S₂-SEROTONERGIC RECEPTOR INHIBITION (KETANSERIN), COMBINED WITH THROMBOXANE A₂/PROSTAGLANDIN ENDOPEROXIDE RECEPTOR BLOCKADE (BM 13177) : ENHANCED ANTI-PLATELET EFFECT

Subsequent to an initial activation, several products are released from the platelets, and -potentially- contribute to the recruitment of new cells to build up the eventual platelet haemostatic plug or thrombus. Among the various accussates, serotonin as well as the arachidonic acid derivatives thromboxane A₂ (TXA₂) and prostaglandin endoperoxides (PGEND) seem to be involved as causative mediators, in particular when acting in concert on the same target cells. Indeed, in vitro at concentrations achievable after oral administration to man, either ketanserin (K), an S₂-serotonergic receptor antagonist or BM 13177 (BM), an antagonist at TXA₂/PGEND receptors, pre-incubated separately for 5 rain at 37°C with human citrated platelet-rich plasma, reduces to some extent the rate of the second-wave, irreversible platelet aggregation elicited by critical concentrations (1 to 2 × 10⁻⁶ M) of ADP. However, the combindation of both agonists results in a significantly more pronounced inhibition than achieved with the single products (K 1 × 10⁻⁷ M : 26.1 ± S.E.M. 9.9 %, n = 8. p < 0.05; BM 1 × 10⁻⁷7 M : 25.1 ± S.E.M. 8.7%, n = 8, p < 0.05; K ± BM at 1 × 10⁻⁷ M each ; 65.5 ± S.E.M. 10.3 %, n = 8; p < 0.05 versus K or BM separately). In vivo in rats, a modest prolongation of the bleeding time occurs with K (1.25 mg/kg orally -2 h : 410 sec, median values n = 9, p < 0.05) but not with BM (40 mg/kg orally, -2 h : 250 sec, n = 9) in comparison with controls (190 sec, n = 9); the amount of initial blood loss as a parameter for anti-vasoconstriction is significantly increased by K (140.4 μl/30 sec) but not by BM (77.2 μl/30 sec) in comparison with controls (35 μl/30 sec). Again, the combined treatment with both agonists results in a marked prolongation of the bleeding times (> 2065 sec, n = 9, p < 0.05) without further significant increase of the initial blood loss, indicating the interplay between serotonin and TXA₂/PGEND to be of primary importance for the aggregation of platelets in damaged vessels.