Nitric oxide is a signal molecule that has an extensive role in the regulation of cellular function. In particular, nitric oxide is required for the dilation of arteries and low levels in the endothelial lining of the arteries is thought to lead to inelasticity and high blood pressure, a disorder termed endothelial dysfunction. Nitric oxide is synthesised in the body from arginine. It has been shown that dietary arginine can affect a number of physiological systems, and some evidence suggests that dietary arginine may be able to modulate nitric oxide synthesis. However, the ability of arginine to modulate nitric oxide synthesis is controversial because most dietary arginine is converted to urea during first pass metabolism and therefore it is unclear how much arginine is subsequently available for the synthesis of nitric oxide. Secondly, under normal physiological conditions the plasma arginine concentrations are much higher than required for nitric oxide synthesis and therefore it is unclear as the the benefits of further raising plasma levels.
The arginine paradox then describes the conflicting observation that dietary arginine can affect human physiology in multiple ways, yet the biochemistry of arginine suggests that this should not be possible. One possible explanation for this paradox is the tight regulation and compartmentalisation of arginine metabolism, with the channelling of dietary arginine to subcellular microdomains of endothelial cells. A recent study fed healthy human subjects radiolabeled arginine in an effort to trace its metabolism through the body and elucidate its metabolic fate1. The results showed that 60 % of the ingested arginine was converted to urea during first pass metabolism, irrespective of the dose. despite this, the dietary arginine still caused large increases in plasma levels of arginine post ingestion. However, the plasma levels only accounted for 2 % of the conversion of arginine to nitric oxide, the the conversion of arginine to nitric oxide only accounted for 0.1 % of the ingested dose.
Therefore it is likely that the conversion of arginine to nitric oxide is not regulated by the plasma level of arginine, but by tight and meticulous compartmentalisation. In other words, kinetically separate pools of arginine are used to synthesise nitric oxide and raising plasma levels of arginine is not effective at raising nitric oxide synthesis rates. That dietary arginine is effective at raising nitric oxide synthesis might be explained by conversion of arginine to nitric oxide during first pass metabolism, before the arginine has entered the plasma. Evidence for this came from high rates of arginine hydrolysis in the liver during first pass metabolism following ingestion of the radiolabeled arginine. Another point raised by the authors was that it is likely that arginine is more effective at raising nitric oxide levels and improving flow mediated dilation in those with impaired baseline levels. The tight compartmentalised regulation of nitric oxide synthesis might prevent dietary arginine having such a large impact on nitric oxide synthesis in healthy subjects.
RdB
