Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Feb 1;99(3):433–438. doi: 10.1172/JCI119177

The vascular effects of L-Arginine in humans. The role of endogenous insulin.

D Giugliano 1, R Marfella 1, G Verrazzo 1, R Acampora 1, L Coppola 1, D Cozzolino 1, F D'Onofrio 1
PMCID: PMC507816  PMID: 9022076

Abstract

This study aimed at evaluating whether increased availability of the natural precursor of nitric oxide, L-arginine, could influence systemic hemodynamic and rheologic parameters in humans and whether the effects of L-arginine are mediated by endogenous insulin. 10 healthy young subjects participated in the following studies: study I, infusion of L-arginine (1 g/min for 30 min); study II, infusion of L-arginine plus octreotide (25 microg as i.v. bolus + 0.5 microg/min) to block endogenous insulin and glucagon secretion, plus replacement of basal insulin and glucagon; study III, infusion of L-arginine plus octreotide plus basal glucagon plus an insulin infusion designed to mimic the insulin response of study I. L-Arginine infusion significantly reduced systolic (11+/-3, mean+/-SE) and diastolic (8+/-2 mmHg, P < 0.001) blood pressure, platelet aggregation (20+/-4%), and blood viscosity (1.6+/-0.2 centipois, P < 0.01), and increased leg blood flow (97+/-16 ml/min), heart rate, and plasma catecholamine levels (P < 0.01). In study II, plasma insulin levels remained suppressed at baseline; in this condition, the vascular responses to L-arginine were significantly reduced, except for plasma catecholamines which did not change significantly. In study III, the plasma insulin response to L-arginine was reestablished; this was associated with hemodynamic and rheologic changes following L-arginine not significantly different from those recorded in study I. These findings show that systemic infusion of L-arginine in healthy subjects induces vasodilation and inhibits platelet aggregation and blood viscosity. These effects are mediated, in part, by endogenous released insulin.

Full Text

The Full Text of this article is available as a PDF (169.7 KB).

