentiation of in vivo stimuli reverse aspirin inhibition of platelet thrombus formation in stenosed canine coronary arteries. Thromb Res. 1998;50:507–16.CrossRefGoogle Scholar
82. Gurbel, PA, Bliden, KP, Hiatt, BL, O’Conner, CM. Clopidogrel for coronary stenting response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908–13.CrossRefGoogle ScholarPubMed
83. Mobley, JE, Bresee, SJ, Wortham, DC, Craft, RM, Snider, CC, Carroll, RC. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol. 2004;93:456–8.CrossRefGoogle ScholarPubMed
84. Gurbel, PA, Samara, WM, Bliden, KP. Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis. Platelets. 2004;15:95–9.CrossRefGoogle ScholarPubMed
85. Payne, DA, Jones, CI, Hayes, PD, Thompson, MM, London, NJ, Bell, PR, et al. Beneficial effects of clopidogrel combined with aspirin in reducing cerbral emboli in patients undergoing carotid endarterectomy. Circulation. 2004;109:1476–81.CrossRefGoogle Scholar
86. Escolar, G, Bastida, E, Castillo, R, Ordinas, A. Ticlopidine inhibits platelet thrombus formation studied in a flowing system. Thromb Res. 1987;45:561–71.CrossRefGoogle Scholar
87. Vivekananthan, DP, Bhatt, DL, Chew, DP, Zidar, FJ, Chan, AW, Moliterno, DJ, et al Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol. 2004;94:358–60.CrossRefGoogle ScholarPubMed
88. Chew, DP, Bhatt, DL, Robbins, MA, Mukherjee, D, Roffi, M, Schneider, JP, et al. Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein. Am J Cardiol. 2001;88:672–4.CrossRefGoogle ScholarPubMed
89. Lincoff, AM, Kereiakes, DJ, Mascelli, MA, Deckelbaum, LI, Barnathan, ES, Patel, KK, et al. Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization. Circulation. 2001;104:163–7.CrossRefGoogle ScholarPubMed
90. Xiao, Z, Théroux, P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol. 2004;43:1982–8.CrossRefGoogle ScholarPubMed
91. Gurbel, PA, Malinin, AI, Callahan, KP, Serebruany, VL, O’Connor, CM. Effect of loading with clopidogrel at the time of coronary stenting on platelet aggregation and glycoprotein IIb/IIIa expression and platelet-leukocyte aggregate formation. Am J Cardiol. 2002;90:312–5.CrossRefGoogle ScholarPubMed
92. Klinkhardt, U, Graff, J, Harder, S. Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P-selectin expression in a human ex vivo in vitro model. Clin Pharmacol Ther. 2002;71:176–85.CrossRefGoogle ScholarPubMed
93. Gibbs, CR, Lip, GY. Do we still need dipyridamole? Br J Clin Pharmacol. 1998;45:323–8.CrossRefGoogle ScholarPubMed
94. Moncada, S, Korbut, R. Dipyridamole and other phosphodiesterase inhibitors act as antithrombotic agents by potentiating endogenous prostacyclin. Lancet. 1978;I:1286–9.CrossRefGoogle Scholar
95. Bult, H, Fret, HR, Jordaens, FH, Herman, AG. Dipyridamole potentiates platelet inhibition by nitric oxide. Thromb Heamost. 1991;66:343–9.Google ScholarPubMed
96. Kjaer, A, Meyer, C, Nielsen, FS, Parving, H, Hesse, B. Dipyridamole, cold pressor test, and demonstration of endothelial dysfunction: a PET study of myocardial perfusion in diabetes. J Nuc Med. 2003;44:19–23.Google ScholarPubMed
97. Lupi, A, Buffon, A, Finocchiaro, ML, Conti, E, Maseri, A, Crea, F. Mechanisms of adenosine-induced epicardial coronary artery dilatation. Eur Heart J. 1997;18:614–7.CrossRefGoogle ScholarPubMed
98. Gamboa, A, Ertl, AC, Costa, F, Farley, G, Manier, ML, Hachey, DL, et al. Blockade of nucleoside transport is required for delivery of intraarterial adenosine into the interstitium. Circulation. 2003;108:2631–5.CrossRefGoogle ScholarPubMed
99. Diener, HC, Cunha, L, Forbes, C, Sivenius, J, Smets, P, Lowenthal, A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. Neurol Sci. 1996; 143:1–13.CrossRefGoogle ScholarPubMed
100. FitzGerald, GA. Dipyridamole. N Engl J Med. 1987;316:1247–56.Google ScholarPubMed
101. Liem, LK, Choong, LH, Woo, KT. Action of dipyridamole and warfarin on growth of human endothelial cells cultured in serumfree media. Clin Biochem. 2001;34:141–7.CrossRefGoogle ScholarPubMed
102. Harker, LA, Kadatz, RA. Mechanism of action of dipyridamole. Thromb Res. Suppl 1983;4:39–46.CrossRefGoogle ScholarPubMed
