Effect of (+/-)-2-(dimethylamino)-1-[[o-(m-methoxyphenethyl)phenoxy] methyl]ethyl hydrogen succinate on experimental models of peripheral obstructive disease.

Abstract

Peripheral obstructive disease in tail or hind limb was experimentally induced by intravenous injection of kappa-carrageenin or intra-arterial injection of sodium laurate in rats, and the suppressive effect of (+/-)-2-(dimethylamino)-1-[[o-(m-methoxyphenethyl)phenoxy] methyl]ethyl hydrogen succinate (MCI-9042, CAS 125926-17-2) on the peripheral obstructive diseases was examined. The injection of kappa-carrageenin induced a thrombotic infarction of the tail vessel in rats. The administration of MCI-9042 dose-dependently suppressed the peripheral infarction with an ED50 value of 16 mg/kg p.o. Ticlopidine, a reference antiplatelet drug, did not affect the peripheral infarction even at 50 mg/kg p.o. Cyproheptadine, however, an S2-serotonergic antagonist, potently suppressed the peripheral infarction with an ED50 of 3.5 mg/kg p.o. After the injection of sodium laurate into the femoral artery in rats peripheral lesions of the paw were generated and extended. MCI-9042 significantly prevented the progression of the disease at doses of 10 mg/kg p.o. and above. When the daily administration of MCI-9042 was started from 1 day after the laurate injection, it was also effective as well as by pretreatment. Ticlopidine was significantly effective only at 100 mg/kg p.o. as pretreatment. From the present study, it is considered that platelet-derived serotonin plays an important role in the development of peripheral obstructive disease and MCI-9042 suppressed the disease through its S2-serotonergic antagonism.