Comprehensive Physiology Wiley Online Library

Sympathetic Neural Activity to the Cardiovascular System: Integrator of Systemic Physiology and Interindividual Characteristics

Full Article on Wiley Online Library



Abstract

The sympathetic nervous system is a ubiquitous, integrating controller of myriad physiological functions. In the present article, we review the physiology of sympathetic neural control of cardiovascular function with a focus on integrative mechanisms in humans. Direct measurement of sympathetic neural activity (SNA) in humans can be accomplished using microneurography, most commonly performed in the peroneal (fibular) nerve. In humans, muscle SNA (MSNA) is composed of vasoconstrictor fibers; its best‐recognized characteristic is its participation in transient, moment‐to‐moment control of arterial blood pressure via the arterial baroreflex. This property of MSNA contributes to its typical “bursting” pattern which is strongly linked to the cardiac cycle. Recent evidence suggests that sympathetic neural mechanisms and the baroreflex have important roles in the long term control of blood pressure as well. One of the striking characteristics of MSNA is its large interindividual variability. However, in young, normotensive humans, higher MSNA is not linked to higher blood pressure due to balancing influences of other cardiovascular variables. In men, an inverse relationship between MSNA and cardiac output is a major factor in this balance, whereas in women, beta‐adrenergic vasodilation offsets the vasoconstrictor/pressor effects of higher MSNA. As people get older (and in people with hypertension) higher MSNA is more likely to be linked to higher blood pressure. Skin SNA (SSNA) can also be measured in humans, although interpretation of SSNA signals is complicated by multiple types of neurons involved (vasoconstrictor, vasodilator, sudomotor and pilomotor). In addition to blood pressure regulation, the sympathetic nervous system contributes to cardiovascular regulation during numerous other reflexes, including those involved in exercise, thermoregulation, chemoreflex regulation, and responses to mental stress. © 2014 American Physiological Society. Compr Physiol 4:825‐850, 2014.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Schematic summary of central neural mechanisms involved in baroreflex regulation of the heart and circulation. Baroreceptor afferent signals synapse at the nucleus tractus solitarii (NTS), after which glutaminergic excitatory fibers relay the cardiovascular information in two major directions: to the nucleus ambiguous (NA) and cardiac vagal motoneurones, and to the caudal ventrolateral medulla (CVLM). GABA‐ergic fibers from CVLM project to sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) where they cause inhibition of subsequent efferent pre‐ and postganglionic sympathetic activities. Inhibitory neural connections are shown as dotted lines. Adapted from (), with permission of Oxford University Press.
Figure 2. Figure 2. Inter‐individual variability of mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR) in young healthy subjects. Note that variability in CO and TPR is much greater than that of MAP. CV: coefficient of variation. From (), with permission.
Figure 3. Figure 3. Relationships between MSNA and CO, MSNA and TPR and MSNA and MAP in young healthy men. MSNA was directly related to TPR, showing that it is a good index of whole body “net” vasoconstrictor tone in this group. The inverse relationship between MSNA and CO helps to balance the pressor effects of MSNA, contributing to the lack of relationship between MSNA and MAP. From (), with permission.
Figure 4. Figure 4. Long‐term effects of afferent carotid sinus baroreceptor stimulation, showing prolonged decrease in mean arterial pressure for a period of 3 weeks. This effect was not seen in sino‐aortic denervated (SAD) animals. PBA: prolonged baroreflex activation. From (), with permission.
Figure 5. Figure 5. Maintained responsiveness of MSNA to carotid baroreceptor stimulation (using the neck collar technique) during arm cycling exercise as compared to resting conditions. ECSP: estimated carotid sinus pressure. From (), with permission.
Figure 6. Figure 6. Marked decrease in MSNA following exercise training in patients with congestive heart failure (CHF). Note lack of change in MSNA in CHF patients who did not exercise, and also lack of change in MSNA in control subjects following exercise training. From (), with permission of Elsevier.
Figure 7. Figure 7. Relationships between MSNA responses to mental stress and MSNA responses to arousal or cold stress in a group of young healthy young men (see text for discussion). MSNA responses to mental stress were significantly related to MSNA responses to arousal, both when expressed as bursts/min and as bursts/100 heartbeats. There was no relationship between responses evoked by arousal and the cold test. From (), with permission.


Figure 1. Schematic summary of central neural mechanisms involved in baroreflex regulation of the heart and circulation. Baroreceptor afferent signals synapse at the nucleus tractus solitarii (NTS), after which glutaminergic excitatory fibers relay the cardiovascular information in two major directions: to the nucleus ambiguous (NA) and cardiac vagal motoneurones, and to the caudal ventrolateral medulla (CVLM). GABA‐ergic fibers from CVLM project to sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) where they cause inhibition of subsequent efferent pre‐ and postganglionic sympathetic activities. Inhibitory neural connections are shown as dotted lines. Adapted from (), with permission of Oxford University Press.


Figure 2. Inter‐individual variability of mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR) in young healthy subjects. Note that variability in CO and TPR is much greater than that of MAP. CV: coefficient of variation. From (), with permission.


Figure 3. Relationships between MSNA and CO, MSNA and TPR and MSNA and MAP in young healthy men. MSNA was directly related to TPR, showing that it is a good index of whole body “net” vasoconstrictor tone in this group. The inverse relationship between MSNA and CO helps to balance the pressor effects of MSNA, contributing to the lack of relationship between MSNA and MAP. From (), with permission.


Figure 4. Long‐term effects of afferent carotid sinus baroreceptor stimulation, showing prolonged decrease in mean arterial pressure for a period of 3 weeks. This effect was not seen in sino‐aortic denervated (SAD) animals. PBA: prolonged baroreflex activation. From (), with permission.


Figure 5. Maintained responsiveness of MSNA to carotid baroreceptor stimulation (using the neck collar technique) during arm cycling exercise as compared to resting conditions. ECSP: estimated carotid sinus pressure. From (), with permission.


Figure 6. Marked decrease in MSNA following exercise training in patients with congestive heart failure (CHF). Note lack of change in MSNA in CHF patients who did not exercise, and also lack of change in MSNA in control subjects following exercise training. From (), with permission of Elsevier.