Selected References

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

  1. Arnal J. F., Münzel T., Venema R. C., James N. L., Bai C. L., Mitch W. E., Harrison D. G. Interactions between L-arginine and L-glutamine change endothelial NO production. An effect independent of NO synthase substrate availability. J Clin Invest. 1995 Jun;95(6):2565–2572. doi: 10.1172/JCI117957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. BORN G. V. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962 Jun 9;194:927–929. doi: 10.1038/194927b0. [DOI] [PubMed] [Google Scholar]
  3. Bacchus R. A., London D. R. The measurement of arginine in plasma. Clin Chim Acta. 1971 Jul;33(2):479–482. doi: 10.1016/0009-8981(71)90515-8. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Baudouin S. V., Bath P., Martin J. F., Du Bois R., Evans T. W. L-arginine infusion has no effect on systemic haemodynamics in normal volunteers, or systemic and pulmonary haemodynamics in patients with elevated pulmonary vascular resistance. Br J Clin Pharmacol. 1993 Jul;36(1):45–49. doi: 10.1111/j.1365-2125.1993.tb05890.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Bogle R. G., Coade S. B., Moncada S., Pearson J. D., Mann G. E. Bradykinin and ATP stimulate L-arginine uptake and nitric oxide release in vascular endothelial cells. Biochem Biophys Res Commun. 1991 Oct 31;180(2):926–932. doi: 10.1016/s0006-291x(05)81154-4. [DOI] [PubMed] [Google Scholar]
  8. Förstermann U., Closs E. I., Pollock J. S., Nakane M., Schwarz P., Gath I., Kleinert H. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension. 1994 Jun;23(6 Pt 2):1121–1131. doi: 10.1161/01.hyp.23.6.1121. [DOI] [PubMed] [Google Scholar]
  9. Giugliano D., Marfella R., Verrazzo G., Acampora R., Donzella C., Quatraro A., Coppola L., D'Onofrio F. Abnormal rheologic effects of glyceryl trinitrate in patients with non-insulin-dependent diabetes mellitus and reversal by antioxidants. Ann Intern Med. 1995 Sep 1;123(5):338–343. doi: 10.7326/0003-4819-123-5-199509010-00003. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Imaizumi T., Hirooka Y., Masaki H., Harada S., Momohara M., Tagawa T., Takeshita A. Effects of L-arginine on forearm vessels and responses to acetylcholine. Hypertension. 1992 Oct;20(4):511–517. doi: 10.1161/01.hyp.20.4.511. [DOI] [PubMed] [Google Scholar]
  12. Kharitonov S. A., Lubec G., Lubec B., Hjelm M., Barnes P. J. L-arginine increases exhaled nitric oxide in normal human subjects. Clin Sci (Lond) 1995 Feb;88(2):135–139. doi: 10.1042/cs0880135. [DOI] [PubMed] [Google Scholar]
  13. Koenig W., Sund M., Lowe G. D., Lee A. J., Resch K. L., Tunstall-Pedoe H., Keil U., Ernst E. Geographical variations in plasma viscosity and relation to coronary event rates. Lancet. 1994 Sep 10;344(8924):711–714. doi: 10.1016/s0140-6736(94)92207-1. [DOI] [PubMed] [Google Scholar]
  14. Laakso M., Edelman S. V., Brechtel G., Baron A. D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990 Jun;85(6):1844–1852. doi: 10.1172/JCI114644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Laakso M., Edelman S. V., Brechtel G., Baron A. D. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes. 1992 Sep;41(9):1076–1083. doi: 10.2337/diab.41.9.1076. [DOI] [PubMed] [Google Scholar]
  16. MacAllister R. J., Calver A. L., Collier J., Edwards C. M., Herreros B., Nussey S. S., Vallance P. Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effect? Clin Sci (Lond) 1995 Aug;89(2):183–190. doi: 10.1042/cs0890183. [DOI] [PubMed] [Google Scholar]
  17. Marfella R., Verrazzo G., Acampora R., La Marca C., Giunta R., Lucarelli C., Paolisso G., Ceriello A., Giugliano D. Glutathione reverses systemic hemodynamic changes induced by acute hyperglycemia in healthy subjects. Am J Physiol. 1995 Jun;268(6 Pt 1):E1167–E1173. doi: 10.1152/ajpendo.1995.268.6.E1167. [DOI] [PubMed] [Google Scholar]
  18. Moncada S., Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993 Dec 30;329(27):2002–2012. doi: 10.1056/NEJM199312303292706. [DOI] [PubMed] [Google Scholar]
  19. Nakaki T., Hishikawa K., Suzuki H., Saruta T., Kato R. L-arginine-induced hypotension. Lancet. 1990 Sep 15;336(8716):696–696. doi: 10.1016/0140-6736(90)92196-o. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Paolisso G., Giugliano D., Scheen A. J., Franchimont P., D'Onofrio F., Lefèbvre P. J. Primary role of glucagon release in the effect of beta-endorphin on glucose homeostasis in normal man. Acta Endocrinol (Copenh) 1987 Jun;115(2):161–169. doi: 10.1530/acta.0.1150161. [DOI] [PubMed] [Google Scholar]
  22. Parati G., Casadei R., Groppelli A., Di Rienzo M., Mancia G. Comparison of finger and intra-arterial blood pressure monitoring at rest and during laboratory testing. Hypertension. 1989 Jun;13(6 Pt 1):647–655. doi: 10.1161/01.hyp.13.6.647. [DOI] [PubMed] [Google Scholar]
  23. Pei D., Jones C. N., Bhargava R., Chen Y. D., Reaven G. M. Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test. Diabetologia. 1994 Aug;37(8):843–845. doi: 10.1007/BF00404344. [DOI] [PubMed] [Google Scholar]
  24. Smulders R. A., Stehouwer C. D., Olthof C. G., van Kamp G. J., Teerlink T., de Vries P. M., Donker A. J. Plasma endothelin levels and vascular effects of intravenous L-arginine infusion in subjects with uncomplicated insulin-dependent diabetes mellitus. Clin Sci (Lond) 1994 Jul;87(1):37–43. doi: 10.1042/cs0870037. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Stroes E. S., Koomans H. A., de Bruin T. W., Rabelink T. J. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet. 1995 Aug 19;346(8973):467–471. doi: 10.1016/s0140-6736(95)91322-x. [DOI] [PubMed] [Google Scholar]
  27. Trovati M., Massucco P., Mattiello L., Cavalot F., Mularoni E., Hahn A., Anfossi G. Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: a mechanism potentially involved in insulin-induced modulation of vascular tone. Diabetologia. 1995 Aug;38(8):936–941. doi: 10.1007/BF00400582. [DOI] [PubMed] [Google Scholar]
  28. Trovati M., Massucco P., Mattiello L., Piretto V., Cavalot F., Mularoni E., Anfossi G. The insulin-induced increase of guanosine-3',5'-cyclic monophosphate in human platelets is mediated by nitric oxide. Diabetes. 1996 Jun;45(6):768–770. doi: 10.2337/diab.45.6.768. [DOI] [PubMed] [Google Scholar]
  29. Vallance P., Collier J., Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989 Oct 28;2(8670):997–1000. doi: 10.1016/s0140-6736(89)91013-1. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES