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Thromb Haemost 1986; 56(01): 080-085
DOI: 10.1055/s-0038-1661607
Original Article
Schattauer GmbH Stuttgart

Effect of Indomethacin and Dazoxiben on Intravascular Platelet Aggregation in the Anaesthetized Rabbit

A C Honey
Searle Research & Development, High Wycombe, Buckinghamshire, UK
,
N Lad
Searle Research & Development, High Wycombe, Buckinghamshire, UK
,
D P Tuffin
Searle Research & Development, High Wycombe, Buckinghamshire, UK
› Author Affiliations
Further Information

Publication History

Received 07 February 1986

Accepted after revision 03 June 1986

Publication Date:
13 July 2018 (online)

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Summary

Collagen (10-40 μg kg−1), thrombin (1-10 units kg−1), adenosine diphosphate (ADP; 3-300 pμ kg−1), 1-0-hexadecyl Paf-acether and 1-0-octadecyl Paf-acether (1-300 ng kg−1) administered by bolus intravenous injection each caused dose-dependent thrombocytopoenia accompanied by marked hypotension in anaesthetized rabbits. Responses to ADP and the Paf-acether derivatives were transient in nature (3-8 min) whereas those induced by collagen and thrombin were always of longer duration (5-20 min) and frequently fatal at high doses. Responses to collagen, thrombin, and the Paf-acether derivatives were invariably accompanied by substantial, dose-related increases in plasma levels of thromboxane B2 in samples obtained 30 s after agonist administration, whereas following ADP, no change in plasma thromboxane B2 was detected at any dose level. Indomethacin (3.0 mg kg−1 by infusion) had no effect on responses to thrombin or Paf-acether, partially inhibited collagen-induced thrombocytopenia, and potentiated responses to ADP. In contrast, dazoxiben (10 mg kg−1 by infusion) partially but significantly inhibited responses to thrombin, whereas those induced by collagen, Paf-acether or ADP were unchanged. These results indicate that in this model of intravascular aggregation, whilst platelet responses to collagen and thrombin appear partially dependent on intact cyclic endoperoxide and thromboxane A2 synthetic capacity respectively, responses to ADP and Paf-acether are independent of arachidonate metabolism via cyclo-oxygenase despite measurably increased TXB2 formation in the latter case.

