Arginine is considered a semi-essential or conditionally essential amino acid. This means that under normal conditions the body can produce enough arginine to avoid symptoms of deficiency, but in stressful states, such as serious illness or aging, you have to eat more arginine to satisfy your body’s needs.
Arginine is a component of body proteins, and your body needs to have enough arginine to be able to build proteins, including muscle proteins. In this role, arginine plays a similar role to all the other amino acids that comprise body proteins.
Arginine also plays a variety of other roles in the body that collectively give arginine the reputation of “anti-aging” amino acid. The most prominent role is as a precursor for the production of nitric oxide (NO). As such, arginine can benefit heart health, blood pressure, and other functions related to NO.
Arginine is also the precursor for creatine and polyamine production. Creatine helps produce energy for exercise, and polyamines are crucial to cell growth and proliferation. Polyamines interact with DNA and RNA in the cells of the body, and a decrease in polyamines has been associated with aging.
The Metabolism of Arginine
Bear with me as I delve into a bit more of the science of arginine. The pathways of arginine metabolism are shown in the figure below.
Arginine is part of the so-called urea cycle that rids the body of toxic ammonia (NH3) by converting it to non-toxic urea for excretion by the kidneys. Let’s walk through the metabolism of arginine and the urea cycle step by step.
- The first step in the cycle is the combining of NH3 with carbon dioxide (CO2) to form carbamoyl phosphate.
- Carbamoyl phosphate combines with ornithine to form citrulline.
- Citrulline combines with the amino acid aspartate to form arginino-succinate.
- Arginino-succinate is then broken down to form arginine, with fumarate as a by-product.
- Arginine is converted to ornithine, with urea as a by-product.
It is called a cycle because there is no net change in the key players in the cycle (arginine, ornithine, and citrulline), while NH3 is converted to urea. The conversion of arginine to ornithine, with urea as a by-product, accounts for the majority of arginine metabolism.
There are other important pathways of arginine metabolism shown in the figure above. Notice how arginine also converts to citrulline and as a result produces nitric oxide (NO). As a vasodilator, NO relaxes the inner muscles of your blood vessels and causes the vessels to widen, thereby helping to increase blood flow and lower blood pressure.
Another pathway of arginine breakdown results in the production of creatine. Creatine plays an important role in energy metabolism in muscle during exercise. Finally, some of the ornithine resulting from arginine can then be converted to polyamines.
But let’s not get lost too much in the details of the urea cycle, which for the purposes of understanding arginine benefits are not so very important. I just want to make the point that arginine is a key player in a crucial set of cyclical reactions that keep the body operating smoothly. A deficiency of arginine will stall the urea cycle, and the result will be a buildup of toxic NH3 in the blood.
Arginine and Nitric Oxide (NO)
Most reports ascribe the cardiovascular benefits of arginine to its role in producing NO. Arginine is the only precursor of NO. NO is important in a variety of physiological functions. NO production occurs mostly in the cells lining the vascular system and has a number of protective effects on the cardiovascular system. It helps regulate blood pressure by relaxing (dilating) the blood vessels. NO also plays a role in maintaining the function of the central nervous system. Its role in the nervous system is particularly important in penile erection. Drugs such as sildenafil (Viagra) require at least some local NO production to function.
Only about 5% of arginine metabolism occurs by the pathway that produces NO. Nonetheless, the production of NO is highly dependent on the availability of arginine. An increase in arginine consumption, particularly as a nutritional supplement, increases NO production throughout the body, as evidenced by this study my team and I published in the American Journal of Physiology, Endocrinology, and Metabolism.
Supplementing with Arginine
Several studies have shown that supplementing with arginine improves vascular function by overcoming the deleterious effects of asymmetric dimethylarginine (ADMA), a cardiovascular risk factor. AMDA is elevated in a wide variety of conditions that increase the risk of cardiovascular disease, including hypertension, high cholesterol and triglycerides in the blood, peripheral artery disease, congestive heart failure, and preeclampsia. Other risk factors, including the blood concentrations of homocysteine, myeloperoxidase (MPO), and malondialehyde (MDA) are also improved with daily arginine supplementation.
- A wide variety of other benefits of arginine supplementation have been purported. The benefits of arginine supplementation on wound healing have been documented for more than 50 years.
