Arginine and Mixed Amino Acids Increase Protein Accretion in the Growth-Restricted and Normal Ovine Fetus by Different Mechanisms

Abstract

Protein metabolism may be perturbed in intrauterine growth restriction (IUGR). Arginine is indispensable for growth and nitrogen balance in young mammals. Fetuses with IUGR therefore may benefit from arginine supplementation. The purpose of this study was to determine 1) the effects of IUGR on protein metabolism in the ovine fetus and 2) the effects of arginine or mixed amino acid (AA) infusion on protein metabolism in these fetuses. Pregnant ewes and their fetuses were catheterized at 110 d gestation and randomly assigned to control or IUGR groups. IUGR was induced by repetitive placental embolization. Parameters of fetal protein metabolism were determined from [ring-2 H 5 ]phenylalanine kinetics at baseline and in response to a 4-h infusion of either arginine or an isonitrogenous AA mixture. There were no differences in protein metabolism between control and IUGR groups either at baseline or in response to arginine or AA treatment. Both arginine and AA infusion increased fetal protein accretion in both groups. Arginine did this by decreasing protein turnover, synthesis, and breakdown. AAs increased protein turnover and synthesis while decreasing protein breakdown. AA infusion resulted in a significantly higher increase in protein accretion than arginine infusion. Thus, in the ovine fetus, placental embolization has no clear effect on protein metabolism. Arginine and AAs both stimulate protein accretion but do so in distinctly different ways. Mixed AA infusion has a greater effect on protein accretion than arginine alone and therefore may be a better strategy for stimulating fetal growth. Intrauterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity (1,2). Although there are many possible causes, the key feature of IUGR is impaired fetal growth and, hence, by inference, impaired protein accretion. However, there are few data describing the alterations in protein metabolism that must underlie IUGR.In the IUGR human neonate, the few studies available are conflicting (3-5). Protein accretion rates are reported to be normal, although both increased (3,4) and reduced (5) protein synthesis and turnover have been reported. A previous study on protein kinetics in the ovine fetus in which growth was restricted by heat stress showed no significant changes in protein synthesis, breakdown, or accretion (6). However, a number of reports provide indirect evidence of altered protein metabolism in human fetuses with IUGR. In human pregnancies that are complicated with IUGR, fetal plasma AA concentrations are reduced (7,8), and this persists after birth (9). Concentrations of most essential AAs are lower, particularly those of the branched-chain AAs valine, isoleucine, and leucine (7,9). The maternal plasma AA concentrations are higher than in uncomplicated pregnancies and often not significantly different from nonpregnant controls (8).There is also indirect evidence of impaired urea production in association with IUGR. Plasma and urinary urea levels are

Prolonged maternal amino acid infusion in late-gestation pregnant sheep increases fetal amino acid oxidation

“…To extend these findings we undertook a morphological analysis of the fetal pancreas, but we did not see an increase in the amount of pancreatic ␣-cells, which secrete glucagon; nor did we find a change in the amount of pancreatic ␤-cells, which was not surprising given the lack of change in fetal insulin concentrations. Interestingly, short-term administration of amino acids, either into the pregnant mother or directly into the fetus, acutely increases fetal insulin concentrations (4,7,16); however, our data indicate that this response is not sustained. A detailed understanding of the effects of a prolonged amino acid infusion on fetal insulin and glucagon requires further study.…”

“…Direct infusion of amino acids into the fetus will avoid competitive inhibition at the placenta among amino acids with similar properties. For example, when balanced mixtures of amino acids have been infused directly into the late-gestation sheep fetus for 2 and 4 h, fetal plasma amino acid concentrations, including threonine, protein synthesis rates, and accretion rates increased (7,19). Importantly, insulin concentrations also were increased as a result of such direct amino acid infusions, unlike in the present study (7).…”

“…For example, when balanced mixtures of amino acids have been infused directly into the late-gestation sheep fetus for 2 and 4 h, fetal plasma amino acid concentrations, including threonine, protein synthesis rates, and accretion rates increased (7,19). Importantly, insulin concentrations also were increased as a result of such direct amino acid infusions, unlike in the present study (7). Third, fetal insulin and IGF-I concentrations did not change as a result of supplementation in our study, and previous work suggests that protein synthesis rates are maximal only when amino acids are present with a concurrent increase in insulin or IGF-I concentrations (30,31,43).…”

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep

“…The anabolic hormones insulin and IGF-I likely affect the fetal response to a direct amino acid infusion and have been shown to promote fetal protein synthesis and accretion (22,(37)(38)(39). Insulin promotes fetal amino acid utilization, oxidation, and protein synthesis in a variety of animal models, both independently and synergistically with supplemental amino acids (5,9,30,40). For example, protein synthesis rates in neonatal piglets are maximal in response to an amino acid load only with concurrent increases in insulin or IGF-I concentrations (30,31,40).…”

Urea production and arginine metabolism are reduced in the growth restricted ovine foetus

“…This change in maternal urea concentrations may again reflect altered demand for maternal amino Table 6 The effects of arginine and amino acid infusions on arterial plasma amino acid concentrations (expressed in mmol/l) acids. Arginine infusion stimulates protein accretion in both control and embolised animals (de Boo et al, 2005) which would increase foetal demand for amino acids from the maternal circulation, thus potentially decreasing maternal amino acid oxidation and urea production. Amino acid infusion had similar effects.…”