QUANTITATIVE MEASUREMENT OF VARIOUS 5-HT RECEPTOR ANTAGONISTS ON PLATELET ACTIVATION-INDUCED BY SEROTONIN

The effects of S-2-serotonergic receptor antagonists, ketanserin, MCI- 9042, and one of its major metabolite, M-1, were evaluated on human pl atelet activation induced by serotonin. A newly developed method for d etecting 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. Al l the three antagonists in a dose-dependent manner suppressed serotoni n-induced platelet aggregation. The ID50 values for ketanserin, MCI-90 42, and M-1 are 10 nM, 0.6 mu M, and 40 nM, respectively. The effects of these antagonists were also evaluated on [Ca++]i elevation and shap e change, the measurement of which does not require the presence of pl asma proteins. These antagonists effectively inhibited [Ca++]i elevati on 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 reducti on in overall potency. The ID50 values obtained in this study are esse ntially equivalent to those reported for S-2-serotonergic receptor bin ding in rabbit platelets, suggesting that these agents are also potent antagonists serotonin-induced activation of human platelets.