Arginine Immunonutrition in Critically Ill Patients: A Clinical Dilemma

Joyce K. Stechmiller, PhD, ARNP; Beverly Childress, MSN; Tricia Porter, BSN


Am J Crit Care. 2004;13(1) 

In This Article

Function of Arginine

Arginine plays a role in protein synthesis, as a substrate for the urea cycle and the production of nitric oxide, and as a secretagogue for growth hormone, prolactin, and insulin (Figure 1). Whereas most amino acids are 16% nitrogen, arginine is 32% nitrogen.[18,19,20,21] Arginine is synthesized primarily in the kidney from gut-derived citrulline via the urea cycle, which also detoxifies ammonia and facilitates excretion of nitrogen.[22] Ornithine is a metabolite of arginine and is involved in the synthesis of polyamines, which are important for cellular division.

Figure 1.

Function of arginine.

Arginine is metabolized via 2 pathways[23] (Figure 2). In the first pathway arginine is broken down by either arginase I or arginase II. Arginase I, an enzyme found primarily in the liver, breaks down arginine into ornithine and urea, a step required in hepatic and intestinal synthesis of urea from ammonia.[24,25,26,27] Arginase II, a mitochondrial enzyme found throughout the cells of the body, is primarily involved in intracellular metabolism of arginine. Although arginase I may be more directly responsible for the production of polyamines, arginase II may direct the synthesis of arginine into or nithine and proline. Proline is converted into hydroxyproline and then to collagen,[18,19,20,21] a substance necessary for wound healing.

Figure 2.

Arginine metabolism.

The second pathway of arginine metabolism is responsible for producing nitric oxide,[23] which is associated with alterations in the structure and function of the intestinal mucosa,[28] the liver,[29] and the kidney[30] and with dysfunction in gastrointestinal motility. Three isoenzymes, known as nitric oxide synthases (NOSs), produce nitric oxide: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Of the 3 enzymes, nNOS and eNOS are calcium dependent; iNOS is calcium independent and is produced in response to cytokines and endotoxin signals.[23] Once induced, iNOS produces high levels of nitric oxide.[31]

Nitric oxide has several properties that aid local response to acute injury and reduce the risk of wound infection.[22] Synthesized by the vascular endothelium via eNOS, nitric oxide causes vascular relaxation, which regulates blood pressure.[32] Nitric oxide also regulates cardiac contractility via nNOS and acts as a neurotransmitter that facilitates numerous functions, including memory formation.[32] In addition, a nitric oxide–dependent mechanism is responsible for mediating neurogenic vasodilatation and for regulating functions of the respiratory, genitourinary, and gastrointestinal tracts.[32] Platelet aggregation is also controlled by nitric oxide.[32] During stress and immunologic reactions, nitric oxide is released in large quantities[32] and is involved in nonspecific immunity and the pathophysiology of septic shock, inflammation, and other hyperdynamic states. The oxide also has cytotoxic properties and is thought to mediate the cytotoxic effects of macrophages on microbes, parasites, and tumors (Figure 3).

Figure 3.

Inflammatory effects of nitric oxide (NO).


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