Role of 5-hydroxytryptamine in platelet thrombus formation and mechanisms of inhibition of thrombus formation by 5-hydroxytryptamine2A antagonists in rabbits.

Abstract

The role of 5-hydroxytryptamine (5-HT) in platelet thrombus formation and in the mechanisms of inhibition of thrombus formation by 5-HT2A antagonists was investigated using a turbidimetric method. Collagen-induced platelet aggregation occurred simultaneously with a release of 5-HT from the platelets. The supernatant of collagen-aggregated platelets induced a further aggregation volume-dependently. This supernatant-induced aggregation was inhibited by either 5-HT2A antagonists or adenosine-diphosphate (ADP) scavenging. 5-Hydroxytryptamine and a small amount of the supernatant shifted the dose-response curves of collagen to the left. The aggregation velocity and the onset of aggregation by collagen were significantly increased by the supernatant, but not by 5-HT. The 5-HT2A antagonists, ketanserin and MCI-9042, returned the dose-response curves of the maximum aggregation and of the aggregation velocity of collagen, which were already amplified by the supernatant, to the original values. The onset of aggregation was delayed by the antagonists, but was not completely returned to the original points. There were distinct differences between the effects of endogenous 5-HT, derived from platelets which were stimulated by collagen, and those of exogenous 5-HT on both extensive platelet activation and amplification of the collagen-induced aggregation. These findings suggest that endogenous 5-HT activates platelets in synergism with ADP. The 5-HT2A antagonists used, block the synergism via 5-HT2A receptors and lead to inhibition of a positive feedback loop of thrombus formation.