Arginine and fetal growth in ovine models of intrauterine growth restriction

This research was conducted to test the hypothesis that parenteral arginine supplementation is effective in enhancing birth weights of intrauterine growth restricted (IUGR) fetuses. Underfed and prolific ewes were used as experimental models. The first study characterized the pharmacokinetics of arginine and citrulline and assessed the potential of citrulline to serve as a precursor for enhancing arginine availability in fetal and maternal plasma. Six late pregnant ewes and their fetuses were instrumented to access arterial and venous circulations. Intravenous boluses of 155 mumol of L-arginine-HCl or L-citrulline per kg body weight were administered to each ewe. Administration of citrulline was more effective than arginine in achieving a sustained increase in concentrations of arginine in maternal and fetal blood. Accordingly, the clearance rate of citrulline was lower and its biological half-life in maternal blood greater, when compared with arginine. The second experiment determined if administration of arginine to underfed ewes is effective in ameliorating or preventing IUGR. Ewes were fed either 100% or 50% of the National Research Council recommended nutrient requirements for pregnant sheep. Between Day 60 of pregnancy and parturition control-fed ewes received saline solution and underfed ewes received either saline solution or L-arginine-HCl solution (155 mumol of arginine/kg body weight) intravenously three times daily (n=5/treatment group). Birth weights of lambs were lower in saline-infused underfed ewes. There was no difference in birth weights of lambs from control-fed and arginine-treated underfed ewes. The third experiment determined whether administration of arginine could improve survival rates of lambs and enhance fetal growth in ewes carrying multiple fetuses. Between Days 100 and 121 of pregnancy, ewes received an intravenous infusion of either saline solution (n=14) or L-arginine-HCl solution (345 mumol of arginine/kg body weight, n=20) three times daily. Parenteral administration of arginine increased the percentage of lambs born alive and enhanced the birth weights of quadruplets. Collectively, these results indicate that (1) parenteral administration of arginine improves pregnancy outcomes in underfed and prolific ewes; and (2) the use of arginine or citrulline may have important implications for the design of an effective treatment for preventing or ameliorating IUGR in mammals.