Figure 7. Relationships between MSNA responses to mental stress and MSNA responses to arousal or cold stress in a group of young healthy young men (see text for discussion). MSNA responses to mental stress were significantly related to MSNA responses to arousal, both when expressed as bursts/min and as bursts/100 heartbeats. There was no relationship between responses evoked by arousal and the cold test. From (), with permission.
References
 1. Abate NI , Mansour YH , Tuncel M , Arbique D , Chavoshan B , Kizilbash A , Howell‐Stampley T , Vongpatanasin W , Victor RG . Overweight and sympathetic overactivity in black Americans. Hypertension 38: 379‐383, 2001.
 2. Adrian ED , Bronk DW , Phillips G . Discharges in mammalian sympathetic nerves. J Physiol 74: 115‐133, 1932.
 3. Alvarez GE , Halliwill JR , Ballard TP , Beske SD , Davy KP . Sympathetic neural regulation in endurance‐trained humans: Fitness vs. fatness. J Appl Physiol 98: 498‐502, 2005.
 4. Anderson EA , Sinkey CA , Lawton WJ , Mark AL . Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension 14: 177‐183, 1989.
 5. Anderson EA , Sinkey CA , Mark AL . Mental stress increases sympathetic nerve activity during sustained baroreceptor stimulation in humans. Hypertension 17: III43‐III49, 1991.
 6. Anderson EA , Wallin BG , Mark AL . Dissociation of sympathetic nerve activity in arm and leg muscle during mental stress. Hypertension 9: III114‐III119, 1987.
 7. Angell‐James JE . Characteristics of single aortic and right subclavian baroreceptor fiber activity in rabbits with chronic renal hypertension. Circ Res 32: 149‐161, 1973.
 8. Barcroft H , Brod J , Hejl BZ , Hirsjarvi EA , Kitchin AH . The mechanism of the vasodilatation in the forearm muscle during stress (mental arithmetic). Clin Sci 19: 577‐586, 1960.
 9. Barrett CJ , Ramchandra R , Guild SJ , Lala A , Budgett DM , Malpas SC . What sets the long‐term level of renal sympathetic nerve activity: A role for angiotensin II and baroreflexes? Circ Res 92: 1330‐1336, 2003.
 10. Barretto AC , Santos AC , Munhoz R , Rondon MU , Franco FG , Trombetta IC , Roveda F , de Matos LN , Braga AM , Middlekauff HR , Negrao CE . Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Int J Cardiol 135: 302‐307, 2009.
 11. Beske SD , Alvarez GE , Ballard TP , Davy KP . Gender difference in cardiovagal baroreflex gain in humans. J Appl Physiol 91: 2088‐2092, 2001.
 12. Bini G , Hagbarth KE , Hynninen P , Wallin BG . Thermoregulatory and rhythm‐generating mechanisms governing the sudomotor and vasoconstrictor outflow in human cutaneous nerves. J Physiol 306: 537‐552, 1980.
 13. Boulant JA . Hypothalamic neurons regulating body temperature. In: Fregly MJ and Blatteis CM , editors. Handbook of Physiology, Section 4: Environmental Physiology. New York: Oxford University Press, 1996, pp. 105‐126.
 14. Boulant JA . Neuronal basis of Hammel's model for set‐point thermoregulation. J Appl Physiol 100: 1347‐1354, 2006.
 15. Brod J , Fencl V , Hejl Z , Jirka J . Circulatory changes underlying blood pressure elevation during acute emotional stress (mental arithmetic) in normotensive and hypertensive subjects. Clin Sci 18: 269‐279, 1959.
 16. Bronk DW , Ferguson LK , Margaria R , Solandt DY . The activity of the cardiac sympathetic centers. Am J Phys 117: 237‐249, 1936.
 17. Brothers RM , Keller DM , Wingo JE , Ganio MS , Crandall CG . Heat‐stress‐induced changes in central venous pressure do not explain interindividual differences in orthostatic tolerance during heat stress. J Appl Physiol 110: 1283‐1289, 2011.
 18. Brothers RM , Wingo JE , Hubing KA , Del Coso J , Crandall CG . Effect of whole body heat stress on peripheral vasoconstriction during leg dependency. J Appl Physiol 107: 1704‐1709, 2009.
 19. Brown AM , Saum WR , Tuley FH . A comparison of aortic baroreceptor discharge in normotensive and spontaneously hypertensive rats. Circ Res 39: 488‐496, 1976.
 20. Bruno RM , Sudano I , Ghiadoni L , Masi L , Taddei S . Interactions between sympathetic nervous system and endogenous endothelin in patients with essential hypertension. Hypertension 57: 79‐84, 2011.
 21. Butt C , Pathmadeva C , Spencer C . Forearm and calf blood flow in response to cortical arousal in normal male and female subjects. Clin Auton Res 9: 103‐107, 1999.
 22. Callister R , Suwarno NO , Seals DR . Sympathetic activity is influenced by task difficulty and stress perception during mental challenge in humans. J Physiol 454: 373‐387, 1992.
 23. Caraffa‐Braga E , Granata L , Pinotti O . Changes in blood‐flow distribution during acute emotional stress in dogs. Pflugers Arch 339: 203‐216, 1973.
 24. Carlson JT , Hedner J , Elam M , Ejnell H , Sellgren J , Wallin BG . Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 103: 1763‐1768, 1993.
 25. Carlson SH and Wyss JM . Neurohormonal regulation of the sympathetic nervous system: new insights into central mechanisms of action. Curr Hypertens Rep 10: 233‐240, 2008.
 26. Carroll D , Smith GD , Shipley MJ , Steptoe A , Brunner EJ , Marmot MG . Blood pressure reactions to acute psychological stress and future blood pressure status: A 10‐year follow‐up of men in the Whitehall II study. Psychosom Med 63: 737‐743, 2001.
 27. Carter JR , Durocher JJ , Kern RP . Neural and cardiovascular responses to emotional stress in humans. Am J Physiol Regul Integr Comp Physiol 295: R1898‐R1903, 2008.
 28. Carter JR , Kupiers NT , Ray CA . Neurovascular responses to mental stress. J Physiol 564: 321‐327, 2005.
 29. Carter JR , Ray CA , Cooke WH . Vestibulosympathetic reflex during mental stress. J Appl Physiol 93: 1260‐1264, 2002.
 30. Casey DP and Joyner MJ . Skeletal muscle blood flow responses to hypoperfusion at rest and during rhythmic exercise in humans. J Appl Physiol 107: 429‐437, 2009.
 31. Cates MJ , Dickinson CJ , Hart EC , Paton JF . Neurogenic hypertension and elevated vertebrobasilar arterial resistance: Is there a causative link? Curr Hypertens Rep 14: 261‐269, 2012.
 32. Cates MJ , Steed PW , Abdala AP , Langton PD , Paton JF . Elevated vertebrobasilar artery resistance in neonatal spontaneously hypertensive rats. J Appl Physiol 111: 149‐156, 2011.
 33. Cechetto DF and Saper CB . Role of the cerebral cortex in autonomic function. In: Loewy AD and Spyer KM , editors. Central Regulation of Autonomic Functions. New York: Oxford University Press, 1990, pp. 208‐233.
 34. Charkoudian N . Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol 109: 1221‐1228, 2010.
 35. Charkoudian N , Eisenach JH , Joyner MJ , Roberts SK , Wick DE . Interactions of plasma osmolality with arterial and central venous pressures in control of sympathetic activity and heart rate in humans. Am J Physiol Heart Circ Physiol 289: H2456‐H2460, 2005.
 36. Charkoudian N , Gusman E , Joyner MJ , Wallin BG , Osborn J . Integrative mechanisms of blood pressure regulation in humans and rats: Cross‐species similarities. Am J Physiol Regul Integr Comp Physiol 298: R755‐R759, 2010.
 37. Charkoudian N , Halliwill JR , Morgan BJ , Eisenach JH , Joyner MJ . Influences of hydration on post‐exercise cardiovascular control in humans. J Physiol 552: 635‐644, 2003.
 38. Charkoudian N , Joyner MJ , Barnes SA , Johnson CP , Eisenach JH , Dietz NM , Wallin BG . Relationship between muscle sympathetic nerve activity and systemic hemodynamics during nitric oxide synthase inhibition in humans. Am J Physiol Heart Circ Physiol 291: H1378‐H1383, 2006.
 39. Charkoudian N , Joyner MJ , Johnson CP , Eisenach JH , Dietz NM , Wallin BG . Balance between cardiac output and sympathetic nerve activity in resting humans: Role in arterial pressure regulation. J Physiol 568: 315‐321, 2005.
