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Thromb Haemost 1993; 69(05): 509-514
DOI: 10.1055/s-0038-1651642
Original Article
Thrombosis Model
Schattauer GmbH Stuttgart

Effects of Antithrombotic Drugs in a Rat Model of Aspirin-Insensitive Arterial Thrombosis

W A Schumacher
1   The Department of Pharmacology, Princeton, NJ, USA
,
T E Steinbacher
1   The Department of Pharmacology, Princeton, NJ, USA
,
C L Heran
1   The Department of Pharmacology, Princeton, NJ, USA
,
J R Megill
2   The Department of Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
,
S K Durham
2   The Department of Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
› Author Affiliations
Further Information

Publication History

Received 13 October 1992

Accepted after revision 14 January 1993

Publication Date:
25 July 2018 (online)

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Summary

These studies describe experimental conditions where aspirin is less effective than other antiplatelet and anticoagulant drugs in inhibiting acute arterial thrombosis. External electrolytic injury of the rat carotid artery was used to induce occlusive thrombi in 97% of vehicle-treated rats. Thrombi were revealed by light and electron microscopy to be comprised primarily of platelets enmeshed in a fibrin network. The thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl chloromethy ketone (PPACK; 6 mg/kg, i. v.) decreased thrombus weight by 90%. Aspirin alone (1, 10 and 30 mg/kg, i. v.), dipyridamole alone (5 mg/kg i. v.) and aspirin (1 and 10 mg/kg, i. v.) in combination with dipyridamole (5 mg/kg, i. v.) did not inhibit thrombosis. The platelet-activating factor (PAF) antagonist, WEB 2086, (1 mg/kg i. v.) was also ineffective. Other drugs had intermediate activity. Thrombi were decreased 56% by the thromboxane receptor antagonist, BMS 180,291, either alone (5.8 mg/kg i.v.) or in combination with aspirin (10 mg/kg, i.v.). Heparin (900 U/kg, i.v.), warfarin (0.25 mg/kg, p.o. once daily for 3 days) and ticlopidine (200 mg/ kg, p.o. once daily for 3 days) reduced thrombus weight by 63, 73 and 43% respectively. Reductions in thrombus weight were always associated with improvements in either average blood flow or vessel patency.

 

