Sildenafil improves skeletal muscle oxygenation during exercise in men with intermittent claudication

American Journal of Physiology - Regulatory Integrative and Comparative Physiology

Volumn 307, Issue 4, 2014, Pages

  Roseguini, Bruno T ^a   Hirai, Daniel M ^a   Alencar, Maria C ^a   Ramos, Roberta P ^a   Silva, Bruno M ^a   Wolosker, Nelson ^b   Neder, J Alberto ^a,c   Nery, Luiz E ^a  

^a FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

^b UNIVERSITY OF SÃO PAULO   (Brazil)

^c KINGSTON GENERAL HOSPITAL   (Canada)

Author keywords

Blood flow; Exercise; Intermittent claudication; Sildenafil

Indexed keywords

ANGIOTENSIN 2 RECEPTOR ANTAGONIST; ANTITHROMBOCYTIC AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CALCIUM CHANNEL BLOCKING AGENT; CARBON DIOXIDE; CYCLIC GMP; DEOXYHEMOGLOBIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIURETIC AGENT; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MYOGLOBIN; PLACEBO; SILDENAFIL;

ABSENCE OF SIDE EFFECTS; ADULT; AGED; ARTICLE; BLOOD PRESSURE; CLINICAL ARTICLE; CONTROLLED STUDY; CROSSOVER PROCEDURE; DEOXYGENATION; DIASTOLIC BLOOD PRESSURE; DOUBLE BLIND PROCEDURE; GAS EXCHANGE; GASTROCNEMIUS MUSCLE; HUMAN; HUMAN TISSUE; INTERMITTENT CLAUDICATION; MALE; NEAR INFRARED SPECTROSCOPY; OXYGENATION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SKELETAL MUSCLE; SYSTOLIC BLOOD PRESSURE; TREADMILL EXERCISE; VASCULAR SMOOTH MUSCLE; WALKING;

BLOOD FLOW; EXERCISE; INTERMITTENT CLAUDICATION; SILDENAFIL;

AGED; BIOLOGICAL MARKERS; BLOOD PRESSURE; BRAZIL; CROSS-OVER STUDIES; DOUBLE-BLIND METHOD; EXERCISE TEST; EXERCISE TOLERANCE; HEMOGLOBINS; HUMANS; INTERMITTENT CLAUDICATION; LOWER EXTREMITY; MALE; MIDDLE AGED; MUSCLE, SKELETAL; OXYGEN; OXYGEN CONSUMPTION; PHOSPHODIESTERASE 5 INHIBITORS; PIPERAZINES; PURINES; RECOVERY OF FUNCTION; SPECTROSCOPY, NEAR-INFRARED; SULFONES; TIME FACTORS; TREATMENT OUTCOME; VASODILATOR AGENTS; WALKING;

EID: 84907677038     PISSN: 03636119     EISSN: 15221490     Source Type: Journal    
DOI: 10.1152/ajpregu.00183.2014     Document Type: Article

References (64)

