Chronic L-Arginine Supplementation Enhances Endurance Exercise Tolerance in Heart Failure Patients

Abstract

The purpose of the study was to determine the potential beneficial effect of six weeks oral L-arginine supplementation (LAS) on endurance exercise, an important determinant of daily-life activity in patients with chronic stable heart failure (CHF). After an initial incremental maximal exercise test, CHF patients performed an identical thirty-minute interval endurance exercise test before and after six weeks with (L-arginine group; ARG) or without LAS (control group; CTL). Hemodynamic, respiratory, and metabolic parameters were determined at rest, during exercise, and during recovery. Mean heart rate decreased throughout exercise and recovery after LAS (- 8.2 ± 1.4 b · min^-1; p = 0.003 and - 6.7 ± 1.6 b · min^-1; p < 0.001, respectively), systemic blood pressure and respiratory parameters remaining unchanged. Resting L-argininaemia increased from 102 ± 11 to 181 ± 37 µmol · l^-1 (p < 0.004) and exercise-induced peak increase in plasma lactate was blunted after LAS (4.13 ± 0.75 vs. 3.13 ± 0.39 mmol · l^-1; p = 0.02). No significant change was observed in the control group. In heart failure patients, six weeks oral LAS enhances endurance exercise tolerance, reducing both heart rate and circulating lactates. This suggests that chronic LAS might be useful as a therapeutic adjuvant in order to improve the patient's physical fitness.

