Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication

American Journal of Physiology - Heart and Circulatory Physiology

Volumn 309, Issue 5, 2015, Pages H897-H905

  Da Silva, Natan D ^a   Roseguini, Bruno T ^b   Chehuen, Marcel ^a   Fernandes, Tiago ^a   Mota, Glória F ^a   Martin, Priscila K M ^c   Han, Sang W ^c   Forjaz, Cláudia L M ^a   Wolosker, Nelson ^a   De Oliveira, Edilamar M ^a  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b PURDUE UNIVERSITY   (United States)

^c FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Blood flow; Intermittent claudication; microRNA 126; microRNAs; N acetylcysteine

Indexed keywords

ACETYLCYSTEINE; ANGIOGENIC FACTOR; BIOLOGICAL MARKER; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENDOTHELIN 1; GLUTATHIONE DISULFIDE; MESSENGER RNA; MICRORNA; MICRORNA 126; MONOCYTE CHEMOTACTIC PROTEIN 1; PHOSPHATIDYLINOSITOL 3 KINASE; VASCULAR CELL ADHESION MOLECULE 1; ANTIOXIDANT; CCL2 PROTEIN, HUMAN; ENDOTHELIN; MIRN126 MICRORNA, HUMAN; VASCULOTROPIN A;

ADULT; ARTICLE; CLINICAL ARTICLE; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFECT; ENDOTHELIAL DYSFUNCTION; HEMODYNAMICS; HUMAN; HYPEREMIA; INFLAMMATION; INTERMITTENT CLAUDICATION; LEG BLOOD FLOW; MALE; MEDIATOR RELEASE; MIDDLE AGED; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL; TREADMILL EXERCISE; WALKING; AGED; BLOOD; LEG; ORAL DRUG ADMINISTRATION; VASCULARIZATION;

ACETYLCYSTEINE; ADMINISTRATION, ORAL; AGED; ANTIOXIDANTS; CHEMOKINE CCL2; ENDOTHELINS; HUMANS; HYPEREMIA; INFLAMMATION; INTERMITTENT CLAUDICATION; LEG; MALE; MICRORNAS; MIDDLE AGED; NITRIC OXIDE SYNTHASE TYPE III; PHOSPHATIDYLINOSITOL 3-KINASES; VASCULAR CELL ADHESION MOLECULE-1; VASCULAR ENDOTHELIAL GROWTH FACTOR A; WALKING;

EID: 84940728700     PISSN: 03636135     EISSN: 15221539     Source Type: Journal    
DOI: 10.1152/ajpheart.00158.2015     Document Type: Article

References (66)

