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.

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All the nitric oxide synthases 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.

The discordance between the in vivo results^increased NO production under certain conditions^and the in vitro enzyme studies described above is known as the "arginine paradox." There are a few explanations for the "arginine paradox." NOS may be inhibited by asymmetric dimethylarginine or ADMA, which is known to be elevated in hypercholesterolemia and which increases mononuclear cell (monocyte and T-lymphocyte) adhesiveness in hypercholesterolemics. ADMA is formed by post-translational methylation of L-arginine residues in proteins and is released from the proteins following their hydrolysis. The "arginine paradox" may be explained in part by increasing levels of L-arginine overcoming the inhibition of NOS by ADMA. In addition to hypercholesterolemia, elevated levels of ADMA are associated with hypertension, diabetes, preeclampsia, smoking and aging. Elevation of ADMA may be due to altered metabolism of this substance by dimethylarginine dimethylaminohydrolase or DDAH. DDAH is the major enzyme involved in ADMA catabolism. Decreased levels of DDAH have been found in diabetic and hypercholesterolemic animal models.

Other explanations of the "arginine paradox" include the presence of other inhibitors of NOS yet to be discovered, impaired transport of L-arginine into or within endothelial cells and impaired regeneration of L-arginine from L-citrulline. There is another interesting possibility. A non-enzymatic pathway by which NO may be produced has recently been described. Endothelial dysfunction is associated with increased oxidative stress resulting in increased formation of such reactive oxygen species as hydrogen peroxide and superoxide anions. Further, during conditions of oxidative stress, enzymatic synthesis of NO may decrease, and NO reacts with superoxide anions to form the reactive nitrogen species peroxynitrite. Under these conditions, L-arginine can essentially scavenge hydrogen peroxide and superoxide to form NO non-enzymatically. Interestingly, in this non-enzymatic reaction, L-arginine, as well as the non-biological D-arginine, can both form NO.

NO formed from supplemental L-arginine can play a major role in the possible anti-atherogenic activity of L-arginine. NO inhibits mononuclear cell adhesion, platelet aggregation, proliferation of vascular smooth muscle, production of some reactive oxygen species, such as superoxide anions, and promotion of endothelium-dependent dilation. Leukocyte adhesion, platelet aggregation, smooth muscle proliferation, endothelial dysfunction and oxidative stress are all part of the process of atherogenesis. L-arginine may also have anti-atherogenic activity independent of its role in the enzymatic formation of NO.

L-arginine may itself have antioxidant activity. L-arginine has been found to inhibit the oxidation of low-density lipoproteins (LDL) to oxidized LDL (oxLDL). The oxidation of LDL to oxLDL is believed to be a pivotal early step in atherogenesis. L-arginine may also scavenge superoxide anions and hydrogen peroxide (see above), as well as inhibit lipid peroxidation.

L-arginine has been shown to have immunomodulatory activity. For example, in human breast cancer, supplementation with this amino acid has been reported to increase the quantity and cytotoxic activity of natural killer (NK) cells and lymphokine-activated-killer (LAK) cells. L-arginine is considered an immunonutrient and is added to enteral and parenteral feedings for burn, sepsis and trauma patients. The mechanism of L-arginine's possible immunomodulating activity is not entirely clear. It may, at least in part, be again due to L-arginine's role in the production of NO. Production of NO, with consequent decrease of the cyclic AMP/cyclic GMP ratio in NK cells, would favor the production of interleukin-1, which is known to activate NK cells and may directly enhance NK cell cytotoxicity. L-arginine is also a precursor in the synthesis of the tetrapeptide tuftsin, which itself appears to have immunomodulatory activity. Tuftsin's activity appears to depend on two of the four amino acids present in its structure, L-arginine and L-proline. L-arginine also participates in the synthesis of L-proline.

L-arginine's possible activity in wound repair may be due to its precursor role in the formation of L-ornithine and, ultimately, L-proline. L-proline is a key element in collagen biosynthesis.

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