Aging is associated with reduced endothelial function. There is indirect evidence for reduced prostacyclin (PGI(2))-mediated vasodilation with aging, but it is unknown whether this is because of reduced dilation to PGI(2) or altered production. In addition, the contribution of endothelial NO to PGI(2)-mediated dilation is unknown. Using plethysmography to determine forearm blood flow, we studied the effect of PGI(2) in 10 older (61 to 73 years) and 10 younger (19 to 45 years) subjects using 3 escalating intra-arterial doses of PGI(2) (epoprostenol). PGI(2) was also administered after NO synthase inhibition with N(G)-monomethyl-l-arginine acetate. The percent of change in forearm vascular conductance (mean+/-SEM) from baseline after PGI(2) was significantly lower (P=0.002) in the aging individuals (52+/-11%, 164+/-23%, and 221+/-27% versus 115+/-20%, 249+/-19%, and 370+/-35%). In addition, the group-by-dose interaction was also significant (P=0.018). After NO synthase inhibition, the dose-response curve to PGI(2) was blunted in the young subjects but unchanged in the older subjects; the difference between the groups was no longer significant. Our data suggest that the reduced dilator effects of PGI(2) in older individuals are attributable to a reduction in the contribution of endothelial-derived NO versus alterations in the direct effects of PGI(2) on vascular smooth muscle.