The mother of nitric oxide wields tremendous power for greater health …
Arginine Battles Cardiovascular Aging
Judging from the enormous number of scientific studies done with arginine, there are many morbidities for which arginine is needed
By Will Block
he Mayo Clinic says that most people get enough arginine, and do not need to take supplements. They are not alone in this opinion. WebMD says essentially the same thing—that the body normally makes enough and added amounts are not needed. This is a common belief, especially within the medical community. Yet, the Mayo Clinic also states that “symptoms of arginine deficiency include poor wound healing, hair loss, skin rash, constipation, and fatty liver …” and that, although “[a]rginine is considered a semi-essential amino acid … supplementation is sometimes needed.” That might include “people with protein malnutrition, excessive ammonia production, excessive lysine intake, burns, infections, peritoneal dialysis, rapid growth, urea synthesis disorders, or sepsis may not have enough arginine.” Hmph!
Judging from the enormous number of scientific studies done with arginine, there are many other morbidities for which arginine is needed, including the all-encompassing category of aging, an inescapable condition of “normal” life as we know it. A recent review makes this abundantly clear with regard to cardiovascular senescence. More about this to come.
At the very least, for 25% of
the U.S. population, 2.6 g/day of
arginine is not enough.
The Amount of Arginine in the Typical American Diet
From an analysis of the Third National Health and Nutrition Examination Survey,* a public-use nutrition survey of the non-institutionalized U.S. population, it was found that the mean arginine intake for the U.S. adult population is 4.4 g/day, with 25% of the population consuming less than 2.6 g/day. Arginine consumption varied according to demographic and cardiovascular risk factors in the population. This means that the analysis—distributed by the National Institutes of Health as a “public access” paper—gives credence to the idea that low arginine availability may be a factor in the development of atherosclerosis and cardiovascular disease. At the very least, for 25% of the population, 2.6 g/day is not enough. Nor is 4.4 g/day likely to be enough. Indeed, the amount that can reasonably be obtained from food may not be sufficient.
Arginine is frequently billed as a conditionally-essential amino acid in our diets. This does not make a lot of sense. When there is a deficiency, various inflammatory and oxidative processes result, especially in the vascular endothelium, the lining of the blood vessels in our bodies. The consequences of these processes cause grave damage to the endothelium, degrading many of its properties that are crucial for proper function, the result of which may result in the development of atherosclerosis.
NO is the champion of the
crusade against cardiovascular disease;
it is the glorious knight
in a good fight.
In the course of vascular system events, the normal functions of the endothelium are highly dependent on sufficient production of nitric oxide (NO). Production is accomplished through the activation of an enzyme, endothelial nitric oxide synthase (eNOS), made and released by vascular endothelial cells, which acts on arginine to produce NO.
When excessive oxidative vascular injury occurs, caused for example by the stresses of obesity or hypertension, reactive and destructive oxygen species form, a plenitude of which can lead to the inhibition of eNOS, thereby decreasing NO production. If, at the same time, there is too little arginine present, eNOS forms a highly reactive oxide causing further vascular endothelial injury and inflammation.
Glorious NO’s Battle
In such an arginine-deprived environment, atherosclerosis proceeds apace and the battle is lost to cardiovascular disease. NO is the champion of the crusade against this disease; it is the glorious knight in a good fight. What’s truly important to recognize is that NO can only be produced in the body from arginine, and that it is a principal agent of blood vessel relaxation (vasodilation). Without enough NO, clogged arteries (aka atherosclerosis), chest pain, coronary artery disease, heart failure, intermittent claudication/peripheral vascular disease (resulting in muscle pain), swelling of blood vessel that causes headaches (vascular headaches), and erectile dysfunction prevail. On other fronts, arginine also triggers the body to make protein and has been studied for wound healing, bodybuilding, enhancement of sperm production (spermatogenesis), and prevention of wasting in people with critical illnesses.
How Much is Enough?
