[Frontiers in Bioscience, Elite, 7, 417-422, June 1, 2015]

Physical exercise reduces synthesis of ADMA, SDMA, and L-Arg

Graziano Riccioni 1 , Luca Scotti 2 , Maria Teresa Guagnano 3 , Gabriella Bosco 3 , Valentina Bucciarelli 2 , Emanuela Di Ilio 2 , Lorenza Speranza 3 , Filippo Martini 2 , Tonino Bucciarelli 2

1Cardiology Care Unit, San Camillo de Lellis Hospital, Manfredonia, Foggia, Italy, 2Clinical Biochemistry, Department of Biomedical Science, G. D’Annunzio, University of Chieti, Italy, 3Department of Internal Medicine and Aging Science, University G. D’Annunzio, Chieti, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
    2.1. Study design
    2.2. Patients
    2.3. Sample collection, storage and preparation
    2.4. Biochemical analysis
    2.5. Physical exercise
    2.6. Statistical analysis
3. Results
    3.1. Characteristic of subjects
4. Discussion
5. References

1. ABSTRACT

Increased levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and low plasma level of L-arginine (L-ARG) are all conditions likely to decrease nitric oxide (NO) production. Aim of this study is to evaluate ADMA, SDMA, and L-ARG plasmatic levels before and after physical exercise in patients with coronary artery disease (CAD). We studied 30 patient with mean age 52 ± 4.5 years. After inclusion in the study, before the execution of physical exercise, heparinized blood sample was drawn from an indwelling arterial line for determination of ADMA, L-ARG and SDMA (baseline values). Subsequently a blood sample was drawn after the physical exercise. The mean plasma concentrations of ADMA (0.68 0.06 vs 0.48 ± 0.05 mol/L) and SDMA (0.45 ± 0.03 vs 0.30 ± 0.03 ýmol/L) were significantly lower after physical exercise in comparison to baseline value, while L-ARG mean levels were increased (44.20 ± 10.5 vs 74.13 ± 11.2 ýmol/L). Physical exercise has a beneficial effect by reducing plasmatic ADMA and SDMA levels, and increasing L-ARG substrate for endothelial NO.

5. REFERENCES

1. T Heitzer, T Schlinzig, K Krohn, T Meinertz, T Munzel: Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104, 2673–2678 (2001)
Doi: 10.1161/hc4601.099485
PMid:11723017

2. S Moncada, EA Higgs: The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 147, 193. 201 (2006)

3. D Tousoulis, AM Kampoli, C Tentolouris, N Papageorgiou, C Stefanadis: The role of nitric oxide on endothelial function. Curr Vasc Pharmacol 10, 4. 18 (2012)

4. S Blackwell: The biochemistry, measurement and current clinical significance of asymmetric dimethylarginine. Ann Clin Biochem 47, 17. 28 (2010)

5. P Vallance: Importance of asymmetrical dimethylarginine in cardiovascular risk. Lancet 358, 2096–2097 (2001)
Doi: 10.1016/S0140-6736(01)07229-4

6. RH Boger, LM Sullivan, E Schwedhelm, TJ Wang, R Maas, EJ Benjamin, F Schulze, V Xanthakis, RA Benndorf, RS Vasan: Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community. Circulation 119, 1592. 1600 (2009)

7. K Hanai, T Babazono, I Nyumura, K Toya, N Tanaka, M Tanaka, A Ishii, Y Iwamoto: Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant 24, 1884 – 1888 (2008)
Doi: 10.1093/ndt/gfn716
PMid:19131352

8. RH Böger, R Maas, F Schulze, E Schwedhelm: Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality.. an update on patient populations with a wide range of cardiovascular risk. Pharmacol Res 60, 481. 487 (2009)

9. TM Lu, YA Ding, SJ Lin, WS Lee, HC Tai: Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 24, 1912–1919 (2003)
Doi: 10.1016/j.ehj.2003.08.013 PMid:14585249

10. RJ Shephard, GJ Balady: Exercise as cardiovascular therapy. Circulation 99, 963–972 (1999)
Doi: 10.1161/01.CIR.99.7.963

