Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits.
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.
Holm
P
P
Novo Nordisk A/S, Novo Allé, 2880 Bagsvaerd, Denmark. phlm@novo.dk
Korsgaard
N
N
Shalmi
M
M
Andersen
H L
HL
Hougaard
P
P
Skouby
S O
SO
Stender
S
S
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism*; D002404:Catheterization; D002784:Cholesterol / Q000032:analysis*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D010052:Ovariectomy; D011759:Pyrrolidines / Q000494:pharmacology*; D011817:Rabbits; D011960:Receptors, Estrogen / Q000819:agonists
D011759:Pyrrolidines; D011960:Receptors, Estrogen; D009599:Nitroprusside; D004958:Estradiol; C108255:levormeloxifene; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester