Oral L-arginine for Improving Vascular Function in Hypercholesterolemia, PVD, and Atherosclerotic Heart Disease
November 1999; Volume 2: 121-124
By Matthew J. Sorrentino, MD
During physical activity blood flow to the heart must increase to meet the metabolic needs of the heart muscle. L-arginine is an amino acid that has recently been touted and tested for its effect on blood flow to the heart. These tests have yielded promising results: L-arginine is not all hype, and may actually improve vascular function.
Background
Coronary blood flow is regulated by both local and systemic factors. Patients with hypercholesterolemia and atherosclerotic heart disease, however, develop abnormal function of their arteries. Instead of vasodilating, diseased arteries tend to vasoconstrict, decreasing blood flow and increasing the potential for clot formation. Ideally, treatment of atherosclerotic disease should heal dysfunctional endothelium and restore normal vascular reactivity. L-arginine, either by supplementation or from the diet, may be one treatment for improving the health of the vasculature.
Physiology
The endothelial cell layer lining arteries was previously thought to be an inert barrier that separated the blood from arterial smooth muscle. In the early 1980s it was discovered that an intact endothelium was necessary for vasodilation of arteries. A substance named endothelium-derived relaxing factor (EDRF) was proposed as an agent synthesized by endothelial cells that helped regulate arterial tone. Numerous substances have been shown to stimulate EDRF release from endothelial cells through activation of cell surface receptors or ion channels. These stimulators include acetylcholine, bradykinin, histamine, ADP, ATP, thrombin, substance P, and physical factors such as blood flow and pulse pressure.
Mechanism of Action
EDRF is most likely nitric oxide (NO) or a complex containing it.1 The enzyme nitric oxide synthase generates NO from the amino acid L-arginine. NO is responsible for vasodilator tone in the coronary arteries and the regulation of blood pressure in the systemic arteries. Exogenous nitroglycerin acts through the same pathway to cause vasodilation. NO has also been shown to inhibit platelet aggregation and adhesion and may have a role in preventing thrombotic complications.2
Strategies for restoring endothelium-dependent vasodilation and allowing healing of dysfunctional coronary arteries are now being developed. Cholesterol lowering has been shown to improve endothelial function and clinically to reduce ischemia.3-5 Other strategies include preventing EDRF degradation through free radical scavengers (superoxide dismutase) or replenishing the supply of EDRF by supplementation of the precursor L-arginine.
Animal Studies
L-arginine supplementation may be antiatherogenic. Dietary supplements of L-arginine in hypercholesterolemic rabbits block the progression of intimal thickening in coronary arteries, carotid arteries, and the aorta, and preserve normal endothelium-dependent relax-ation.6-8 These antiatherogenic effects have yet to be demonstrated in humans.
L-arginine is the precursor of endothelium-dependent relaxation factor.
a. True
b. False
Clinical Studies
Early studies have shown that intravenous administration of L-arginine infusion acutely improved endothelium-dependent vasodilation9 and oral L-arginine (7 g tid for a four-week treatment period) supplementation improved vasodilation.10
L-arginine has been shown to improve coronary blood flow both in the epicardial coronary arteries and in the microcirculation. Short-term intracoronary infusion of L-arginine improved the endothelial response to acetylcholine in hypercholesterolemic subjects.11 Intravenous L-arginine has been shown to attenuate the paradoxical vasoconstrictor response in atherosclerotic coronary arteries but only in arteries with early lesions and not in arteries with advanced lesions.12
L-arginine also improves coronary blood flow in patients with angiographically normal coronary arteries but abnormal responses to acetylcholine.13 These patients are thought to have either impaired coronary microvasculature or diffuse coronary artery atherosclerosis. Oral L-arginine has been shown to improve coronary blood flow in this group of patients and improve chest pain symptoms.14 Cardiac transplant patients also exhibit diffuse endothelial dysfunction that can be reversed by intravenous infusion of L-arginine.15 This improvement is more likely to occur in vessels without intimal thickening. Microcirculatory functional improvement indicates that early dysfunction is more likely to respond than advanced disease.