11. S Gielen, G Schuler, V Adams: Cardiovascular effects of exercise training: molecular mechanisms. Circulation 122, 1221. 1238 (2010)

12. P Kokkinos, J Myers, JP Kokkinos, A Pittaras, P Narayan, A Manolis, P Karasik, M Greenberg, V Papademetriou, S Singh, Exercise capacity and mortality in black and white men. Circulation 117, 614–622 (2008)
Doi: 10.1161/CIRCULATIONAHA.107.734764 PMid:18212278

13. JE Manson, P Greenland, AZ LaCroix, ML Stefanick, CP Mouton, A Oberman, MG Perri, DS Sheps, M Pettinger, DS Siscovick: Walking compared with vigorous exercise for the prevention of cardiovascular events in women. N Engl J Med 347, 716–725 (2002)
Doi: 10.1056/NEJMoa021067 PMid:12213942

14. T Teerlink, RJ Nijveldt, S de Jong, PA van Leeuwen: Determination of Arginine, Asymmetric Dimethylarginine, and Symmetric Dimethylarginine in Human Plasma and Other Biological Samples by High. Performance Liquid Chromatography. Anal Biochem 303, 131–137 (2002)
Doi: 10.1006/abio.2001.5575
PMid:11950212

15. BJ Maron, PD Thompson, MJ Ackerman, G Balady, S Berger, D Cohen, R Dimeff, PS Douglas, DH Glover, AM Hutter, MD Jr., Krauss, MS Maron, MJ Mitten, WO Roberts, JC Puffer: American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Recommendations and considerations related to pre. participation screening for cardiovascular abnormalities in competitive athletes: 2007 update: a scientific statement from the American Heart Association 16. Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 115, 1643. 1455 (2007)

16. PD Thompson, D Buchner, IL Pina, GJ Balady, MA Williams, BH Marcus, K Berra, SN Blair, F Costa, B Franklin, GF Fletcher, NF Gordon, RR Pate, BL Rodriguez, AK Yancey, NK Wenger, American Heart Association Council on Clinical Cardiology Subcommittee on Exercise, Rehabilitation, and Prevention, American Heart Association Council on Nutrition, Physical Activity, and Metabolism Subcommittee on Physical Activity. Exercise and physical activity in the prevention an treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity) Circulation 107, 3109. 3116 (2003)

17. N Jairath: Implications of gender differences on coronary artery disease risk reduction in women. AACN Clin Issues 12, 17. 28 (2001)

18. EB Beck, S Erbs, S Möbius. Winkler, V Adams, FJ Woitek, T Walther, R Hambrecht, FW Mohr, M Stumvoll, M Blüher, G Schuler, A Linke: Exercise training restores the endothelial response to vascular growth factors in patients with stable coronary artery disease. Eur J Prev Cardiol Rehabil 19, 412. 418 (2012)

19. HS Dod, R Bhardwaj, V Sajja, G Weidner, GR Hobbs, GW Konat, S Manivannan, W Sharib, BE Warden, NC Nanda, BJ Beto, D Ornish, AC Jain: Effect of intensive lifestyle changes on endothelial function and on inflammatory markers of atherosclerosis. Am J Cardiol 105, 362. 367 (2010)

20. MH Laughlin, DK Bowles, DJ Duncker: The coronary circulation in exercise training. Am J Physiol Heart Circ Physiol 302, 10. 23 (2010)

21. C Walther, S Gielen, R Hambrecht: The effect of exercise training on endothelial function in cardiovascular disease in humans. Exerc Sport Sci Rev 32, 129. 134 (2004)

22. S Möbius. Winkler, A Linke, V Adams, G Schuler, S Erbs: How to improve endothelial repair mechanisms: the lifestyle approach. Exp Rev Cardiovasc Ther 8, 573. 580 (2010)

23. Djordjevic, D., Jakovljevic, V., Cubrilo. D., Zlatkovic, M., Zivkovic, V., Djuric, D. : Coordination between nitric oxide and superoxide anion radical during progressive exercise in elite soccer players. Open. Biochem. J. 2010, 4, 100. 1006.

