Inhibition of balloon injury-induced neointimal formation by olmesartan and pravastatin in rats with insulin resistance.
The combined effect of an angiotensin II type 1 receptor blocker and a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor on vascular lesion formation in the insulin-resistant state has not been examined. We tested whether or not combined treatment is superior to single-drug treatment for inhibiting vascular lesion formation in insulin-resistant rats. The rats were maintained on a fructose-rich diet for 4 weeks and then treated with olmesartan (1 mg/kg/day) and/or pravastatin (10 mg/kg/day) for 3 weeks. After 1 week of drug treatment, balloon injury of the carotid arteries was performed. Two weeks later, the injured arteries were harvested for morphometry and immunostaining. Olmesartan and pravastatin each modestly attenuated neointimal formation without significant changes in blood pressure or serum lipid levels. The combination of olmesartan and pravastatin significantly suppressed the neointimal formation compared with either monotherapy. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells was increased by olmesartan but not by pravastatin. Olmesartan and pravastatin each decreased the number of Ki-67-positive cells, which indicates cell proliferation, to the same extent. The combined treatment increased the number of TUNEL-positive cells but did not affect the number of Ki-67-positive cells. The combined treatment decreased the insulin level and increased the number of circulating endothelial progenitor cells. These results suggest that the combination of olmesartan and pravastatin is beneficial for the treatment of vascular diseases in the insulin-resistant state independently of blood pressure or cholesterol levels.
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Ming
M
Chen
Toshihiro
T
Ichiki
Hideki
H
Ohtsubo
Ikuyo
I
Imayama
Keita
K
Inanaga
Ryouhei
R
Miyazaki
Kenji
K
Sunagawa
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002340:Carotid Artery Diseases / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D020212:Carotid Artery Injuries / Q000209:etiology / Q000473:pathology; D017536:Carotid Artery, Common / Q000473:pathology; D002452:Cell Count; D049109:Cell Proliferation; D005632:Fructose / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007093:Imidazoles / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D017035:Pravastatin / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D013777:Tetrazoles; D005632:Fructose; C437965:olmesartan; D017035:Pravastatin