1. Allen JD, Giordano T, Kevil CG. Nitrite and nitric oxide metabolism in peripheral artery disease. Nitric Oxide Biol Chem 26: 217-222, 2012.
2. Anderson JD, Epstein FH, Meyer CH, Hagspiel KD, Wang H, Berr SS, Harthun NL, Weltman A, Dimaria JM, West AM, Kramer CM. Multifactorial determinants of functional capacity in peripheral arterial disease: uncoupling of calf muscle perfusion and metabolism. J Am Coll Cardiol 54: 628-635, 2009.
3. Ankle Brachial Index Collaboration, Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, Chambless LE, Folsom AR, Hirsch AT, Dramaix M, deBacker G, Wautrecht JC, Kornitzer M, Newman AB, Cushman M, Sutton-Tyrrell K, Fowkes FG, Lee AJ, Price JF, d'Agostino RB, Murabito JM, Norman PE, Jamrozik K, Curb JD, Masaki KH, Rodriguez BL, Dekker JM, Bouter LM, Heine RJ, Nijpels G, Stehouwer CD, Ferrucci L, McDermott MM, Stoffers HE, Hooi JD, Knottnerus JA, Ogren M, Hedblad B, Witteman JC, Breteler MM, Hunink MG, Hofman A, Criqui MH, Langer RD, Fronek A, Hiatt WR, Hamman R, Resnick HE, Guralnik J, McDermott MM. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA 300: 197-208, 2008.
4. Armstrong DM, Armstrong Ada C, Figueiredo RC, Florentino JE, Saad PF, Fox-Talbot K, Halushka MK, Berkowitz DE, Taha MO, Fagundes DJ. Sildenafil citrate protects skeletal muscle of ischemiareperfusion injury: immunohistochemical study in rat model. Acta Cir Bras 28: 282-287, 2013.
5. Bakke EF, Hisdal J, Jorgensen JJ, Kroese A, Stranden E. Blood pressure in patients with intermittent claudication increases continuously during walking. Eur J Vasc Endovasc Surg 33: 20-25, 2007.
6. Beckitt TA, Day J, Morgan M, Lamont PM. Calf muscle oxygen saturation and the effects of supervised exercise training for intermittent claudication. J Vasc Surg 56: 470-475, 2012.
7. Boger RH, Bode-Boger SM, Thiele W, Junker W, Alexander K, Frolich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 95: 2068-2074, 1997.
8. Brass EP. Intermittent claudication: new targets for drug development. Drugs 73: 999-1014, 2013.
9. Brevetti G, Giugliano G, Brevetti L, Hiatt WR. Inflammation in peripheral artery disease. Circulation 122: 1862-1875, 2010.
10. Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM. ACC/AHA expert consensus document Use of sildenafil (Viagra) in patients with cardiovascular disease American College of Cardiology/American Heart Association. J Am Coll Cardiol 33: 273-282, 1999.
11. Comerota AJ, Throm RC, Kelly P, Jaff M. Tissue (muscle) oxygen saturation (StO2): a new measure of symptomatic lower-extremity arterial disease. J Vasc Surg 38: 724-729, 2003.
12. Dawson DL, Cutler BS, Hiatt WR, Hobson RW, Martin JD, Bortey EB, Forbes WP, Strandness DE Jr. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med 109: 523-530, 2000.
13. de Liefde II, Hoeks SE, van Gestel YR, Bax JJ, Klein J, van Domburg RT, Poldermans D. Usefulness of hypertensive blood pressure response during a single-stage exercise test to predict long-term outcome in patients with peripheral arterial disease. Am J Cardiol 102: 921-926, 2008.
14. DeLorey DS, Kowalchuk JM, Heenan AP, Dumanoir GR, Paterson DH. Prior exercise speeds pulmonary O2 uptake kinetics by increases in both local muscle O2 availability and O2 utilization. J Appl Physiol 103: 771-778, 2007.
15. 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.
16. Gardner AW, Ritti-Dias RM, Stoner JA, Montgomery PS, Scott KJ, Blevins SM. Walking economy before and after the onset of claudication pain in patients with peripheral arterial disease. J Vasc Surg 51: 628-633, 2010.
17. Grassi B, Pogliaghi S, Rampichini S, Quaresima V, Ferrari M, Marconi C, Cerretelli P. Muscle oxygenation and pulmonary gas exchange kinetics during cycling exercise on-transitions in humans. J Appl Physiol 95: 149-158, 2003.
18. Guazzi M. Sildenafil and phosphodiesterase-5 inhibitors for heart failure. Curr Heart Fail Rep 5: 110-114, 2008.
19. Guimaraes GV, d'Avila VM, Pires P, Bacal F, Stolf N, Bocchi E. Acute effects of a single dose of phosphodiesterase type 5 inhibitor (sildenafil) on systemic arterial blood pressure during exercise and 24-hour ambulatory blood pressure monitoring in heart transplant recipients. Transpl Proc 39: 3142-3149, 2007.
