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: Taketoshi Ogawa, Atsuhiro Sugidachi, Naoki Tanaka, Koichi Fujimoto, Fumitoshi Asai
• Journal: Vascular pharmacology (Vascul Pharmacol) Vol. 41 Issue 1 Pg. 7-13 (Feb 2004) ISSN: 1537-1891 [Print] United States
• PMID: 15135326 (Publication Type: Journal Article)

Chemical References

• Pyrrolidines
• R-102444
• Receptor, Serotonin, 5-HT2A
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin Antagonists

Topics

• Administration, Oral
• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Male
• Peripheral Vascular Diseases (drug therapy, physiopathology)
• Pyrrolidines (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptor, Serotonin, 5-HT2A (physiology)
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin Antagonists (administration & dosage)
• Vasodilation (drug effects, physiology)