In a recent study, conducted at the Karol Marcinkowski University of Medical Science, Poznan, Poland, researchers enrolled 54 subjects (30 men, 24 women), otherwise healthy outpatients, who were divided based on blood pressure (BP) measurements into either a healthy control group (19 subjects) or a hypertensive treatment group (35 patients). The latter were freshly diagnosed with mild hypertension but had received no drugs or supplements prior to classification as hypertensive. Then the subjects were randomized to either 2 or 4 g of supplemental arginine three times daily (for a total of either 6 or 12 g/day) or placebo.
Hypertension has long been thought to be one of the highest cardiovascular risk factors, because it represents a significant disturbance in the balance of vasomotor influences. It can cause disruptions that affect functional vasoconstriction, which can result in vessel closure and block microcirculation. Hypertension can also engender structural alterations that may affect the vascular endothelium so that there is decreased bioavailability of NO. Once called endothelium-derived relaxing factor, NO is responsible for establishing and maintaining resting vascular tone, regulating blood flow to meet the metabolic demands of tissue, and adapting vessel diameter to inflow volume. This has been upheld by long-term follow-up studies in the offspring of hypertensive patients. These have achieved a deeper understanding of the prognostic and genetic importance of reduced NO bioavailability in hypertension.
Without an adequate and
continuous supply of arginine,
substrates, and several
cofactors (which include
folate, citrulline and the antioxidants
vitamin C and E), the formation of
NO would not occur.
The Arginine Paradox
When NO is generated in the endothelium, L-arginine is converted to L-citrulline via eNOS. However, without an adequate and continuous supply of arginine, substrates, and several cofactors (which include folate* and, according to one recent report, citrulline and the antioxidants vitamin C and E), the formation of NO would not occur. Even though the intracellular concentrations of arginine normally exceed the level required for the maximal enzyme kinetics of NOS by a long shot, supplementation with arginine improves endothelial function, slows atherosclerotic plaque formation, and alters autonomic function. These changes are all consistent with enhanced NO biosynthesis. This seeming paradox may be explained by the tendency of NOS to compartmentalize and the relative, rather than absolute, deficiency of arginine. Elevated plasma levels of asymmetric dimethylarginine (ADMA), a competitive antagonist of eNOS, in several clinical states (e.g., hypercholesterolemia, insulin resistance, type 2 diabetes mellitus, hypertension, and renal failure) might also contribute to the arginine paradox. When arginine is taken as a supplement, it displaces the competitive inhibitor, improves intracellular transport of this amino acid, and restores NO production to physiological levels. But it will work better if it is served up with cofactors.
NO Discovery Stimulated Arginine Interest
The study of arginine supplementation increased dramatically after the arginine/nitric oxide pathway was discovered. Among the findings of many of these studies was the demonstration of a beneficial effect of arginine on NO production and for reducing systemic blood pressure (BP). A review of these studies found that the results were not uniform and rather inconclusive, with dosages of arginine safely administered at even 30 g in single i.v. infusions. Studies of BP utilized oral doses of arginine ranging from 5–20 g daily, with most of them within the 6–9 g range. These data determined the choice of arginine administration regimens in the Polish study.
This study was designed to investigate the effects of arginine on BP, both for the purpose of hypertensive patient qualification and arginine therapy assessment. In large trials, lowering of BP by 2–3 mmHg by antihypertensive drugs is considered significant and leads to favorable outcomes, including the recognition that reducing even mild hypertension can lower the high risk of cardiovascular events, even when compounded by the presence of other risk factors.
Hypertension was diagnosed with mean awake BP values ≥135 mmHg systolic or 85 mmHg diastolic or average night-time values of ≥120 mmHg systolic or 70 mmHg diastolic or 24-h BP values ≥125 mmHg systolic or 80 mmHg diastolic. Physical and laboratory examinations, which included blood and urine tests, were normal. There were no cases of hyperlipidemia in the subjects. All patients had normal renal and liver function.
Arginine lowered both systolic and
diastolic BP—comparable to levels
achieved by antihypertensive drugs.
