Background: Glutamine deficiency in critical illness is associated with increased morbidity and mortality. We hypothesized that ammonium chloride (NH4Cl) and alpha-ketoglutaric acid (alpha-KGA) infusions could increase glutamine availability possibly through de novo synthesis in the liver. Methods: Anesthetized post-absorptive pigs were allocated to four groups (n = 8). The study groups received either a 4-h intravenous infusion of alpha-KGA, 11.4 mu mol/kg/min and NH4+, 9.7 mu mol/kg/min (group 1), or alpha-KGA, 2.85 mu mol/kg/min and NH4+, 46.3 mu mol/kg/min (group 2), or alpha-KGA, 11.4 mu mol/kg/min (group 3), or isotonic saline (control group). Plasma concentrations of glutamine and glutamine exchange in liver, intestine and skeletal muscle were investigated. Results: Plasma glutamine concentrations in group 1 (58% increase) were greater (P < 0.05) compared with the control group (14% decrease) and group 3 (13% decrease), and in group 2 (91% increase) compared with the control group, group 3 (P < 0.0001) and group 1 (P < 0.05). Intestinal glutamine extractions in group 2 were significantly greater (P < 0.01) compared with all other groups. Neither the liver nor the hind leg increased its release of glutamine. Arterial pH decreased (all P < 0.001) to 7.39 +/- 0.01 in the control group, 7.30 +/- 0.01 in group 1, 7.19 +/- 0.01 in group 2 and 7.35 +/- 0.01 in group 3. Conclusion: Infusions of alpha-KGA and NH4Cl, to a pH range of 7.20-7.30, did not enhance hind leg or hepatic glutamine release. The increased plasma concentrations of glutamine were effects of NH4Cl, not alpha-KGA, and caused either by de novo synthesis or decreased degradation.