Background-Impaired endothelium-dependent NO-mediated vasodilation is a key feature of essential hypertension and may precede the increase in blood pressure. We investigated whether transport of the NO precursor L-arginine is related to decreased endothelial function. Methods and Results-Radiotracer kinetics([3H]L-arginine)were used to measure forearm and peripheral blood mononuclear cell arginine uptake in hypertensive subjects(n=12)and in 2 groups of healthy volunteers with(n=15)and without(n=15)a family history of hypertension. In conjunction, forearm blood flow responses to acetylcholine and sodium nitroprusside were measured before and after a supplemental intra-arterial infusion of L-arginine. In vivo and in vitro measures of L-arginine transport were substantially reduced in the essential hypertension and positive family history groups compared with the negative family history group; however, no difference was detected in peripheral blood mononuclear cell mRNA or protein expression levels for the cationic amino acid transporter CAT-1. Plasma concentrations of L-arginine and NG,NG-dimethylarginine(ADMA)did not differ between groups. L-Arginine supplementation improved the response to acetylcholine only in subjects with essential hypertension and positive family history. Conclusions-Similar to their hypertensive counterparts, normotensive individuals at high risk for the development of hypertension are characterized by impaired L-arginine transport, which may represent the link between a defective L-arginine/NO pathway and the onset of essential hypertension. The observed transport defect is not due to apparent alterations in CAT-1 expression or elevated endogenous ADMA.