Our study demonstrates that species plays an important role in the response of PF to drug-induced prolongation of APD and EADs. Rabbit PFs constitute the most sensitive model for detecting drug-induced, potential long APD and proarrhythmogenic effects in vitro.
Ketanserin, a selective 5-HT2-receptor antagonist, inhibits the reversible aggregation induced by 5-hydroxytryptamine (5-HT) in human platelet-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 active against 5-HT-induced platelet aggregation after both in vitro and oral administration to human volunteers. At concentrations up to 500 times in excess of the IC50 for 5-HT-induced platelet reactions, ketanserin does not affect the aggregation induced by ADP, epinephrine, collagen or Thrombofax, the prostaglandin biosynthesis of thrombin-stimulated platelets, nor the active uptake of 14C-5-HT by platelets. 5-Hydroxytryptamine amplifies the human platelet aggregation induced by threshold concentrations of ADP, collagen, epinephrine, norepinephrine and induced irreversible aggregation of platelets pre-sensitized with Thrombofax. This amplification by 5-hydroxytryptamine results in a platelet response typical for the potentiated agonist; for the combination of the monoamine with collagen, the serotonergic amplification results in enhanced aggregation, release of beta-TG and PF4 and excessive formation of TXB2. Ketanserin, after both in vitro and oral administration to man reduces the amplified response to the level of the potentiated agonist. The present evidence suggests the presence of functional 5-HT2 receptors on the human platelet, different from those involved in the uptake of the monoamine.
Ketanserin, a selective 5-HT2 serotonergic receptor antagonist, reduces in vitro the release-associated human platelet aggregation induced by threshold concentrations of collagen and curtails the second wave of aggregation/release induced by critical concentrations of ADP in particular and, to a lesser extent, of 1-epinephrine. Its inhibitory effect on the second waves becomes more pronounced when the reaction is already attenuated by moderate cyclo-oxygenase inhibition with esculetin, by yohimbine or by propranolol. The first wave of aggregation induced by ADP or 1-epinephrine is not affected. Such an inhibition of secondary platelet recruitment by ketanserin in vitro may be due to an inhibition of the 5-HT2 receptor-mediated amplifying effects of platelet-released 5-HT or to a non-specific interference with the platelet membrane, reducing the release of mediators from the platelets. Reduction of the increased plasma BTG levels in patients after ketanserin may result from such release-inhibiting mechanisms.
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