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. 1999 May;81(5):512–517. doi: 10.1136/hrt.81.5.512

Effects of L-arginine on lower limb vasodilator reserve and exercise capacity in patients with chronic heart failure

Y Kanaya 1, M Nakamura 1, N Kobayashi 1, K Hiramori 1
PMCID: PMC1729027  PMID: 10212170

Abstract

OBJECTIVE—To determine whether the reactive hyperaemic response of the lower limb increases with improved exercise capacity after acute supplementation with L-arginine, the precursor of nitric oxide, in patients with chronic heart failure.
METHODS—19 patients with chronic heart failure were enrolled in the study. Rest calf blood flow and femoral occlusion induced calf blood flow changes were measured by venous occlusion plethysmography before and after intravenous infusion of 10% L-arginine solution (5 ml/kg for 30 minutes) or placebo. Postexercise calf blood flow was also measured after the experimental infusion. During both postinfusion periods, several exercise capacity indices were determined by a symptom limited cardiopulmonary exercise test using a bicycle ergometer.
RESULTS—Baseline calf blood flow, systemic blood pressure, and heart rate showed no significant changes in either of the two experimental conditions. However, the occlusion induced blood flow response was significantly enhanced by L-arginine infusion (mean (SEM) peak flow, 19.6 (1.5) v 28.9 (3.1) ml/min/dl calf tissue; p < 0.01), but not by placebo (peak flow, 19.1 (1.4) v 20.9 (1.8) ml/min/dl calf tissue; NS). Calf blood flow response after exercise was also higher after L-arginine infusion than after placebo (peak flow, 4.8 (0.4) v 6.0 (0.8) ml/min/dl calf tissue; p < 0.05). L-arginine infusion had no significant effect compared with placebo on exercise capacity indices such as peak oxygen uptake (17.1 (1.0) v 15.8 (1.1) ml/min/kg; NS), anaerobic threshold (10.5 (0.6) v 10.4 (0.7) ml/min/kg; NS), and exercise time (296 (23) v 283 (22) s; NS).
CONCLUSIONS—Acute supplementation with the nitric oxide precursor L-arginine increased lower limb reactive hyperaemia but did not lead to any significant improvement in exercise capacity in patients with chronic heart failure.


Keywords: congestive heart failure; nitric oxide; endothelium; arginine; exercise

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Figure 1  .

Figure 1  

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Study protocol. Blood, blood sampling; BP/HR, blood pressure and heart rate; CBF, calf blood flow; EX test, symptom limited cardiopulmonary exercise test; RH, reactive hyperaemia.

Figure 2  .

Figure 2  

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Calf blood flow response after abrupt release of five minute thigh occlusion before (∘) and after (•) infusion of L-arginine (upper panel) and placebo (lower panel) in patients with chronic heart failure. Error bars = SEM.

Figure 3  .

Figure 3  

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Calf blood flow response after ergometric exercise after L-arginine (•) and placebo (∘) infusion in patients with chronic heart failure. Error bars = SEM.

Figure 4  .