103. Nishimura, H, Naritomi, H, Iwamoto, Y, Tachibana, H, Sugita, M. In vivo evaluation of antiplatelet agents in gerbil model of carotid artery thrombosis. Stroke. 1996;27:1099–103.CrossRefGoogle ScholarPubMed
104. Aktas, B, Utz, A, Hoenig-Liedl, P, Walter, U, Geiger, J. Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets in vitro and in vivo/ex vivo studies. Stroke. 2003;34:764–9.CrossRefGoogle ScholarPubMed
105. Eisert, WG. Near-field amplification of antithrombotic effects of dipyridamole through vessel wall cells. Neurology. 2001;57 Suppl 2:S20–3.CrossRefGoogle ScholarPubMed
106. Guideri, F, Capecchi, PL, Acampa, M, Cuomo, A, Lazzerini, PE, De Giorgi, L, et al. Oral low-dose dipyridamole protects from intravenous high-dose dipyridamole-induced ischemia. A stress echocardiographic study. Int J Cardiol. 2002;83:209–16.CrossRefGoogle ScholarPubMed
107. Suzuki, K, Miura, T, Miki, T, Tsuchida, A, Shimamoto, K. Infarct-size limitation by preconditioning is enhanced by dipyridamole administered before but not after preconditioning: evidence for the role of interstitial adenosine level during precondition as a primary determinant of cardioprotection. J Cardiovasc Pharmacol. 1998;31:1–9.CrossRefGoogle ScholarPubMed
108. Klabunde, RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol. 1983;93:21–6.CrossRefGoogle ScholarPubMed
109. Bijlstra, P, van Ginneken, EE, Huls, M, van Dijk, R, Smits, P, Rongen, GA. Glyburide inhibits dipyridamole-induced forearm vasodilation but not adenosine-induced forearm vasodilation. Clin Pharmacol Ther. 2004;75:147–56.CrossRefGoogle Scholar
110. Abd-Elfattah, AS, Hoehner, J, Wechsler, AS. Identification of nucleoside transport binding sites in the human myocardium. Mol Cell Biochem. 1998;180:105–10.CrossRefGoogle ScholarPubMed
111. Nees, S, Herzog, V, Becker, BF, Bock, M, Des Rosiers, C, Gerlach, E. The coronary endothelium: a highly active metabolic barrier for adenosine. Basic Res Cardiol. 1985; 80:515–29.CrossRefGoogle ScholarPubMed
112. Weyrich, AS, Denis, MM, Kuhlmann-Eyre, JR, Spencer, ED, Dixon, DA, Marathe, GK, et al. Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates. Circulation. 2005; 111;633–42.CrossRefGoogle ScholarPubMed
113. Howell, JG, Zibari, GB, Brown, MF, Burney, DL, Sawaya, DE, Olinde, JG, et al. Both ischemic and pharmacological preconditioning decrease hepatic leukocyte/endothelial cell interactions. Transplantation. 2000;69:300–3.CrossRefGoogle ScholarPubMed
114. Bouma, MG, van den Wildenberg, FA, Buurman, WA. The anti-inflammatory potential of adenosine in ischemia-reperfusion injury: established and putative beneficial actions of a retaliatory metabolite. Shock. 1997;8:313–20.CrossRefGoogle ScholarPubMed
115. Grisham, MB, Hernandez, LA, Granger, DN. Adenosine inhibits ischemia-reperfusion-induced leukocyte adherence and extravasation. Am J Physiol. 1989;257(5 Pt 2):H1334–9.Google ScholarPubMed
116. Iuliano, L, Pedersen, JZ, Rotilio, G, Ferro, D, Violi, F. A potent chain-breaking antioxidant activity of the cardiovascular drug dipyridamole. Free Rad Biol Med. 1995;18:239–47.CrossRefGoogle ScholarPubMed
117. Iuliano, L, Colavita, AR, Camastra, C, Bello, V, Quintarelli, C, Alessandroni, M, et al. Protection of low density lipoprotein oxidation at chemical and cellular level by the antioxidant drug dipyridamole. Br J Pharmacol. 1996;119:1438–46.CrossRefGoogle ScholarPubMed
118. Nozik-Grayck, E, Piantadosi, CA, van Adelsberg, J, Alper, SL, Huang, YT. Protection of perfused lung from oxidant injury by inhibitors of anion exchange. Am J Physiol. 1997;273(2 Pt 1):L296–304.Google ScholarPubMed
119. Blake, AD. Dipyridamole is neuroprotective for cultured rat embryonic cortical neurons. Biochem Biophys Res Comm. 2004;314:501–4.CrossRefGoogle ScholarPubMed
120. Kim, JA, Tran, ND, Zhou, W, Fisher, M. Dipyridamole enhances tissue plasminogen activator release by brain capillary endothelial cells. Thromb Res. 2004;115:435–8.CrossRefGoogle ScholarPubMed
121. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1–13.CrossRefGoogle Scholar
122. ESPRIT study group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomized controlled trial. Lancet. 2006;367:1665–73.CrossRefGoogle Scholar