ROLE OF SEROTONIN IN ARTERIOLAR THROMBOSIS AND SECONDARY VASOSPASM

Platelets are implicated both in the thrombotic reaction to an intimal lesion of the arteriolar wall and to the resulting vasospasm even if the two phenomena are not linked directly. The spastic reaction is a consequence of the thrombotic process because without localized platelet activation (thrombus formation) there is no vasospastic reaction, but by pharmacological manipulation, the thrombotic reaction can develop without resulting vasospasm. We developed an original experimental model that allowed us to study the thrombotic reaction secondary to localized endothelial injury in arterioles of the mesentery of the rat, as well as the vasospastic reaction downstream to the site of thrombus formation. In this setting, we studied the reactivity of Sprague-Dawley rats treated with three 5-HT2 serotonergic antagonists (ketanserin, ritanserin, and naftidrofuryl) and that of Fawn-Hooded rats (a strain affected by a congenital reduction of platelet dense granules, with a resulting decrease in platelet content of serotonin, ADP, and catecholamines). Naftidrofuryl had antithrombotic properties similar to those of ritanserin but was less potent than ketanserin. It possessed antispastic activity against the reaction secondary to intravascular platelet activation. Its potency was similar to that of ketanserin but greater than that of ritanserin. Naftidrofuryl had no significant antispastic activity against platelet-derived agents reaching the arteriolar wall from the adventitial side. Compared to the Sprague-Dawley rat, Fawn-Hooded rats had a minimal reduction of the thrombotic process and of the intraluminal induced vasospasm but similar response to adventitial stimulation of the arterial wall by vasoactive factors released from a neighboring hemostatic plug. These results suggest that the serotonin-induced release by endothelial cells of vasorelaxing factors partially antagonizes its direct vasconstrictor effect on vascular smooth muscle cells. This endothelium-mediated vasorelaxing action is unmasked by 5-HT2 serotonergic antagonists such as ketanserin (70-mu-M/kg) and naftidrofuryl (60-mu-M/kg). The small effect observed in the Fawn-Hooded rats is probably related to the fact that in this model the defect in platelet-dense granules and their content is partial.