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Original article

Vol. 142 No. 2728 (2012)

Nitric oxide mediates the blood pressure response to mental stress in humans

  • Lionel Trueb
  • Mattia Lepori
  • Hervé Duplain
  • Urs Scherrer
  • Claudio Sartori
Cite this as:
Swiss Med Wkly. 2012;142:w13627


OBJECTIVE: Nitric oxide (NO) regulates arterial pressure by modulating peripheral vascular tone and sympathetic vasoconstrictor outflow. NO synthesis is impaired in several major cardiovascular disease states. Loss of NO-induced vasodilator tone and restraint on sympathetic outflow could result in exaggerated pressor responses to mental stress.

METHODS: We, therefore, compared the sympathetic (muscle sympathetic nerve activity) and haemodynamic responses to mental stress performed during saline infusion and systemic inhibition of NO-synthase by NG-monomethyl-L-arginine (L-NMMA) infusion.

RESULTS: The major finding was that mental stress which during saline infusion increased sympathetic nerve activity by ~50 percent and mean arterial pressure by ~15 percent had no detectable sympathoexcitatory and pressor effect during L-NMMA infusion. These findings were not related to a generalised impairment of the haemodynamic and/or sympathetic responsiveness by L-NMMA, since the pressor and sympathetic nerve responses to immersion of the hand in ice water were preserved during L-NMMA infusion.

CONCLUSION: Mental stress causes pressor and sympathoexcitatory effects in humans that are mediated by NO. These findings are consistent with the new concept that, in contrast to what has been generally assumed, under some circumstances, NO has a blood pressure raising action in vivo.


