(related to a sidelined project from arna)...........
J Cardiovasc Pharmacol. 2011 Aug 4. [Epub ahead of print]
Modulation of vasoactivity and platelet aggregation by selective 5-HT receptor antagonism in humans.
Moerland M, Kemme M, Dijkmans A, Bergougnan L, Burggraaf J.
Source * Centre for Human Drug Research, Leiden, The Netherlands, #Sanofi-Aventis, Chilly-Mazarin, France.
Abstract BACKGROUND: Distinct serotonin (5-HT) receptors are involved in platelet aggregation and vasoconstriction. Compounds that simultaneously and selectively inhibit the pertaining 5-HT receptors may therefore represent a therapeutic strategy for arterial thrombosis, observed frequently after atherosclerotic plaque rupture. The vasoactive and antiplatelet effects of the combined 5-HT1B and 5-HT2A receptor blocker SL65.0472-00 were investigated in humans to elucidate the functional involvement of these receptors.
METHODS: Twenty-four volunteers, divided into two groups of 12, received an oral dose of 20 mg SL65.0472-00 or placebo in a randomized, double-blind, crossover study. Pre-dose and at 2, 4 and 6 hours after dosing, intra-arterial infusions of 5-HT1B agonist sumatriptan (n=12) or 5-HT (n=12) were administered. Forearm blood flow (FBF) was measured using plethysmography and platelet aggregation was measured using whole blood aggregometry induced by a combination of a threshold collagen concentration and an excess of 5-HT. Treatments were compared using ANOVA.
RESULTS: After placebo treatment, infusion of 1 ng/kg/min 5-HT induced vasodilatation (FBF +80% change from baseline), while infusion of 30 and 80 ng/kg/min 5-HT resulted in vasoconstriction (FBF -25% and -50%). After SL65.0472-00 treatment all 5-HT doses induced vasodilatation (FBF +25-60%). Sumatriptan dose-dependently decreased FBF (maximally -35%), but this effect was not altered by SL65.0472-00 treatment. 5-HT-induced platelet aggregation was effectively inhibited by 90% after SL65.0472-00 treatment for at least 6 hours.
CONCLUSIONS: SL65.0472-00 has potent antagonistic effect on 5-HT-induced vasoconstriction and platelet aggregation but not on sumatriptan-induced vasoconstriction. This suggests that in humans, SL65.0472-00 is a 5-HT2A blocker without clear 5-HT1B antagonistic activity. |
