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Mechanisms of Disease: L-arginine in coronary atherosclerosis—a clinical perspective

Nature Clinical Practice Cardiovascular Medicine volume 4, pages 274–283 (2007)Cite this article

Abstract

L-Arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide in the vascular endothelium, thus its effects are mediated largely by increases in nitric oxide production. L- Arginine has antioxidant and antiapoptotic properties, increases smooth muscle relaxation, inhibits the expression of adhesion molecules and chemotactic peptides, decreases endothelin-1 expression, and inhibits platelet aggregation. This amino acid also improves endothelial function in patients with coronary artery disease and dilates human epicardial atheromatous coronary arteries. Despite the positive results from small case–control studies, it is still unclear whether chronic administration of L-arginine has any effect on clinical outcome in patients with coronary artery disease. In addition, other indirect strategies, such as the inhibition of arginase, could prove more effective at improving intracellular L-arginine bioavailability than exogenous L-arginine administration. The potential clinical usefulness of L-arginine, therefore, needs further evaluation in large, prospective clinical trials. Here, we present a critique of the existing literature about the role of L-arginine in the prevention of atherosclerosis.

Key Points

  • L-Arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide in the vascular endothelium

  • Evidence indicates that intra-arterial or intravenous infusion of L-arginine rapidly improves nitric oxide bioavailability in the coronary arteries in both animal models and humans

  • Oral treatment with L-arginine seems to improve endothelial function in high-risk patients, but this effect is not observed in healthy individuals, or in patients with coronary atherosclerosis or myocardial infarction who are receiving optimum medical treatment

  • Although L-arginine is not associated with any serious adverse effects, there is still no conclusive evidence for its use for primary or secondary prevention of adverse cardiovascular events

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Figure 1: Pathways of NO generation from L-arginine
Figure 2: eNOS 'uncoupling' and the synthesis of superoxide radicals instead of NO

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References

  1. Tousoulis D et al. (2002) L-arginine in cardiovascular disease: dream or reality? Vasc Med 7: 203–211

    Article  Google Scholar 

  2. Hecker M et al. (1990) The metabolism of L-arginine and its significance for the biosynthesis of endothelium derived relaxing factors: cultured cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci USA 87: 8612–8616

    Article  CAS  Google Scholar 

  3. Ward ME et al. (2005) Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. J Clin Invest 115: 3128–3139

    Article  CAS  Google Scholar 

  4. Kleinert H et al. (2004) Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 500: 255–266

    Article  CAS  Google Scholar 

  5. Forstermann U and Munzel T (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113: 1708–1714

    Article  Google Scholar 

  6. Tousoulis D et al. (2006) Nitric oxide in coronary artery disease: effects of antioxidants. Eur J Clin Pharmacol 62 (Suppl 13): S101–S107

    Article  Google Scholar 

  7. Nagase S et al. (1997) A novel nonenzymatic pathway for the generation of nitric oxide by the reaction of hydrogen peroxide and D- or L-arginine. Biochem Biophys Res Commun 233: 150–153

    Article  CAS  Google Scholar 

  8. Boger RH (2004) Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the 'L-arginine paradox' and acts as a novel cardiovascular risk factor. J Nutr 134 (Suppl): S2842–S2847

    Article  Google Scholar 

  9. Boger RH (2006) Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond. Ann Med 38: 126–136

    Article  Google Scholar 

  10. Channon KM and Guzik TJ (2002) Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. J Physiol Pharmacol 53: 515–524

    CAS  PubMed  Google Scholar 

  11. Tangphao O et al. (1999) L-arginine and nitric oxide-related compounds in plasma: comparison of normal and arginine free diets in a 24 h cross over study. Vasc Med 4: 27–32

    Article  CAS  Google Scholar 

  12. Bode-Boger SM et al. (1998) L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol 46: 489–497

    Article  CAS  Google Scholar 

  13. Miller AL (2006) The effects of sustained-release-L-arginine formulation on blood pressure and vascular compliance in 29 healthy individuals. Altern Med Rev 11: 23–29

    PubMed  Google Scholar 

  14. Boger RH and Ron ES (2005) L-arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor. Altern Med Rev 10: 14–23

    PubMed  Google Scholar 

  15. Bosmans JM et al. (1999) Continuous perivascular L-arginine delivery increases total vessel area and reduces neointimal thickening after experimental balloon dilatation. Arterioscler Thromb Vasc Biol 19: 767–776

    Article  CAS  Google Scholar 

  16. Panza JA et al. (1993) Effect of increased availability of endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation 87: 1475–1481