  1. Haynes WG, Noon JP, Walker BR, Webb DJ. Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J Hypertens. 1993;11(12):1375–80.
  2. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333(6174):664–6.
  3. Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest. 1994;94(6):2511–5.
  4. Zanzinger J, Czachurski J, Seller H. Inhibition of sympathetic vasoconstriction is a major principle of vasodilation by nitric oxide in vivo. Circ Res. 1994;75(6):1073–7.
  5. Hakim MA, Hirooka Y, Coleman MJ, Bennett MR, Dampney RA. Evidence for a critical role of nitric oxide in the tonic excitation of rabbit renal sympathetic preganglionic neurones. J Physiol. 1995;482(Pt 2):401-7.
  6. Kumagai K, Suzuki H, Ichikawa M, Jimbo M, Murakami M, Ryuzaki M, et al. Nitric oxide increases renal blood flow by interacting with the sympathetic nervous system. Hypertension. 1994;24(2):220–6.
  7. Liu JL, Murakami H, Zucker IH. Effects of NO on baroreflex control of heart rate and renal nerve activity in conscious rabbits. Am J Physiol. 1996;270(6 Pt 2):R1361–70.
  8. Ma S, Abboud FM, Felder RB. Effects of L-arginine-derived nitric oxide synthesis on neuronal activity in nucleus tractus solitarius. Am J Physiol. 1995;268(2 Pt 2):R487–91.
  9. Owlya R, Vollenweider L, Trueb L, Sartori C, Lepori M, Nicod P, et al. Cardiovascular and sympathetic effects of nitric oxide inhibition at rest and during static exercise in humans. Circulation. 1997;96(11):3897–903.
  10. Sakuma I, Togashi H, Yoshioka M, Saito H, Yanagida M, Tamura M, et al. NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone? Circ Res. 1992;70(3):607–11.
  11. Sander M, Chavoshan B, Victor RG. A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension. 1999;33(4):937–42.
  12. Zanzinger J, Czachurski J, Seller H. Inhibition of basal and reflex-mediated sympathetic activity in the RVLM by nitric oxide. Am J Physiol. 1995;268(4 Pt 2):R958–62.
  13. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86(1):228–34.
  14. Linder L, Kiowski W, Buhler FR, Luscher TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation. 1990;81(6):1762–7.
  15. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 1993;87(5):1468–74.
  16. Treasure CB, Vita JA, Cox DA, Fish RD, Gordon JB, Mudge GH, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation. 1990;81(3):772–9.
  17. Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993;92(2):652–62.
  18. Anggard E. Nitric oxide: mediator, murderer, and medicine. Lancet. 1994;343(8907):1199–206.
  19. Randin D, Vollenweider P, Tappy L, Jequier E, Nicod P, Scherrer U. Suppression of alcohol-induced hypertension by dexamethasone. N Engl J Med. 1995;332(26):1733–7.
  20. Falkner B, Onesti G, Angelakos ET, Fernandes M, Langman C. Cardiovascular response to mental stress in normal adolescents with hypertensive parents. Hemodynamics and mental stress in adolescents. Hypertension. 1979;1(1):23–30.
  21. Vallbo AB, Hagbarth KE, Torebjork HE, Wallin BG. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev. 1979;59(4):919–57.
  22. Vollenweider P, Tappy L, Randin D, Schneiter P, Jequier E, Nicod P, et al. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest. 1993;92(1):147–54.
  23. Lindqvist M, Melcher A, Hjemdahl P. Hemodynamic and sympathoadrenal responses to mental stress during nitric oxide synthesis inhibition. Am J Physiol Heart Circ Physiol. 2004;287(5):H2309–15.
  24. Anderson EA, Wallin BG, Mark AL. Dissociation of sympathetic nerve activity in arm and leg muscle during mental stress. Hypertension. 1987;9(6 Pt 2):III114–9.
  25. Callister R, Suwarno NO, Seals DR. Sympathetic activity is influenced by task difficulty and stress perception during mental challenge in humans. J Physiol. 1992;454:373–87.
  26. Jones PP, Spraul M, Matt KS, Seals DR, Skinner JS, Ravussin E. Gender does not influence sympathetic neural reactivity to stress in healthy humans. Am J Physiol. 1996;270(1 Pt 2):H350–7.
  27. Halliwill JR, Lawler LA, Eickhoff TJ, Dietz NM, Nauss LA, Joyner MJ. Forearm sympathetic withdrawal and vasodilatation during mental stress in humans. J Physiol. 1997;504(Pt 1):211–20.
  28. Freyschuss U, Hjemdahl P, Juhlin-Dannfelt A, Linde B. Cardiovascular and sympathoadrenal responses to mental stress: influence of beta-blockade. Am J Physiol. 1988;255(6 Pt 2):H1443–51.
  29. Kingwell BA, Thompson JM, Kaye DM, McPherson GA, Jennings GL, Esler MD. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation. 1994;90(1):234–40.
  30. Spieker LE, Corti R, Binggeli C, Luscher TF, Noll G. Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans. J Am Coll Cardiol. 2000;36(1):213–8.
  31. Kurihara N, Alfie ME, Sigmon DH, Rhaleb NE, Shesely EG, Carretero OA. Role of nNOS in blood pressure regulation in eNOS null mutant mice. Hypertension. 1998;32(5):856–61.
  32. Cardillo C, Kilcoyne CM, Quyyumi AA, Cannon RO, 3rd, Panza JA. Role of nitric oxide in the vasodilator response to mental stress in normal subjects. Am J Cardiol. 1997;80(8):1070–4.
  33. Joyner MJ, Dietz NM. Nitric oxide and vasodilation in human limbs. J Appl Physiol. 1997;83(6):1785–96.
  34. Seddon MD, Chowienczyk PJ, Brett SE, Casadei B, Shah AM. Neuronal nitric oxide synthase regulates basal microvascular tone in humans in vivo. Circulation. 2008;117(15):1991–6.
  35. Yeung AC, Vekshtein VI, Krantz DS, Vita JA, Ryan TJ, Jr., Ganz P, et al. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med. 1991;325(22):1551–6.