Antagonism of u46619-induced aggregation of human and canine platelets by four txa2 receptor antagonists

Abstract

We compared the abilities of four TXA2/PGH2 receptor antagonists AH 23,848, SQ 29,548, BM 13.177 and BM 13.505, to inhibit aggregation of human and canine platelet rich plasma (PRP) induced by the stable cyclic endoperoxide analog, U46619, alone (human) or in combination with epinephrine (dog). The rank orders of potency of these antagonists, which correlated well between human (h) and canine (c) preparations were [IC50]: SQ 29,548 [28 nM (h) and 92 nM (c)] > AH 23,848 [0.5 μM (h) and 0.6 μM (c)]− BM 13.505 [0.4 pM (h) and 0.8 pM (c)] > BM 13.177 [3.9 μM (h) and 4.4 pM (c)]. The second wave of aggregation of human PRP induced by epinephrine and platelet activating factor (PAF) was abolished by similar concentrations of the TXA2/PGH2 antagonists, whereas aggregation of canine PRP induced by ADP, serotonin plus epinephrine, or PAF was unaffected by these concentrations of the TXA2/PGH2 antagonists. Epinephrine plus U46619-stimulated aggregation of canine PRP was abolished by RX 781094 (1 μM)but not by prazosin (10 −4 M), selective α 2- and α 1-adrenoceptor antagonists, respectively. Thus, four selective TXA2/PGH2 receptor antagonists, compared in two species, yield IC50's ranging from 28 nM to 4 μM and nearly identical rank orders of potency.