- Arginine supplementation has been shown to enhance exercise performance, but not all studies have confirmed this effect.
- Arginine supplementation combined with omega-3 fatty acids has been shown to decrease infections and improve outcomes in diabetes, organ transplant rejection, and other inflammatory conditions, although these later claims have not been substantiated in clinical trials
Arginine and Protein Synthesis
The role of arginine in regulating the synthesis of new muscle and skin protein is, in my opinion, underappreciated. Under most conditions sufficient arginine is produced to avoid any deficiency. Further, since arginine is present in most dietary proteins, it is almost always the case that there is enough arginine in the body to meet requirements for protein synthesis. Nonetheless, supplementing with arginine, when given in the context of a formulation that includes all the essential amino acids (EAAs), can amplify the stimulatory effect on protein synthesis.
We conducted a study that showed how increasing the proportion of arginine in an otherwise balanced mixture of amino acids from 10% to 50% of the total amino acids in the formulation significantly increased the rate of both muscle and skin protein synthesis. The effect was equal to that of increasing the proportion of leucine (the “main” amino acid in muscle building) to 50%.
Further, the increased effectiveness of the amino acid mixture with high arginine was due to the arginine per se, not to the production of NO. The arginine effect on protein synthesis persisted even when a drug was given to block the production of NO. Importantly, the arginine effect on protein synthesis could only be observed when all the essential amino acids were given along with the arginine—arginine alone is ineffective in stimulating protein synthesis.
Arginine and Hormone Secretion
Arginine increases the amount of insulin the pancreas releases when you eat a sugar/carb-rich meal, and this effect is independent of NO. This results in improved control of the blood glucose level, as an increased response of insulin will minimize the spike in blood glucose after a meal containing a high-carbohydrate load. Increased insulin can also have a positive effect on muscle building.
Arginine also increases the rate of growth hormone secretion. (You can find out more about the beneficial effect amino acids have on growth hormone in this blog I wrote.) This effect is so well established that there is a clinical test in which arginine is given to determine if there is a normal response of growth hormone. However, the amount of arginine normally given in this test is very large (30 grams).
Arginine and “Anti-Aging”
Many of the benefits of arginine could be considered anti-aging. Aging can cause an increased risk for cardiovascular disease, poor metabolic control of the blood glucose level, impaired wound healing, decreased muscle mass and function, and lower levels of growth hormone. Arginine supplementation, either alone or preferably with the other EAAs, can lessen the deleterious effects of all of these aging responses.
Even when expressed in more subjective terms, arginine seems to benefit older individuals. Improvements in functions such as mental capacity, anxiety and stress, deep sleep, muscular performance, sexual performance (males), and overall feelings of well-being have been reported in preliminary studies, although more studies in this area are required before solid conclusions can be drawn.
Side Effects of Arginine Supplementation
The most common side effects of arginine supplementation are abdominal pain and diarrhea. Other less common responses may include gout, bloating, low blood pressure, and allergies. However, these side effects are observed only with doses in the 15- to 30-gram dosage range. Much smaller doses can have beneficial effects in terms of NO production and stimulation of muscle protein synthesis. The side effects will also be minimized when arginine is provided in the context of a complete formulation of essential amino acids.
It’s hard to believe that when equal amounts of citrulline and arginine are given the blood level of arginine actually increases more after citrulline consumption, but that is the case.
Citrulline is able to increase arginine levels more so than arginine because arginine metabolism occurs largely in the liver. As arginine is absorbed by the gastrointestinal tract it must pass through the liver before reaching the peripheral circulation. Most of the arginine is extracted by the liver before it ever reaches the peripheral blood.
In contrast, not much citrulline is taken up by the liver, so it reaches the peripheral circulation more readily. When blood containing large amounts of citrulline circulates through the kidneys, the citrulline is efficiently taken up and converted to arginine, which is then released into the peripheral blood. The result is that the blood arginine level actually increases more when citrulline is consumed than when the same amount of arginine is consumed. For this reason, citrulline may be a better choice as a nutritional supplement than arginine, not only because a smaller amount of citrulline can give the same effect as a larger dose of arginine, but also because the incidence of gastrointestinal distress will be less after citrulline consumption.