 40. Charkoudian N , Joyner MJ , Sokolnicki LA , Johnson CP , Eisenach JH , Dietz NM , Curry TB , Wallin BG . Vascular adrenergic responsiveness is inversely related to tonic activity of sympathetic vasoconstrictor nerves in humans. J Physiol 572: 821‐827, 2006.
 41. Chida Y and Steptoe A . Greater cardiovascular responses to laboratory mental stress are associated with poor subsequent cardiovascular risk status: A meta‐analysis of prospective evidence. Hypertension 55: 1026‐1032, 2010.
 42. Cowley AW, Jr , Liard JF , Guyton AC . Role of baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ Res 32: 564‐576, 1973.
 43. Crandall CG , Cui J , Wilson TE . Effects of heat stress on baroreflex function in humans. Acta Physiol Scand 177: 321‐328, 2003.
 44. Crandall CG , Johnson JM , Kosiba WA , Kellogg DL, Jr . Baroreceptor control of the cutaneous active vasodilator system. J Appl Physiol 81: 2192‐2198, 1996.
 45. Cui J , Sathishkumar M , Wilson TE , Shibasaki M , Davis SL , Crandall CG . Spectral characteristics of skin sympathetic nerve activity in heat‐stressed humans. Am J Physiol Heart Circ Physiol 290: H1601‐H1609, 2006.
 46. Dampney RA , Coleman MJ , Fontes MA , Hirooka Y , Horiuchi J , Li YW , Polson JW , Potts PD , Tagawa T . Central mechanisms underlying short‐ and long‐term regulation of the cardiovascular system. Clin Exp Pharmacol Physiol 29: 261‐268, 2002.
 47. Dampney RA , McAllen RM . Differential control of sympathetic fibres supplying hindlimb skin and muscle by subretrofacial neurones in the cat. J Physiol 395: 41‐56, 1988.
 48. Davy KP , Tanaka H , Andros EA , Gerber JG , Seals DR . Influence of age on arterial baroreflex inhibition of sympathetic nerve activity in healthy adult humans. Am J Physiol 275: H1768‐H1772, 1998.
 49. de Mello Franco FG , Santos AC , Rondon MU , Trombetta IC , Strunz C , Braga AM , Middlekauff H , Negrao CE , Pereira Barretto AC . Effects of home‐based exercise training on neurovascular control in patients with heart failure. Eur J Heart Fail 8: 851‐855, 2006.
 50. Delius W , Hagbarth KE , Hongell A , Wallin BG . General characteristics of sympathetic activity in human muscle nerves. Acta Physiol Scand 84: 65‐81, 1972.
 51. Delius W , Hagbarth KE , Hongell A , Wallin BG . Manoeuvres affecting sympathetic outflow in human skin nerves. Acta Physiol Scand 84: 177‐186, 1972.
 52. DiBona GF , Kopp UC . Neural control of renal function. Physiol Rev 77: 75‐197, 1997.
 53. DiCarlo SE , Bishop VS . Central baroreflex resetting as a means of increasing and decreasing sympathetic outflow and arterial pressure. Ann N Y Acad Sci 940: 324‐337, 2001.
 54. DiCarlo SE , Bishop VS . Onset of exercise shifts operating point of arterial baroreflex to higher pressures. Am J Physiol 262: H303‐H307, 1992.
 55. Dinenno FA , Joyner MJ . Alpha‐adrenergic control of skeletal muscle circulation at rest and during exercise in aging humans. Microcirculation 13: 329‐341, 2006.
 56. Donadio V , Kallio M , Karlsson T , Nordin M , Wallin BG . Inhibition of human muscle sympathetic activity by sensory stimulation. J Physiol 544: 285‐292, 2002.
 57. Donadio V , Karlsson T , Elam M , Wallin BG . Interindividual differences in sympathetic and effector responses to arousal in humans. J Physiol 544: 293‐302, 2002.
 58. Donadio V , Liguori R , Elam M , Karlsson T , Giannoccaro MP , Pegenius G , Giambattistelli F , Wallin BG . Muscle sympathetic response to arousal predicts neurovascular reactivity during mental stress. J Physiol 590: 2885‐2896, 2012.
 59. Donadio V , Liguori R , Elam M , Karlsson T , Montagna P , Cortelli P , Baruzzi A , Wallin BG . Arousal elicits exaggerated inhibition of sympathetic nerve activity in phobic syncope patients. Brain 130: 1653‐1662, 2007.
 60. Dorward PK , Riedel W , Burke SL , Gipps J , Korner PI . The renal sympathetic baroreflex in the rabbit. Arterial and cardiac baroreceptor influences, resetting, and effect of anesthesia. Circ Res 57: 618‐633, 1985.
 61. Doumas M , Faselis C , Tsioufis C , Papademetriou V . Carotid baroreceptor activation for the treatment of resistant hypertension and heart failure. Curr Hypertens Rep 14: 238‐246, 2012.
 62. Ebert TJ , Cowley AW, Jr . Baroreflex modulation of sympathetic outflow during physiological increases of vasopressin in humans. Am J Physiol 262: H1372‐H1378, 1992.
 63. Eckberg DL , Rea RF , Andersson OK , Hedner T , Pernow J , Lundberg JM , Wallin BG . Baroreflex modulation of sympathetic activity and sympathetic neurotransmitters in humans. Acta Physiol Scand 133: 221‐231, 1988.
 64. Elam M , McKenzie D , Macefield V . Mechanisms of sympathoexcitation: Single‐unit analysis of muscle vasoconstrictor neurons in awake OSAS subjects. J Appl Physiol 93: 297‐303, 2002.
 65. Engelman K , Portnoy B . A sensitive double‐isotope derivative assay for norepinephrine and epinephrine. Normal resting human plasma levels. Circ Res 26: 53‐57, 1970.
 66. Ergul S , Parish DC , Puett D , Ergul A . Racial differences in plasma endothelin‐1 concentrations in individuals with essential hypertension. Hypertension 28: 652‐655, 1996.
 67. Esler M . The sympathetic system and hypertension. Am J Hypertens 13: 99S‐105S, 2000.
 68. Esler M . The 2009 Carl Ludwig Lecture: Pathophysiology of the human sympathetic nervous system in cardiovascular diseases: The transition from mechanisms to medical management. J Appl Physiol 108: 227‐237, 2010.
 69. Esler M . Sympathetic nervous activation in essential hypertension: Commonly neglected as a therapeutic target, usually ignored as a drug side effect. Hypertension 55: 1090‐1091, 2010.
 70. Esler M . The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension. Exp Physiol 96: 611‐622, 2011.
 71. Esler M , Eikelis N , Schlaich M , Lambert G , Alvarenga M , Dawood T , Kaye D , Barton D , Pier C , Guo L , Brenchley C , Jennings G , Lambert E . Chronic mental stress is a cause of essential hypertension: Presence of biological markers of stress. Clin Exp Pharmacol Physiol 35: 498‐502, 2008.
 72. Esler M , Eikelis N , Schlaich M , Lambert G , Alvarenga M , Kaye D , El‐Osta A , Guo L , Barton D , Pier C , Brenchley C , Dawood T , Jennings G , Lambert E . Human sympathetic nerve biology: Parallel influences of stress and epigenetics in essential hypertension and panic disorder. Ann N Y Acad Sci 1148: 338‐348, 2008.
 73. Esler M , Jennings G , Korner P , Willett I , Dudley F , Hasking G , Anderson W , Lambert G . Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension 11: 3‐20, 1988.
 74. Esler M , Lambert G , Brunner‐La Rocca HP , Vaddadi G , Kaye D . Sympathetic nerve activity and neurotransmitter release in humans: Translation from pathophysiology into clinical practice. Acta Physiol Scand 177: 275‐284, 2003.
 75. Esler MD , Krum H , Schlaich M , Schmieder RE , Bohm M , Sobotka PA . Renal sympathetic denervation for treatment of drug‐resistant hypertension: One‐year results from the Symplicity HTN‐2 randomized, controlled trial. Circulation 126: 2976‐2982, 2012.
 76. Esler MD , Krum H , Sobotka PA , Schlaich MP , Schmieder RE , Bohm M . Renal sympathetic denervation in patients with treatment‐resistant hypertension (The Symplicity HTN‐2 Trial): A randomised controlled trial. Lancet 376: 1903‐1909, 2010.
 77. Esler MD , Turner AG , Kaye DM , Thompson JM , Kingwell BA , Morris M , Lambert GW , Jennings GL , Cox HS , Seals DR . Aging effects on human sympathetic neuronal function. Am J Physiol 268: R278‐R285, 1995.
 78. Evans RR , Phillips BG , Singh G , Bauman JL , Gulati A . Racial and gender differences in endothelin‐1. Am J Cardiol 78: 486‐488, 1996.