20. Kenjale AA, Ham KL, Stabler T, Robbins JL, Johnson JL, Vanbruggen M, Privette G, Yim E, Kraus WE, Allen JD. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol 110: 1582-1591, 2011.
21. Kloner RA. Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions. Am J Cardiol 96: 42M-46M, 2005.
22. Komiyama T, Shigematsu H, Yasuhara H, Muto T. Near-infrared spectroscopy grades the severity of intermittent claudication in diabetics more accurately than ankle pressure measurement. Br J Surg 87: 459-466, 2000.
23. Komiyama T, Shigematsu H, Yasuhara H, Muto T. An objective assessment of intermittent claudication by near-infrared spectroscopy. Eur J Vasc Surg 8: 294-296, 1994.
24. Kukreja RC. Sildenafil and cardioprotection. Curr Pharmaceut Design 19: 6842-6847, 2013.
25. Liao JK, Bettmann MA, Sandor T, Tucker JI, Coleman SM, Creager MA. Differential impairment of vasodilator responsiveness of peripheral resistance and conduit vessels in humans with atherosclerosis. Circ Res 68: 1027-1034, 1991.
26. Liu Y, Shakur Y, Kambayashi J. Phosphodiesterases as targets for intermittent claudication. Handb Exp Pharmacol 204: 211-236, 2011.
27. McCully KK, Halber C, Posner JD. Exercise-induced changes in oxygen saturation in the calf muscles of elderly subjects with peripheral vascular disease. J Gerontol 49: B128-B134, 1994.
28. McDermott MM. Functional impairment in peripheral artery disease and how to improve it in 2013. Curr Cardiol Rep 15: 347, 2013.
29. McDermott MM, Greenland P, Liu K, Guralnik JM, Criqui MH, Dolan NC, Chan C, Celic L, Pearce WH, Schneider JR, Sharma L, Clark E, Gibson D, Martin GJ. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA 286: 1599-1606, 2001.
30. McDermott MM, Liu K, Ferrucci L, Tian L, Guralnik JM, Liao Y, Criqui MH. Decline in functional performance predicts later increased mobility loss and mortality in peripheral arterial disease. J Am Coll Cardiol 57: 962-970, 2011.
31. 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.
32. Muller MD, Drew RC, Blaha CA, Mast JL, Cui J, Reed AB, Sinoway LI. Oxidative stress contributes to the augmented exercise pressor reflex in peripheral arterial disease patients. J Physiol 590: 6237-6246, 2012.
33. 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.
34. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Brit J Clin Pharmacol 53 Suppl 1: 5S-12S, 2002.
35. Oliver JJ, Hughes VE, Dear JW, Webb DJ. Clinical potential of combined organic nitrate and phosphodiesterase type 5 inhibitor in treatment-resistant hypertension. Hypertension 56: 62-67, 2010.
36. Oliver JJ, Melville VP, Webb DJ. Effect of regular phosphodiesterase type 5 inhibition in hypertension. Hypertension 48: 622-627, 2006.
37. Percival JM, Adamo CM, Beavo JA, Froehner SC. Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy. Handb Exp Pharmacol 204: 323-344, 2011.
38. Percival JM, Whitehead NP, Adams ME, Adamo CM, Beavo JA, Froehner SC. Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy. J Pathol 228: 77-87, 2012.
39. Pipinos II, Judge AR, Selsby JT, Zhu Z, Swanson SA, Nella AA, Dodd SL. The myopathy of peripheral arterial occlusive disease: part 1. Functional and histomorphological changes and evidence for mitochondrial dysfunction. Vasc Endovascular Surg 41: 481-489, 2007.
40. 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.
41. Pollak AW, Meyer CH, Epstein FH, Jiji RS, Hunter JR, Dimaria JM, Christopher JM, Kramer CM. Arterial spin labeling MR imaging reproducibly measures peak-exercise calf muscle perfusion: a study in patients with peripheral arterial disease and healthy volunteers. JACC Cardiovasc Imag 5: 1224-1230, 2012.
42. Reffelmann T, Kloner RA. Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease. Circulation 108: 239-244, 2003.
43. Rosoky RM, Wolosker N, Puech-Leao P. Performance of patients with intermittent claudication undergoing physical training, with or without an aggravation of arterial disease: retrospective cohort study. Clinics 61: 535-538, 2006.
