L-arginine is a basic natural amino acid. Its occurrence in mammalian protein was discovered by Hedin in 1895.

• l-Arginine is engaged in several metabolic pathways within the human body.
• It serves as a precursor for the synthesis not only of proteins but also of urea, polyamines, proline, glutamate, creatine and agmatine.
• As part of this, l-arginine is an essential component of the urea cycle, the only pathway in mammals that allows the elimination of toxic ammonia from the body.
• Ornithine, the by-product of this reaction, is a precursor for the synthesis of polyamines, molecules essential for cell proliferation and differentiation.
• l-Arginine is also required for the synthesis of creatine, an essential energy source for muscle contraction.
• Agmatine, which has a clonidine-like action on blood pressure, is also formed from l-arginine, though its physiological function is not yet fully understood.
• However, current interest in l-arginine is focused mainly on its close relationship with the important signal molecule nitric oxide (NO). l-Arginine is the only substrate in the biosynthesis of NO, which plays critical roles in diverse physiological processes in the human body including neurotransmission, vasorelaxation, cytotoxicity and immunity.

Fig. 1. Overview of mammalian arginine metabolism. Only enzymes that directly use or produce arginine, ornithine, or citrulline are identified, and not all reactants and products are shown. Inhibition of specific enzymes is indicated by dashed lines and the dash within a circle. Amino acid residues within proteins are identified by brackets.
Key to abbreviations: ADC, arginine decarboxylase; AGAT, arginine: glycine amidinotransferase; ARG, arginase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; DDAH, dimethylarginine dimethylaminohydrolase; Me2, dimethyl; OAT, ornithine aminotransferase; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase; P5C, l-D1-pyrroline-5-carboxylate; PRMT, protein–arginine methyltransferase. It is worth mentioning that the processes described in Fig. 1 do not all occur within each cell; instead, they are differentially expressed according to cell type, age and developmental stage, diet, and state of health or disease. In fact, Fig. 1 is somewhat misleading in that it summarises the metabolism of arginine at a whole body level; it does not represent arginine metabolism in any particular cell type, nor does it indicate which enzymes are expressed under different conditions, which enzymes are regulated, the presence of various inter- and intracellular transport systems or how substrates are divided into the different pathways.

The clinical pharmacology of L-arginine

L-arginine and the gastrointestinal tract
NO donors have been repeatedly shown to protect gastric mucosa against damage induced by various agents. In addition, reports from different laboratories have demonstrated the importance of endogenous NO in the protection of gastric mucosa.
Two studies from Pique’s laboratory have shown that NO plays a vasodilatory role in gastric microcirculation during acid secretion. Other studies have accredited the role of NO as an endogenous modulator of leukocyte adhesion. In support, Calatayud et al. have shown that transdermal nitroglycerine protected against indomethacin-induced gastric ulceration through maintenance of mucosal blood flow and reduction of leukocyte–endothelial cell rolling and adherence. Moreover, Wallace has stated that reduction of gastric blood flow is the main predisposing factor in the induction of non-steroidal anti-inflammatory drugs (NSAID) gastropathy. Other than the role of NO in maintenance of blood flow, NO may protect against NSAID damage by promotion of prostaglandin synthesis. A mutual interaction has been observed between NOS and cyclooxygenase (COX) enzymes. NO donors were shown to enhance COX activity whereas NOS inhibitors blocked prostaglandin E2 (PGE2) production.
In a study from our lab, we demonstrated the role of NO in protecting against indomethacin-induced gastric ulceration. Intraperitoneal (i.p.) injection of l-arginine (300 mg/kg) 30 min before i.p. injection of 30 mg/kg indomethacin to rats almost completely protected the rats against indomethacin-induced gastric ulceration by a mechanism independent of modulation of acid secretion, mucin content or pepsin activity, but via maintenance of mucosal NO. On the other hand, pre-treatment of rats with the NOS inhibitors l-NAME (50 mg/kg), a non-selective constitutive nitric oxide synthase/inducible nitric oxide synthase (cNOS/iNOS) inhibitor, or the selective iNOS inhibitor aminoguanidine (AMG) (50 mg/kg) worsens the ulcer index (the sum of the length (mm) of all lesions in the fundic region) Fig. 3). In support to the anti-ulcerogenic effect of l-arginine, reports by Lazaratos et al. and Jimenez et al. have indicated the protective role of l-arginine against the ulcerogenic action of endothelin-1 and ibuprofen, respectively.

Fig. 3. Ulcer index (mm) of normal, indomethacin, l-NAME, aminoguanidine, and l-arginine treated rats. Results are mean ± SEM of 6–10 animals. **Significantly different from indomethacin at p < 0:01.

Reports have not restricted the role of NO to gastric protection, but also discussed the acceleration of ulcer healing. Konturek et al. have shown that glyceryl trinitrate is capable of ulcer healing and that suppression of NO synthesis resulted in impaired ulcer healing. It is possible that NO directly accelerates ulcer repair by promoting the growth of smooth muscles, as suggested by Hogaboam et al.
In a recent study (in press), we have tested the effect of NO modulation on peptic ulcer healing using the NO precursor; l-arginine, a competitive inhibitor of NOS, l-NAME and the NO donor; nitroglycerine (NTG). Rats were injected with a single oral dose of indomethacin (30 mg/kg) and then treated with l-arginine, NTG or l-NAME, once daily for 7 days starting 4 h after the indomethacin injection. Gross lesion examination and histological assessment were done. Gastric tissue content of NO, PGE2 and mucin were detected. In addition, oxidative stress markers including glutathione (GSH) and lipid peroxides were measured. l-Arginine and NTG were found to accelerate the healing of indomethacin-induced ulcers, as evident in macroscopic and histological examination, to restore normal levels of NO and GSH and to significantly attenuate the increase in PGE2 and lipid peroxides induced by indomethacin. On the other hand, l-NAME was found to exacerbate the mucosal damage.

