INHIBITION OF 5-HYDROXYTRYPTAMINE-INDUCED AND 5-HYDROXYTRYPTAMINE-AMPLIFIED HUMAN PLATELET-AGGREGATION BY KETANSERIN (R-41-468), A SELECTIVE 5-HT(2)-RECEPTOR ANTAGONIST

Ketanserin, a selective 5-HT2-receptor antagonist, inhibits the revers ible aggregation induced by 5-hydroxy tryptamine (5-HT) in human plate let-rich plasma (PRP). In this respect, the compound is equipotent to cyproheptadine and more active than methysergide (IC50,: 1.66 x 10(-8) M, 1.44 x 10(-8) M and 5.62 x 10(-8) M respectively). Ketanserin is a ctive against 5-HT-induced platelet aggregation after both in vitro an d oral administration to human volunteers. At concentrations up to 500 times in excess of the IC50 for 5-HT-induced platelet reactions, keta nserin does not affect the aggregation induced by ADP, epinephrine, co llagen or Thrombofax(R), the prostaglandin biosynthesis of thrombin-st imulated platelets, nor the active uptake of C-14-5-HT by platelets. 5 -Hydroxytryptamine amplifies the human platelet aggregation induced by threshold concentrations of ADP, collagen, epinephrine, norepinephrin e and induced irreversible aggregation of platelets pre-sensitized wit h Thrombofax(R). This amplification by 5-hydroxytryptamine results in a platelet response typical for the potentiated agonist; for the combi nation of the monoamine with collagen, the serotonergic amplification results in enhanced aggregation, release of beta-TG and PF4 and excess ive formation of TXB(2). Ketanserin, after both in vitro and oral admi nistration to man reduces the amplified response to the level of the p otentiated agonist. The present evidence suggests the presence of func tional 5-HT2 receptors on the human platelet, different from those inv olved in the uptake of the monoamine.