The rates of whole body nitric oxide (NO) synthesis, plasma arginine flux, and de novo arginine synthesis and their relationships to urea production, were examined in a total of seven healthy adults receiving an L-amino acid diet for 6 days. NO synthesis was estimated by the rate of conversion of the ['5N] indicating that -11% of the plasma arginine flux originates via conversion of plasma citrulline to arginine. Thus, the fraction of the plasma arginine flux associated with NO and also urea synthesis in healthy humans is small, although the plasma arginine compartment serves as a significant precursor pool (54%) for whole body NO formation. This tracer model should be useful for exploring these metabolic relationships in vivo, under specific pathophysiologic states where the L-arginine-NO pathway might be altered.Arginine serves various important metabolic functions, including roles in protein synthesis, nitrogen transport and elimination (1, 2), and as the precursor of nitric oxide (NO), which is a current area of considerable research interest (3-5). Oxidation of arginine by a homodimeric group of nitric oxide synthases yields citrulline and nitric oxide in stoichiometric amounts, with each containing a nitrogen atom derived from the guanidino moiety of arginine. NO undergoes oxidative degradation to the stable end products nitrite (NO-) and nitrate (NO-). In the in vivo system, NO-is readily oxidized to NO{ via hemoglobin, and so NO is eventually detected in plasma or urine as NOK (5) and its measurement has been used to estimate the rate of whole body NO synthesis.It has been suggested that therapeutic modulation of nitric oxide production may be achieved by supplying the precursor arginine (6-9) or by inhibiting NO production with L-arginine analogs (10-12). However, before profound changes in exogenous arginine intake levels or a pharmacologic inhibition of NO formation can be safely recommended, it is desirable to gain a better understanding of the regulation of whole body arginine metabolism in human subjects and its quantitative interrelationships with the L-arginine-NO pathway.In our previous studies, using stable isotopic tracer techniques, we have investigated whole body arginine metabolism and the use of arginine for NO synthesis, by measurement of the transfer of the guanidino nitrogen of plasma arginine to urinary NO-. These studies have been carried out in healthy humans receiving variable levels of arginine intake (13-15), and in infants with pulmonary hypertension (16). We have now extended these earlier investigations of whole body arginine homeostasis and the metabolism of urea cycle intermediates by examining the kinetics of arginine metabolism throughout a continuous 24-35-hr period. Using this design, it has been possible, for the first time to our knowledge, to determine the in vivo rate of conversion of [15N]guanidino arginine to [15N]ureido citrulline and NO, presumably due to the NO synthase reaction. We compared this estimate with the rate of transfer of the guanidino nitroge...

We investigated the effects of a high dietary supplement of arginine on plasma arginine, ornithine, and leucine kinetics and on urea production and excretion in five healthy young adult men. Subjects received either 56 or 561 mg arginine.kg-1.day-1 for 6 days via a complete L-amino acid diet, and on day 7 a tracer protocol (first 3 h fasted; next 5 h fed) was conducted, involving primed constant intragastric infusions of L-[15N2-guanidino,5,5-2H2]arginine, L-[5-13C]ornithine, L-[5,5,5-2H3]leucine, and [15N2]urea, with a prime of H13CO3. Plasma arginine and ornithine fluxes increased significantly (P < 0.05) with arginine supplementation, as did the rate of conversion of plasma labeled arginine to ornithine (P < 0.05) and rate of ornithine oxidation (P < 0.001). However, absolute changes in ornithine kinetics were less than those for arginine or those based on changes expected from the change in arginine intake, implying a complex compartmentation in both whole body arginine and ornithine metabolism. The plasma NO3 concentration, daily output of total NO3, and conversion of [15N]arginine to NO3 did not differ between the diets. Urea production and excretion were reduced significantly with arginine supplementation, suggesting an anabolic effect on the whole body nitrogen economy, possibly via the raised plasma insulin levels (P = 0.013) during the prandial phase.

Arginine serves multiple roles in the pathophysiological response to burn injury. Our previous studies in burn patients demonstrated a limited net rate of arginine de novo synthesis despite a significantly increased arginine turnover (flux), suggesting that this amino acid is a conditionally indispensable amino acid after major burns. This study used [15N2-guanidino-5,5-2H2]arginine and [5-13C]ornithine as tracers to assess the rate of arginine disposal via its conversion to and subsequent oxidation of ornithine; [5,5-2H2]proline and [5,5,5-2H3]leucine were also used to assess proline and protein kinetics. Nine severely burned patients were studied during a protein-free fast ("basal" or fast) and total parenteral nutrition (TPN) feedings. Compared with values from healthy volunteers, burn injury significantly increased 1) fluxes of arginine, ornithine, leucine, and proline; 2) arginine-to-ornithine conversion; 3) ornithine oxidation; and 4) arginine oxidation. TPN increased arginine-to-ornithine conversion and proportionally increased irreversible arginine oxidation. The elevated arginine oxidation, with limited net de novo synthesis from its immediate precursors, further implies that arginine is a conditionally indispensable amino acid in severely burned patients receiving TPN.

We propose a mean lysine requirement of 30 mg x kg(-1) x d(-1) for healthy Indian adults, which is the same amount we proposed previously for Western populations.