Figure 4  

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Changes in peak oxygen uptake (peak V̇O2) (left), anaerobic threshold (AT) (centre), and exercise (EX) time (right) measured after infusion of L-arginine (∘) and placebo (•) in patients with chronic heart failure.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams V., Yu J., Möbius-Winkler S., Linke A., Weigl C., Hilbrich L., Schuler G., Hambrecht R. Increased inducible nitric oxide synthase in skeletal muscle biopsies from patients with chronic heart failure. Biochem Mol Med. 1997 Aug;61(2):152–160. doi: 10.1006/bmme.1997.2598. [DOI] [PubMed] [Google Scholar]
  2. Baron A. D. Hemodynamic actions of insulin. Am J Physiol. 1994 Aug;267(2 Pt 1):E187–E202. doi: 10.1152/ajpendo.1994.267.2.E187. [DOI] [PubMed] [Google Scholar]
  3. Bode-Böger S. M., Böger R. H., Alfke H., Heinzel D., Tsikas D., Creutzig A., Alexander K., Frölich J. C. L-arginine induces nitric oxide-dependent vasodilation in patients with critical limb ischemia. A randomized, controlled study. Circulation. 1996 Jan 1;93(1):85–90. doi: 10.1161/01.cir.93.1.85. [DOI] [PubMed] [Google Scholar]
  4. Bode-Böger S. M., Böger R. H., Creutzig A., Tsikas D., Gutzki F. M., Alexander K., Frölich J. C. L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects. Clin Sci (Lond) 1994 Sep;87(3):303–310. doi: 10.1042/cs0870303. [DOI] [PubMed] [Google Scholar]
  5. Chiba M., Nakamura M., Kanaya Y., Kobayashi N., Ueshima K., Kawazoe K., Hiramori K. Improvement in lower limb vasodilatory reserve and exercise capacity in patients with chronic heart failure due to valvular heart disease. Eur Heart J. 1997 Dec;18(12):1931–1936. doi: 10.1093/oxfordjournals.eurheartj.a015202. [DOI] [PubMed] [Google Scholar]
  6. Creager M. A., Gallagher S. J., Girerd X. J., Coleman S. M., Dzau V. J., Cooke J. P. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992 Oct;90(4):1248–1253. doi: 10.1172/JCI115987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Drexler H., Hayoz D., Münzel T., Hornig B., Just H., Brunner H. R., Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol. 1992 Jun 15;69(19):1596–1601. doi: 10.1016/0002-9149(92)90710-g. [DOI] [PubMed] [Google Scholar]
  8. 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 Feb 1;99(3):433–438. doi: 10.1172/JCI119177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Giugliano D., Marfella R., Verrazzo G., Acampora R., Nappo F., Ziccardi P., Coppola L., D'Onofrio F. L-arginine for testing endothelium-dependent vascular functions in health and disease. Am J Physiol. 1997 Sep;273(3 Pt 1):E606–E612. doi: 10.1152/ajpendo.1997.273.3.E606. [DOI] [PubMed] [Google Scholar]
  10. Habib F. M., Springall D. R., Davies G. J., Oakley C. M., Yacoub M. H., Polak J. M. Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet. 1996 Apr 27;347(9009):1151–1155. doi: 10.1016/s0140-6736(96)90610-8. [DOI] [PubMed] [Google Scholar]
  11. Hare J. M., Loh E., Creager M. A., Colucci W. S. Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction. Circulation. 1995 Oct 15;92(8):2198–2203. doi: 10.1161/01.cir.92.8.2198. [DOI] [PubMed] [Google Scholar]
  12. Henquin J. C., Meissner H. P. Effects of amino acids on membrane potential and 86Rb+ fluxes in pancreatic beta-cells. Am J Physiol. 1981 Mar;240(3):E245–E252. doi: 10.1152/ajpendo.1981.240.3.E245. [DOI] [PubMed] [Google Scholar]
  13. Higashi Y., Oshima T., Ono N., Hiraga H., Yoshimura M., Watanabe M., Matsuura H., Kambe M., Kajiyama G. Intravenous administration of L-arginine inhibits angiotensin-converting enzyme in humans. J Clin Endocrinol Metab. 1995 Jul;80(7):2198–2202. doi: 10.1210/jcem.80.7.7608279. [DOI] [PubMed] [Google Scholar]
  14. Hirooka Y., Imaizumi T., Tagawa T., Shiramoto M., Endo T., Ando S., Takeshita A. Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation. 1994 Aug;90(2):658–668. doi: 10.1161/01.cir.90.2.658. [DOI] [PubMed] [Google Scholar]
  15. Joannides R., Haefeli W. E., Linder L., Richard V., Bakkali E. H., Thuillez C., Lüscher T. F. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 1995 Mar 1;91(5):1314–1319. doi: 10.1161/01.cir.91.5.1314. [DOI] [PubMed] [Google Scholar]
  16. Jondeau G., Katz S. D., Toussaint J. F., Dubourg O., Monrad E. S., Bourdarias J. P., LeJemtel T. H. Regional specificity of peak hyperemic response in patients with congestive heart failure: correlation with peak aerobic capacity. J Am Coll Cardiol. 1993 Nov 1;22(5):1399–1402. doi: 10.1016/0735-1097(93)90549-g. [DOI] [PubMed] [Google Scholar]
