Whole Body Nitric Oxide Synthesis in Healthy Men Determined from [$^{15}$N]arginine-to-[$^{15}$N]citrulline Labeling

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 [$^{15}$N]guanidino nitrogen of arginine to plasma [$^{15}$N]ureido citrulline and compared with that based on urinary nitrite (NO$_{2}^{-}$)/nitrate (NO$_{3}^{-}$) excretion. Six subjects received on dietary day 7, a 24-hr (12-hr fed/12-hr fasted) primed, constant, intravenous infusion of L-[guanidino- $^{15}$N$_{2}$]arginine and [$^{13}$C]urea. A similar investigation was repeated with three of these subjects, plus an additional subject, in which they received L-[ureido-$^{13}$C]citrulline, to determine plasma citrulline fluxes. The estimated rates (mean $\pm $ SD) of NO synthesis over a period of 24 hr averaged 0.96 $\pm $ 0.1 $\mu $mol$\cdot $kg$^{-1}\cdot $hr$^{-1}$ and 0.95 $\pm $ 0.1 $\mu $mol$\cdot $kg$^{-1}\cdot $hr$^{-1}$, for the [$^{15}$N]citrulline and the nitrite/nitrate methods, respectively. About 15% of the plasma arginine turnover was associated with urea formation and 1.2% with NO formation. De novo arginine synthesis averaged 9.2 $\pm $ 1.4 $\mu $mol$\cdot $kg$^{-1}\cdot $hr$^{-1}$, indicating that $\approx $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.