Regulation of nitric oxide production in health and disease

Abstract

Purpose of review: The purpose of this review is to highlight recent publications examining nitric oxide production in health and disease and its association with clinical nutrition and alterations in metabolism.

Recent findings: The role of the cofactor tetrahydrobiopterin in nitric oxide production and its relation with arginine availability is indicated as an important explanation for the arginine paradox. This offers potential for nitric oxide regulation by dietary factors such as arginine or its precursors and vitamin C. Because diets with a high saturated fat content induce high plasma fatty acid levels, endothelial nitric oxide production is often impaired due to a reduction in nitric oxide synthase 3 phosphorylation. Increasing the arginine availability by arginine therapy or arginase inhibition was, therefore, proposed as a potential therapy to treat hypertension. Recent studies in septic patients and transgenic mice models found that inadequate de-novo arginine production from citrulline reduces nitric oxide production. Citrulline supplementation may, therefore, be a novel therapeutic approach in conditions of arginine deficiency.

Summary: Both lack and excess of nitric oxide production in diseases can have various important implications in which dietary factors can play a modulating role. Future research is needed to expand our understanding of the regulation and adequate measurement of nitric oxide production at the organ level and by the different nitric oxide synthase isoforms, also in relation to clinical nutrition.

Figure 1. NO synthesis pathway

Schematic overview of the NO synthesis pathway, involving both enzymatic (via NOS; major pathway) and non-enzymatic pathways. L-arginine is converted to NO and citrulline in the presence of NADPH and oxygen. The NOS pathways depend on essential cofactors (BH4, FAD, FMN and heme) for their activity; NOS1 and NO3 are also Ca²⁺ dependent. De novo arginine production from citrulline involves the enzymes ASS and ASL. Potential factors that can be modified by dietary intake are indicated by a gray background.