To give or not to give? Lessons from the arginine paradox.

Arginine is one of the 20 amino acids (AA) found in proteins and synthesized by human cells. However, arginine is also the substrate for a series of reactions leading to the synthesis of other AA and is an obligatory substrate for two enzymes with diverging actions, arginases and nitric oxide synthases (NOS), giving origin to urea and NO, respectively. NO is a very potent vasodilator when produced by endothelial NOS (eNOS). The 'arginine paradox' is the fact that, despite intracellular physiological concentration of arginine being several hundred micromoles per liter, far exceeding the ∼5 μM K(M) of eNOS, the acute provision of exogenous arginine still increases NO production. Clinically, an additional paradox is that the largest controlled study on chronic oral arginine supplementation in patients after myocardial infarction had to be interrupted for excess mortality in treated patients. Expression and activity of arginases, which produce urea and divert arginine from NOS, are positively related to exogenous arginine supplementation. Therefore, the more arginine is introduced, the more it is destroyed, eventually leading to impaired NO production. In this review, conditions influencing the low arginine concentrations found in plasma will be reviewed, revising the paradigm that simple replenishment of what is lacking will always produce beneficial consequences.