Glimepiride exhibits prophylactic effect on atherosclerosis in cholesterol-fed rabbits.
OBJECTIVE
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
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.
Shakuto
Shuji
S
Pharmacology, Lead Optimization, Drug Innovation and Approval Division, Aventis Pharma Ltd., 1-3-2 Minamidai, Kawagoe, Saitama 350-1165, Japan. shuji.shakuto@aventis.com
Oshima
Kenichi
K
Tsuchiya
Eiko
E
D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000097:blood / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008054:Lipid Peroxides / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D011817:Rabbits; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D002791:Cholesterol, Dietary; D007166:Immunosuppressive Agents; D007328:Insulin; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D013453:Sulfonylurea Compounds; D017392:Thiobarbituric Acid Reactive Substances; D014280:Triglycerides; C099252:oxidized low density lipoprotein; C057619:glimepiride; D003300:Copper