Estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, although the mechanism of benefit is unknown. We undertook studies to determine the acute and chronic effect of estrogen administration on endothelium-dependent vasodilation and estrogen-deficient postmenopausal women. Thirty-one postmenopausal women, age 61+/-8 years (mean+/-SD) participated in this study. The effects of estrogen administration on the forearm vascular responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside were studied during acute intra-arterial infusion of 5% dextrose solution and of 17 beta-estradiol and after 3 weeks of transdermal 17 beta-estradiol administration. Acute intra-arterial infusion of 17 beta-estradiol, which increased forearm venous estradiol levels from 16+/-10 to 318+/-217 pg/ml, potentiated the forearm vasodilation induced by acetylcholine by 50+/-68% (p<0.001) but did not affect the forearm vasodilation induced by sodium nitroprusside. However, after 3 weeks of transdermal estradiol administration (.1 mg patch every 3 days), achieving an estradiol level of 121+/-64 pg/ml, the vasodilator responses to acetylcholine and to sodium nitroprusside were unchanged from baseline. Repeat infusion of estradiol in 8 women, while on the patch, increased estradiol levels to 276+/-91 pg/ml and again potentiated the vasodilator response to acetylcholine to a similar degree to that observed in the baseline studies. Thus, we conclude that acute intra-arterial infusion of 17 beta-estradiol potentiates endothelium-dependent vasodilation in the forearm of postmenopausal women. However, this effect was not maintained with chronic (3 week), systemic estradiol administration. The different effects of acute and chronic estradiol may be due to the lower plasma levels achieved, the development of tolerance, or different cellular mechanisms of action with chronic administration.