 79. Everson SA , Kaplan GA , Goldberg DE , Salonen JT . Anticipatory blood pressure response to exercise predicts future high blood pressure in middle‐aged men. Hypertension 27: 1059‐1064, 1996.
 80. Fadel PJ , Ogoh S , Watenpaugh DE , Wasmund W , Olivencia‐Yurvati A , Smith ML , Raven PB . Carotid baroreflex regulation of sympathetic nerve activity during dynamic exercise in humans. Am J Physiol Heart Circ Physiol 280: H1383‐H1390, 2001.
 81. Fagius J , Berne C . Increase in muscle nerve sympathetic activity in humans after food intake. Clin Sci (Lond) 86: 159‐167, 1994.
 82. Fagius J , Wallin BG . Long‐term variability and reproducibility of resting human muscle nerve sympathetic activity at rest, as reassessed after a decade. Clin Auton Res 3: 201‐205, 1993.
 83. Fagius J , Wallin BG . Sympathetic reflex latencies and conduction velocities in normal man. J Neurol Sci 47: 433‐448, 1980.
 84. Fagius J , Wallin BG . Sympathetic reflex latencies and conduction velocities in patients with polyneuropathy. J Neurol Sci 47: 449‐461, 1980.
 85. Ferrier C , Jennings GL , Eisenhofer G , Lambert G , Cox HS , Kalff V , Kelly M , Esler MD . Evidence for increased noradrenaline release from subcortical brain regions in essential hypertension. J Hypertens 11: 1217‐1227, 1993.
 86. Flaa A , Eide IK , Kjeldsen SE , Rostrup M . Sympathoadrenal stress reactivity is a predictor of future blood pressure: An 18‐year follow‐up study. Hypertension 52: 336‐341, 2008.
 87. Foley CM , McAllister RM , Hasser EM . Thyroid status influences baroreflex function and autonomic contributions to arterial pressure and heart rate. Am J Physiol Heart Circ Physiol 280: H2061‐H2068, 2001.
 88. Foley CM , Mueller PJ , Hasser EM , Heesch CM . Hindlimb unloading and female gender attenuate baroreflex‐mediated sympathoexcitation. Am J Physiol Regul Integr Comp Physiol 289: R1440‐R1447, 2005.
 89. Folkow B . Physiological aspects of the “defence” and “defeat” reactions. Acta Physiol Scand Suppl 640: 34‐37, 1997.
 90. Forsyth RP . Sympathetic nervous system control of distribution of cardiac output in unanesthetized monkeys. Fed Proc 31: 1240‐1244, 1972.
 91. Fraga R , Franco FG , Roveda F , de Matos LN , Braga AM , Rondon MU , Rotta DR , Brum PC , Barretto AC , Middlekauff HR , Negrao CE . Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol. Eur J Heart Fail 9: 630‐636, 2007.
 92. Gallagher KM , Fadel PJ , Smith SA , Stromstad M , Ide K , Secher NH , Raven PB . The interaction of central command and the exercise pressor reflex in mediating baroreflex resetting during exercise in humans. Exp Physiol 91: 79‐87, 2006.
 93. Goodwin GM , McCloskey DI , Mitchell JH . Cardiovascular and respiratory responses to changes in central command during isometric exercise at constant muscle tension. J Physiol 226: 173‐190, 1972.
 94. Grassi G , Quarti‐Trevano F , Seravalle G , Arenare F , Volpe M , Furiani S , Dell'Oro R , Mancia G . Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension 57: 846‐851, 2011.
 95. Grassi G , Seravalle G , Colombo M , Bolla G , Cattaneo BM , Cavagnini F , Mancia G . Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans. Circulation 97: 2037‐2042, 1998.
 96. Grassi G , Seravalle G , Dell'Oro R , Turri C , Bolla GB , Mancia G . Adrenergic and reflex abnormalities in obesity‐related hypertension. Hypertension 36: 538‐542, 2000.
 97. Greenwood JP , Scott EM , Stoker JB , Walker JJ , Mary DA . Sympathetic neural mechanisms in normal and hypertensive pregnancy in humans. Circulation 104: 2200‐2204, 2001.
 98. Gribbin B , Pickering TG , Sleight P . Decrease in baroreflex sensitivity with increasing arterial pressure and with increasing age. Br Heart J 31: 791‐798, 1969.
 99. Gribbin B , Pickering TG , Sleight P , Peto R . Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 29: 424‐431, 1971.
 100. Groeschel M , Braam B . Connecting chronic and recurrent stress to vascular dysfunction: No relaxed role for the renin‐angiotensin system. Am J Physiol Renal Physiol 300: F1‐F10, 2011.
 101. Gudbjornsdottir S , Lonnroth P , Sverrisdottir YB , Wallin BG , Elam M . Sympathetic nerve activity and insulin in obese normotensive and hypertensive men. Hypertension 27: 276‐280, 1996.
 102. Guimaraes S , Moura D . Vascular adrenoceptors: an update. Pharmacol Rev 53: 319‐356, 2001.
 103. Guyenet PG . Role of the ventral medulla oblongata in blood pressure regulation. In: Lowey AD and Spyer KM , editors. Central Regulation of Autonomic Functions. Oxford: Oxford University Press, 1990.
 104. Guyenet PG . The sympathetic control of blood pressure. Nat Rev Neurosci 7: 335‐346, 2006.
 105. Guyton AC , Coleman TG , Cowley AV, Jr , Scheel KW , Manning RD, Jr , Norman RA, Jr . Arterial pressure regulation. Overriding dominance of the kidneys in long‐term regulation and in hypertension. Am J Med 52: 584‐594, 1972.
 106. Guyton AC , Coleman TG , Cowley AW, Jr , Liard JF , Norman RA, Jr , Manning RD, Jr . Systems analysis of arterial pressure regulation and hypertension. Ann Biomed Eng 1: 254‐281, 1972.
 107. Hagbarth KE , Hallin RG , Hongell A , Torebjork HE , Wallin BG . General characteristics of sympathetic activity in human skin nerves. Acta Physiol Scand 84: 164‐176, 1972.
 108. Hagbarth KE , Vallbo AB . Pulse and respiratory grouping of sympathetic impulses in human muscle‐nerves. Acta Physiol Scand 74: 96‐108, 1968.
 109. Halliwill JR , Lawler LA , Eickhoff TJ , Dietz NM , Nauss LA , Joyner MJ . Forearm sympathetic withdrawal and vasodilatation during mental stress in humans. J Physiol 504: 211‐220, 1997.
 110. Halliwill JR , Minson CT . Effect of hypoxia on arterial baroreflex control of heart rate and muscle sympathetic nerve activity in humans. J Appl Physiol 93: 857‐864, 2002.
 111. Halliwill JR , Morgan BJ , Charkoudian N . Peripheral chemoreflex and baroreflex interactions in cardiovascular regulation in humans. J Physiol 552: 295‐302, 2003.
 112. Halliwill JR , Taylor JA , Eckberg DL . Impaired sympathetic vascular regulation in humans after acute dynamic exercise. J Physiol 495: 279‐288, 1996.
 113. Hamner JW , Taylor JA . Automated quantification of sympathetic beat‐by‐beat activity, independent of signal quality. J Appl Physiol 91: 1199‐1206, 2001.
 114. Hansen J , Jacobsen TN , Victor RG . Is nitric oxide involved in the tonic inhibition of central sympathetic outflow in humans? Hypertension 24: 439‐444, 1994.
 115. Hansen J , Sander M . Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia. J Physiol 546: 921‐929, 2003.
 116. Hart EC , Charkoudian N , Wallin BG , Curry TB , Eisenach J , Joyner MJ . Sex and ageing differences in resting arterial pressure regulation: The role of the beta‐adrenergic receptors. J Physiol 589: 5285‐5297, 2011.
 117. Hart EC , Charkoudian N , Wallin BG , Curry TB , Eisenach JH , Joyner MJ . Sex differences in sympathetic neural‐hemodynamic balance: Implications for human blood pressure regulation. Hypertension 53: 571‐576, 2009.
 118. Hart EC , Joyner MJ , Wallin BG , Charkoudian N . Sex, ageing and resting blood pressure: Gaining insights from the integrated balance of neural and haemodynamic factors. J Physiol 590: 2069‐2079, 2012.
 119. Hart EC , Joyner MJ , Wallin BG , Johnson CP , Curry TB , Eisenach JH , Charkoudian N . Age‐related differences in the sympathetic‐hemodynamic balance in men. Hypertension 54: 127‐133, 2009.
 120. Hart EC , Joyner MJ , Wallin BG , Karlsson T , Curry TB , Charkoudian N . Baroreflex control of muscle sympathetic nerve activity: A nonpharmacological measure of baroreflex sensitivity. Am J Physiol Heart Circ Physiol 298: H816‐H822, 2010.
