Aurintricarboxylic Acid Reduces Platelet Deposition in Stenosed and Endothelially Injured Rabbit Carotid Arteries more Effectively than other Antiplatelet Interventions

Summary

In the present study we tested the effects of different antithrombotic interventions on platelet deposition in experimentally-stenotic rabbit carotid arteries with endothelial injury. Platelet deposition, quantitated by labeling autologous platelets with ₁₁₁ In-oxine, was significantly reduced compared to control animals by all interventions tested, i.e., R 68070, a drug with thromboxane A₂ synthase and receptor blocking properties, BN 52021, a PAF receptor antagonist, aurintricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (Gp) Ib/von Wille-brand factor (vWf) interaction, AZ-1, a monoclonal antibody against rabbit GPIIb/IIIa, the platelet receptor for fibrinogen, and AP-1, a monoclonal antibody against rabbit tissue factor. ATA was significantly more effective than all the other interventions in reducing platelet deposition in the stenotic vessels. We conclude that inhibition of Gp Ib/vWf interaction may be a more suitable target for antithrombotic therapy under conditions of high shear stress, like those produced in this model.

• References

• 1 Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM. Specific platelet mediators and unstable coronary artery lesions: Experimental evidence and clinical implications. Circulation 1989; 80: 198-205
• 2 Hirsh PD, Hillis LD, Campbell WB, Firth BG, Willerson JT. Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease. N Engl J med 1981; 304: 685-691
• 3 Van den Berg EK, Schmitz JM, Benedict CR, Malloy CR, Willerson JT, Dehmer GJ. Transcardiac serotonin concentration is increased in selected patients with limiting angina and complex coronary lesion morphology. Circulation 1989; 79: 116-124
• 4 Folts JD, Crowell Jr EB, Rowe CG. Platelet aggregation in partially obstructed vessels and its elimination by aspirin. Circulation 1976; 54: 365-370
• 5 Golino P, Buja LM, Ashton JH, Kulkarni P, Taylor A, Willerson JT. Effect of thromboxane and serotonin reeeptor antagonists on intraeoronary platelet deposition in dogs with experimentally stenosed coronary arteries. Circulation 1988; 78: 701-711
• 6 Ashton JH, Schmitz JM, Campbell WB, Ogletrce ML, Raheja S, Taylor AL, Fitzgerald C, Buja LM, Willerson JT. Inhibition of cyclic How variations in stenosed canine coronary arteries by thromboxane A,/prostaglandin H , receptor antagonists. Circ Res 1986; 59: 568-578
• 7 Ashton JH, Benedict CR, Eitzgerald C, Raheja S, Taylor A, Campbell W, Buja LM, Willerson JT. Serotonin is a mediator of cyclic flow variations in stenosed canine coronary arteries. Circulation 1986; 73: 572-578
• 8 Eidt JL, Allison PNoble S, Ashton HT, Golino P, MeNatt J, Buja LM, Willerson JT. Thrombin is an important mediator of platelet aggregation in stenosed canine coronary arteries with endothelial injury. J Clin Invest 1989; 84: 18-25
• 9 Yao SK, Ober J, Benedict CR, Rosolowsky M, Anderson HV, Cui K, Maffrand JP, Campbell WB, Bula LM, Willerson JT. 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
• 10 Golino P, Ambrosio G, Ragni M, Pascucci I, Triggiani M, Oriente A, McNatt J, Buja LM, Conderelli M, Chiaricllo M, Willerson JT. Short-term and long-term role of platelet activating factor as a mediator of in vivo platelet aggregation. Circulation 1993; 88: 1205-1214
• 11 Golino P, Ashton JH, Buja LM. Local platelet activation causes vasoconstriction of large cpicardial canine coronary arteries in vivo: thromboxane A₂and serotonin are possible mediators. Circulation 1989; 79: 154-166
• 12 Pawashe AB, Golino P, Ambrosio G, Migliaccio F, Ragni M, Pascucci I, Chiariello M, Bach R, Garen A, Konigsberg WK, Ezekowitz MD. A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries. Circ Res 1994; 74: 56-63
• 13 Kroll MH, Harris TS, Moake JL, Handin RI, Schafer AI. von Willebrand factor binding to platelet Gp lb initiates signals for platelet activation. J Clin Invest 1991; 88: 1568-1573
