Quantitative measurement of various 5-HT receptor antagonists on platelet activation induced by serotonin.

The effects of S2-serotonergic receptor antagonists, ketanserin, MCI-9042, and one of its major metabolite, M-1, were evaluated on human platelet activation induced by serotonin. A newly developed method for detecting particles in suspensions was used to assess serotonin-induced platelet aggregation. Serotonin added to platelets in plasma induced transient formation of small aggregates but not that of large ones. All the three antagonists in a dose-dependent manner suppressed serotonin-induced platelet aggregation. The ID50 values for ketanserin, MCI-9042, and M-1 are 10 nM, 0.6 microM, and 40 nM, respectively. The effects of these antagonists were also evaluated on [Ca+2]i elevation and shape change, the measurement of which does not require the presence of plasma proteins. These antagonists effectively inhibited [Ca+2]i elevation and shape change induced by serotonin. The ID50 value for MCI-9042 was approximately 1/10 for platelet aggregation. These findings suggest that MCI-9042 tightly binds to plasma proteins with resultant reduction in overall potency. The ID50 values obtained in this study are essentially equivalent to those reported for S2-serotonergic receptor binding in rabbit platelets, suggesting that these agents are also potent antagonists serotonin-induced activation of human platelets.