24. F Ribeiro, AJ Alves, JA Duarte, J Oliveira: Is exercise training an effective therapy targeting endothelial dysfunction and vascular wall inflammation? Int J Cardiol 141, 214. 221 (2010)

25. H Matsuoka, S Itoh, M Kimoto, K Kohno, O Tamai, Y Wada, H Yasukawa, G Iwami, S Okuda, T Imaizumi: Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension. Hypertension 29, 242–247 (1997)
Doi: 10.1161/01.HYP.29.1.242
PMid:9039109

26. H Miyazaki, H Matsuoka, JP Cooke, M Usui, S Ueda, S Okuda, T Imaizumi: Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 99, 1141–1146 (1999)
Doi: 10.1161/01.CIR.99.9.1141
PMid:10069780

27. A Pandolfi, A Grilli, C Cilli, A Patruno, A Giaccari, S Di Silvestre, MA De Lutiis, G Pellegrini, F Capani, A Consoli, M Felaco: Phenotype modulation in cultures of vascular smooth muscle cells from diabetic rats: association with increased nitric oxide synthase expression and superoxide anion generation. J Cell Physiol 196, 378. 385 (2003)

28. JJ Whyte, MH Laughlin: The effects of acute and chronic exercise on the vasculature. Acta Physiol 199, 441. 450 (2010)

29. DA Leaf, MT Kleinman, M Hamilton, RW Deitrick: The exercise. induced oxidative stress paradox: the effects of physical exercise training. Am J Med Sci 317, 295. 300 (1999)

30. AJ Cardounel, Y Xia, JL Zweier: Different effects of endogenous nitric oxide synthase inhibitors on nitric oxide and superoxide production. Circulation 102, II. 117 (2000)

31. N Sen, MF Ozlu, EO Akgul, S Kanat, T Cayci, O Turak, H Yaman, E Sokmen, F Ozcan, O Maden, AD Demir, A Covic, M Kanbay: Elevated plasma asymmetric dimethylarginine level in acute myocardial infarction patients as a predictor of poor prognosis and angiographic impaired reperfusion. Atherosclerosis 219, 304. 310 (2011)

32. L Sibal, SC Agarwal, PD Home, RH Boger: The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease. Curr Cardiol Rev 6, 82. 90 (2010)

33. J Leiper, P Vallance: Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 43, 542. 548 (1999)

34. E Schepers, G Glorieux, A Dhondt, L Leybaert, R Vanholder: Role of symmetric dimethylarginine in vascular damage by increasing ROS via store. operated calcium influx in monocytes. Nephrol Dial Transplant 24, 1429. 1435 (2009)

35. G Riccioni, L Speranza, L Scotti, V Bucciarelli, E Di Ilio, N D’Orazio, M Pesce, A Aceto, V Sorrenti, A Frigiola, T Bucciarelli: The effect of pharmacological treatment on ADMA in patients with heart failure. Front Biosci 3, 1310. 1314 (2011)

36. G Riccioni, V Bucciarelli, L Scotti, A Aceto, N D’Orazio, E Di Ilio, T Bucciarelli: Relationship between asymmetric dimethylarginine and asymptomatic carotid atherosclerosis. J Biol Regul Homeost Agents 24, 351. 358 (2010)

37. JT Kielstein, C Zoccali: Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis 46, 186. 202. (2005)

38. P Vallance, A Leone, A Calver, J Collier, S Moncada: Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339, 572–575 (1992)
Doi: 10.1016/0140-6736(92)90865-Z

39. C Fleck, F Schweitzer, E Karge, M Busch, G Stein: Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in patients with chronic kidney diseases. Clin Chim Acta 336, 1. 12 (2003)

Key Words: ADMA, SDMA L-arginine, Nitric Oxide; Coronary Artery Disease, Physical Exercise

Send correspondence to: Graziano Riccioni, Intensive Cardiology Care Unit, San Camillo de Lellis Hospital, 71043 Manfredonia, Foggia, Italy, Tel: 39-0884-510470, Fax: 39-0882-227022, E-mail: griccionI@hotmail.com