1. Arosio E, De Marchi S, Zannoni M, Prior M, Lechi A. Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 77: 754–759, 2002.
2. Basic VT, Jacobsen A, Sirsjo A, Abdel-Halim SM. TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes. Int J Mol Med 34: 228–236, 2014.
3. Borgstrom L, Kagedal B. Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man. Biopharm Drug Dispos 11: 131–136, 1990.
4. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol 31: 217–222, 1986.
5. Brass EP. Intermittent claudication: new targets for drug development. Drugs 73: 999–1014, 2013.
6. Brevetti G, Giugliano G, Brevetti L, Hiatt WR. Inflammation in peripheral artery disease. Circulation 122: 1862–1875, 2010.
7. Brevetti G, Piscione F, Cirillo P, Galasso G, Schiano V, Barbato E, Scopacasa F, Chiariello M. In concomitant coronary and peripheral arterial disease, inflammation of the affected limbs predicts coronary artery endothelial dysfunction. Atherosclerosis 201: 440–446, 2008.
8. Brevetti G, Silvestro A, Di Giacomo S, Bucur R, Di Donato A, Schiano V, Scopacasa F. Endothelial dysfunction in peripheral arterial disease is related to increase in plasma markers of inflammation and severity of peripheral circulatory impairment but not to classic risk factors and atherosclerotic burden. J Vasc Surg 38: 374–379, 2003.
9. Camuglia AC, Maeder MT, Starr J, Farrington C, Kaye DM. Impact of N-acetylcysteine on endothelial function, B-type natriuretic peptide and renal function in patients with the cardiorenal syndrome: a pilot cross over randomised controlled trial. Heart Lung Circ 22: 256–259, 2013.
10. Corn SD, Barstow TJ. Effects of oral N-acetylcysteine on fatigue, critical power, and W= in exercising humans. Respir Physiol Neurobiol 178: 261–268, 2011.
11. Crecelius AR, Richards JC, Luckasen GJ, Larson DG, Dinenno FA. Reactive hyperemia occurs via activation of inwardly rectifying potassium channels and Na+//K+-ATPase in humans. Circ Res 113: 1023–1032, 2013.
12. Dekhuijzen PN. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 23: 629–636, 2004.
13. Delaney CL, Miller MD, Chataway TK, Spark JI. A randomised controlled trial of supervised exercise regimens and their impact on walking performance, skeletal muscle mass and calpain activity in patients with intermittent claudication. Eur J Vasc Endovasc Surg 47: 304–310, 2014.
14. Duscha BD, Robbins JL, Jones WS, Kraus WE, Lye RJ, Sanders JM, Allen JD, Regensteiner JG, Hiatt WR, Annex BH. Angiogenesis in skeletal muscle precede improvements in peak oxygen uptake in peripheral artery disease patients. Arterioscler Thromb Vasc Biol 31: 2742–2748, 2011.
15. Ferreira LF, Campbell KS, Reid MB. N-acetylcysteine in handgrip exercise: plasma thiols and adverse reactions. Int J Sport Nutr Exerc Metab 21: 146–154, 2011.
16. Ferreira LF, Reid MB. Muscle-derived ROS and thiol regulation in muscle fatigue. J Appl Physiol 104: 853–860, 2008.
17. Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY, Srivastava D. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 15: 272–284, 2008.
18. Fish JE, Srivastava D. MicroRNAs: opening a new vein in angiogenesis research. Sci Signal 2: pe1, 2009.
19. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 382: 1329–1340, 2013.
20. Gardner AW, Parker DE, Montgomery PS, Sosnowska D, Casanegra AI, Ungvari Z, Csiszar A, Sonntag WE. Greater endothelial apoptosis and oxidative stress in patients with peripheral artery disease. Int J Vasc Med 2014: 160534, 2014.
21. Gliemann L, Olesen J, Bienso RS, Schmidt JF, Akerstrom T, Nyberg M, Lindqvist A, Bangsbo J, Hellsten Y. Resveratrol modulates the angiogenic response to exercise training in skeletal muscles of aged men. Am J Physiol Heart Circ Physiol 307: H1111–H1119, 2014.
22. Goligorsky MS. Microvascular rarefaction: the decline and fall of blood vessels. Organogenesis 6: 1–10, 2010.
23. Gomez-Cabrera MC, Domenech E, Romagnoli M, Arduini A, Borras C, Pallardo FV, Sastre J, Vina J. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr 87: 142–149, 2008.
24. Hiatt WR, Regensteiner JG, Wolfel EE, Carry MR, Brass EP. Effect of exercise training on skeletal muscle histology and metabolism in peripheral arterial disease. J Appl Physiol 81: 780–788, 1996.
25. Hiatt WR, Rogers RK, Brass EP. The treadmill is a better functional test than the 6-minute walk test in therapeutic trials of patients with peripheral artery disease. Circulation 130: 69–78, 2014.
