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Inhibitory effect of a selective thromboxane A 2 receptor antagonist, EP 092, on platelet aggregation in whole blood ex vivo and in vivo
Author(s) -
Booth R.F.G.,
Honey A.C.,
Lad N.,
Tuffin D.P.,
Wade P.J.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb11830.x
Subject(s) - ex vivo , in vivo , thromboxane a2 , platelet , thromboxane , thromboxane b2 , guinea pig , chemistry , whole blood , pharmacology , antagonist , medicine , endocrinology , receptor , biology , biochemistry , microbiology and biotechnology
1 The inhibitory effect of a selective prostaglandin H 2 (PGH 2 )/thromboxane A 2 receptor antagonist, EP 092, on platelet aggregatory responses in whole blood ex vivo (guinea‐pig: Rhesus monkey) and intravascular aggregation in vivo (rabbit) has been investigated. 2 Collagen (0.1–10.0 μgml −1 ) caused a concentration‐dependent decrease in single platelet count in samples of both guinea‐pig and Rhesus monkey citrated whole blood incubated ex vivo . EP 092 administered to guinea‐pigs by intravenous (0.1–3.0 mg kg −1 ) or oral (1.0–10.0 mg kg −1 ) routes significantly inhibited the platelet responses to collagen (ED 50 values 1.3 ± 0.2 and 1.4 ± 0.2 mg kg −1 respectively). Similar potency against collagen‐induced whole blood aggregation was observed in Rhesus monkey blood samples following EP 092 given orally (ED 50 0.9 ± 0.3 mg kg −1 ). 3 The duration of action of EP 092 against collagen aggregatory responses ex vivo in both guinea‐pigs and Rhesus monkeys was between 3 and 6h following oral administration at 3.0 mg kg −1 . 4 The inhibitory activity demonstrated by EP 092 against collagen‐induced aggregation of Rhesus monkey whole blood ex vivo was not accompanied by any significant reduction in thromboxane A 2 formation except at the highest dose tested (10 mg kg −1 ). 5 The intravascular aggregatory response induced by collagen or thrombin in the anaesthetized rabbit was significantly inhibited by an intravenous infusion of EP 092 (10 mg kg −1 ). EP 092 appeared less potent and its effect was of shorter duration in this preparation compared with its inhibitory effect on ex vivo aggregation, being evident immediately after infusion of drug but not after a further 30 min. 6 It is concluded that collagen‐induced platelet aggregatory responses in guinea‐pig and Rhesus monkey whole blood ex vivo and rabbit in vivo exhibit a thromboxane‐dependent component which can be inhibited in a dose‐related fashion by pretreatment with the thromboxane antagonist EP 092. In the rabbit, moreover, the data support the possibility of a role for thromboxane in the intravascular aggregatory response to thrombin.