Suppression of intimal hyperplasia by a 5-lipoxygenase inhibitor, MK-886: studies with a photochemical model of endothelial injury.
Intimal thickening is a major complication following percutaneous transluminal coronary angioplasty, which leads to restenosis and requires reoperation. We have investigated the effect of a 5-lipoxygenase inhibitor, MK-886, a leukotriene B4 (LTB4) receptor antagonist, ONO-4057 or a LTC4 and LTD4 receptor antagonist, ONO-1078, on intimal thickening. Photochemical reaction between green light and systemically administered Rose Bengal produced intimal thickening in the rat femoral artery. Each drug was administered orally, once a day for 7 days, starting just after the endothelial injury. Both MK-886 administration, 10 mg/kg, and ONO-4057 administration, 100 mg/kg, suppressed intimal thickening level examined three weeks after endothelial injury, while similarly administered ONO-1078 did not. In cultured rat-derived smooth muscle cells, LTB4, an active metabolite of 5-lipoxygenase whose biosynthesis in air pouch exudate was suppressed by MK-886, stimulated cell migration. Based on these observations, the 5-lipoxygenase may have a key role in intimal thickening via its metabolites such as LTB4.
Kondo
K
K
Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
Umemura
K
K
Ohmura
T
T
Hashimoto
H
H
Nakashima
M
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004730:Endothelium, Vascular / Q000473:pathology; D005263:Femoral Artery / Q000473:pathology*; D006965:Hyperplasia; D007211:Indoles / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D010782:Photolysis; D051381:Rats; D017208:Rats, Wistar; D017539:Tunica Intima / Q000473:pathology*; D002722:Chlorobenzenes
D007211:Indoles; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes