Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits

被引:60
作者
Holm, P
Korsgaard, N
Shalmi, M
Andersen, HL
Hougaard, P
Skouby, SO
Stender, S
机构
[1] NOVO NORDISK AS,DK-2880 BAGSVAERD,DENMARK
[2] UNIV COPENHAGEN,RIGSHOSP,DEPT OBSTET & GYNECOL,DK-2100 COPENHAGEN,DENMARK
[3] ODENSE UNIV,INST CLIN,DK-5000 ODENSE,DENMARK
关键词
17; beta-estradiol; levormeloxifene; atherosclerosis; nitric oxide; endothelium;
D O I
10.1172/JCI119597
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17 beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 mu g/ml N-G-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of L-NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given L-NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas L-NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of L-NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given L-NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis.
引用
收藏
页码:821 / 828
页数:8
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