Effect of (+/-)-2-(dimethylamino)-1-[[o-(m-methoxyphenethyl)phenoxy] methyl]ethyl hydrogen succinate on experimental models of peripheral obstructive disease.
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.
Hara
H
H
Pharmaceuticals Laboratory, Mitsubishi Kasei Corporation, Yokohama, Japan.
Shimada
H
H
Kitajima
A
A
Tamao
Y
Y
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002351:Carrageenan; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D007238:Infarction / Q000188:drug therapy / Q000503:physiopathology; D007850:Lauric Acids; D008297:Male; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D013386:Succinates / Q000627:therapeutic use*; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy; D013988:Ticlopidine / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D007850:Lauric Acids; D013386:Succinates; C030358:lauric acid; C064294:sarpogrelate; D002351:Carrageenan; D013988:Ticlopidine