44. Senthilkumar A, Smith RD, Khitha J, Arora N, Veerareddy S, Langston W, Chidlow JH Jr, Barlow SC, Teng X, Patel RP, Lefer DJ, Kevil CG. Sildenafil promotes ischemia-induced angiogenesis through a PKGdependent pathway. Arterioscler Thromb Vasc Biol 27: 1947-1954, 2007.
45. Sheffield-Moore M, Wiktorowicz JE, Soman KV, Danesi CP, Kinsky MP, Dillon EL, Randolph KM, Casperson SL, Gore DC, Horstman AM, Lynch JP, Doucet BM, Mettler JA, Ryder JW, Ploutz-Snyder LL, Hsu JW, Jahoor F, Jennings K, White GR, McCammon SD, Durham WJ. Sildenafil increases muscle protein synthesis and reduces muscle fatigue. Clin Transl Sci 6: 463-468, 2013.
46. Sieminski DJ, Gardner AW. The relationship between free-living daily physical activity and the severity of peripheral arterial occlusive disease. Vasc Med 2: 286-291, 1997.
47. 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 TNFα), 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.
48. 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.
49. Skoglund PH, Ostergren J, Svensson P. Ambulatory pulse pressure predicts cardiovascular events in patients with peripheral arterial disease. Blood Pressure 21: 227-232, 2012.
50. Sperandio PA, Borghi-Silva A, Barroco A, Nery LE, Almeida DR, Neder JA. Microvascular oxygen delivery-to-utilization mismatch at the onset of heavy-intensity exercise in optimally treated patients with CHF. Am J Physiol Heart Circ Physiol 297: H1720-H1728, 2009.
51. Sperandio PA, Oliveira MF, Rodrigues MK, Berton DC, Treptow E, Nery LE, Almeida DR, Neder JA. Sildenafil improves microvascular O2 delivery-to-utilization matching and accelerates exercise O2 uptake kinetics in chronic heart failure. Am J Physiol Heart Circ Physiol 303: H1474-H1480, 2012.
52. Sprague RS, Goldman D, Bowles EA, Achilleus D, Stephenson AH, Ellis CG, Ellsworth ML. Divergent effects of low-O2 tension and iloprost on ATP release from erythrocytes of humans with type 2 diabetes: implications for O2 supply to skeletal muscle. Am J Physiol Heart Circ Physiol 299: H566-H573, 2010.
53. Supuran CT, Mastrolorenzo A, Barbaro G, Scozzafava A. Phosphodiesterase 5 inhibitors-drug design and differentiation based on selectivity, pharmacokinetic and efficacy profiles. Curr Pharmaceut Design 12: 3459-3465, 2006.
54. Svensson P, de Faire U, Niklasson U, Ostergren J. Office blood pressure underestimates ambulatory blood pressure in peripheral arterial disease in comparison to healthy controls. J Human Hypertension 18: 193-200, 2004.
55. Turtle EJ, Drummond ID, Webb DJ. Improvement in symptoms of peripheral arterial disease with sildenafil therapy. Scottish Med J 58: e7-9, 2013.
56. Turton EP, Spark JI, Mercer KG, Berridge DC, Kent PJ, Kester RC, Scott DJ. Exercise-induced neutrophil activation in claudicants: a physiological or pathological response to exhaustive exercise? Eur J Vasc Endovasc Surg 16: 192-196, 1998.
57. Vardi Y, Bulus M, Reisner S, Nassar S, Aboud L, Sprecher E, Gruenwald I. Effects of sildenafil citrate (Viagra) on hemodynamic parameters during exercise testing and occurrence of ventricular arrhythmias in patients with erectile dysfunction and cardiovascular disease. Eur Urol 43: 544-551, 2003.
58. Vita JA, Hamburg NM. Does endothelial dysfunction contribute to the clinical status of patients with peripheral arterial disease? Can J Cardiol 26 Suppl A: 45A-50A, 2010.
59. Walker DK, Ackland MJ, James GC, Muirhead GJ, Rance DJ, Wastall P, Wright PA. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 29: 297-310, 1999.
60. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 83: 3C-12C, 1999.
61. Williams G, Shi-Wen X, Abraham D, Selvakumar S, Baker DM, Tsui JC. Nitric oxide manipulation: a therapeutic target for peripheral arterial disease? Cardiol Res Pract 2012: 656247, 2012.
62. Wolosker N, Nakano L, Rosoky RA, Munia MA, Netto BM, Puech-Leao, P. Endovascular treatment for intermittent claudication in patients who do not improve with clinical treatment. Clinics 60: 193-200, 2005.
63. 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.
64. Yosefy C, Jafari J, Klainman E, Brodkin B, Handschumacher MD, Vaturi M. The prognostic value of post-exercise blood pressure reduction in patients with hypertensive response during exercise stress test. Int J Cardiol 111: 352-357, 2006.