 121. Head GA , Burke SL . Sympathetic responses to stress and rilmenidine in 2K1C rabbits: Evidence of enhanced nonvascular effector mechanism. Hypertension 43: 636‐642, 2004.
 122. Hinojosa‐Laborde C , Mifflin SW . Sex differences in blood pressure response to intermittent hypoxia in rats. Hypertension 46: 1016‐1021, 2005.
 123. Ichinose M , Saito M , Fujii N , Ogawa T , Hayashi K , Kondo N , Nishiyasu T . Modulation of the control of muscle sympathetic nerve activity during incremental leg cycling. J Physiol 586: 2753‐2766, 2008.
 124. Ichinose M , Saito M , Kondo N , Nishiyasu T . Time‐dependent modulation of arterial baroreflex control of muscle sympathetic nerve activity during isometric exercise in humans. Am J Physiol Heart Circ Physiol 290: H1419‐H1426, 2006.
 125. Ichinose M , Saito M , Wada H , Kitano A , Kondo N , Nishiyasu T . Modulation of arterial baroreflex dynamic response during muscle metaboreflex activation in humans. J Physiol 544: 939‐948, 2002.
 126. Iggo A , Vogt M . Preganglionic sympathetic activity in normal and in reserpine‐treated cats. J Physiol 150: 114‐133, 1960.
 127. Janig W . Regulation of organ systems by the lower brain stem. In: The Integrative Action of the Autonomic Nervous System: Neurobiology of Homeostasis. Cambridge, UK: Cambridge University Press, 2006.
 128. Jarvis SS , Shibata S , Bivens TB , Okada Y , Casey BM , Levine BD , Fu Q . Sympathetic activation during early pregnancy in humans. J Physiol 590: 3535‐3543, 2012.
 129. Jennings JR , Kamarck TW , Everson‐Rose SA , Kaplan GA , Manuck SB , Salonen JT . Exaggerated blood pressure responses during mental stress are prospectively related to enhanced carotid atherosclerosis in middle‐aged Finnish men. Circulation 110: 2198‐2203, 2004.
 130. Johns EJ , Kopp UC , Dibona GF . Neural control of renal function. Compr Physiol 1: 731‐767, 2011.
 131. Jones PP , Shapiro LF , Keisling GA , Jordan J , Shannon JR , Quaife RA , Seals DR . Altered autonomic support of arterial blood pressure with age in healthy men. Circulation 104: 2424‐2429, 2001.
 132. Joyner MJ , Dietz NM . Nitric oxide and vasodilation in human limbs. J Appl Physiol 83: 1785‐1796, 1997.
 133. Judy WV , Farrell SK . Arterial baroreceptor reflex control of sympathetic nerve activity in the spontaneously hypertensive rat. Hypertension 1: 605‐614, 1979.
 134. Kamiya A , Kawada T , Yamamoto K , Michikami D , Ariumi H , Miyamoto T , Shimizu S , Uemura K , Aiba T , Sunagawa K , Sugimachi M . Dynamic and static baroreflex control of muscle sympathetic nerve activity (SNA) parallels that of renal and cardiac SNA during physiological change in pressure. Am J Physiol Heart Circ Physiol 289: H2641‐H2648, 2005.
 135. Kamiya A , Kawada T , Yamamoto K , Michikami D , Ariumi H , Miyamoto T , Uemura K , Sugimachi M , Sunagawa K . Muscle sympathetic nerve activity averaged over 1 minute parallels renal and cardiac sympathetic nerve activity in response to a forced baroreceptor pressure change. Circulation 112: 384‐386, 2005.
 136. Kara T , Narkiewicz K , Somers VK . Chemoreflexes–physiology and clinical implications. Acta Physiol Scand 177: 377‐384, 2003.
 137. Kaufman MP . The exercise pressor reflex in animals. Exp Physiol 97: 51‐58, 2012.
 138. Kaufman MP , Hayes SG . The exercise pressor reflex. Clin Auton Res 12: 429‐439, 2002.
 139. Kawano Y , Yoshida K , Matsuoka H , Omae T . Chronic effects of central and systemic administration of losartan on blood pressure and baroreceptor reflex in spontaneously hypertensive rats. Am J Hypertens 7: 536‐542, 1994.
 140. Keller DM , Low DA , Wingo JE , Brothers RM , Hastings J , Davis SL , Crandall CG . Acute volume expansion preserves orthostatic tolerance during whole‐body heat stress in humans. J Physiol 587: 1131‐1139, 2009.
 141. Keller DM , Wasmund WL , Wray DW , Ogoh S , Fadel PJ , Smith ML , Raven PB . Carotid baroreflex control of leg vascular conductance at rest and during exercise. J Appl Physiol 94: 542‐548, 2003.
 142. Kellogg DL, Jr , Johnson JM , Kosiba WA . Baroreflex control of the cutaneous active vasodilator system in humans. Circ Res 66: 1420‐1426, 1990.
 143. Kellogg DL, Jr , Pergola PE , Piest KL , Kosiba WA , Crandall CG , Grossmann M , Johnson JM . Cutaneous active vasodilation in humans is mediated by cholinergic nerve cotransmission. Circ Res 77: 1222‐1228, 1995.
 144. Khalil RA . Modulators of the vascular endothelin receptor in blood pressure regulation and hypertension. Curr Mol Pharmacol 4: 176‐186, 2011.
 145. Kienbaum P , Karlssonn T , Sverrisdottir YB , Elam M , Wallin BG . Two sites for modulation of human sympathetic activity by arterial baroreceptors? J Physiol 531: 861‐869, 2001.
 146. Kneale BJ , Chowienczyk PJ , Brett SE , Coltart DJ , Ritter JM . Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J Am Coll Cardiol 36: 1233‐1238, 2000.
 147. Kocsis B , Karlsson T , Wallin BG . Cardiac‐ and noncardiac‐related coherence between sympathetic drives to muscles of different human limbs. Am J Physiol 276: R1608‐R1616, 1999.
 148. Kohan DE , Rossi NF , Inscho EW , Pollock DM . Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev 91: 1‐77, 2011.
 149. Kumagai H , Oshima N , Matsuura T , Iigaya K , Imai M , Onimaru H , Sakata K , Osaka M , Onami T , Takimoto C , Kamayachi T , Itoh H , Saruta T . Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure. Hypertens Res 35: 132‐141, 2012.
 150. Lambert EA , Lambert GW . Stress and its role in sympathetic nervous system activation in hypertension and the metabolic syndrome. Curr Hypertens Rep 13: 244‐248, 2011.
 151. Leimbach WN, Jr , Wallin BG , Victor RG , Aylward PE , Sundlof G , Mark AL . Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 73: 913‐919, 1986.
 152. Lohmeier TE , Dwyer TM , Irwin ED , Rossing MA , Kieval RS . Prolonged activation of the baroreflex abolishes obesity‐induced hypertension. Hypertension 49: 1307‐1314, 2007.
 153. Lohmeier TE , Hildebrandt DA , Dwyer TM , Barrett AM , Irwin ED , Rossing MA , Kieval RS . Renal denervation does not abolish sustained baroreflex‐mediated reductions in arterial pressure. Hypertension 49: 373‐379, 2007.
 154. Lohmeier TE , Iliescu R , Dwyer TM , Irwin ED , Cates AW , Rossing MA . Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex. Am J Physiol Heart Circ Physiol 299: H402‐H409, 2010.
 155. Lohmeier TE , Irwin ED , Rossing MA , Serdar DJ , Kieval RS . Prolonged activation of the baroreflex produces sustained hypotension. Hypertension 43: 306‐311, 2004.
 156. Lovick TA . Differential control of cardiac and vasomotor activity by neurones in nucleus paragigantocellularis lateralis in the cat. J Physiol 389: 23‐35, 1987.
 157. Low DA , Keller DM , Wingo JE , Brothers RM , Crandall CG . Sympathetic nerve activity and whole body heat stress in humans. J Appl Physiol 111: 1329‐1334, 2011.
 158. Lundin S , Ricksten SE , Thoren P . Interaction between “mental stress” and baroreceptor reflexes concerning effects on heart rate, mean arterial pressure and renal sympathetic activity in conscious spontaneously hypertensive rats. Acta Physiol Scand 120: 273‐281, 1984.
 159. Lundin S , Ricksten SE , Thoren P . Renal sympathetic activity in spontaneously hypertensive rats and normotensive controls, as studied by three different methods. Acta Physiol Scand 120: 265‐272, 1984.
 160. Macefield VG , Elam M , Wallin BG . Firing properties of single postganglionic sympathetic neurones recorded in awake human subjects. Auton Neurosci 95: 146‐159, 2002.
 161. Macefield VG , Henderson LA . Real‐time imaging of the medullary circuitry involved in the generation of spontaneous muscle sympathetic nerve activity in awake subjects. Hum Brain Mapp 31: 539‐549, 2010.
