Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/8/2006
Publication Date: 7/1/2006
Citation: Villalpando, S., Gopal, J., Balasubramanyam, A., Bandi, V.P., Guntupalli, K., Jahoor, F. 2006. In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis. American Journal of Clinical Nutrition. 84(1):197-203. Interpretive Summary: Amino acids are the building blocks of the proteins that we eat and the proteins that make up our bodies. They are also used to make numerous compounds that are necessary for normal functioning of all the organs of the body. One such amino acid is arginine. It is necessary for detoxification of ammonia and the healing of wounds in injured patients. In addition, a substance called nitric oxide (NO), which regulates blood pressure by dilating blood vessels, is made from arginine. It is believed that patients who have sepsis, that is systemic infection(s), develop low blood pressure because they are making too much NO from arginine. However, there is no data to support this hypothesis in humans. We therefore determined how much arginine was being made by septic patients with low blood pressure and the rate at which these patients were making NO. We found that the septic patients were making less arginine and had lower blood levels compared to healthy individuals. Although they had high levels of NO in their blood, this was not because they were making more NO. It was because their kidney was not getting rid of it in the urine fast enough. Hence, the low blood pressure of patients with sepsis is not associated with a faster conversion of arginine to NO.
Technical Abstract: Arginine is important in the response to infections and is a precursor for the synthesis of the vasodilator nitric oxide (NO). Low plasma arginine is correlated with a worse prognosis in patients with sepsis, and increased NO has been implicated in the hypotension of sepsis. Data on in vivo arginine and NO kinetics are lacking in hypotensive septic adults. We aimed to measure in vivo arginine production and the intravascular NO synthesis rate in hypotensive septic patients. Arginine flux and the fractional and absolute synthesis rates of plasma NO were measured in fasted healthy (n = 10) and hypotensive septic (n = 6) adults by using a 6-h constant infusion of [15N2-guanidino] arginine. Urinary excretion of the NO metabolites nitrite and nitrate (NOx) and plasma concentrations of NOx, arginine, and creatinine were also measured. All patients had hyperdynamic septic shock and impaired renal function. Compared with the control subjects, the patients had slower arginine flux (99 +/- 8 compared with 50 +/- 7 micromol x kg (-1) x h (-1); P < 0.01), lower plasma arginine concentrations (75 +/- 8 compared with 40 +/- 11 micromol/L; P < 0.01), higher plasma NOx concentrations (30 +/- 4 compared with 65 +/- 1.8 micromol/L), and a slower fractional synthesis rate of NOx. There was no significant difference in the absolute synthesis rate of NOx between groups. In patients with sepsis, the plasma NOx concentration correlated with the glomerular filtration rate and plasma creatinine but not with mean arterial pressure. Patients with septic shock have a shortage in the availability of arginine associated with a slower production. Impaired renal excretion of NOx is a contributor to the high plasma NOx in these patients.