Prolongation of rat tail bleeding time by ketanserin: Mechanisms of action

Abstract

Serotonin (5-HT) may play a regulatory role in platelet-vessel wall interaction. This can be reliably investigated by measuring bleeding time. Ketanserin is a recently developed selective 5-HT 2 receptor antagonist, reportedly effective against both platelet and vascular 5-HT activation. Ketanserin (5–10 mg/kg) significantly prolonged tail bleeding time measured in conscious rats by two different techniques. While mianserin (a 5-HT 2 receptor antagonist exhibiting α-adrenolytic activity) also prolonged bleeding time, methysergide, metergoline and cyproheptadine did not. All three compounds acted as 5-HT 2 receptor antagonists with appreciable affinity for 5-HT 1 receptors. On the other hand, bleeding time was prolonged by either prazosin (a selective α 1-adrenoceptor antagonist) or labetalol (an α 1- and β-receptor antagonist). In contrast it was not affected by phentolamine or nicergoline ( α 1- α 2-receptor antagonists) nor by propranolol (a β-receptor antagonist). The effect of prazosin was significantly increased by combining it with either ketaserin or metergoline. Depletion of platelet serotonin by reserpine did not result in any modification of bleeding time, unless reserpine was combined with an inhibitor of 5-HT synthesis. Platelet activation by 5-HT was neither potentiated by norepinephrine nor prevented by prazosin or phentolamine whereas ketanserin and methysergide were equally effective inhibitors. These findings argue against a role of platelet and/or vascular 5-HT 2 receptors in the antihemostatic effect of ketanserin in rats. This drug prolongs bleeding time by antagonising vascular adrenoceptors (prazosin-like effect) and/or by preventing a synergistic interaction between 5-HT and catecholamines at the vascular level.