 162. Macefield VG , Rundqvist B , Sverrisdottir YB , Wallin BG , Elam M . Firing properties of single muscle vasoconstrictor neurons in the sympathoexcitation associated with congestive heart failure. Circulation 100: 1708‐1713, 1999.
 163. Macefield VG , Wallin BG . Firing properties of single vasoconstrictor neurones in human subjects with high levels of muscle sympathetic activity. J Physiol 516 (Pt 1): 293‐301, 1999.
 164. Macefield VG , Wallin BG , Vallbo AB . The discharge behaviour of single vasoconstrictor motoneurones in human muscle nerves. J Physiol 481 (Pt 3): 799‐809, 1994.
 165. Mahfoud F , Ukena C , Schmieder RE , Cremers B , Rump LC , Vonend O , Weil J , Schmidt M , Hoppe UC , Zeller T , Bauer A , Ott C , Blessing E , Sobotka PA , Krum H , Schlaich M , Esler M , Bohm M . Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Circulation 128: 132‐140, 2013.
 166. Malpas SC . Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev 90: 513‐557, 2010.
 167. Malpas SC . What sets the long‐term level of sympathetic nerve activity: Is there a role for arterial baroreceptors? Am J Physiol Regul Integr Comp Physiol 286: R1‐R12, 2004.
 168. Masuo K , Lambert GW , Esler MD , Rakugi H , Ogihara T , Schlaich MP . The role of sympathetic nervous activity in renal injury and end‐stage renal disease. Hypertens Res 33: 521‐528, 2010.
 169. Matsukawa K , Shindo T , Shirai M , Ninomiya I . Direct observations of sympathetic cholinergic vasodilatation of skeletal muscle small arteries in the cat. J Physiol 500 (Pt 1): 213‐225, 1997.
 170. Matsukawa T , Gotoh E , Uneda S , Miyajima E , Shionoiri H , Tochikubo O , Ishii M . Augmented sympathetic nerve activity in response to stressors in young borderline hypertensive men. Acta Physiol Scand 141: 157‐165, 1991.
 171. Matsukawa T , Sugiyama Y , Mano T . Age‐related changes in baroreflex control of heart rate and sympathetic nerve activity in healthy humans. J Auton Nerv Syst 60: 209‐212, 1996.
 172. Matsukawa T , Sugiyama Y , Watanabe T , Kobayashi F , Mano T . Gender difference in age‐related changes in muscle sympathetic nerve activity in healthy subjects. Am J Physiol 275: R1600‐R1604, 1998.
 173. Matthews KA , Woodall KL , Allen MT . Cardiovascular reactivity to stress predicts future blood pressure status. Hypertension 22: 479‐485, 1993.
 174. McAllen RM , May CN , Shafton AD . Functional anatomy of sympathetic premotor cell groups in the medulla. Clin Exp Hypertens 17: 209‐221, 1995.
 175. McCubbin JW , Green JH , Page IH . Baroceptor function in chronic renal hypertension. Circ Res 4: 205‐210, 1956.
 176. McLachlan EM . Transmission of signals through sympathetic ganglia–modulation, integration or simply distribution? Acta Physiol Scand 177: 227‐235, 2003.
 177. Miki K , Kosho A , Hayashida Y . Method for continuous measurements of renal sympathetic nerve activity and cardiovascular function during exercise in rats. Exp Physiol 87: 33‐39, 2002.
 178. Moffitt JA , Foley CM , Schadt JC , Laughlin MH , Hasser EM . Attenuated baroreflex control of sympathetic nerve activity after cardiovascular deconditioning in rats. Am J Physiol 274: R1397‐R1405, 1998.
 179. Montani JP , Van Vliet BN . Commentary on ‘Current computational models do not reveal the importance of the nervous system in long‐term control of arterial pressure’. Exp Physiol 94: 396‐397, 2009.
 180. Montani JP , Van Vliet BN . Understanding the contribution of Guyton's large circulatory model to long‐term control of arterial pressure. Exp Physiol 94: 382‐388, 2009.
 181. Morgan BJ , Crabtree DC , Palta M , Skatrud JB . Combined hypoxia and hypercapnia evokes long‐lasting sympathetic activation in humans. J Appl Physiol 79: 205‐213, 1995.
 182. Narkiewicz K , Kato M , Phillips BG , Pesek CA , Davison DE , Somers VK . Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation 100: 2332‐2335, 1999.
 183. Narkiewicz K , Pesek CA , Kato M , Phillips BG , Davison DE , Somers VK . Baroreflex control of sympathetic nerve activity and heart rate in obstructive sleep apnea. Hypertension 32: 1039‐1043, 1998.
 184. Narkiewicz K , Phillips BG , Kato M , Hering D , Bieniaszewski L , Somers VK . Gender‐selective interaction between aging, blood pressure, and sympathetic nerve activity. Hypertension 45: 522‐525, 2005.
 185. Narkiewicz K , van de Borne P , Montano N , Hering D , Kara T , Somers VK . Sympathetic neural outflow and chemoreflex sensitivity are related to spontaneous breathing rate in normal men. Hypertension 47: 51‐55, 2006.
 186. Negrao CE , Middlekauff HR . Adaptations in autonomic function during exercise training in heart failure. Heart Fail Rev 13: 51‐60, 2008.
 187. Ng AV , Callister R , Johnson DG , Seals DR . Age and gender influence muscle sympathetic nerve activity at rest in healthy humans. Hypertension 21: 498‐503, 1993.
 188. Ng AV , Callister R , Johnson DG , Seals DR . Sympathetic neural reactivity to stress does not increase with age in healthy humans. Am J Physiol 267: H344‐H353, 1994.
 189. Nishida Y , Tandai‐Hiruma M , Kemuriyama T , Hagisawa K . Long‐term blood pressure control: Is there a set‐point in the brain? J Physiol Sci 62: 147‐161, 2012.
 190. O'Leary DS , Sheriff DD . Is the muscle metaboreflex important in control of blood flow to ischemic active skeletal muscle in dogs? Am J Physiol 268: H980‐H986, 1995.
 191. Ogoh S , Brothers RM , Barnes Q , Eubank WL , Hawkins MN , Purkayastha S , A OY, Raven PB . Cardiopulmonary baroreflex is reset during dynamic exercise. J Appl Physiol 100: 51‐59, 2006.
 192. Ogoh S , Fisher JP , Fadel PJ , Raven PB . Increases in central blood volume modulate carotid baroreflex resetting during dynamic exercise in humans. J Physiol 581: 405‐418, 2007.
 193. Ogoh S , Wasmund WL , Keller DM , A OY, Gallagher KM , Mitchell JH , Raven PB . Role of central command in carotid baroreflex resetting in humans during static exercise. J Physiol 543: 349‐364, 2002.
 194. Osborn JW , Averina VA , Fink GD . Commentary on ‘Understanding the contribution of Guyton's large circulatory model to long‐term control of arterial pressure’. Exp Physiol 94: 388‐389, 2009.
 195. Osborn JW , Averina VA , Fink GD . Current computational models do not reveal the importance of the nervous system in long‐term control of arterial pressure. Exp Physiol 94: 389‐396, 2009.
 196. Osborn JW , Jacob F , Guzman P . A neural set point for the long‐term control of arterial pressure: Beyond the arterial baroreceptor reflex. Am J Physiol Regul Integr Comp Physiol 288: R846‐R855, 2005.
 197. Paton JF , Spyer KM . Central nervous control of the cardiovascular system. In: Mathias CJ , Bannister R editors. Autonomic Failure (5 ed). Oxford: Oxford University Press, 2013, pp. 34‐51.
 198. Pearson J , Lucas RA , Crandall CG . Elevated local skin temperature impairs cutaneous vasoconstrictor responses to a simulated haemorrhagic challenge while heat stressed. Exp Physiol 98: 444‐450, 2013.
 199. Potts JT . Inhibitory neurotransmission in the nucleus tractus solitarii: Implications for baroreflex resetting during exercise. Exp Physiol 91: 59‐72, 2006.
 200. Prabhakar NR , Dick TE , Nanduri J , Kumar GK . Systemic, cellular and molecular analysis of chemoreflex‐mediated sympathoexcitation by chronic intermittent hypoxia. Exp Physiol 92: 39‐44, 2007.
 201. Querido JS , Kennedy PM , Sheel AW . Hyperoxia attenuates muscle sympathetic nerve activity following isocapnic hypoxia in humans. J Appl Physiol 108: 906‐912, 2010.
