Shuji Shakuto1, Kenichi Oshima, Eiko Tsuchiya. 1. Pharmacology, Lead Optimization, Drug Innovation and Approval Division, Aventis Pharma Ltd., 1-3-2 Minamidai, Kawagoe, Saitama 350-1165, Japan. shuji.shakuto@aventis.com
Abstract
AIMS/HYPOTHESIS: The purpose of this study was to examine the potential prophylactic effect of glimepiride on experimental atherosclerosis in rabbits and to elucidate the mechanism of action. METHODS: Rabbits were fed an atherogenic diet containing 1% cholesterol and glimepiride 0.1mg/kg/day for 10 weeks. Plasma lipid levels were determined every 2 weeks. The percentage of atherogenic lesions of thoracic aorta stained with oil red O was calculated and histological examination of the lesions was performed. Lipid and lipid peroxide contents in thoracic aorta and liver were also determined. In addition, the inhibitory effect of glimepiride on human coronary arterial endothelial cell-mediated LDL oxidation was evaluated. RESULTS: Accumulation of lipid-laden foam cells in the focal areas of arterial intima was observed in oil red O-positive atherosclerotic lesions. Glimepiride treatment produced significant reduction of atherosclerotic lesions (control, 57.5+/-7.1% versus glimepiride, 20.6+/-4.8%; P<0.01) with no significant change observed in levels of plasma lipids. There were marked decreases in lipid and lipid peroxide contents in the thoracic aorta in glimepiride-treated rabbits with no significant change in levels of liver lipids. In cultured human coronary arterial endothelial cells, glimepiride inhibited oxidative modification of LDL in a dose-dependent manner (IC(50)=8.8 x 10(-7)M) without cytotoxicity. CONCLUSIONS/ INTERPRETATION: These findings suggest that glimepiride prevents the development of aortic atherosclerosis in fat-fed rabbits. The underlying mechanism may be inhibition of endothelial cell-mediated LDL oxidation.
AIMS/HYPOTHESIS: The purpose of this study was to examine the potential prophylactic effect of glimepiride on experimental atherosclerosis in rabbits and to elucidate the mechanism of action. METHODS:Rabbits were fed an atherogenic diet containing 1% cholesterol and glimepiride 0.1mg/kg/day for 10 weeks. Plasma lipid levels were determined every 2 weeks. The percentage of atherogenic lesions of thoracic aorta stained with oil red O was calculated and histological examination of the lesions was performed. Lipid and lipid peroxide contents in thoracic aorta and liver were also determined. In addition, the inhibitory effect of glimepiride on human coronary arterial endothelial cell-mediated LDL oxidation was evaluated. RESULTS: Accumulation of lipid-laden foam cells in the focal areas of arterial intima was observed in oil red O-positive atherosclerotic lesions. Glimepiride treatment produced significant reduction of atherosclerotic lesions (control, 57.5+/-7.1% versus glimepiride, 20.6+/-4.8%; P<0.01) with no significant change observed in levels of plasma lipids. There were marked decreases in lipid and lipid peroxide contents in the thoracic aorta in glimepiride-treated rabbits with no significant change in levels of liver lipids. In cultured human coronary arterial endothelial cells, glimepiride inhibited oxidative modification of LDL in a dose-dependent manner (IC(50)=8.8 x 10(-7)M) without cytotoxicity. CONCLUSIONS/ INTERPRETATION: These findings suggest that glimepiride prevents the development of aortic atherosclerosis in fat-fed rabbits. The underlying mechanism may be inhibition of endothelial cell-mediated LDL oxidation.