Effect of YM-254890, a specific Galphaq/11 inhibitor, on experimental peripheral arterial disease in rats.
The protective effect of YM-254890, a specific Galphaq/11 inhibitor, on laurate-induced peripheral arterial disease in rats was compared with those of prostaglandin E1 (PGE1), beraprost, and clopidogrel. YM-254890 inhibited ADP-induced ex vivo rat platelet aggregation at a dose of 3 microg/kg. Furthermore, YM-254890 strongly inhibited phenylephrine-, serotonin- and endothelin-1-induced contractions in the rat aorta, and improved dermal blood flow after the laurate injection. The intra-arterial single bolus administration of YM-254890 15 min after the laurate injection dose-dependently inhibited the progression of the lesion, with significance, at 3 microg/kg without affecting systemic blood pressure. PGE1 and beraprost, when administered before the laurate injection, were effective, but their potencies were less than that of YM-254890. Clopidogrel significantly suppressed lesion progression when administered at 30 mg/kg twice a day for 3 days, which completely inhibited platelet aggregation. These results suggest that the local administration of YM-254890 may be useful for treating peripheral arterial disease.
Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Toshio
T
Uemura
Hajime
H
Takamatsu
Tomihisa
T
Kawasaki
Masatoshi
M
Taniguchi
Eisaku
E
Yamamoto
Yuichi
Y
Tomura
Wataru
W
Uchida
Keiji
K
Miyata
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D000077144:Clopidogrel; D020405:Dermis / Q000098:blood supply / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors*; D006339:Heart Rate / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D066298:In Vitro Techniques; D007850:Lauric Acids; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D016491:Peripheral Vascular Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D007850:Lauric Acids; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; C475455:YM-254890; C030358:lauric acid; C048081:beraprost; D000077144:Clopidogrel; D011464:Epoprostenol; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D013988:Ticlopidine