  • References

  • 1 Hladovec J. Experimental arterial thrombosis in rats with continuous registration. Thromb Diath Heamorrh 1973; 29: 407-410
    PubMedGoogle Scholar
  • 2 Philp RB, Francey I, Warren BA. Comparison of antithrombotic activity of heparin, ASA, sulfinpyrazone and VK744 in a rat model of arterial thrombosis. Haemostasis 1978; 7: 282-293
    PubMedGoogle Scholar
  • 3 Vigdahl RL, Ferber RH, Parrish SL. Evaluation of antiinflammatory and antithrombotic drugs in pulmonary and arterial thrombosis. Thromb Res 1979; 16: 117-127
    CrossrefPubMedGoogle Scholar
  • 4 Massad L, Plotkine M, Capdeville C, Boulu RG. Electrically induced arterial thrombosis model in the conscious rat. Thromb Res 1987; 48: 1-10
    CrossrefPubMedGoogle Scholar
  • 5 Philp RB, Paul ML, Killackey JJ, Killackey BA. The influence of dose, time of administration, body temperature and salicylate kinetics on the antithrombotic action of acetylsalicylic acid in male rats. Haemostasis 1983; 13: 42-52
    PubMedGoogle Scholar
  • 6 Kaiser B, Markwardt F. Experimental studies on the antithrombotic action of a highly effective synthetic thrombin inhibitor. Thromb Haemostas 1986; 55: 194-196
    PubMedGoogle Scholar
  • 7 Schumacher WA, Heran CH, Steinbacher TE, Megill JR, Bird JE, Giancarli MR, Durham SK. Thrombin inhibition compared with other antithrombotic drugs in rats. Thromb Res 1992; 68: 157-166
    CrossrefPubMedGoogle Scholar
  • 8 Parris J, Fournau P, Granero M, Veins C. Antithrombotic effect of very low doses of acetylsalicylic acid in rats. Thromb Res 1983; 28: 313-321
    PubMedGoogle Scholar
  • 9 Ashida S, Sakuma K, Abiko Y. Antithrombotic effects of ticlopidine, acetylsalicylic acid and dipyridamole in vascular shunt model in rats. Thromb Res 1980; 17: 663-671
    CrossrefPubMedGoogle Scholar
  • 10 Reyers I, de Gaetano G, Donati MB. Warfarin anticoagulation prevents experimental arterial thrombosis in rats without inducing heamorrhage. Thromb Res 1983; 28: 465-468
    PubMedGoogle Scholar
  • 11 Louie S, Gurewich V. The antithrombotic effect of aspirin and dipyridamole in relation to prostaglandin synthesis. Thromb Res 1983; 30: 323-335
    CrossrefPubMedGoogle Scholar
  • 12 Buchanan MR, Dejana E, Gent M, Mustard JF, Hirsh J. Enhanced platelet accumulation onto injured carotid arteries in rabbits after aspirin treatment. J Clin Invest 1981; 67: 503-508
    CrossrefPubMedGoogle Scholar
  • 13 Merino J, Livio M, Rajtar G, de Gaetano G. Salicylate reverses in vitro aspirin inhibition of rat platelet and vascular prostaglandin generation. Biochem Pharmacol 1980; 29: 1093-1096
    CrossrefPubMedGoogle Scholar
  • 14 Kanayama T, Kimura Y, Iseki K, Hayashi Y, Tamao Y. Mizogami. Antithrombotic effects of KP-10614, a novel and stable prostacyclin (PGI2) analog. J Pharmacol Exp Ther 1990; 255: 1210-1217
    PubMedGoogle Scholar
  • 15 Rao GHR. Influence of anti-platelet drugs on platelet-vessel wall interactions. Prostaglandins Leukotrienes Med 1987; 30: 133-145
    CrossrefPubMedGoogle Scholar
  • 16 Violi F, Pratico D, Iuliano L, Balsano F. Dipyridamole potentiales the inhibition of platelet aggregation by aspirin (in human platelet rich plasma and whole blood). J Lipid Mediators 1991; 4: 61-68
    PubMedGoogle Scholar
  • 17 Moncoda S, Korbut R. Dipyridamole and other phosphodiesterase inhibitors act as antithrombotic agents by potentiating endogenous prostacyclin. Lancet 1978; 1: 1286-1289
    PubMedGoogle Scholar
  • 18 Hanson SR, Harker LA. Effects of platelet-modifying drugs on arterial thromboembolism in baboons. J Clin Invest 1985; 75: 1591-1599
    CrossrefPubMedGoogle Scholar
  • 19 Ogletree ML, Harris DN, Schumacher WA, Webb ML, Hedberg A, Misra RN. Pharmacological profile of BMS 180,291: A potent, longacting, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist. J Pharmacol Exp Ther 1993; 264: 570-578
    PubMedGoogle Scholar
  • 20 Fitzgerald DJ, Doran J, Jackson E, FitzGerald GA. Coronary vascular occlusion mediated via thromboxane A2-prostaglandin endoperoxide receptor activation in vivo. J Clin Invest 1986; 77: 496-502
    CrossrefPubMedGoogle Scholar
  • 21 Van der Giessen WJ, Zijlstra FJ, Berk L, Vedouw PD. The effect of the thromboxane receptor antagonist BM 13.177 on experimentally induced coronary artery thrombosis in the pig. Eur J Pharmacol 1988; 147: 241-248
    CrossrefPubMedGoogle Scholar
  • 22 Schumacher WA, Heran CL, Hartl KS, Ogletree L. Activity of the short-acting thromboxane receptor antagonist, SQ 30,741, in thrombolytic and vasospastic models in monkeys. J Pharmacol Exp Ther 1990; 253: 841-846
    PubMedGoogle Scholar
  • 23 Nakano T, Kanasaki K, Arita H. Role of protein kinase C in U46619-induced platelet shape change, aggregation and secretion. Thromb Res 1989; 56: 299-306
    CrossrefPubMedGoogle Scholar
  • 24 Cargill DI, Cohen DS, Van Valen RG, Klimek JJ, Levin RP. Aggregation, release and densitization induced in platelets from five species by platelet activating factor (PAF). Thromb Haemostas 1983; 49: 204-207
    PubMedGoogle Scholar
  • 25 Martins MA, Martins PMR, Castro Faria Neto HC, Bozza PT, Dias PMFI, Cordeiro RSB, Vargaftig BB. Intravenous injections of PAFacether induce platelet aggregation in rats. Eur J Pharmacol 1988; 149: 89-96
    CrossrefPubMedGoogle Scholar
  • 26 Smith GF, Neubauer BL, Sundboom JL, Best KL, Boode RL, Tanzer LR, Merriman RL, Frank JD, Herrmann RG. Correlation of the in vivo anticoagulant, antithrombotic, and antimetastatic efficacy of warfarin in the rat. Thromb Res 1988; 50: 163-174
    CrossrefPubMedGoogle Scholar