There were no adverse reactions in the subgroups receiving arginine, which was well tolerated—all subjects completed the study. The groups of patients receiving arginine for four weeks displayed BP reductions, with statistically significant reductions in the 24-hour and daytime BP parameters of the hypertensive patients, who received 4 g of arginine three times a day (12 g/day). Arginine lowered both systolic and diastolic BP, with a stronger hypotensive effect observed during the day. According to the researchers, the reductions were comparable to those achieved by antihypertensive drugs, with a mean daytime drop of 6 mmHg systolic and 5 mmHg diastolic. These reductions have been associated with substantial reductions in cardiovascular disease mortality, risk of stroke, and risk of myocardial infarction. Reductions in the subjects with normal blood pressure taking arginine did not reach statistical significance.
Arginine Fights Cardiovascular Aging
A comprehensive review of supplemental arginine was recently published by researchers at the Molecular Cardiology Research Institute, Tufts Medical Center, Boston. In their overview, the researchers report that as age advances, arteries lose their ability to effectively dilate owing to endothelial dysfunction. The result of this senescence is the increased age-associated risk of cardiovascular disease (CVD). It is anticipated that mortality from CVD will worsen owing to the effects of aging. With more than 35 million Americans now 65 years of age or older, the sordid fact is that the majority of these individuals have some form of CVD.
Thus, the researchers analyzed papers showing that arginine plays a number of valuable roles in a variety of physiological processes, including nitrogen detoxification, immunocompetence, growth hormone (GH) secretion, and insulin secretion.
The review was focused principally on the ability of arginine to protect vascular endothelial function as a novel nutritional strategy to possibly stave off the progression of vascular dysfunction with aging and cardiovascular disease. Emphasis was placed on arginine’s propensity to alter the vascular inflammatory and systemic hormonal milieu, which in turn may have a profound effect on vascular endothelial function.
Aging Advances Vascular Endothelial Dysfunction
Even in the absence of other risk factors, aging per se is an independent atherogenic spur, increasing morbidity and mortality from CVD, myocardial infarction, and stroke. As aging advances, vascular dysfunction becomes pervasive and peripheral vasodilatory capacity is diminished due to the deterioration of endothelial dysfunction. Importantly, the vascular endothelium is responsible for numerous autocrine, paracrine, and endocrine functions. These include vascular tone regulation and inflammation, cell growth, platelet function, and thrombosis. NO, the potent vasoactive hormone released by endothelial cells, plays a key role in maintaining the vascular wall in a quiescent state in response to sheer stress via its ability to dampen inflammation, and reduce cellular proliferation, among other capabilities.
One of the factors exacerbating
endothelial dysfunction with aging
is reduced NO production and
One of the factors exacerbating endothelial dysfunction with aging is reduced NO production and bioavailability. The diminishment of NO contributes to a shifting of the vascular wall toward a defense posture—with the increased expression of chemokines, cytokines, and adhesion molecules—leading to leukocyte recruitment and platelet aggregation. Thus the atherosclerotic process is initiated or progressed. Endothelial dysfunction is a precursor to atherogenesis and because of its correlation with aging, it is a primary phenotypic expression for normal human aging. Moreover, this aspect of vascular senescence may be the principal causative agent for the increased CVD risk associated with aging.
Other age-related declines associated with endothelial dysfunction include memory loss, reduced activity competence for daily living, and an onslaught of the numerous diseases of aging. These include erectile dysfunction, renal dysfunction, hypertension, and stroke. The deterioration of endothelial dysfunction is predictive of future cardiovascular events, and constant impairment of endothelial function virtually assures adverse outcomes. On the other hand, improving endothelial function reverses cardiovascular decline.
As described above, NO production requires substrates and cofactors. When produced and released, NO diffuses into vascular smooth muscle cells causing relaxation. As well, NO affects potassium channels, calcium levels, and the muscle protein myosin. All together, these changes serve to regulate regional blood flow through flow-mediated dilation. Other substrate and cofactors required for this reaction include oxygen, NADPH, flavin, heme, and tetrahydrobiopterin (BH4). Folate is now thought to improve vascular function by mimicking BH4 activity. Aging aggravates any dysfunctionality caused by missteps in substrate and cofactor modulation. The resulting complicity reduces NO bioavailability, attenuates vasodilation, and alters regional circulation and tissue perfusion. Reduced substrate activity may also be detrimental, limiting and reducing both NO formation and vasodilation.
