title: Effects of R-102444, an orally active 5-HT2A 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-hydroxytryptamine2A (5-HT2A) 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 microM)-precontracted rat caudal artery in a concentration-dependent manner. The intravenous administration of R-96544 (0.3-3 microg/kg) to anesthetized rats inhibited the pressor response to 5-HT (50 microg/kg i.v.) 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 p.o., produced only a moderate antiplatelet effect. Oral administration of R-102444 (1 mg/kg/day, o.d.) 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 p.o., o.d.), 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-HT2A 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-HT2A receptor activation.
authors.affiliation: Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Asai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D016491:Peripheral Vascular Diseases / Q000188:drug therapy* / Q000503:physiopathology; D011759:Pyrrolidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D011759:Pyrrolidines; C421542:R-102444; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists