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Title: Arginine, citrulline and nitric oxide metabolism in sepsis

item KAO, CHRISTINA - Children'S Nutrition Research Center (CNRC)
item BANDI, VENKATA - Baylor College Of Medicine
item GUNTUPALLI, KALPALATHA - Baylor College Of Medicine
item WU, MANHONG - Children'S Nutrition Research Center (CNRC)
item CASTILLO, LETICIA - Children'S Nutrition Research Center (CNRC)
item JAHOOR, FAROOK - Children'S Nutrition Research Center (CNRC)

Submitted to: Clinical Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/23/2008
Publication Date: 7/1/2009
Citation: Kao, C.C., Bandi, V., Guntupalli, K.K., Wu, M., Castillo, L., Jahoor, F. 2009. Arginine, citrulline and nitric oxide metabolism in sepsis. Clinical Science. 117(1):23-30.

Interpretive Summary: Nitric oxide (NO) is a compound produced by the body that helps to expand blood vessels and lower blood pressure. NO is formed from another compound called arginine. Sepsis is the body's response to infection. It is unclear whether NO is harmful in sepsis because it lowers blood pressure or if it is beneficial because it helps to maintain function of essential organs. In addition, there may be a deficiency of arginine in sepsis, and this in turn could affect the production of NO. In this study, we measured the amount of arginine, citrulline (another amino acid used to make arginine), and NO produced by the body in individuals with sepsis compared to healthy controls. We found that septic individuals and healthy controls had similar rates of production of arginine and NO. However, the rate of production of citrulline and the concentrations in the blood of arginine and citrulline were lower in sepsis compared to in controls. These findings suggest that inadequate production of citrulline may lead to inadequate arginine availability in sepsis.

Technical Abstract: Arginine has vasodilatory effects, via its conversion by nitric oxide (NO) synthase into NO, and immunomodulatory actions that play important roles in sepsis. Protein breakdown affects arginine availability, and the release of asymmetric dimethylarginine, an inhibitor of NO synthase, may therefore affect NO synthesis in patients with sepsis. The objective of the present study was to investigate whole-body in vivo arginine and citrulline metabolism and NO synthesis rates, and their relationship to protein breakdown in patients with sepsis or septic shock and in healthy volunteers. Endogenous leucine flux, an index of whole-body protein breakdown rate, was measured in 13 critically ill patients with sepsis or septic shock and seven healthy controls using an intravenous infusion of [1-13C]leucine. Arginine flux, citrulline flux and the rate of conversion of arginine into citrulline (an index of NO synthesis) were measured with intravenous infusions of [15N2]guanidino-arginine and [5,5-2H2]citrulline. Plasma concentrations of nitrite plus nitrate, arginine, citrulline and asymmetric dimethylarginine were measured. Compared with controls, patients had a higher leucine flux and higher NO metabolites, but arginine flux, plasma asymmetric dimethylarginine concentration and the rate of NO synthesis were not different. Citrulline flux and plasma arginine and citrulline were lower in patients than in controls. Arginine production was positively correlated with the protein breakdown rate. Whole-body arginine production and NO synthesis were similar in patients with sepsis and septic shock and healthy controls. Despite increased proteolysis in sepsis, there is a decreased arginine plasma concentration, suggesting inadequate de novo synthesis secondary to decreased citrulline production.