L-Arginine

Alternative Medicine Review, June, 2005

Introduction

L-Arginine is a semi-essential amino acid involved in numerous areas of human physiology, including production of nitric oxide (NO)--a key messenger molecule involved in vascular regulation, immune activity, and endocrine function. Arginine is also involved in protein production, wound healing, erectile function, and fertility. Arginine is not considered essential because humans can synthesize it de novo from glutamine, glutamate, and proline. However, dietary intake remains the primary determinant of plasma arginine levels, since the rate of arginine biosynthesis does not compensate for depletion or inadequate supply. (1,2)

Arginine is the most abundant nitrogen carrier in humans, containing four nitrogen atoms per molecule. Arginine is not a major inter-organ nitrogen shuttle; instead, it plays an important role in nitrogen metabolism and ammonia detoxification as an intermediate in the urea cycle. (3)

Biochemistry

Arginine is synthesized in mammals from glutamine via pyrroline 5-carboxylate (P5C) synthase and proline oxidase in a multi-step metabolic conversion. (4) In adults, most endogenous arginine is produced from citrulline, a by-product of glutamine metabolism in the gut and liver. Citrulline is released into the circulation and taken up primarily by the kidney for conversion into arginine. (5)

Supplemental arginine is readily absorbed. (6) About 50-percent of ingested arginine is rapidly converted in the body to ornithine, primarily by the enzyme arginase. (7) Because of this fast turnover, sustained-release preparations are being investigated as a way to maintain a steadier blood level over time. Ornithine, in turn, can be metabolized to glutamate and proline, or through the enzyme ornithine decarboxylase into the polyamine pathway for degradation into compounds such as putrescine and other polyamines.

In addition, arginine is a precursor for the synthesis of nitric oxide, proteins, urea, creatine, vasopressin, and agmatine. (8) Arginine that is not metabolized by arginase to ornithine is processed by one of four other enzymes: nitric oxide synthase (to become nitric oxide); arginine:glycine amidinotransferase (to become creatine); arginine decarboxylase (to become agmatine); or arginyl-tRNA synthetase (to become arginyl-tRNA, a precursor to protein synthesis). Arginine is also an allosteric activator of N-acetylglutamate synthase, which synthesizes N-acetylglutamate from glutamate and acetyl-CoA. (9)

Mechanisms of Action

Arginine is the biological precursor of nitric oxide (NO), an endogenous gaseous messenger molecule involved in a variety of endothelium-dependent physiological effects in the cardiovascular system. (10) Much of arginine's influence on the cardiovascular system is due to endothelial NO synthesis, which results in vascular smooth muscle relaxation and subsequent vasodilation, as well as inhibition of monocyte adhesiveness, platelet aggregation, and smooth muscle proliferation. A great deal of research has explored the biological roles and properties of nitric oxide, (11,12) which is also of critical importance in maintenance of normal blood pressure, (13) myocardial function, (14) inflammatory response, (15) apoptosis, (16) and protection against oxidative damage. (17)

Arginine is a potent immunomodulator. Supplemental arginine appears to up-regulate immune function and reduce the incidence of postoperative infection. Significant decreases in cell adhesion molecules and pro-inflammatory cytokine levels have also been observed. Arginine supplementation (30 g/day for three days) has been shown to significantly enhance natural killer (NK) cell activity, lymphokine-activated killer cell cytotoxicity, and lymphocyte mitogenic reactivity in patients with locally advanced breast cancer. (18,19)

Arginine has significant effects on endocrine function--particularly adrenal and pituitary secretion--in humans and animals. Arginine administration can stimulate the release of catecholamines, (20) insulin and glucagon, (21) prolactin, (22) and growth hormone (GH); (23,24) however, little is known about the specific mechanism(s) by which arginine exerts these effects.

Clinical Indications

Cardiovascular Conditions

Arginine's effects on cardiovascular function are due to arginine-induced endothelial NO production. Endothelial nitric oxide synthase (eNOS) catalyzes this reaction, which produces NO and ornithine. Nitric oxide diffuses into the underlying smooth muscle and stimulates guanylyl cyclase, producing guanosine-3',5'-cyclic monophosphate (cGMP), which in turn causes muscle relaxation and vasodilation. Arginine supplementation has been shown to increase flow-mediated brachial artery dilation in normal individuals as well as those with hyperlipidemia and hypertension. (25,26) Nitric oxide is also responsible for creating an environment in the endothelium that is anti-atherogenic. Adequate NO production inhibits processes at the core of the atherosclerotic lesion, including platelet aggregation, monocyte adhesion and migration, smooth muscle proliferation, and vasoconstriction.