Intrathoracic Platelet Accumulation in the Guinea-Pig Induced by Intravenous Administration of Arachidonic Acid - Effect of Cyclooxygenase and Thromboxane Synthetase Inhibitors

Summary

Intravenous administration of arachidonic acid to guinea-pigs caused a dose-related, rapid accumulation of ⁵¹Cr-labelled platelets in the thorax. Inhibitors of cyclooxygenase inhibited the platelet accumulation, induced by arachidonic acid (30 mg/kg), at doses which did not alter the thoracic blood volume (as measured by ¹³¹I-labelled human albumin). Thromboxane synthetase inhibitors had different effects on platelet accumulation depending on the dose. CGS 12970 (3 mg/kg) and N(1-carboxyheptyl) imidazole (100 mg/kg) reduced platelet accumulation. High doses of CGS 12970 and CGS 13080 caused an apparent enhancement of platelet accumulation which was associated with pooling of blood in the thorax, as measured by either ¹³¹I-labelled human albumin or ⁵¹Cr-labelled erythrocytes. This increase in thoracic blood volume was abolished if the guinea-pigs were also pretreated with diclofenac (1 mg/kg) in addition to the thromboxane synthetase inhibitor. Increases in thoracic blood volume were also obtained following infusions of PGI₂ but not PGD₂ or PGE₂.

Keywords

In vivo platelet aggregation - Thromboxane synthetase inhibitors - Cyclooxygenase inhibition

• References

• 1 Silver MJ, Hoch W, Kocsis JJ, Ingerman CH, Smith JB. Arachidonic acid causes sudden death in rabbits. Science 1974; 183: 1085-1087
• 2 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
• 3 Cerskus AL, Ali M, Zamecnik J, McDonald JW D. Effects of in vivo formation of thromboxane B₂ and prostaglandin D₂ during arachidonate infusion in rabbits. Thromb Res 1978; 12: 549-553
• 4 Cerskus AL, Ali M, McDonald JW D. Thromboxane B₂ and 6 keto prostaglandin F_1αa synthesis during infusion of collagen and arachidonic acid in rabbits. Inhibition by aspirin and sulfinpyrazone. Thromb Res 1980; 18: 693-703
• 5 Vargaftig BB, Lefort J, Chignard M. Comparative pharmacology of arachidonic acid in various animal species: Platelet mediated and platelet independent reactions. Agents Actions 1978; 8: 157-158
• 6 Vargaftig BB, Lefort J, Prancan AV, Chignard M, Benveniste J. Platelet lung in vivo interactions: An artifact of a multipurpose model. Haemostasis 1979; 8: 171-182
• 7 DiMinno G, Silver MJ. Mouse antithrombotic assay: A simple method for the evaluation of antithrombotic agents in vivo. Potentiation of antithrombotic activity by Ethyl alcohol. J Pharmacol Exp Ther 1983; 225: 57-60
• 8 Barrett PA, Butler KD, Morley J, Page CP, Paul W, White AM. Inhibition by heparin of platelet accumulation in vivo. Thromb Haemostas 1984; 51: 366-370
• 9 Page CP, Paul W, Morley J. An in vivo model for studying platelet aggregation and disaggregation. Thromb Haemostas 1982; 47: 210-213
• 10 Butler KD, Pay GF, Roberts JM, White AM. The effect of sulphinpyrazone and other drugs on the platelet response during the acute phase of the active Arthus reaction in guinea-pigs. Thromb Res 1979; 15: 319-340
• 11 Butler KD, White AM. Inhibition of thrombocytopenic episodes caused by the Arthus reaction, the sub-lethal Forssman reaction and ADP. Artery 1980; 8: 457-469
• 12 Smith JR, White AM. Fibrin, red cell and platelet interactions in an experimental model of thrombosis. Br J Pharmac 1982; 77: 29-38
• 13 Butler KD, Maguire ED, Smith JR, Turnbull AA, Wallis RB, White AM. Prolongation of rat tail bleeding time caused by an oral dose of a thromboxane synthetase inhibitor which has little effect on platelet aggregation. Thromb Haemostas 1982; 47: 46-49
• 14 Koth W, Nowak G, Markwardt F. Monitoring of microthrombosis in experimental animals by continuous recording of ¹²⁵I-fibrin deposits and ⁵¹Cr-labelled platelets in the lungs. Acta Biol Med Germ Band 1980; 39: 157-162
• 15 Busch C, Lundqvist H, Saldeen T. Quantitative determination of intravascular coagulation in vivo in various organs in the dog. Thrombos Diathes Haemorrh 1971; 26: 315-324
• 16 Busch C. Quantitative determinations of pulmonary microembolism in the dog. Comparison of in vivo and in vitro methods. Upsala J Med Sci 1974; 79: 72-83
• 17 Maguire ED, Wallis RB. In vivo redirection of prostaglandin endoperoxide into 6-keto PGF_1α formation by thromboxane synthetase inhibitors in the rat. Thromb Res 1983; 32: 15-27
• 8 Deckmyn H, Houtte EV, Vestraete M, Vermylen J. Manipulation of the local thromboxane and prostacyclin balance in vivo by the antithrombotic compounds Dazoxiben, acetylsalicyclic acid and Nafazatrom. Biochem Pharmacol 1983; 32: 2757-2762
• 19 Fitzgerald GA, Brash AR, Oates JA, Petersen AK. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthetase in man. J Clin Invest 1983; 72: 1336-1343
• 20 Orchard MA, Waddell KA, Lewis PJ, Blair IA. Thromboxane synthetase inhibition causes redirection of prostaglandin endoperox-ides to prostaglandin D₂ during collagen stimulated aggregation of human platelet rich plasma. Thromb Res 1985; 39: 701-710
• 21 McNab MW, Foltz EL, Graves BS, Rinehart RK, Tripp SL, Feliciano NR, Sen S. The effects of a new thromboxane synthetase inhibitor, CGS 13080 in Man. J Clin Pharmacol 1984; 24: 76-83
• 22 Hamberg H, Fredholm BB. Isomerisation of prostaglandin H₂ into prostaglandin D₂ in the presence of serum albumin. Biochem Biophys Acta 1976; 431: 189-193
• 23 Whittle BJ R, Moncada S, Vane JR. Comparison of the effects of prostacyclin (PGI₂), prostaglandin E₁ and prostaglandin D₂ on platelet aggregation in different species. Prostaglandin 1978; 16: 373-388
• 24 Bertélé V, Falanga A, Tomasiak M, Chiabrando C, Cerletti C, Gaetano Gde. Pharmacologic inhibition of thromboxane synthetase and platelet aggregation: Modulatory role of cylooxygenase products. Blood 1984; 63: 1460-1466
• 25 Hamid S, Whittle BJ R. Interaction of prostaglandin D₂ with prostacyclin, carbacyclin and the hydantoin prostaglandin, BW245C, in guinea-pig platelets. Br J Pharmac 1985; 85: 285-290
• 26 Hyman AL, Spannhake EW, Kadowitz PJ. Prostaglandins and the lung. Amer Rev Resp Dis 1978; 117: 111-136
• 27 Kadowitz PJ, Chapnick BH, Feigen LP, Hyman AL, Nelson PK, Spannhake EW. Pulmonary and systemic vasodilator effects of the newly discovered prostaglandin, PGI₂ . J Appl Physiol Resp Environ 1978; 45: 408-413
• 28 Mullane KM, Moncada S, Vane JR. Formation and disappearance of prostacyclin in the circulation. In: Prostacyclin Vane JR, Bergstrom S. (eds.) Raven Press; New York: 1979: 221-244