• 14 Ware JA, Johnson PC, Smith M, Salzman EW. Effect of common agonists on cytoplasmic ionized calcium concentration in platelets. J Clin Invest 1986; 77: 878-886
• 15 Plow EF, Marguerie GA. The induction of the fibrinogen receptor on human platelets by epinephrine and the combination of epinephrine and ADP. J Biol Chem 1980; 225: 10971-1097
• 16 Golino P, Ambrosio G, Pascucci I, Ragni M, Russolillo E, Chiariello M. Experimental carotid stenosis and endothelial injury in the rabbit: an in vivo model to study intravascular platelet aggregation. Thromb Haemost 1992; 67: 302-305
• 17 Golino P, Cappelli M, Ambrosio G, Ragni M, Russolillo E, Condorelli M, Chiariello M. Endothelium-Derived Relaxing Factor Modulates Platelet Aggregation in an In Vivo Model of Recurrent Platelet Activation. Circ Res. 1992; 71: 1447-1456
• 18 Thakur ML, Welch MJ, Joist JH, Coleman RE. Indium-HI labeled platelets: Studies on preparation and evaluation of in vitro and in vivo functions. Thromb Res 1976; 9: 345-352
• 19 De Clerck F, Beetens J, de Chaffoy de CourcellesD, Freyne E, Janssen PP A J. R 68070: Thromboxane A₂synthase inhibition and thromboxane A₂/prostaglandin endoperoxide receptor blockade combined in one molecule I. Biochemical profile In vitro. Thromb Haemost 1989; 61: 35-42
• 20 Golino P, Ambrosio G, Villari B, Ragni M, Focaccio A, Pace L, De Clerck F, Condorelli M, Chiariello M. Endogenous prostaglandin endoperoxides may alter infarct size in the presence of thromboxane synthase inhibition. Studies in a rabbit model of coronary artery occlusion-reperfusion J Am Coll Cardiol 1993; 21: 493-502
• 21 Braquet P, Etienne A, Touvay C, Bourgain RH, Lefort J. Vargaftig BB Involvement of platelet activating factor in respiratory anaphylaxis, demonstrated by the PAF-acether antagonist BN 52021. Lancet 1986; 1: 1501
• 22 Lagente V, Touvay C, Randon J. Interference of the PAF-aeether antagonist BN 52021 with passive anaphylaxis in the guinea pig. Prostaglandins 1987; 33265-33274
• 23 Phillips MD, Moake JL, Nolaseo L, Turner N. Aurintricarboxylie acid: A novel inhibitor of the association of von Willebrand factor and platelets. Blood 1988; 72: 1898-1903
• 24 Strony J, Phillips M, Brands D, Moake J, Adelman B. Aurintricarboxylic acid in a canine model of coronary artery thrombosis. Circulation 1990; 81: 1106-1114
• 25 Badimon L, Badimon JJ. Mechanisms of arterial thrombosis in nonparallel streamlines: Platelet thrombi grow on the apex of stenotic severely injured vessel wall. Experimental studies in the pig model J Clin Invest 1989; 84: 1134-1144
• 26 Goldsmith HE, Karino T. Quantitative cardiovascular studies: Clinical and research application of cngencering principles. Baltimore: MD: University Park; 1978: 289-351
• 27 Goldsmith HL, Turitto VT. Rheological aspects of thrombosis and hemostasis: basic principles and applications. Haemostasis 1986; 55: 415-435
• 28 Strony J, Beaudoin A, Brands D, Adelman B. Analysis of shear stress and hemodynamic factors in a model of coronary artery stenosis and thrombosis. Am J Physiol 1993; 265: H1787-H1796
• 29 Badimon L, Badimon JJ, Galvez A, Chesebro JH, Fuster V. Influenee of arterial damage and wall shear rate on platelet deposition: Ex vivo study in a swine model. Arteriosclerosis 1986; 6: 312-321
• 30 Weiss HJ, Turitto VT, Baumgartner HR. Role of shear rate and platelets in promoting fibrin formation on rabbit subendothelium. J Clin Invest 1986; 78: 1072-1083
• 31 Ruggeri ZM. Receptor-specific antiplatelet therapy. Circulation 1989; 80: 1920-1922
• 32 Lewis Jr HD, Davies JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 1983; 309: 396-403
• 33 Willerson JT, Yao SK, McNatt J, Benedict CR, Anderson HV, Golino P, Murphree SS, Buja LM. Frequency and severity of cyclic flow alterations and platelet aggregation predict the severity of neointimal proliferation following experimental coronary stenosis and endothelial injury. Proc Natl AcadSci USA 1991; 88: 10624-10628