Keywords

Rabbit intravascular aggregation - Indomethacin - Dazoxiben
 

  • References

  • 1 Packham MA, Warrior ES, Glynn MF, Senyi AS, Mustard JF. Alteration of the response of platelets to surface stimuli by pyrazole compounds. J Exp Med 1967; 126: 171-191
    CrossrefPubMedSearch in Google Scholar
  • 2 Buchanan MR, Hirsh J. A comparison of the effects of aspirin and dipyridamole on platelet aggregation in vivo and ex vivo. Thromb Res 1978; 13: 517-529
    CrossrefPubMedSearch in Google Scholar
  • 3 Silver MJ, Hoch W, Kocsis JJ, Ingerman CM, Smith JB. Arachidonic acid causes sudden death in rabbits. Science 1973; 183: 1085-1087
    PubMedSearch in Google Scholar
  • 4 Kohler C, Wooding W, Ellenbogen L. Intravenous arachidonate in the mouse - a model for the evaluation of antithrombotic drugs. Thromb Res 1976; 9: 67-80
    CrossrefPubMedSearch in Google Scholar
  • 5 Garcia Rafanell J, Forn J. Intravenous arachidonate-induced respiratory distress: comparative study of three in vivo models for the measurement of antithrombotic activity. J Pharmacol Meth 1982; 7: 231-238
    CrossrefPubMedSearch in Google Scholar
  • 6 Wu KK, Armstrong ML, Hoak JC. Platelet aggregates in hypercholesterolemic rhesus monkeys. Thromb Res 1974; 7: 917-924
    PubMedSearch in Google Scholar
  • 7 Hornstra G. Method to determine the degree of ADP-induced platelet aggregation in circulating rat blood (‘Filter loop technique’). Br J Haematol 1970; 19: 321-329
    CrossrefPubMedSearch in Google Scholar
  • 8 Bee D, Leach E, Martin JF, Suggett AJ. The effects of vincristine on platelet aggregation studies by a filter loop technique in the rat. Br J Pharmac 1980; 69: 227-231
    CrossrefPubMedSearch in Google Scholar
  • 9 Badimon L, Fuster V, Chesebro JH, Dewanjee MK. New “ex vivo” radioisotopic method of quantitation of platelet deposition - studies in four animal species. Thromb Haemostas 1983; 50: 639-644
    PubMedSearch in Google Scholar
  • 10 Page CP, Paul W, Morley J. An in vivo model for studying platelet aggregation and disaggregation. Thromb Haemostas 1982; 47: 210-213
    PubMedSearch in Google Scholar
  • 11 Smith GM, Freuler F. The measurement of intravascular aggregation by continuous platelet counting. Bibl Anat 1973; 12: 257-265
    PubMedSearch in Google Scholar
  • 12 Holmes IB, Smith GM, Freuler F. The effect of intravenous adenosine diphosphate on the number of circulating platelets in experimental animals: Inhibition by prostaglandin E1? dipyridamole, SH-869 and VK-774. Thromb Haemostas 1977; 37: 36-46
    PubMedSearch in Google Scholar
  • 13 Mallarkey G, Smith GM. In vivo platelet aggregation in the rat: dependence on extracellular divalent cation and inhibition by nonsteroidal anti-inflammatory drugs. Br J Pharmac 1984; 81: 31-39
    CrossrefPubMedSearch in Google Scholar
  • 14 Mallarkey G, Smith GM. The effect of arachidonic acid metabolism on intravascular platelet aggregation in rats. Thromb Res 1984; 36: 091-102
    CrossrefPubMedSearch in Google Scholar
  • 15 Mallarkey G, Smith GM. A comparative study of the involvement of the prostaglandin H2/thromboxane A2 pathway in intravascular platelet aggregation in guinea pigs and rats. Br J Pharmac 1985; 84: 425-430
    CrossrefPubMedSearch in Google Scholar
  • 16 Honey A, Lad N, Tuff DP. Effect of indomethacin and dazoxiben on intravascular aggregation in the anaesthetized rabbit. Thromb Haemostas 1985; 54: 209 (Abstr)
    PubMedSearch in Google Scholar
  • 17 Banerjee AK, Tuffin DP, Walker JL. Pharmacological effects of (±)-11-deoxy, 16-phenoxy-prostaglandin Ex derivatives in the cardiovascular system. Br J Pharmac 1985; 84: 71-79
    PubMedSearch in Google Scholar
  • 18 Mallarkey G, Smith GM. The involvement of platelets and the coronary vasculature in collagen-induced sudden death in rabbits. Thromb Haemostas 1985; 53: 70-74
    PubMedSearch in Google Scholar
  • 19 Holmes IB, Freuler F. Use of the Technicon autocounter for animal platelet counting and for continuous monitoring of circulating platelet number. Pharmac Ther 1979; 5: 257-265
    CrossrefPubMedSearch in Google Scholar
  • 20 Tuffin DP, Davey P, Dyer RL, Lunt DO, Wade PJ. Specific binding of [3H]-1-0-octadecyl Paf-acether to washed human platelets. In: Mechanisms of stimulus-response coupling in platelets Adv in Medicine and Biology; Plenum NY: 1985: 83-96
