Effect of 17 beta-estradiol in hypercholesterolemic rabbits with severe endothelial dysfunction

17 beta-Estradiol prevents early vascular lesion development and may also a ffect advanced atherosclerosis. To test the antiatherosclerotic effect of e strogen under conditions that resemble more advanced human atherosclerosis with severe endothelial dysfunction, we have investigated the effect of 17 beta-estradiol in hypercholesterolemic rabbits treated with the nitric oxid e synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME). Chroni c L-NAME administration attenuated endothelial nitric oxide (EDNO)-mediated vascular responses leading to significantly accelerated atherosclerotic pl aque development. 17 beta-Estradiol treatment alone inhibited aortic lesion formation with concurrent increase in EDNO-mediated responses. The benefic ial effect of estrogen persisted in the L-NAME-treated rabbits, suggesting that the antiatherogenic action of 17 beta-estradiol involves NO-independen t mechanisms as well. Serum cholesterol levels were not altered by any of t he treatments. 17 beta-Estradiol treatment significantly increased EDNO pro duction under these conditions as well. The reduction in plaque size by 17 beta-estradiol was always accompanied by increased EDNO production, suggest ing a strong association between these two events. The results demonstrate that estrogen treatment may exert protection against atherosclerosis even i n patients with severe endothelial dysfunction.