Understanding the Metabolic Possibilities for L?Arginine Tolerance Development

L?arginine (ARG) has gained popularity as a dietary supplement in the last decade after its role as the endogenous substrate for endothelial nitric oxide synthase (eNOS) was identified. Of concern, the therapeutic benefits of ARG, often clearly observed during short?term dosing, are not evident after long?term use. Initial metabolic studies in cells show ARG tolerance in endothelial cells to be mediated by eNOS down?regulation, secondary to oxidative stress and glucose accumulation. Modulation in ARG transport mechanism (via cationic amino acid transporters), eNOS cofactor (tetrahydrobiopterin), arginase, as well as the metabolic intermediate (Nw?hydroxyl ARG) formed during ARG utilization by eNOS have all shown promising potential towards the development of ARG tolerance. While asymmetric?dimethyl?L?arginine is a potent inhibitor of eNOS and competitive analog of ARG, it has been found not to be responsible in developing ARG tolerance under physiological or diseased conditions. AMPactivated protein kinase has been recently identified as the fundamental modulator of short?term and long?term ARG responses in cells. Translatability of these findings in vivo will prove beneficial and crucial for the design of safe and effective use of ARG as alternative and complementary medicine.