Effects of R-102444, an orally active 5-HT 2A receptor antagonist, in rat models of peripheral vascular disease

Abstract

R-102444 is a prodrug that is metabolized into R-96544, a potent and selective 5-hydroxytryptamine 2A (5-HT 2A) receptor antagonist. The effects of R-102444 on peripheral vascular disease were examined using two different rat models: one induced by lauric acid and the other by ergotamine plus epinephrine. R-96544 (0.3–30 nM) relaxed the 5-HT (3 μM)-precontracted rat caudal artery in a concentration-dependent manner. The intravenous administration of R-96544 (0.3–3 μg/kg) to anesthetized rats inhibited the pressor response to 5-HT (50 μg/kg iv) dose dependently. The oral administration of R-102444 (1 mg/kg) to rats resulted in a marked inhibition of platelet aggregation induced by 5-HT plus ADP, and statistically significant inhibition was still evident 8 h after the dosing. In contrast, sarpogrelate, at a dose of 100 mg/kg po, produced only a moderate antiplatelet effect. Oral administration of R-102444 (1 mg/kg/day, OD) significantly prevented the progression of peripheral vascular lesion induced by the injection of lauric acid into a rat femoral artery, whereas sarpogrelate (100 mg/kg/day) showed only a minimal effect. Both 5-day treatments with R-102444 (1–30 mg/kg/day po, OD), one commenced 1 h before the injection of epinephrine plus ergotamine and one just after injection, resulted in the prevention of rat tail gangrene in a dose-dependent manner, whereas sarpogrelate (100 mg/kg) produced a minimal protection in this model. Based on these results, we conclude that 5-HT 2A receptor activation is involved in peripheral vascular disease in the rat and that R-102444 is a useful oral agent for the investigation of diseases involving 5-HT 2A receptor activation.