Essential With Aging
Surgery or trauma causes growth and repair to accelerate, and under these catabolic conditions arginine becomes conditionally essential, especially with age. This is also true when, with aging, numerous organ systems deteriorate, such as with sarcopenia (i.e., lean tissue loss). Indeed, aging and CVD are synonymous with inflammation, a condition which normally leads to recovery and restoration of tissue integrity, but may not, when the inflammatory process persists.
Endothelial dysfunction may be
the principal causative agent for
the increased CVD risk
associated with aging.
Even in the absence of clear risk factors or clinical disease, inflammation and oxidative stress can ultimately result in pathogenesis. Consequently, aging alone can be thought of as a catabolic/inflammatory state. It is for this reason that the use of arginine as a nutritional strategy to protect the vasculature from the negative effects of aging and disease should be considered essential, and not just conditionally essential.
Arginine Enhances Vascular Function
As we have already stated, arginine can help with angina, atherosclerosis, heart failure, coronary artery disease (CAD), erectile dysfunction, and intermittent claudication/peripheral vascular disease. All of these are related to its effects on vascular endothelial function.
In one study conducted in men with CAD, a dose of 7 g taken 3 times per day (21 g/day) for 3 days increased plasma levels of arginine, while improving endothelium-dependent dilation. A similar study with hypercholesterolemic young adults, using the same dose over a 4-week period found that plasma arginine levels doubled, while endothelial-dependent dilation increased nearly 3½ fold.
Also, in a prospective, double-blind, randomized crossover trial, 16 g of arginine for 14 days or placebo in 12 healthy old participants (age 73.8 ± 2.7 years) found that arginine improved endothelial-dependent vasodilation (5.7% ± 1.2%), whereas placebo had no effect. Serum levels of arginine increased significantly, but placebo had no effect. In several studies with older patients with stable CAD, arginine supplementation has also been shown to improve flow-mediated dilation. However, other studies have shown that older patients with CAD and concomitant renal dysfunction may not benefit from arginine supplementation and similarly, that acute intravenous infusion of arginine has no effect on endothelial-dependent vasodilation in healthy older individuals. Also, the effects of 9 g of arginine per day for 1 month on endothelium-dependent vasodilation in healthy postmenopausal women increased plasma arginine, but without any change in flow-mediated dilation. Others have shown that lower amounts of arginine have no effect on plasma levels of arginine, forearm blood flow, or endothelial-dependent vasodilation in healthy men.
In several studies with older patients
with stable CAD, arginine
supplementation has also been shown
to improve flow-mediated dilation.
From the results of a recently concluded meta-analysis, it would appear that arginine’s effects, at least at low levels, are dependent on initial endothelial health. Supplementation does not seem to affect endothelial-dependent flow-mediated dilation (FMD) in healthy individuals when vascular endothelial function has not already deteriorated, owing possibly to an existing sufficiency of NO activity. This would explain the failure of low levels of arginine supplementation to increase FMD in such subjects. But in those with more endothelial dysfunction, arginine would appear to be very useful indeed.
Not for All Aging Populations?
Even though studies have shown that short-term arginine therapy improves endothelial function in older patients with peripheral artery disease, arginine may not work for all aging populations. In this cohort, there has even been a study showing detrimental effects on endothelial function. Using 3 g/day of arginine for six months, the result was reduced NO availability, FMD, and other measures. Two possible causes for these outcomes are that additional arginine may lessen the sensitivity of smooth muscle cells to NO release due to arginine tolerance and that there may be a counter-regulatory nitrate tolerance for prolonged exposure. There are other causes, but none are clear. The possibility always remains that without adequate cofactors, the bioavailability of which also diminishes with age, arginine’s benefits are thwarted.
Countervailing the above-mentioned is a study of long-term arginine administration showing a favorable effect on coronary endothelial function in those with coronary endothelial dysfunction and nonobstructive CAD. However, a highly publicized study published in JAMA found that arginine supplementation was associated with higher postinfarction mortality, but these results were probably due to inadequate analysis along with high statin use (see
“L-Arginine Therapy in Acute Myocardial Infarction: Why the Negative Results? Could It Have Been Prevented?” in the January 2006 issue of Life Extension News). From that article, “However, we do not recommend that those who have recently had heart attacks take L-arginine (even with the addition of vitamin C, folic acid, and CoQ10) until there is more knowledge about the reasons for this study’s results.” The formidable Adrian Barbul, M.D., has chimed in on this to cast added doubt.