 202. Querido JS , Wehrwein EA , Hart EC , Charkoudian N , Henderson WR , Sheel AW . Baroreflex control of muscle sympathetic nerve activity as a mechanism for persistent sympathoexcitation following acute hypoxia in humans. Am J Physiol Regul Integr Comp Physiol 301: R1779‐R1785, 2011.
 203. Rabbitts JA , Strom NA , Sawyer JR , Curry TB , Dietz NM , Roberts SK , Kingsley‐Berg SM , Charkoudian N . Influence of endogenous angiotensin II on control of sympathetic nerve activity in human dehydration. J Physiol 587: 5441‐5449, 2009.
 204. Raven PB , Fadel PJ , Ogoh S . Arterial baroreflex resetting during exercise: A current perspective. Exp Physiol 91: 37‐49, 2006.
 205. Rees DD , Palmer RM , Hodson HF , Moncada S . A specific inhibitor of nitric oxide formation from L‐arginine attenuates endothelium‐dependent relaxation. Br J Pharmacol 96: 418‐424, 1989.
 206. Roveda F , Middlekauff HR , Rondon MU , Reis SF , Souza M , Nastari L , Barretto AC , Krieger EM , Negrao CE . The effects of exercise training on sympathetic neural activation in advanced heart failure: A randomized controlled trial. J Am Coll Cardiol 42: 854‐860, 2003.
 207. Rowell LB , Savage MV , Chambers J , Blackmon JR . Cardiovascular responses to graded reductions in leg perfusion in exercising humans. Am J Physiol 261: H1545‐H1553, 1991.
 208. Rudas L , Crossman AA , Morillo CA , Halliwill JR , Tahvanainen KU , Kuusela TA , Eckberg DL . Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine. Am J Physiol 276: H1691‐H1698, 1999.
 209. Rusch NJ , Shepherd JT , Webb RC , Vanhoutte PM . Different behavior of the resistance vessels of the human calf and forearm during contralateral isometric exercise, mental stress, and abnormal respiratory movements. Circ Res 48: I118‐I130, 1981.
 210. Saito M , Mano T , Iwase S , Koga K , Abe H , Yamazaki Y . Responses in muscle sympathetic activity to acute hypoxia in humans. J Appl Physiol 65: 1548‐1552, 1988.
 211. Sakai K , Agassandian K , Morimoto S , Sinnayah P , Cassell MD , Davisson RL , Sigmund CD . Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest 117: 1088‐1095, 2007.
 212. Salmanpour A , Brown LJ , Shoemaker JK . Spike detection in human muscle sympathetic nerve activity using a matched wavelet approach. J Neurosci Methods 193: 343‐355, 2010.
 213. Salmanpour A , Brown LJ , Steinback CD , Usselman CW , Goswami R , Shoemaker JK . Relationship between size and latency of action potentials in human muscle sympathetic nerve activity. J Neurophysiol 105: 2830‐2842, 2011.
 214. Salmanpour A , Shoemaker JK . Baroreflex mechanisms regulating the occurrence of neural spikes in human muscle sympathetic nerve activity. J Neurophysiol 107: 3409‐3416, 2012.
 215. Saltin B . Exercise hyperaemia: Magnitude and aspects on regulation in humans. J Physiol 583: 819‐823, 2007.
 216. Schad H , Seller H . A method for recording autonomic nerve activity in unanesthetized, freely moving cats. Brain Res 100: 425‐430, 1975.
 217. Scheffers IJ , Kroon AA , Schmidli J , Jordan J , Tordoir JJ , Mohaupt MG , Luft FC , Haller H , Menne J , Engeli S , Ceral J , Eckert S , Erglis A , Narkiewicz K , Philipp T , de Leeuw PW . Novel baroreflex activation therapy in resistant hypertension: Results of a European multi‐center feasibility study. J Am Coll Cardiol 56: 1254‐1258, 2010.
 218. Scherrer U , Randin D , Tappy L , Vollenweider P , Jequier E , Nicod P . Body fat and sympathetic nerve activity in healthy subjects. Circulation 89: 2634‐2640, 1994.
 219. Schobel HP , Frank H , Naraghi R , Geiger H , Titz E , Heusser K . Hypertension in patients with neurovascular compression is associated with increased central sympathetic outflow. J Am Soc Nephrol 13: 35‐41, 2002.
 220. Seals DR . Sympathetic neural adjustments to stress in physically trained and untrained humans. Hypertension 17: 36‐43, 1991.
 221. Shafton AD , McAllen RM . Location of cat brain stem neurons that drive sweating. Am J Physiol Regul Integr Comp Physiol 304: R804‐R809, 2013.
 222. Shoemaker JK , Wong SW , Cechetto DF . Cortical circuitry associated with reflex cardiovascular control in humans: does the cortical autonomic network “speak” or “listen” during cardiovascular arousal. Anat Rec (Hoboken) 295: 1375‐1384, 2012.
 223. Skarphedinsson JO , Elam M , Jungersten L , Wallin BG . Sympathetic nerve traffic correlates with the release of nitric oxide in humans: Implications for blood pressure control. J Physiol 501 (Pt 3): 671‐675, 1997.
 224. Skatrud JB , Morgan B . Hypertension and sleep apnoea. J Sleep Res 4: 34‐36, 1995.
 225. Smith SA , Querry RG , Fadel PJ , Gallagher KM , Stromstad M , Ide K , Raven PB , Secher NH . Partial blockade of skeletal muscle somatosensory afferents attenuates baroreflex resetting during exercise in humans. J Physiol 551: 1013‐1021, 2003.
 226. Smyth HS , Sleight P , Pickering GW . Reflex regulation of arterial pressure during sleep in man. A quantitative method of assessing baroreflex sensitivity. Circ Res 24: 109‐121, 1969.
 227. Somers VK , Dyken ME , Clary MP , Abboud FM . Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 96: 1897‐1904, 1995.
 228. Somers VK , Mark AL , Abboud FM . Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension 11: 608‐612, 1988.
 229. Stauffer BL , Westby CM , Greiner JJ , Van Guilder GP , Desouza CA . Sex differences in endothelin‐1‐mediated vasoconstrictor tone in middle‐aged and older adults. Am J Physiol Regul Integr Comp Physiol 298: R261‐R265, 2010.
 230. Steinback CD and Kevin Shoemaker J . Differential regulation of sympathetic burst frequency and amplitude following acute hypoxia in humans. Am J Physiol Regul Integr Comp Physiol 303: R633‐R638, 2012.
 231. Stephens DP , Aoki K , Kosiba WA , Johnson JM . Nonnoradrenergic mechanism of reflex cutaneous vasoconstriction in men. Am J Physiol Heart Circ Physiol 280: H1496‐H1504, 2001.
 232. Stephens DP , Bennett LA , Aoki K , Kosiba WA , Charkoudian N , Johnson JM . Sympathetic nonnoradrenergic cutaneous vasoconstriction in women is associated with reproductive hormone status. Am J Physiol Heart Circ Physiol 282: H264‐H272, 2002.
 233. Strom NA , Meuchel LW , Mundy DW , Sawyer JR , Roberts SK , Kingsley‐Berg SM , Charkoudian N . Cutaneous sympathetic neural responses to body cooling in type 2 diabetes mellitus. Auton Neurosci 159: 15‐19, 2011.
 234. Sugenoya J , Iwase S , Mano T , Sugiyama Y , Ogawa T , Nishiyama T , Nishimura N , Kimura T . Vasodilator component in sympathetic nerve activity destined for the skin of the dorsal foot of mildly heated humans. J Physiol 507 (Pt 2): 603‐610, 1998.
 235. Sundlof G , Wallin BG . Human muscle nerve sympathetic activity at rest. Relationship to blood pressure and age. J Physiol 274: 621‐637, 1978.
 236. Sundlof G , Wallin BG . The variability of muscle nerve sympathetic activity in resting recumbent man. J Physiol 272: 383‐397, 1977.
 237. Svedenhag J , Wallin BG , Sundlof G , Henriksson J . Skeletal muscle sympathetic activity at rest in trained and untrained subjects. Acta Physiol Scand 120: 499‐504, 1984.
 238. Sverrisdottir YB , Johannsson G , Jungersten L , Wallin BG , Elam M . Is the somatotropic axis related to sympathetic nerve activity in healthy ageing men? J Hypertens 19: 2019‐2024, 2001.
 239. Tan PS , Killinger S , Horiuchi J , Dampney RA . Baroreceptor reflex modulation by circulating angiotensin II is mediated by AT1 receptors in the nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol 293: R2267‐R2278, 2007.
 240. Tanaka M , McKinley MJ , McAllen RM . Preoptic‐raphe connections for thermoregulatory vasomotor control. J Neurosci 31: 5078‐5088, 2011.
 241. Tank J , Diedrich A , Szczech E , Luft FC , Jordan J . Baroreflex regulation of heart rate and sympathetic vasomotor tone in women and men. Hypertension 45: 1159‐1164, 2005.
