Arginine (A) may play a significant role in fetal growth, by stimulating insulin secretion and as a precursor for both polyamine synthesis and nitric oxide production. To determine whether increased maternal plasma A concentrations can enhance delivery of A to the fetus, uterine, umbilical, and net uteroplacental (UP) A uptake rates were measured in 12 pregnant ewes at 129.6 Ϯ 0.4 d gestation (mean Ϯ SEM) during normal and after 3 h of increased maternal plasma A concentrations. With a 2.7-fold increase in maternal plasma A concentrations (p Ͻ 0.001), there were significant increases in uterine A uptake (13.8 Ϯ 1.0 to 41.3 Ϯ 7.7 mol/min, p Ͻ 0.005), umbilical A uptake (3.3 Ϯ 0.5 to 5.2 Ϯ 0.8 mol·min Ϫ1 ·kg Ϫ1 fetus, p Ͻ 0.005), UP A uptake (17.8 Ϯ 6.2 to 89.2 Ϯ 20.3 mol·min Ϫ1 ·kg Ϫ1 placenta, p Ͻ 0.01), fetal arterial A concentration (98.7 Ϯ 6.3 to 137.1 Ϯ 9.9 M, p Ͻ 0.001), maternal A disposal rate (143.7 Ϯ 9.4 to 217.0 Ϯ 6.7 mol/min, p Ͻ 0.001), fetal A disposal rate (7.9 Ϯ 0.8 to 9.9 Ϯ 1.1 mol·min Ϫ1 ·kg Ϫ1 , p Ͻ 0.05), fetal A oxidation rate (1.31 Ϯ 0.24 to 1.84 Ϯ 0.36 mol·min Ϫ1 ·kg Ϫ1 , p Ͻ 0.05), and plasma insulin concentration in both fetus (16 Ϯ 2 to 20 Ϯ 2 U/mL, p Ͻ 0.001) and mother (24 Ϯ 3 to 32 Ϯ 4 U/mL, p Ͻ 0.001). Thus, increased maternal plasma A concentration increases maternal, UP, and fetal A net uptake, and increases insulin secretion in mother and fetus. The 4.2-fold larger increase in UP than net fetal A uptake could represent preferential UP A metabolism relative to fetal A metabolism, relatively limited placental-fetal A transport capacity compared with uterine A uptake capacity, or both; responsible mechanisms remain unknown. Arginine is a conditionally indispensable amino acid in the mammalian fetus and neonate (1, 2), and maintenance of fetal arginine supply and plasma concentrations are important for optimal fetal growth. The mechanisms by which arginine promotes fetal growth, however, are multifaceted and have not been adequately investigated. Arginine is an insulin secretagogue in ovine and human fetuses (3-7) and in human newborns (8 -10); thus the role of arginine in fetal growth may include an insulin-mediated anabolic effect. In addition, arginine could stimulate growth as a precursor for polyamine synthesis (11) and nitric oxide production (12-14).In contrast, arginine deficiency has been shown to induce growth restriction in experimental animals (15, 16). A potential therapy for fetal growth restriction, therefore, could include maternal plasma arginine supplementation in an attempt to increase fetal arginine supply. It is not known, however, whether increasing maternal plasma arginine concentration could increase net fetal arginine uptake, fetal plasma arginine concentration, or fetal insulin concentration. In addition, the characteristics of placental arginine uptake, metabolism, and transport to the fetus have not been determined. Therefore, this study was designed to determine how maternal arginine supplementation affects maternal, uteroplacental, and fetal arginine net ...