Therapeutic and Metabolic Responses of Citrulline vs. Arginine Supplementation

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Arginine depletion is a phenomenon observed in septic patients, and is associated with greater mortality as its severity increases. Among numerous other functions, arginine is the precursor for the signaling molecule nitric oxide that plays a central role in immunity, in the control of blood pressure, and in the regulation of the microcirculation and tissue perfusion. Although the mechanism responsible for the depletion and fate of arginine has yet to be identified, arginine supplementation has been proposed to restore arginine availability. However, it is not clear if arginine supplementation is always effective or beneficial, because it can result in hyperproduction of nitric oxide and contribute to hypotension, cardio depression and vascular hyporeactivity in septic shock. Supplementing with citrulline, the precursor for the endogenous synthesis of arginine, has the potential to be more effective than arginine supplementation, but may also result in excessive nitric oxide production. An alternative approach that simultaneously addresses the depletion of arginine and hyperproduction of nitric oxide is the use of ADI-PEG 20. This pegylated bacterial enzyme catalyzes the conversion of arginine into citrulline, which can be re-utilized by the citrulline `recycling pathway'. This pathway provides intracellular arginine to sustain most processes that require this amino acid, but at the same time modulating the hyperproduction of nitric oxide during sepsis. Our central hypothesis is that sepsis causes dysregulation of arginine metabolism resulting in plasma arginine depletion and contributing to macro- and microcirculatory failure that leads to organ dysfunction. The objectives of the proposed research are to elucidate the mechanisms of ARG depletion in pediatric swine models of sepsis and evaluate different strategies to restore ARG availability, prevent hypotension and mitigate tissue injury. To test our central hypothesis and attain our objectives we propose the following specific aims: Specific Aim1: Quantify the disposal rate of arginine by the liver and the pathways involved in its utilization in swine models of sepsis. Specific Aim2: Determine arginine availability in septic pigs supplemented with citrulline or arginine and its effect on nitric oxide production, blood pressure, protein synthesis and markers of tissue injury. Specific Aim3: Determine arginine availability and cardiovascular function, including blood pressure and tissue markers of hypoxia during sepsis in ADI-PEG 20-arginine-depleted pigs. To achieve these aims we will use methicillin- resistant S. aureus and pathogenic E. Coli swine models of sepsis-induced multiple organ dysfunction. A multitracer stable isotope protocol will be used to quantify whole body and hepatic arginine metabolism, and the analysis of the relevant enzymes and transporters will provide the molecular basis for the changes observed. Blood pressure, plasma metabolites, and markers of organ function and tissue injury will be analyzed to determine the effect of the different interventions on cardiovascular function, tissue perfusion and organ injury.