Electrical stimulation of the rat carotid artery causes a deep medial injury and the formation of a platelet-rich thrombus.
Occlusive thrombosis at sites of vessel wall injury was significantly reduced after the oral administration of clopidogrel, a potent analogue of ticlopidine, which showed dose-dependent inhibition of the thrombus formation (ED50 = 1.0 ±0.2 mg/kg, p.o.). Accumulation of thrombotic material was also considerably reduced after the i. v. administration of SR 27417, a highly potent and selective platelet activating factor receptor antagonist (ED50 = μg/kg, i.v.), nafagrel, a thromboxane A2 synthetase inhibitor (ED50 = 1.3 mg/kg, i.v.) and hirudin (ED50 = 140 μg/ kg, i.v.). A high dose (20 mg/kg, i.v.) of the anti-adhesive tetrapeptide Arg-Gly-Asp-Ser (RGDS) showed only a slight effect on thrombus formation whereas aspirin was ineffective.
These results confirm that ADP and thromboxane A2 play key roles in the initiation and progression of arterial thrombus formation and suggest that platelet activating factor may also modulate thrombosis in this experimental model.
References
1
Hass WK,
Easton D,
Adams HP.
A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-507
5
Weber MAJ,
Hasford J,
Taillens C.
Low-dose aspirin versus anticoagulants for prevention of coronary graft occlusion. Am J Cardiol 1990; 66: 1461-1468
9
Maffrand JP,
Bernat A,
Delebassée D,
Defreyn G,
Cazenave JP,
Gordon JL.
ADP plays a key role in thrombogenesis in rats. Thromb Haemostas 1988; 59: 225-230
10
Herbert JM,
Tissinier A,
Defreyn G,
Maffrand JP.
Inhibitory effect of clopidogrel on platelet adhesion and intimal proliferation following arterial injury. Arteriosclerosis and Thrombosis 1993; 13: 1171-1179
11
Simpson PJ,
Smith CB,
Rosenthal G.
Reduction in the incidence of thrombosis by the thromboxane synthetase inhibitor CGS 13080 in a canine model of coronary artery injury. J Pharmacol Exp Ther 1986; 238: 497-501
13
De Clerk F,
Van Corp L,
Beetens J.
Arachidonic acid metabolites, ADP and thrombin modulate occlusive thrombus formation over extensive injury in the rat. Blood Coag Fibrinol 1990; 1: 247-258
16
Herbert JM,
Bernat A,
Valette G,
Gigo V,
Lale A,
Laplace MC,
Lespy L,
Savi P,
Maffrand JP,
Le Fur G.
Biochemical and pharmacological activities of SR 27417, a highly potent, long acting platelet activating factor receptor antagonist. J Pharmacol Exp Ther 1991; 259: 44-51
17
Golino P,
Buja LM,
Ashton JM,
Kulkarni P,
Taylor A,
Willerson JT.
Effect of thromboxane and serotonin receptor antagonists in intracoronary platelet deposition in dogs with experimentally stenosed coronary arteries. Circulation 1988; 78: 701-711
21
Plotkine M,
Massad L,
Allix M.
A new arterial thrombosis model to study antithrombotic agents: efficacy of naftidrofuryl. Clin Hemorheol 1989; 9: 339-349
23
Reyers I,
Mussoni L,
Donati MB,
De Gaetano G.
Failure of aspirin at different doses to modify experimental thrombosis in rats. Thromb Res 1980; 18: 669-674
24
Reyers I,
Hennissen A,
Donati MB,
Hornstra G,
De Gaetano G.
Aspirin and the prevention of experimental arterial thrombosis: difficulty in establishing unequivocal effectiveness. Thromb Haemostas 1985; 54: 619-621
25
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
26
Killackey JJF,
Killackey BA,
Philip RB.
The effects of high doses of aspirin and related benzoic acid derivatives on arterial thrombosis in male rats. Haemostasis 1984; 14: 354-360
29
Oates JA,
FitzGerald GA,
Branch RA,
Jackson EK,
Knapp HR,
Roberts II LJ.
Clinical implications of prostaglandin and thromboxane A2 formation. New Engl J Med 1988; 319: 689-698
30
Vandeplassche L,
Hermans C,
Van de Water A,
Xhonneux R,
De Clerck F.
Differential effects of TXA2 synthetase inhibition, singly or combined with TXA2/βPGH2 receptor antagonism (R 68070) on thrombosis over endothelial cell damage or deep intimal injury in canine coronary arteries. Thromb Haemostas 1989; 62: 170-182
33
Coller BS,
Scudder LE,
Smith SR.
Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein Ilb-IIIa receptor in an experimental model. Blood 1986; 68: 783-786
34
Harfenist EL,
Packham MA,
Mustard JE.
Effect of the cell adhesion – peptide, Arg-Gly-Asp-Ser, on the responses of washed platelets from humans, rabbits and rats. Blood 1988; 71: 132-136
36
Walsh PN,
Griffin JH.
Contribution of human platelets to the proteolytic activation of blood coagulation factors XII and XI. Blood 1981; 57: 106-118
39
Butler KD,
Ambler J,
Dolan S,
Giddings J,
Talbot MD,
Wallis RB.
A non-occlusive model of arterial thrombus formation in the rat and its modification by inhibitors of platelet function, or thrombin activity. Blood Coag Fibrinol 1992; 3: 155-165
41
Terashita ZI,
Imura Y,
Nishikawa K.
Inhibition by CV-3988 of the binding of [3H]-platelet activating factor (PAF) to the platelets. Biochem Pharmacol 1985; 34: 1491-1495
