Chen Ming, Ichiki Toshihiro, Ohtsubo Hideki, Imayama Ikuyo, Inanaga Keita, Miyazaki Ryouhei, Sunagawa Kenji
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Hypertens Res. 2007 Oct;30(10):971-8. doi: 10.1291/hypres.30.971.
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.
血管紧张素II 1型受体阻滞剂与3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂联合使用对胰岛素抵抗状态下血管病变形成的综合影响尚未得到研究。我们测试了联合治疗在抑制胰岛素抵抗大鼠血管病变形成方面是否优于单药治疗。将大鼠置于富含果糖的饮食中饲养4周，然后用奥美沙坦（1毫克/千克/天）和/或普伐他汀（10毫克/千克/天）治疗3周。药物治疗1周后，对颈动脉进行球囊损伤。两周后，采集损伤的动脉进行形态计量学分析和免疫染色。奥美沙坦和普伐他汀各自适度减轻了内膜增生，血压或血脂水平无显著变化。与单一疗法相比，奥美沙坦和普伐他汀联合使用显著抑制了内膜增生。奥美沙坦增加了末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）阳性细胞的数量，但普伐他汀未增加。奥美沙坦和普伐他汀各自将表明细胞增殖的Ki-67阳性细胞数量减少到相同程度。联合治疗增加了TUNEL阳性细胞的数量，但不影响Ki-67阳性细胞的数量。联合治疗降低了胰岛素水平，增加了循环内皮祖细胞的数量。这些结果表明，奥美沙坦和普伐他汀联合使用有利于治疗胰岛素抵抗状态下的血管疾病，且独立于血压或胆固醇水平。
