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

Abstract

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 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-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 -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -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 -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -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.

• Authors: P Holm, N Korsgaard, M Shalmi, H L Andersen, P Hougaard, S O Skouby, S Stender
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 100 Issue 4 Pg. 821-8 (Aug 15 1997) ISSN: 0021-9738 [Print] United States
• PMID: 9259581 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrrolidines
• Receptors, Estrogen
• Nitroprusside
• Estradiol
• levormeloxifene
• Cholesterol
• Nitric Oxide Synthase
• Acetylcholine
• NG-Nitroarginine Methyl Ester

Topics

• Acetylcholine (pharmacology)
• Animals
• Aorta (chemistry, drug effects, physiology)
• Arteriosclerosis (metabolism)
• Catheterization
• Cholesterol (analysis)
• Coronary Vessels (drug effects, physiology)
• Estradiol (pharmacology)
• Female
• In Vitro Techniques
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitric Oxide Synthase (antagonists & inhibitors, physiology)
• Nitroprusside (pharmacology)
• Ovariectomy
• Pyrrolidines (pharmacology)
• Rabbits
• Receptors, Estrogen (agonists)