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Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Germany
Abstract
L-Arginine is a precursor for nitric oxide (NO) synthesis. NO is a ubiquitous mediator that is formed by a family of enzymes
named NO synthases. In the brain, NO acts as a neurotransmitter; in the immune system, NO acts as a mediator of host
defense; and in the cardiovascular system, NO mediates the protective effects of the intact endothelium, acting as a
vasodilator and endogenous antiatherogenic molecule. About 5 g of L-arginine is ingested each day in a normal Western
several controlled clinical trials, long-term administration of L-arginine has been shown to improve the symptoms of
cardiovascular disease. However, in other trials L-arginine was not beneficial, and in a recent study, the authors reported
higher mortality of subjects receiving L-arginine than those receiving placebo. Recently it became clear that endogenous
levels of asymmetric dimethylarginine (ADMA), a competitive inhibitor of L-arginine metabolism by NO synthase, may
determine a subjects response to L-arginine supplementation. L-Arginine appears to exert no effect in subjects with low
ADMA levels, whereas in subjects with high ADMA levels, L-arginine restores the L-arginine/ADMA ratio to normal levels
and thereby normalizes endothelial function. In conclusion, the effects of L-arginine supplementation on human physiology
appear to be multicausal and dose-related. Doses of 38 g/d appear to be safe and not to cause acute pharmacologic
effects in humans. J. Nutr. 137: 1650S1655S, 2007.
L-Arginine: role in physiology and pathophysiology of a family of enzymes named nitric oxide synthases (NO
L-Arginine (2-amino-5-guanidino-pentanoic acid) is a conditionally synthases, NOS)4 (3). Three different isoforms of NOS have
essential, proteinogenic amino acid that is a natural constituent been characterized that are named according to the cell type
of dietary proteins (1). Besides its role in protein metabolism, from which they were first isolated: neuronal NOS (nNOS, NOS
L-arginine is involved in various metabolic pathways, such as I), inducible NOS (iNOS, NOS II), and endothelial NOS (eNOS,
synthesis of creatine, L-ornithine, L-glutamate, and polyamines NOS III) (4). nNOS and eNOS are expressed constitutively, their
(2). Decarboxylation of L-arginine can produce agmatine, a bio- activity is regulated by calcium/calmodulin, and they produce
genic amine metabolite. L-Arginine is also involved in protein NO at low rates. iNOS is induced in inflammatory cell types on
degradation by the ubiquitin-proteasome pathway (2). A bio- cytokine stimulation; its activity is independent of calcium
logically important pathway involves L-arginine as the substrate because of tight binding of calmodulin to the enzyme, and it
produces NO at high rates. Recently, expressional regulation of
eNOS has been observed (5), so that the simple discrimination
1
between constitutively and inducibly expressed enzymes is no
Published in a supplement to The Journal of Nutrition. Presented at the
conference The Sixth Workshop on the Assessment of Adequate and Safe
longer correct; however, this nomenclature is still broadly used.
Intake of Dietary Amino Acids held November 67, 2006 in Budapest. The The reaction mechanism of NO synthases involves a 2-electron
conference was sponsored by the International Council on Amino Acid Science transfer from molecular oxygen via a number of cofactors to
(ICAAS). The organizing committee for the workshop was David H. Baker, Dennis L-arginine, resulting in the release of NO and L-citrulline.
M. Bier, Luc A. Cynober, Yuzo Hayashi, Motoni Kadowaki, Sidney M. Morris, Jr.,
Nv-Hydroxy-L-arginine is formed as a relatively stable interme-
and Andrew G. Renwick. The Guest Editors for the supplement were David H.
Baker, Dennis M. Bier, Luc A. Cynober, Motoni Kadowaki, Sidney M. Morris, Jr., diate product of this reaction (6).
and Andrew G. Renwick. Disclosures: all Editors and members of the organizing NO exerts a range of critical roles in the regulation of the
committee received travel support from ICAAS to attend the workshop and an function of diverse organs throughout the body, depending on
honorarium for organizing the meeting. the cell type and tissue and the NOS isoform responsible. NO
2
Author disclosures: R. H. Bogers travel expenses to attend the meeting were
paid by ICAAS.
plays an important role as a mediator in nonadrenergic, non-
3
Supported by the Deutsche Forschungsgemeinschaft (grants Bo 1431/3-1, Bo cholinergic neurotransmission, in learning and memory, synaptic
1431/3-2, Bo 1431/4-1), the Else-Kroner-Fresenius Foundation, and the German
Heart Foundation.
4
* To whom correspondence should be addressed. E-mail: boeger@uke.uni- Abbreviations used: ADMA, asymmetric dimethylarginine; NO, nitric oxide;
hamburg.de. NOS, nitric oxide synthase.
1654S Supplement
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