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.
Qi
R
R
Department of Clinical and Laboratory Medicine, Yamanashi Medical University, Japan.
Ozaki
Y
Y
Satoh
K
K
Kurota
K
K
Asazuma
N
N
Yatomi
Y
Y
Kume
S
S
D001792:Blood Platelets / Q000187:drug effects / Q000648:ultrastructure; D002118:Calcium / Q000097:blood; D002469:Cell Separation / Q000379:methods; D048429:Cell Size; D006801:Humans; D007650:Ketanserin / Q000494:pharmacology*; D009391:Nephelometry and Turbidimetry / Q000295:instrumentation*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests / Q000295:instrumentation*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013386:Succinates / Q000494:pharmacology*
D010975:Platelet Aggregation Inhibitors; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D012701:Serotonin; D007650:Ketanserin; D002118:Calcium