The Role of Asymmetric Dimethylarginine and Arginine in the Failing Heart and its Vasculature

Marlieke Visser; Walter J. Paulus; Mechteld A.R. Vermeulen; Milan C. Richir; Mariska Davids; Willem Wisselink; Bas A.J.M. de Mol; Paul A.M. van Leeuwen


Eur J Heart Fail. 2010;12(12):1274-1281. 

In This Article

Citrulline and Glutamine Therapy

Another method for upregulating the arginine/ADMA ratio is by increasing the concentration of the arginine precursors, citrulline or glutamine. These compounds may influence the competitive inhibition of NOS.

Citrulline Therapy

The maintenance of high plasma arginine concentrations may be problematic because of its catabolism by arginase. The effectiveness of arginine therapy might be reduced in several cardiovascular disorders in which intestinal and cytosolic arginase expression and activity are enhanced.[38] In contrast to arginine, citrulline is not metabolized in the intestine or liver and it does not induce tissue arginase, it even inhibits its activity. Citrulline is largely absorbed and metabolized by the kidney, where it can be converted into arginine. For these reasons, administration of citrulline might be an alternative way to improve cardiac functioning in diseases that are associated with arginine deficiency or increased arginase activity.

Compared with the high number of studies investigating the effect of arginine, only a few investigators have studied the effect of citrulline supplementation on heart function. In healthy volunteers, administration of oral citrulline augmented NO-dependent signalling.[39] Oral citrulline supplementation increased plasma concentrations of both citrulline and arginine in children undergoing cardiopulmonary bypass surgery and reduced post-operative pulmonary hypertension.[40]

Although these limited results might suggest citrulline supplementation as a promising method in diseases of the heart, more studies are needed to support the use of citrulline administration. Furthermore, it should be taken into account that arginine obtained by synthesis of citrulline is calculated to represent 78% of the whole-body plasma citrulline turnover, whereas only 11% of the whole-body plasma flux of arginine is obtained by de novo synthesis of arginine from citrulline.[41]

Glutamine Therapy

Glutamine is a precursor of citrulline, which in turn is mainly metabolized to arginine in the kidney. This might make supplementation of glutamine a more physiological way to produce arginine.

In a rat model, increased plasma arginine levels obtained from a glutamine-enriched enteral diet induced an increase in splanchnic blood flow.[42] However, the mean daily urinary nitrate excretion in this study did not differ between groups, suggesting that NO production did not play a role in the vasodilatory responses of glutamine. Other studies have shown inhibitory effects of glutamine on endothelial NO synthesis.[43] In contrast to NO production by the constitutive NOS isoforms, glutamine seems to be required for NO production by iNOS. This might explain why optimal plasma glutamine levels are needed for optimal NO synthesis by iNOS, particularly in conditions such as sepsis and infection, which is underlined by several studies that have shown valuable effects of glutamine as an immunological form of nutrition.[44] These studies further suggest that supplementation of glutamine might be more beneficial in disease states of immunological impairment, whereas glutamine might be less advantageous in the failing heart and its vasculature.


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