Arginine - heart failure - endurance exercise - lactate

References

• 1 Balligand J L, Kobzik L, Han X, Kaye D M, Belhassen L, O'Hara D S, Kelly R A, Smith T W, Michel T. Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes.  J Biol Chem. 1995;  270 14582-14586
• 2 Banning A P, Prendergast B. Intravenous L-arginine reduces V·_E/V·CO₂ slope acutely in patients with severe chronic heart failure.  Eur J Heart Fail. 1999;  1 187-190
• 3 Bocchi E A, Vilella de Moraes A V, Esteves-Filho A, Bacal F, Auler J O, Carmona M J, Bellotti G, Ramires A F. L-arginine reduces heart rate and improves hemodynamics in severe congestive heart failure.  Clin Cardiol. 2000;  23 205-210
• 4 Bode-Boger S M, Boger R H, Galland A, Tsikas D, Frolich J C. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship.  Br J Clin Pharmacol. 1998;  46 489-497
• 5 Bradley S J, Kingwell B A, McConell G K. Nitric oxide synthase inhibition reduces leg glucose uptake but not blood flow during dynamic exercise in humans.  Diabetes. 1999;  48 1815-1821
• 6 Chowdhary S, Marsh A M, Coote J H, Townend J N. Nitric oxide and cardiac muscarinic control in humans.  Hypertension. 2004;  43 1023-1028
• 7 Geny B, Saini J, Mettauer B, Lampert E, Piquard F, Follenius M, Epailly E, Schnedecker B, Eisenmann B, Haberey P, Lonsdorfer J. Effect of short-term endurance training on exercise capacity, haemodynamics and atrial natriuretic peptide secretion in heart transplant recipients.  Eur J Appl Physiol. 1996;  73 259-266
• 8 Gimenez M, Cereceda V, Teculescu D, Aug F, Laxenaire M C. Square-wave endurance exercise test (SWEET) for training and assessment in trained and untrained subjects. III. Effect on V·O_2max and maximal ventilation.  Eur J Appl Physiol. 1982;  49 379-387
• 9 Giugliano D, Marfella R, Verrazzo G, Acampora R, Coppola L, Cozzolino D, D'Onofrio F. The vascular effects of L-Arginine in humans. The role of endogenous insulin.  J Clin Invest. 1997;  99 433-438
• 10 Hambrecht R, Hilbrich L, Erbs S, Gielen S, Fiehn E, Schoene N, Schuler G. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation.  J Am Coll Cardiol. 2000;  35 706-713
• 11 Hansen J E, Sue D Y, Wasserman K. Predicted values for clinical exercise testing.  Am Rev Respir Dis. 1984;  129 49-55
• 12 Hare J M, Keaney Jr J F, Balligand J L, Loscalzo J, Smith T W, Colucci W S. Role of nitric oxide in parasympathetic modulation of beta-adrenergic myocardial contractility in normal dogs.  J Clin Invest. 1995;  95 360-366
• 13 Kanaya Y, Nakamura M, Kobayashi N, Hiramori K. Effects of L-arginine on lower limb vasodilator reserve and exercise capacity in patients with chronic heart failure.  Heart. 1999;  81 512-517
• 14 Katz S D, Khan T, Zeballos G A, Mathew L, Potharlanka P, Knecht M, Whelan J. Decreased activity of the L-arginine-nitric oxide metabolic pathway in patients with congestive heart failure.  Circulation. 1999;  99 2113-2117
• 15 Koifman B, Wollman Y, Bogomolny N, Chernichowsky T, Finkelstein A, Peer G, Scherez J, Blum M, Laniado S, Iaina A. 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
• 16 Kraemer M D, Kubo S H, Rector T S, Brunsvold N, Bank A J. Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure.  J Am Coll Cardiol. 1993;  21 641-648
• 17 Linossier M T, Dormois D, Bregere P, Geyssant A, Denis C. Effect of sodium citrate on performance and metabolism of human skeletal muscle during supramaximal cycling exercise.  Eur J Appl Physiol. 1997;  76 48-54
• 18 Maxwell A J, Anderson B E, Cooke J P. Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of HeartBar.  Vasc Med. 2000;  5 11-19
• 19 Maxwell A J, Cooke J P. Cardiovascular effects of L-arginine.  Curr Opin Nephrol Hypertens. 1998;  7 63-70
• 20 Maxwell A J, Zapien M P, Pearce G L, MacCallum G, Stone P H. Randomized trial of a medical food for the dietary management of chronic, stable angina.  J Am Coll Cardiol. 2002;  39 37-45
• 21 Meyer K. Exercise training in heart failure: recommendations based on current research.  Med Sci Sports Exerc. 2001;  33 525-531
• 22 Mills P C, Marlin D J, Scott C M, Smith N C. Metabolic effects of nitric oxide synthase inhibition during exercise in the horse.  Res Vet Sci. 1999;  66 135-138
• 23 Nagaya N, Uematsu M, Oya H, Sato N, Sakamaki F, Kyotani S, Ueno K, Nakanishi N, Yamagishi M, Miyatake K. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension.  Am J Respir Crit Care Med. 2001;  163 887-891
• 24 Rector T S, Bank A J, Mullen K A, Tschumperlin L K, Sih R, Pillai K, Kubo S H. Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure.  Circulation. 1996;  93 2135-2141
• 25 Schaefer A, Piquard F, Doutreleau S, Mettauer B, Epailly E, Eisenmann B, Lonsdorfer J, Geny B. Reduced exercise capacity is associated with reduced nitric oxide production after heart transplantation.  J Thorac Cardiovasc Surg. 2001;  122 821-822
• 26 Schaefer A, Piquard F, Geny B, Doutreleau S, Lampert E, Mettauer B, Lonsdorfer J. L-arginine reduces exercise-induced increase in plasma lactate and ammonia.  Int J Sports Med. 2002;  23 403-407
• 27 Steinberg H O, Brechtel G, Johnson A, Fineberg N, Baron A D. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release.  J Clin Invest. 1994;  94 1172-1179
• 28 Treasure C B, Alexander R W. The dysfunctional endothelium in heart failure.  J Am Coll Cardiol. 1993;  22 129-134
• 29 Wang Y, Liu X F, Cornish K G, Zucker I H, Patel K P. Effects of nNOS antisense in the paraventricular nucleus on blood pressure and heart rate in rats with heart failure.  Am J Physiol. 2005;  288 205-213
• 30 Wilson J R, Martin J L, Ferraro N. Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: role of cardiac pump dysfunction as determined by the effect of dobutamine.  Am J Cardiol. 1984;  53 1308-1315
• 31 Zelis R, Sinoway L I, Musch T I, Davis D, Just H. Regional blood flow in congestive heart failure: concept of compensatory mechanisms with short and long time constants.  Am J Cardiol. 1988;  62 2-8