Effects of combinations of 5-hydroxytryptamine receptor antagonists on 5-HT-induced human platelet aggregation

We have examined the effects of fourteen 5-HT-receptor antagonists on 5-HT-induced platelet aggregation in whole blood. Two different types of inhibitory profile were obtained. The inhibitory effects of seven of the antagonists (designated type 1) could be surmounted by increasing the concentration of 5-HT; the inhibitory effects of the other antagonists (type 2) were insurmountable by 5-HT. The effects of combinations of pairs of different antagonists were investigated. The inhibitory effects of pairs of type 1 antagonists and of pairs of type 2 antagonists were additive. However, a type 1 antagonist interfered with the inhibitory effects of a type 2 antagonist. The two types of antagonist differed in the rate at which they inhibited 5-HT-induced aggregation, a type 2 antagonist exerting its effect more slowly than a type 1 antagonist. Two possible explanations of these results are considered. It is possible that there are two different types of receptors on the surface of platelets, one causing stimulation and the other causing allosteric inhibition of platelet aggregation. Alternatively, the results may stem from different rates of association and dissociation of the agents at a single 5-HT receptor.