Platelet Aggregation. Platelets from hypercholesterolemic individuals show increased aggregability on aggregometry studies with collagen. Supplementation with 8.4 g/d of L-arginine for two weeks modestly decreased platelet reactivity,16 presumably through increased synthesis of NO, known to inhibit platelet adherence and aggregation.2
Nitroglycerin, an exogenous nitrate, also inhibits platelet reactivity. Both platelet-derived and endothelial-derived NO have been shown to regulate platelet responsiveness. The endothelium is thought to condition platelets as they flow through the vasculature increasing cyclic GMP and decreasing aggregability.
Use in Peripheral Vascular Disease. Boger and colleagues performed a double-blind, controlled study using prolonged intermittent infusion therapy with L-arginine (two intravenous infusions daily of 8 g L-arginine for three weeks) in patients with intermittent claudication.17 The L-arginine patients experienced improved endothelium-dependent vasodilation in the femoral arteries and a significant improvement in pain-free walking distance. The same group of investigators infused L-arginine into individuals with critical limb ischemia from advanced peripheral vascular disease, increasing femoral artery blood flow.18
Use in Heart Failure. A randomized, double-blind, placebo-controlled study in moderate to severe heart failure showed an improvement in walking distance on the six-minute walk test in individuals after six weeks of oral L-arginine supplementation.19 In another study, intravenous infusion of 20 g of L-arginine over a one-hour period increased stroke volume and cardiac output without a change in heart rate, and decreased arterial blood pressure and systemic vascular resistance. These hemodynamic changes return to baseline within an hour of cessation of the infusion.20
Preparations and Dietary Sources
L-arginine is a semi-essential amino acid and can be synthesized in the body. It is considered semi-essential because throughout most of life, people synthesize enough L-arginine. However, supplementation may be required during periods of rapid growth in childhood. L-arginine is present in protein found in meats, nuts, milk, cheese, eggs, fish, and beans. (See Table 1 for foods rich in L-arginine.) L-arginine can stimulate the pituitary gland to release growth hormone and therefore has become a popular supplement for muscle building among athletes.
| Table 1-Foods rich in L-arginine | |||||
| Food | Serving Size | L-arginine Content | Food | Serving Size | L-arginine Content |
| Whelk (sea snail) | 3 oz | 4198 mg | Broiled pork chop | 3.5 oz | 1785 mg |
| Dried spirulina (seaweed) | 3.5 oz | 4147 mg | Clams | 3 oz | 1585 mg |
| Dry roasted soybeans | ½ cup | 2641 mg | Pumpkin or squash seeds | 1 oz | 1536 mg |
| Roasted venison | 3.5 oz | 2175 mg | Alaskan king crab | 3 oz | 1437 mg |
| Roasted light meat turkey without skin | 3.5 oz | 2086 mg | 2% fat cottage cheese | 1 cup | 1417 mg |
| Sockeye salmon | 3 oz | 1390 mg | |||
| Tuna salad | ½ cup | 1982 mg | Chickpeas | 1 cup | 1369 mg |
| Spiny lobster | 3 oz | 1959 mg | Firm tofu | ½ cup | 1323 mg |
| Extra lean ground beef (well done) | 3.5 oz | 1915 mg | Dried pignolia (pine) nuts | 1 oz | 1323 mg |
| Boiled crayfish | 3 oz | 1300 mg | |||
| Roasted chicken (light meat without skin) | 3.5 oz | 1864 mg | Freshwater bass | 3 oz | 1230 mg |
| Hummus | 1 cup | 1109 mg | |||
| Octopus | 3 oz | 1851 mg | Black beans | 1 cup | 944 mg |
L-arginine is available in 500 mg capsules. Typical doses used in vascular studies have been 3 g tid. Bottles of 100 capsules cost between $10 to $15. Recently, Cooke Pharma has marketed a protein bar (HeartBar) that contains 3 g of L-arginine per bar. The bars also contain supplements of vitamins C, E, B6, B12, folic acid, and niacin. The original- and cranberry-flavored bars cost between $1.19 and $1.79 each.