    Article  CAS  Google Scholar 

  17. Hirooka Y et al. (1994) Effect of L-arginine on acetylcholine-induced endothelium-dependent vasodilation differs between coronary and forearm vasculatures in humans. J Am Coll Cardiol 24: 948–955

    Article  CAS  Google Scholar 

  18. Tousoulis D et al. (1999) Effects of L -and D-arginine on the basal tone of human diseased coronary arteries and their responces to substance P. Heart 81: 505–511

    Article  CAS  Google Scholar 

  19. Niebauer J et al. (1999) Local L-arginine delivery after balloon angioplasty reduces monocyte binding and induces apoptosis. Circulation 100: 1830–1835

    Article  CAS  Google Scholar 

  20. Egashira K et al. (1996) Effects of L-arginine supplementation on endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary angiograms. Circulation 94: 130–134

    Article  CAS  Google Scholar 

  21. Ceremuzynski L et al. (1997) Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol 80: 331–333

    Article  CAS  Google Scholar 

  22. Quyyumi AA (1998) Does acute improvement of endothelial dysfunction in coronary artery disease improve myocardial ischemia? A double-blind comparison of parenteral D- and L-arginine. J Am Coll Cardiol 32: 904–911

    Article  CAS  Google Scholar 

  23. Tentolouris C et al. (2000) Serum cholesterol level, cigarette smoking and vasomotor responses to L-arginine in diseased epicardial coronary arteries. Am J Cardiol 85: 500–503

    Article  CAS  Google Scholar 

  24. Tousoulis D et al. (2005) Effects of vitamin C on intracoronary L-arginine dependent coronary vasodilatation in patients with stable angina. Heart 91: 1319–1323

    Article  CAS  Google Scholar 

  25. Suzuki T et al. (2002) Effect of local delivery of L-arginine on in-stent restenosis in humans. Am J Cardiol 89: 363–367

    Article  CAS  Google Scholar 

  26. Clarkson P et al. (1996) Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 97: 1989–1994

    Article  CAS  Google Scholar 

  27. Bode-Boger SM et al. (2003) Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med 8: 77–81

    Article  Google Scholar 

  28. Chin-Dusting JP et al. (1996) Effects of in vivo and in vitro L-arginine supplementation on healthy human vessels. J Cardiovasc Pharmacol 28: 158–166

    Article  CAS  Google Scholar 

  29. Adams MR et al. (1997) Oral L-arginine improves endothelium dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary disease. Atherosclerosis 129: 261–169

    Article  CAS  Google Scholar 

  30. Blum A et al. (1999) Clinical and inflammatory effects of dietary L-arginine in patients with intractable angina pectoris. Am J Cardiol 83: 1488–1490

    Article  CAS  Google Scholar 

  31. Maxwell AJ et al. (2002) Randomized trial of a medical food for the dietary management of chronic stable angina. J Am Coll Cardiol 39: 37–45

    Article  CAS  Google Scholar 

  32. Cannon RO III (2002) Oral L-arginine (and other active ingredients) for ischemic heart diseases. J Am Coll Cardiol 39: 46–48

    Article  CAS  Google Scholar 

  33. Lerman A et al. (1998) Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 97: 2123–2128

    Article  CAS  Google Scholar 

  34. Yin WH et al. (2005) L-arginine improves endothelial function and reduces LDL oxidation in patients with stable coronary artery disease. Clin Nutr 24: 988–997

    Article  CAS  Google Scholar 

  35. Blum A et al. (2000) Oral L-arginine in patients with coronary artery disease on medical management. Circulation 101: 2160–2164

    Article  CAS  Google Scholar 

  36. Walker HA et al. (2001) Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina. J Am Coll Cardiol 38: 499–505

    Article  CAS  Google Scholar 

  37. Oomen CM et al. (2000) Arginine intake and risk of coronary heart disease mortality in elderly men. Arterioscler Thromb Vasc Biol 20: 2134–2139

    Article  CAS  Google Scholar 

  38. Schulman SP et al. (2006) L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA 295: 58–64

    Article  CAS  Google Scholar 

  39. Loscalzo J (2003) Adverse effects of supplemental L-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism? Arterioscler Thromb Vasc Biol 23: 3–5

    Article  CAS  Google Scholar 

  40. Stead LM et al. (2001) Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab 281: E1095–E1100

    Article  CAS  Google Scholar 

  41. Sydow K (2003) ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovasc Res 57: 244–252

    Article  CAS  Google Scholar 

  42. Cassone Faldetta M et al. (2002) L-arginine infusion decreases plasma total homocysteine concentrations through increased nitric oxide production and decreased oxidative status in Type II diabetic patients. Diabetologia 45: 1120–1127