  • 21 Wade PJ, Lunt DO, Lad N, Tuffin DP, McCullagh KG. Effect of calcium and calcium antagonists on [3H]-Paf-acether binding to washed human platelets. Thromb Res 1986; 41: 251-262
    CrossrefPubMedSearch in Google Scholar
  • 22 Joist JH, Dolezel G, Lloyd JV, Kinlough-Rathbone RL, Mustard JF. Platelet factor-3 availability and the platelet release reaction. J Lab Clin Med 1974; 84: 474-482
    PubMedSearch in Google Scholar
  • 23 Harfenist EJ, Packham MA, Kinlough-Rathbone RL, Mustard JF. Inhibitors of ADP-induced platelet aggregation prevent fibrinogen binding to rabbit platelets and cause rapid deaggregation and dissociation of bound fibrinogen. J Lab Clin Med 1981; 97: 680-688
    PubMedSearch in Google Scholar
  • 24 Kinlough-Rathbone RL, Mustard JF, Perry DW, Dajana E, Cazenave J-P, Packham MA, Harfenist EJ. Factors influencing the deaggregation of human and rabbit platelets. Thromb Haemostas 1983; 49: 162-167
    PubMedSearch in Google Scholar
  • 25 Martin JF, Suggett AJ, Jones PB C, Leach E. Effect of acetyl salicylic acid on platelet aggregation and thromboxane B2 production in flowing aortic blood in the rat studied with a filter loop technique. Thromb Res 1982; 27: 251-259
    CrossrefPubMedSearch in Google Scholar
  • 26 Shaw JO, Klusick SJ, Hanahan DJ. Activation of rabbit platelet phospholipase and thromboxane synthesis by 1-0-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (platelet activating factor). Biochim Biophys Acta 1981; 663: 222-229
    CrossrefPubMedSearch in Google Scholar
  • 27 Cazenave J-P, Benveniste J, Mustard JF. Aggregation of rabbit platelets by platelet-activating factor is independent of the release reaction and the arachidonate pathway and inhibited by membrane-active drugs. Lab Invest 1979; 41: 275-285
    PubMedSearch in Google Scholar
  • 28 Vargaftig BB, Chignard M, LeCouedic JP, Beneviste J. One, two, three or more pathways for platelet aggregation. Acta Med Scand 1980; 642: 23-29
    PubMedSearch in Google Scholar
  • 29 Lefer AM, Muller HF, Smith JB. Pathophysiological mechanisms of sudden death induced by platelet activating factor. Br J Pharmac 1984; 83: 125-130
    CrossrefPubMedSearch in Google Scholar
  • 30 Kinlough-Rathbone RL, Packham MA, Reimers H-J, Cazenave J-P, Mustard JF. Mechanisms of platelet shape change, aggregation and release induced by collagen, thrombin or A 23187. J Lab Clin Med 1977; 90: 707-719
    PubMedSearch in Google Scholar
  • 31 Kinlough-Rathbone RL, Cazenave J-P, Packham MA, Mustard JF. Effect of inhibitors of the arachidonate pathway on the release of granule contents from rabbit platelets adherent to collagen. Lab Invest 1980; 42: 28-34
    PubMedSearch in Google Scholar
  • 32 Darius H, Lefer AM. Anti-aggregatory effects of thromboxane receptor antagonists in vivo. Thromb Res 1985; 40: 663-675
    CrossrefPubMedSearch in Google Scholar
  • 33 Hamberg M, Svensson J, Wakabayashi T, Samuelsson B. Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proc Natl Acad Sci USA 1974; 71: 345-349
    CrossrefPubMedSearch in Google Scholar
  • 34 Smith JB. The prostanoids in hemostasis and thrombosis: a review. Am J Pathol 1980; 99: 743-804
    PubMedSearch in Google Scholar
  • 35 Weksler BB, Ley CW, Jaffe EA. Stimulation of endothelial cell prostacyclin production by thrombin, trypsin and the ionophore A 23187. J Clin Invest 1978; 62: 923-930
    CrossrefPubMedSearch in Google Scholar
  • 36 Pearson JD, Carleton JS, Hutchings A. Prostacyclin release stimulated by thrombin or bradykinin in porcine endothelial cells cultured from aorta and umbilical vein. Thromb Res 1983; 29: 115-124
    CrossrefPubMedSearch in Google Scholar
  • 37 Hong SL, McLaughlin NJ, Tzeng C, Patton G. Prostacyclin synthesis and déacylation of phospholipids in human endothelial cells: comparison of thrombin, histamine and ionophore A 23187. Thromb Res 1985; 38: 01-10
    CrossrefPubMedSearch in Google Scholar
  • 38 Randall MJ, Wilding RI R. Acute arterial thrombosis in rabbits: reduced platelet accumulation after treatment with the thromboxane synthetase inhibitor dazoxiben hydrochloride (UK 37248-01). Thromb Res 1981; 28: 607-616
    PubMedSearch in Google Scholar
  • 39 Hall ER, Chen Y-C, Ho T, Wu KK. The reduction of platelet thrombi on damaged vessel wall by a thromboxane synthetase inhibitor in rabbits. Thromb Res 1982; 27: 501-511
    CrossrefPubMedSearch in Google Scholar