Table 3. Gross examination of the effect of treatment with l-arginine, NTG or l-NAME on gastric ulcer induced by indomethacin in rats.

Gastric ulcer was induced by a single oral injection of indomethacin (30 mg/kg), and then 4 h later, treatment schedule was given daily for 1 week as follows: l-arginine (200 mg/kg), NTG (1 mg/kg) and l-NAME (15 mg/kg). Measurements were done 7 days later. Values given are means of 10–15 observations ± SEM. Ulcer index = sum of lengths of all lesions in each stomach; ulcer score indicates severity of gastric lesion, where 1 (ulcerated area 1–6 mm2), 2 (ulcerated area 7–12 mm2), 3 (ulcerated area 13–18 mm2), 4 (ulcerated area 19–24 mm2) and 5 (ulcerated area > 24 mm2) In parallel, Brzozowski et al. have shown that intragastric administration of l-arginine (32.5–300 mg/kg/day) enhanced the healing rate of acetic acid-induced ulcers in a dose-dependent manner, while d-arginine was not effective.

L-ARGININE AND CNS FUNCTION

Very few articles have investigated the effects of l-arginine supplementation on CNS function. However, accumulating evidence is beginning to indicate that NO plays a part in the formation of memory. In vitro, after specific receptor stimulation, NO is released from a postsynaptic source to act pre-synaptically on one or more neurons. This leads to a further increase in the release of glutamate and, as a result, to a stable increase in synaptic transmission, a phenomenon known as long-term potentiation. This is thought to be linked to memory function.
Experiments in animals also suggest that NO is involved in memory, because inhibiting NO synthesis in vivo impairs learning behaviour.

Fig. 5. The role of nitric oxide in the long-term potentiation of neuronal activity. Glutamate released from the presynaptic nerve terminal activates different types of receptors on the dendrites of the postsynaptic neuron. Under normal conditions the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors mediate most of the effects of glutamate. During high-frequency synaptic transmission, however, the activation of N-methyl-d-aspartate (NMDA) receptors results in an increase in intracellular calcium, which stimulates the constitutive nitric oxide synthase (NOS). The nitric oxide (NO) that is produced diffuses back to the presynaptic neuron, where it enhances the release of glutamate. The increased glutamate release leads to greater activation of postsynaptic glutamate receptors, thereby increasing the effectiveness of that synapse. Plus signs indicate stimulation, and l-arg denotes l-arginine.

l-arginine (1.6 g/day) in 16 elderly patients with senile dementia has been found to be effective in reducing lipid peroxidation and increasing cognitive function. In their recent report, Jing et al. explored the possible role of l-arginine in Alzheimer’s disease (AD), taking into consideration known functions for l-arginine in atherosclerosis, redox stress and the inflammatory process, regulation of synaptic plasticity and neurogenesis, and modulation of glucose metabolism and insulin activity. They provided evidence that l-arginine may play a prominent role in protection from age-related degenerative diseases such as AD. Further investigation is still needed to cover this virgin area of research.

L-ARGININE: ANTI-AGING PILOT STUDY

In an open-label randomised limited study conducted by the author,
5 g/day l-arginine base was administered orally once at night for 28 days in 21 subjects with age ranging between 41 and 75 years old (14 between 41 and 49 years, 4 between 50 and 59 years, 2 between 60 and 69 years, and 1 between 70 and 79 years), 16 were males and 5 females, 17 were non-smokers and 4 smokers, and 18 of the 21 subjects were taking other medications to control either hypertension, myocardial ischemia, diabetes, gastro-oesophageal reflux disease (GERD) and hyperacidity, hypothyroidism, neuritis, or rheumatoid. All recruited subjects gave written informed consent that complied with the principles of the Helsinki declaration.
A questionnaire was given to the subjects to be completed weekly for 4 weeks. The subjects were advised to write their health status before and after taking l-arginine. The questionnaire included 30 points regarding their mental, muscular, sexual, circulatory, GIT, and other functions during the 4-week administration. Scoring was recorded from 1 to 5; 1 was a remarkable improvement, 2 was a mild improvement, 3 no difference, 4 was worse than before, and 5 was not applicable. The subjects were also advised to report any adverse reactions developed during the administration of the supplement. In addition, they were asked if they wanted to continue taking the supplement after termination of the study. Tables 4 and 5 summarise the most noteworthy information of this pilot study

Table 5. Additional observations at the end of the 4-week study reported by some subjects.

1. Adjustment of blood pressure in mild hypertension.
2. High energy, especially in the morning w hen waking up.
3. Clear mind.
4. Stamina and resistance to depression and anxiety.
5. Increase in urine output.
6. Improvement of hair and nail growth and hardness.
7. Improvement of skin texture and appearance.
8. Increase in night dreams.
9. Improvement of circulation and temperature of extremities.
10. Reduction of hyperacidity.
11. Overall improvement of GIT system and defecation.
12. Improvement of most vital activities greatly affected in diabetics, including: reduction of neuritis, improvement of glucose metabolism, enhancement of libido and sexual performance and adjustment of body weight.

At the end of the study, none of the 21 cases experienced any side effects or aggravation of health problems from l-arginine administration. All the 21 cases wanted to continue taking the supplement after termination of the study.