26. Koechlin C, Couillard A, Simar D, Cristol JP, Bellet H, Hayot M, Prefaut C. Does oxidative stress alter quadriceps endurance in chronic obstructive pulmonary disease? Am J Respir Crit Care Med 169: 1022–1027, 2004.
27. Lane R, Ellis B, Watson L, Leng GC. Exercise for intermittent claudication. Cochrane Database Syst Rev 7: CD000990, 2014.
28. Mangiafico RA, Malatino LS, Spada RS, Santonocito M, Messina R, Dell’Arte S, Attina T. Treadmill exercise-induced release of endothelin-1 in patients with peripheral arterial occlusive disease at Fontaine stage IIb. Int Angiol 19: 14–17, 2000.
29. Matuszczak Y, Farid M, Jones J, Lansdowne S, Smith MA, Taylor AA, Reid MB. Effects of N-acetylcysteine on glutathione oxidation and fatigue during handgrip exercise. Muscle Nerve 32: 633–638, 2005.
30. McDermott MM, Ferrucci L, Liu K, Criqui MH, Greenland P, Green D, Guralnik JM, Ridker PM, Taylor LM, Rifai N, Tian L, Zheng J, Pearce WH, Schneider JR, Vonesh E. D-dimer and inflammatory markers as predictors of functional decline in men and women with and without peripheral arterial disease. J Am Geriatr Soc 53: 1688–1696, 2005.
31. McDermott MM, Greenland P, Green D, Guralnik JM, Criqui MH, Liu K, Chan C, Pearce WH, Taylor L, Ridker PM, Schneider JR, Martin G, Rifai N, Quann M, Fornage M. D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease. Circulation 107: 3191–3198, 2003.
32. McDermott MM, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, Chan C, Martin GJ, Schneider J, Pearce WH, Taylor LM, Clark E. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern Med 136: 873–883, 2002.
33. McDermott MM, Liu K, Greenland P, Guralnik JM, Criqui MH, Chan C, Pearce WH, Schneider JR, Ferrucci L, Celic L, Taylor LM, Vonesh E, Martin GJ, Clark E. Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. JAMA 292: 453–461, 2004.
34. McKenna MJ, Medved I, Goodman CA, Brown MJ, Bjorksten AR, Murphy KT, Petersen AC, Sostaric S, Gong X. N-acetylcysteine attenuates the decline in muscle Na+,K+-pump activity and delays fatigue during prolonged exercise in humans. J Physiol 576: 279–288, 2006.
35. Medved I, Brown MJ, Bjorksten AR, Murphy KT, Petersen AC, Sostaric S, Gong X, McKenna MJ. N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals. J Appl Physiol 97: 1477–1485, 2004.
36. Michailidis Y, Karagounis LG, Terzis G, Jamurtas AZ, Spengos K, Tsoukas D, Chatzinikolaou A, Mandalidis D, Stefanetti RJ, Papassotiriou I, Athanasopoulos S, Hawley JA, Russell AP, Fatouros IG. Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise. Am J Clin Nutr 98: 233–245, 2013.
37. Neumann FJ, Waas W, Diehm C, Weiss T, Haupt HM, Zimmermann R, Tillmanns H, Kubler W. Activation and decreased deformability of neutrophils after intermittent claudication. Circulation 82: 922–929, 1990.
38. Olamaei N, Dupuis J, Ngo Q, Finnerty V, Vo Thang TT, Authier S, Khairy P, Harel F. Characterization and reproducibility of forearm arterial flow during reactive hyperemia. Physiol Meas 31: 763–773, 2010.
39. Pande RL, Brown J, Buck S, Redline W, Doyle J, Plutzky J, Creager MA. Association of monocyte tumor necrosis factor alpha expression and serum inflammatory biomarkers with walking impairment in peripheral artery disease. J Vasc Surg 61: 155–161, 2015.
40. Pande RL, Hiatt WR, Zhang P, Hittel N, Creager MA. A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication. Vasc Med 15: 181–188, 2010.
41. Paulsen G, Cumming KT, Holden G, Hallen J, Ronnestad BR, Sveen O, Skaug A, Paur I, Bastani NE, Ostgaard HN, Buer C, Midttun M, Freuchen F, Wiig H, Ulseth ET, Garthe I, Blomhoff R, Benestad HB, Raastad T. Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial. J Physiol 592: 1887–1901, 2014.
42. Pendyala L, Creaven PJ. Pharmacokinetic and pharmacodynamic studies of N-acetylcysteine, a potential chemopreventive agent during a phase I trial. Cancer Epidemiol Biomarkers Prev 4: 245–251, 1995.
43. Petersen AC, McKenna MJ, Medved I, Murphy KT, Brown MJ, Della Gatta P, Cameron-Smith D. Infusion with the antioxidant N-acetylcysteine attenuates early adaptive responses to exercise in human skeletal muscle. Acta Physiol (Oxf) 204: 382–392, 2012.
44. Pipinos II, Judge AR, Selsby JT, Zhu Z, Swanson SA, Nella AA, Dodd SL. The myopathy of peripheral arterial occlusive disease. Part 2. Oxidative stress, neuropathy, and shift in muscle fiber type. Vasc Endovascular Surg 42: 101–112, 2008.