  17. Katz S. D., Biasucci L., Sabba C., Strom J. A., Jondeau G., Galvao M., Solomon S., Nikolic S. D., Forman R., LeJemtel T. H. Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol. 1992 Apr;19(5):918–925. doi: 10.1016/0735-1097(92)90271-n. [DOI] [PubMed] [Google Scholar]
  18. Koifman B., Wollman Y., Bogomolny N., Chernichowsky T., Finkelstein A., Peer G., Scherez J., Blum M., Laniado S., Iaina A. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol. 1995 Nov 1;26(5):1251–1256. doi: 10.1016/0735-1097(95)00318-5. [DOI] [PubMed] [Google Scholar]
  19. Kubo S. H., Rector T. S., Bank A. J., Williams R. E., Heifetz S. M. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991 Oct;84(4):1589–1596. doi: 10.1161/01.cir.84.4.1589. [DOI] [PubMed] [Google Scholar]
  20. Kubota T., Imaizumi T., Oyama J., Ando S., Takeshita A. L-arginine increases exercise-induced vasodilation of the forearm in patients with heart failure. Jpn Circ J. 1997 Jun;61(6):471–480. doi: 10.1253/jcj.61.471. [DOI] [PubMed] [Google Scholar]
  21. Laghi Pasini F., Frigerio C., Blardi P., Domini L., De Giorgi L., Borgogni G., Pecchi S., Cati G., Franchi M., Volpi L. Evidence of an adenosine-dependent mechanism in the hypotensive effect of L-arginine in man. Clin Exp Pharmacol Physiol. 1995 Apr;22(4):254–259. doi: 10.1111/j.1440-1681.1995.tb01990.x. [DOI] [PubMed] [Google Scholar]
  22. LeJemtel T. H., Maskin C. S., Lucido D., Chadwick B. J. Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation. 1986 Aug;74(2):245–251. doi: 10.1161/01.cir.74.2.245. [DOI] [PubMed] [Google Scholar]
  23. Lindsay D. C., Holdright D. R., Clarke D., Anand I. S., Poole-Wilson P. A., Collins P. Endothelial control of lower limb blood flow in chronic heart failure. Heart. 1996 May;75(5):469–476. doi: 10.1136/hrt.75.5.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Meredith I. T., Currie K. E., Anderson T. J., Roddy M. A., Ganz P., Creager M. A. Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide. Am J Physiol. 1996 Apr;270(4 Pt 2):H1435–H1440. doi: 10.1152/ajpheart.1996.270.4.H1435. [DOI] [PubMed] [Google Scholar]
  25. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  26. Palmer R. M., Rees D. D., Ashton D. S., Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun. 1988 Jun 30;153(3):1251–1256. doi: 10.1016/s0006-291x(88)81362-7. [DOI] [PubMed] [Google Scholar]
  27. Panza J. A., Casino P. R., Badar D. M., Quyyumi A. A. Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation. 1993 May;87(5):1475–1481. doi: 10.1161/01.cir.87.5.1475. [DOI] [PubMed] [Google Scholar]
  28. 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 Jun 15;93(12):2135–2141. doi: 10.1161/01.cir.93.12.2135. [DOI] [PubMed] [Google Scholar]
  29. Satoh M., Nakamura M., Tamura G., Makita S., Segawa I., Tashiro A., Satodate R., Hiramori K. Inducible nitric oxide synthase and tumor necrosis factor-alpha in myocardium in human dilated cardiomyopathy. J Am Coll Cardiol. 1997 Mar 15;29(4):716–724. doi: 10.1016/s0735-1097(96)00567-0. [DOI] [PubMed] [Google Scholar]
  30. Smulders R. A., Aarsen M., Teerlink T., De Vries P. M., Van Kamp G. J., Donker A. J., Stehouwer C. D. Haemodynamic and biochemical responses to L-arginine and L-lysine infusions in normal subjects: L-arginine-induced vasodilatation cannot be explained by non-specific effects of cationic amino acids. Clin Sci (Lond) 1997 Apr;92(4):367–374. doi: 10.1042/cs0920367. [DOI] [PubMed] [Google Scholar]
  31. 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 Sep;94(3):1172–1179. doi: 10.1172/JCI117433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tagawa T., Imaizumi T., Endo T., Shiramoto M., Harasawa Y., Takeshita A. Role of nitric oxide in reactive hyperemia in human forearm vessels. Circulation. 1994 Nov;90(5):2285–2290. doi: 10.1161/01.cir.90.5.2285. [DOI] [PubMed] [Google Scholar]
  33. Wascher T. C., Posch K., Wallner S., Hermetter A., Kostner G. M., Graier W. F. Vascular effects of L-arginine: anything beyond a substrate for the NO-synthase? Biochem Biophys Res Commun. 1997 May 8;234(1):35–38. doi: 10.1006/bbrc.1997.9994. [DOI] [PubMed] [Google Scholar]
  34. 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 May 1;53(9):1308–1315. doi: 10.1016/0002-9149(84)90085-7. [DOI] [PubMed] [Google Scholar]
  35. Wilson J. R., Martin J. L., Schwartz D., Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation. 1984 Jun;69(6):1079–1087. doi: 10.1161/01.cir.69.6.1079. [DOI] [PubMed] [Google Scholar]
  36. Zelis R., Longhurst J., Capone R. J., Mason D. T. A comparison of regional blood flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation. 1974 Jul;50(1):137–143. doi: 10.1161/01.cir.50.1.137. [DOI] [PubMed] [Google Scholar]

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