 242. Tank J , Heusser K , Diedrich A , Hering D , Luft FC , Busjahn A , Narkiewicz K , Jordan J . Influences of gender on the interaction between sympathetic nerve traffic and central adiposity. J Clin Endocrinol Metab 93: 4974‐4978, 2008.
 243. Tataranni PA , Cizza G , Snitker S , Gucciardo F , Lotsikas A , Chrousos GP , Ravussin E . Hypothalamic‐pituitary‐adrenal axis and sympathetic nervous system activities in Pima Indians and Caucasians. Metabolism 48: 395‐399, 1999.
 244. Thrasher TN . Arterial baroreceptor input contributes to long‐term control of blood pressure. Curr Hypertens Rep 8: 249‐254, 2006.
 245. Thrasher TN . Effects of chronic baroreceptor unloading on blood pressure in the dog. Am J Physiol Regul Integr Comp Physiol 288: R863‐R871, 2005.
 246. Thrasher TN . Unloading arterial baroreceptors causes neurogenic hypertension. Am J Physiol Regul Integr Comp Physiol 282: R1044‐R1053, 2002.
 247. Timio M , Lippi G , Venanzi S , Gentili S , Quintaliani G , Verdura C , Monarca C , Saronio P , Timio F . Blood pressure trend and cardiovascular events in nuns in a secluded order: A 30‐year follow‐up study. Blood Press 6: 81‐87, 1997.
 248. Timio M , Verdecchia P , Venanzi S , Gentili S , Ronconi M , Francucci B , Montanari M , Bichisao E . Age and blood pressure changes. A 20‐year follow‐up study in nuns in a secluded order. Hypertension 12: 457‐461, 1988.
 249. Tompkins RP , Melling CW , Wilson TD , Bates BD , Shoemaker JK . Arrangement of sympathetic fibers within the human common peroneal nerve: Implications for microneurography. J Appl Physiol 115: 1553‐1561, 2013.
 250. Vallbo AB , Hagbarth KE , Wallin BG . Microneurography: how the technique developed and its role in the investigation of the sympathetic nervous system. J Appl Physiol 96: 1262‐1269, 2004.
 251. Van Guilder GP , Westby CM , Greiner JJ , Stauffer BL , DeSouza CA . Endothelin‐1 vasoconstrictor tone increases with age in healthy men but can be reduced by regular aerobic exercise. Hypertension 50: 403‐409, 2007.
 252. Vissing SF , Scherrer U , Victor RG . Increase of sympathetic discharge to skeletal muscle but not to skin during mild lower body negative pressure in humans. J Physiol 481 (Pt 1): 233‐241, 1994.
 253. Vissing SF , Secher NH , Victor RG . Mechanisms of cutaneous vasoconstriction during upright posture. Acta Physiol Scand 159: 131‐138, 1997.
 254. Wahlstrom J , Hagberg M , Johnson PW , Svensson J , Rempel D . Influence of time pressure and verbal provocation on physiological and psychological reactions during work with a computer mouse. Eur J Appl Physiol 87: 257‐263, 2002.
 255. Walgenbach SC , Donald DE . Cardiopulmonary reflexes and arterial pressure during rest and exercise in dogs. Am J Physiol 244: H362‐H369, 1983.
 256. Walgenbach SC , Donald DE . Inhibition by carotid baroreflex of exercise‐induced increases in arterial pressure. Circ Res 52: 253‐262, 1983.
 257. Wallin BG . Sympathetic microneurography. In: Robertson D , Biaggioni I , Burnstock G , Low PA and Paton JF , editors. Primer on the Autonomic Nervous System. London: Academic Press, Elsevier, 2012, pp. 389‐397.
 258. Wallin BG , Burke D , Gandevia S . Coupling between variations in strength and baroreflex latency of sympathetic discharges in human muscle nerves. J Physiol 474: 331‐338, 1994.
 259. Wallin BG and Charkoudian N . Sympathetic neural control of integrated cardiovascular function: Insights from measurement of human sympathetic nerve activity. Muscle Nerve 36: 595‐614, 2007.
 260. Wallin BG , Esler M , Dorward P , Eisenhofer G , Ferrier C , Westerman R , Jennings G . Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans. J Physiol 453: 45‐58, 1992.
 261. Wallin BG , Hart EC , Wehrwein EA , Charkoudian N , Joyner MJ . Relationship between breathing and cardiovascular function at rest: Sex‐related differences. Acta Physiol (Oxf) 200: 193‐200, 2010.
 262. Wallin BG , Kunimoto MM , Sellgren J . Possible genetic influence on the strength of human muscle nerve sympathetic activity at rest. Hypertension 22: 282‐284, 1993.
 263. Wallin BG , Thompson JM , Jennings GL , Esler MD . Renal noradrenaline spillover correlates with muscle sympathetic activity in humans. J Physiol 491 (Pt 3): 881‐887, 1996.
 264. Wasmund WL , Westerholm EC , Watenpaugh DE , Wasmund SL , Smith ML . Interactive effects of mental and physical stress on cardiovascular control. J Appl Physiol 92: 1828‐1834, 2002.
 265. Wenner MM , Rose WC , Delaney EP , Stillabower ME , Farquhar WB . Influence of plasma osmolality on baroreflex control of sympathetic activity. Am J Physiol Heart Circ Physiol 293: H2313‐H2319, 2007.
 266. Widdicombe JG . Action potentials in parasympathetic and sympathetic efferent fibres to the trachea and lungs of dogs and cats. J Physiol 186: 56‐88, 1966.
 267. Williams L , O'Carroll RE , O'Connor RC . Type D personality and cardiac output in response to stress. Psychol Health 24: 489‐500, 2009.
 268. Williamson JW . The relevance of central command for the neural cardiovascular control of exercise. Exp Physiol 95: 1043‐1048, 2010.
 269. Williamson JW , Fadel PJ , Mitchell JH . New insights into central cardiovascular control during exercise in humans: A central command update. Exp Physiol 91: 51‐58, 2006.
 270. Williamson JW , McColl R , Mathews D . Evidence for central command activation of the human insular cortex during exercise. J Appl Physiol 94: 1726‐1734, 2003.
 271. Williamson JW , McColl R , Mathews D , Mitchell JH , Raven PB , Morgan WP . Brain activation by central command during actual and imagined handgrip under hypnosis. J Appl Physiol 92: 1317‐1324, 2002.
 272. Wong BJ . Sensory nerves and nitric oxide contribute to reflex cutaneous vasodilation in humans. Am J Physiol Regul Integr Comp Physiol, 304: R651‐R656, 2013.
 273. Wong BJ , Fieger SM . Transient receptor potential vanilloid type‐1 (TRPV‐1) channels contribute to cutaneous thermal hyperaemia in humans. J Physiol 588: 4317‐4326, 2010.
 274. Wong BJ , Wilkins BW , Minson CT . H1 but not H2 histamine receptor activation contributes to the rise in skin blood flow during whole body heating in humans. J Physiol 560: 941‐948, 2004.
 275. Wright JW , Harding JW . The brain renin‐angiotensin system: A diversity of functions and implications for CNS diseases. Pflugers Arch 465: 133‐151, 2013.
 276. Yamamoto K , Eubank W , Franzke M , Mifflin S . Resetting of the sympathetic baroreflex is associated with the onset of hypertension during chronic intermittent hypoxia. Auton Neurosci 173: 22‐27, 2013.
 277. Young CN , Keller DM , Crandall CG , Fadel PJ . Comparing resting skin sympathetic nerve activity between groups: Caution needed. J Appl Physiol 106: 1751‐1752, 2009.
 278. Yu YH , Blessing WW . Cutaneous vasoconstriction in conscious rabbits during alerting responses detected by hippocampal theta‐rhythm. Am J Physiol 272: R208‐R216, 1997.
 279. Zhang W , Mifflin S . Plasticity of GABAergic mechanisms within the nucleus of the solitary tract in hypertension. Hypertension 55: 201‐206, 2010.
 280. Zhang W , Mifflin SW . Excitatory amino‐acid receptors contribute to carotid sinus and vagus nerve evoked excitation of neurons in the nucleus of the tractus solitarius. J Auton Nerv Syst 55: 50‐56, 1995.

Related Articles:

Systemic Hypertension

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

N. Charkoudian, B.G. Wallin. Sympathetic Neural Activity to the Cardiovascular System: Integrator of Systemic Physiology and Interindividual Characteristics. Compr Physiol 2014, 4: 827-850. doi: 10.1002/cphy.c130038