45. Pipinos II, Judge AR, Zhu Z, Selsby JT, Swanson SA, Johanning JM, Baxter BT, Lynch TG, Dodd SL. Mitochondrial defects and oxidative damage in patients with peripheral arterial disease. Free Radic Biol Med 41: 262–269, 2006.
46. Regensteiner JG. Exercise rehabilitation for the patient with intermittent claudication: a highly effective yet underutilized treatment. Curr Drug Targets Cardiovasc Haematol Disord 4: 233–239, 2004.
47. Reid MB, Stokic DS, Koch SM, Khawli FA, Leis AA. N-acetylcysteine inhibits muscle fatigue in humans. J Clin Invest 94: 2468–2474, 1994.
48. Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Bluher M. Antioxidants prevent healthpromoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 106: 8665–8670, 2009.
49. Roseguini BT, Silva LM, Polotow TG, Barros MP, Souccar C, Han SW. Effects of N-acetylcysteine on skeletal muscle structure and function in a mouse model of peripheral arterial insufficiency. J Vasc Surg 61: 777–786, 2015.
50. Sahin G, Yalcin AU, Akcar N. Effect of N-acetylcysteine on endothelial dysfunction in dialysis patients. Blood Purif 25: 309–315, 2007.
51. Sampson UK, Fowkes FG, McDermott MM, Criqui MH, Aboyans V, Norman PE, Forouzanfar MH, Naghavi M, Song Y, Harrell FE Jr, Denenberg JO, Mensah GA, Ezzati M, Murray C. Global and regional burden of death and disability from peripheral artery disease: 21 world regions, 1990 to 2010. Glob Heart 9: 145–158, 2014.
52. Sanada H, Higashi Y, Goto C, Chayama K, Yoshizumi M, Sueda T. Vascular function in patients with lower extremity peripheral arterial disease: a comparison of functions in upper and lower extremities. Atherosclerosis 178: 179–185, 2005.
53. Sen CK. Glutathione homeostasis in response to exercise training and nutritional supplements. Mol Cell Biochem 196: 31–42, 1999.
54. Signorelli SS, Mazzarino MC, Di Pino L, Malaponte G, Porto C, Pennisi G, Marchese G, Costa MP, Digrandi D, Celotta G, Virgilio V. High circulating levels of cytokines (IL-6 and TNFalpha), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test. Vasc Med 8: 15–19, 2003.
55. Silveira LR, Pilegaard H, Kusuhara K, Curi R, Hellsten Y. The contraction induced increase in gene expression of peroxisome proliferator- activated receptor (PPAR)-gamma coactivator 1alpha (PGC-1alpha), mitochondrial uncoupling protein 3 (UCP3) and hexokinase II (HKII) in primary rat skeletal muscle cells is dependent on reactive oxygen species. Biochim Biophys Acta 1763: 969–976, 2006.
56. Silvestro A, Schiano V, Bucur R, Brevetti G, Scopacasa F, Chiariello M. Effect of propionylcarnitine on changes in endothelial function and plasma levels of adhesion molecules induced by acute exercise in patients with intermittent claudication. Angiology 57: 145–154, 2006.
57. Silvestro A, Scopacasa F, Oliva G, de Cristofaro T, Iuliano L, Brevetti G. Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication. Atherosclerosis 165: 277–283, 2002.
58. Slattery KM, Dascombe B, Wallace LK, Bentley DJ, Coutts AJ. Effect of N-acetylcysteine on cycling performance after intensified training. Med Sci Sports Exerc 46: 1114–1123, 2014.
59. Stather PW, Sylvius N, Wild JB, Choke E, Sayers RD, Bown MJ. Differential microRNA expression profiles in peripheral arterial disease. Circ Cardiovasc Genet 6: 490–497, 2013.
60. Tisi PV, Shearman CP. Biochemical and inflammatory changes in the exercising claudicant. Vasc Med 3: 189–198, 1998.
61. Turton EP, Coughlin PA, Kester RC, Scott DJ. Exercise training reduces the acute inflammatory response associated with claudication. Eur J Vasc Endovasc Surg 23: 309–316, 2002.
62. Ungvari Z, Tucsek Z, Sosnowska D, Toth P, Gautam T, Podlutsky A, Csiszar A, Losonczy G, Valcarcel-Ares MN, Sonntag WE, Csiszar A. Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 68: 877–891, 2013.
63. Wagner PD. The critical role of VEGF in skeletal muscle angiogenesis and blood flow. Biochem Soc Trans 39: 1556–1559, 2011.
64. Wilkinson IB, Webb DJ. Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications. Br J Clin Pharmacol 52: 631–646, 2001.
65. Wolosker N, Nakano L, Rosoky RA, Puech-Leao P. Evaluation of walking capacity over time in 500 patients with intermittent claudication who underwent clinical treatment. Arch Intern Med 163: 2296–2300, 2003.
66. Wolosker N, Rosoky RA, Nakano L, Basyches M, Puech-Leao P. Predictive value of the ankle-brachial index in the evaluation of intermittent claudication. Rev Hosp Clin Fac Med Sao Paulo 55: 61–64, 2000.