Arginine has shown promise as a vascular prophylaxis against endothelial dysfunction induced by acute stressors. Acute cigarette smoking and consumption of a high-fat meal are known to significantly reduce endothelial function. Consequently, arginine taken prior to smoking or with a high-fat meal prevents the deleterious effect of these perturbations on endothelial function according to at least 4 studies.
Arginine as an Anti-Inflammatory Agent
While inflammation/oxidative stress has been identified as the principal factor for endothelial dysfunction, there are other factors including inadequate arginine/BH4 ratio (probably addressed by using folate, as explained above). Another is the abundance of reactive oxygen species generated with aging, which can uncouple NOS from arginine oxidation, resulting in superoxide production and the formation of peroxynitrite instead of NO. Superoxide may cause added BH4 oxidation and eNOS uncoupling. Antioxidants such as vitamin C and E may also be of benefit.
An often missed benefit of arginine is immune function enhancement. In fact, higher plasma concentrations may increase the activity of natural killer cells among other immune agents such as T-cells. Arginine is also noted to exercise an immune-preserving effect under conditions of protein malnutrition. Although arginine’s possible direct effects on inflammation and oxidative stress have barely been examined, animal studies show that arginine prevents upregulation of NADPH oxidase, a known generator of ROS within the aging vasculature.
In patients with chronic kidney and CVD, arginine reduces several important markers of inflammation and oxidative stress ADMA (the endogenous inhibitor of NO), along with inflammatory enzymes, and homocysteine (a ROS stimulator that causes vascular damage and atherosclerosis). Arginine also reduces endothelin-1, a potent vasoconstrictor and important modulator of endothelial dysfunction with advancing age.
Arginine as a Pleotropic Nutrient
It is known that arginine stimulates the release of growth hormone (GH), along with insulin, glucagon, epinephrine, norepinephrine, and prolactin. While many amino acids stimulate insulin secretion, arginine is the most potent, and although insulin resistance is connected to endothelial dysfunction, insulin can improve endothelial-dependent vasodilation independently of NO activity. GH secretion declines with aging and this is associated with declines in muscle mass and bone mineral density as well as increases in adiposity. Decreases in GH release has also been linked to deterioration of various cardiovascular and immunological functions.
If you are older, taking the
needed cofactors, along
with arginine, will strengthen
your cardiovascular system.
So it is good to know that arginine is a powerful stimulator of GH. Numerous studies have demonstrated that patients with GH deficiency have reduced endothelial dysfunction, and augmenting GH in these patients restores endothelial function. Also, acute infusion of GH increases endothelial-dependent vasodilation. GH contributes to arginine-induced, NO-mediated vasodilation and animal models demonstrate that a deficiency induces pro-oxidative states.
GH can significantly reduce cellular mitochondria ROS generation by upregulating the expression of endogenous antoioxidants. GH has many other benefits, increasing the expression of eNOS mRNA, reducing ADMA, and increasing endothelial progenitor cells. Consequently, because arginine increases GH release, it is likely to improve endothelial function by (1) directly activating eNOS; (2) upregulating eNOS protein expression; and (3) preserving NO bioavailability via its antioxidant properties.
Healthy Cardiovascular Aging
If you are young and if you have preserved vascular endothelial function, arginine may have little effect on endothelial-dependent vasodilation. But if you are older, taking arginine will strengthen your cardiovascular system. Certainly, in select aging patient populations with overt endothelial dysfunction and reduced arginine stores, arginine by itself may very well improve vascular function via its ability to augment NO. So much the better if arginine is properly cofactored. And don’t forget that independently, arginine may also improve endothelial function via its ancillary effects on hormonal modulation, along with anti-inflammatory/antioxidant benefits for endothelial cells. Arginine is more essential than you may have previously thought.
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Will Block is the publisher and editorial director of Life Enhancement magazine.