Side Effects
L-arginine is usually well-tolerated but can cause side effects such as nausea and diarrhea. In diabetics, L-arginine may raise sugar levels, which potentially could cause changes in medication requirements.
Conclusion
L-arginine supplements either as capsules or a protein bar are effective in raising L-arginine levels and can give short-term improvement in vascular reactivity. The restoration of normal vascular reactivity can reduce cardiac symptoms and vascular events. The substrate L-arginine appears to increase production of NO improving vascular responsiveness. A major limitation of the use of exogenous nitrates has been the development of nitrate tolerance that can occur soon after the initiation of therapy. Nitrate tolerance seems to occur because of the loss of the vascular effects of the drugs although the exact mechanism is unknown.21 L-arginine therapy may have the same limitations as exogenous nitrates because it works through similar mechanisms. Long-term studies and an evaluation for tolerance have not been done.
Recommendation
A diet rich in the amino acid L-arginine may help patients with hypercholesterolemia, and patients with atherosclerotic disease. Because hypercholesterolemia can impair vascular function, the protein rich in L-arginine should not come from red meats but instead should come from seafood, poultry, nuts, and beans. Diet can supply an adequate amount of L-arginine and is the recommended method of supplementation.
L-arginine supplementation has been shown to:
a. improve vasodilation.
b. decrease platelet reactivity.
c. increase pain-free walking distance in patients with intermittent claudication.
d. increase femoral artery blood flow in patients with critical limb ischemia.
e. All of the above.
References
1. Meredith IT, et al. Role of impaired endothelium-dependent vasodilation in ischemic manifestations of coronary artery disease. Circulation 1993;87(suppl V):V56-V66.
2. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-2012.
3. Treasure CB, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332:481-487.
4. Anderson TJ, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995;332:488-493.
5. van Boven AJ, et al. Reduction of transient myocardial ischemia with pravastatin in addition to the conventional treatment in patients with angina pectoris. REGRESS study group. Circulation 1996;94: 1503-1505.
6. Wang BY, et al Dietary arginine prevents atherogenesis in the coronary artery of the hypercholesterolemic rabbit. J Am Coll Cardiol 1994;23:452-458.
7. Hamon M, et al. Long-term oral administration of L-arginine reduces intimal thickening and enhances neoendothelium-dependent acetylcholine-induced relaxation after arterial injury. Circulation 1994;90:1357-1362.
8. Boger RH, et al. Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: Comparison with lovastatin. Circulation 1997;96: 1282-1290.
9. Creager MA, et al. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992;90:1248-1253.
10. Clarkson P, et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996;97:1989-1994.
11. Drexler H, et al. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 1991;338:1546-1550.
12. Otsuji S, et al. Attenuation of acetylcholine-induced vasoconstriction by L-arginine is related to the progression of atherosclerosis. Am Heart J 1995;129: 1094-1100.
13. Egashira K, et al. Effects of L-arginine supplementation on endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary arteriograms. Circulation 1996;94:130-134.
14. Lerman A, et al. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998;97:2123-2128.
15. Drexler H, et al. Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology. Circulation 1994;89:1615-1623.
16. Wolf A, et al. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol 1997;29:479-485.
17. Boger RH, et al. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol 1998;32: 1336-1344.
18. Bode-Boger SM, et al. L-arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study. Circulation 1996;93:85-90.
19. Rector TS, et al. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation 1996;93: 2135-2141.
20. Koifman B, et al. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol 1995;26:1251-1256.
21. Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med 1998;338:520-531.
November 1999; Volume 2: 121-124
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