A comparative study of the involvement of the prostaglandin H₂/thromboxane A₂ pathway in intravascular platelet aggregation in guinea‐pigs and rats

Abstract

The effects of indomethacin, dazoxiben and EPO45 on collagen-induced platelet aggregation in vivo were studied in guinea-pigs and rats to determine the involvement of the prostaglandin endoperoxide/thromboxane A2 pathway in the aggregatory response. Indomethacin and EPO45 (a thromboxane receptor antagonist) partially inhibited platelet aggregation in rats. It was concluded that only one third of the aggregatory response to collagen was mediated by the products of cyclo-oxygenase conversion of arachidonic acid. In rats, dazoxiben was inactive although the conversion of the prostaglandin endoperoxides to thromboxane A2 was inhibited (measured as thromboxane B2). 6-keto PGF1 alpha was detected in plasma after collagen was injected into dazoxiben-treated rats. In this species therefore, the endoperoxides have significant aggregatory activity whilst the apparent increase in the level of prostacyclin was not sufficient to have any anti-aggregatory effect. All three drugs were active in the guinea-pig. About 60% of the aggregatory response to collagen was due to the products of the cyclo-oxygenase pathway, the main mediator being thromboxane A2. In guinea-pigs, dazoxiben also elevated 6-keto PGF1 alpha in the plasma after an injection of collagen. However, this apparent increase in prostacyclin production did not contribute to the anti-aggregatory effect.

The involvement of platelet activating factor in endotoxin‐induced pulmonary platelet recruitment in the guinea‐pig

“…Indomethacin at a dose shown to inhibit cyclooxygenase completely and the subsequent generation of thromboxane A2 in the guinea-pig (Mallarkey & Smith, 1985) did not significantly inhibit LPS-induced platelet recruitment, suggesting that cyclo-oxygenase metabolites of arachidonic acid are unlikely to play a role in this phenomenon. The ability of indomethacin to inhibit LPS-induced pulmonary platelet recruitment at five fold higher concentrations is therefore unlikely to reflect the contribution of cyclo-oxygenase derived metabolites of arachidonic acid but could be secondary to other properties of this molecule such as inhibition of phospholipase A2 (Blackwell & Flower, 1983), a necessary enzyme in the biosynthesis of Paf in inflammatory cells (Jouvain-Marche et al, 1984) or to inhibition of the formation of oxygen free radicals.…”

Antithrombotic effects of KBT-3022, a novel antiplatelet agent, in an arterial thrombosis model in the guinea-pig

“…Mallarkey and Smith [1985] have also reported that the main mediator of the platelet aggregation induced by intravenously injected collagen in the guinea-pig is TXA 2 . Thus, the platelet aggregation induced by collagen as well as that induced by arachidonic acid is mainly mediated by the cyclooxygenase-TXA 2 pathway.…”

Inhibitory effect of a selective thromboxane A2receptor antagonist, EP 092, on platelet aggregation in whole bloodex vivoandin vivo

“…The apparent difference in the potency of EP 092 between species may be due to the different test design employed (in vivo or ex vivo), but this seems unlikely, since EP 092 has been reported to be as effective at 0.25 and 1.Omgkg-1 in the guinea-pig against collagen-induced intravascular aggregation and bronchoconstriction . Furthermore, a close analogue, EP 045, is active at 1.0 mg kg-1 against collagen responses in the guineapig (Mallarkey & Smith, 1985). It seems improbable that the rate of metabolism and excretion of EP 092 should differ to such an extent in the rabbit that the observed inhibitory potency of EP 092 against collagen-induced platelet responses in vivo is reduced by almost an order of magnitude, and its duration of action decreased from > 6 h to < 0.5 h at 10 mg kg-1.…”