    Article  CAS  Google Scholar 

  43. Lee J et al. (2003) Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA 100: 4843–4848

    Article  CAS  Google Scholar 

  44. Schnabel R et al. (2005) Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene study. Circ Res 97: e53–e59

    Article  CAS  Google Scholar 

  45. Böger GI et al. (2004) Improvement of endothelium dependent vasodilation by simvastatin is potentiated by combination with L-arginine in patients with elevated asymmetric dimethylarginine levels [abstract]. J Am Coll Cardiol 43 (Suppl): 525A

    Article  Google Scholar 

  46. Zoccali C et al. (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358: 2113–2117

    Article  CAS  Google Scholar 

  47. Berkowitz DE et al. (2003) Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 108: 2000–2006

    Article  CAS  Google Scholar 

  48. Vallance P and Leiper J (2004) Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 24: 1023–1030

    Article  CAS  Google Scholar 

  49. Cooke JP et al. (1992) Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest 90: 1168–1172

    Article  CAS  Google Scholar 

  50. Boger RH et al. (1995) Supplementation of hypercholesterolemic rabbits with L-arginine reduces vascular release of superoxide anions and restores NO production. Atherosclerosis 117: 273–284

    Article  CAS  Google Scholar 

  51. Böger RH et al. (1997) Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin. Circulation 96: 1282–1290

    Article  Google Scholar 

  52. Wang BY et al. (1994) Dietary arginine prevents atherogenesis in the coronary artery of hypercholesterolemic rabbits. J Am Coll Cardiol 23: 452–458

    Article  CAS  Google Scholar 

  53. Davies MG et al. (1999) Combination therapy of cholesterol reduction and L-arginine supplementation controls accelerated vein graft atheroma. Ann Vasc Surg 13: 484–493

    Article  CAS  Google Scholar 

  54. Hutchison SJ et al. (1999) Effects of L-arginine on atherogenesis and endothelial dysfunction due to secondhand smoke. Hypertension 34: 44–50

    Article  CAS  Google Scholar 

  55. Le Tourneau T et al. (1999) Role of NO in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling. J Am Coll Cardiol 33: 876–882

    Article  CAS  Google Scholar 

  56. Corseaux D et al. (1998) Enhanced monocyte tissue factor response after experimental balloon angioplasty in hypercholesterolemic rabbits: inhibition with L-arginine. Circulation 98: 1779–1782

    Article  Google Scholar 

  57. Girerd XJ et al. (1990) L-arginine augments endothelium-dependent vasodilation in cholesterol-fed rabbits. Circ Res 67: 1301–1308

    Article  CAS  Google Scholar 

  58. Wang BY et al. (1996) Arginine restores nitric oxide activity and inhibits monocyte accumulation after vascular injury in hypercholesterolemic rabbits. J Am Coll Cardiol 28: 1573–1579

    Article  CAS  Google Scholar 

  59. Boger RH et al. (1998) Dietary L-arginine and alpha-tocopherol reduce vascular oxidative stress and preserve endothelial function in hypercholesterolemic rabbits via different mechanisms. Atherosclerosis 141: 31–4355

    Article  CAS  Google Scholar 

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Acknowledgements

D Tousoulis and RH Böger contributed equally to this work.

Author information

Authors and Affiliations

  1. D Tousoulis is Assistant Professor at the Hippokration Hospital, University of Athens, Athens, Greece.,

    Dimitris Tousoulis

  2. RH Böger is Professor of Clinical Pharmacology and Head of the Clinical Pharmacology Unit at the Institute of Experimental and Clinical Pharmacology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,

    Rainer H Böger

  3. C Antoniades is a Postdoctoral Research Fellow in the Department of Cardiovascular Medicine at the University of Oxford, Oxford, UK.,

    Charalambos Antoniades

  4. Vice-President of Athens University Medical School and Head of the First Department of Cardiology, G Siasos and E Stefanadi are both Research Fellows and C Stefanadis is Professor of Cardiology, at the Athens University Medical School, Athens, Greece.,

    Gerasimos Siasos, Elli Stefanadi & Christodoulos Stefanadis

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  1. Dimitris Tousoulis
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Correspondence to Dimitris Tousoulis.

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Tousoulis, D., Böger, R., Antoniades, C. et al. Mechanisms of Disease: L-arginine in coronary atherosclerosis—a clinical perspective. Nat Rev Cardiol 4, 274–283 (2007). https://doi.org/10.1038/ncpcardio0878

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