Many of supplemental L-arginine’s activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to
nitric oxide or NO. NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. NO is formed from L-arginine via the enzyme
nitric oxide synthase or synthetase (NOS), and the effects of NO are mainly mediated by 3,’5′ -cyclic
guanylate or
cyclic GMP. NO activates the enzyme
guanylate cyclase, which catalyzes the synthesis of
cyclic GMP from
guanosine triphosphate or GTP.
Cyclic GMP is converted to
guanylic acid via the enzyme
cyclic GMP phosphodiesterase. NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. Several isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. The constitutive NOS found in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. The form of NOS induced by immunological or inflammatory stimuli is known as iNOS.
iNOS may be expressed constitutively in select tissues such as lung epithelium. All the
nitric oxidesynthases use
NADPH (reduced nicotinamide
adenine dinucleotide
phosphate) and
oxygen (O2) as cosubstrates, as well as the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide),
tetrahydrobiopterin and heme. Interestingly,
ascorbic acid appears to enhance NOS activity by increasing intracellular
tetrahydrobiopterin. eNOS and nNOS synthesize NO in response to an increased concentration of
calcium ions or in some cases in response to
calcium-independent stimuli, such as shear stress. In vitro studies of NOS indicate that the Km of the enzyme for L-arginine is in the micromolar range. The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range. What this means is that, under physiological conditions, NOS is saturated with its L-arginine substrate. In other words, L-arginine would not be expected to be rate-limiting for the enzyme, and it would not appear that supraphysiological levels of L-arginine which could occur with oral supplementation of the amino acid^would make any difference with regard to NO production. The reaction would appear to have reached its maximum level. However, in vivo studies have demonstrated that, under certain conditions, e.g. hypercholesterolemia, supplemental L-arginine could enhance endothelial-dependent vasodilation and NO production.