Comprehensive Physiology Wiley Online Library

Neural Control of the Circulation: How Sex and Age Differences Interact in Humans

Full Article on Wiley Online Library



Abstract

The autonomic nervous system is a key regulator of the cardiovascular system. In this review, we focus on how sex and aging influence autonomic regulation of blood pressure in humans in an effort to understand general issues related to the cardiovascular system as a whole. Younger women generally have lower blood pressure and sympathetic activity than younger men. However, both sexes show marked interindividual variability across age groups with significant overlap seen. Additionally, while men across the lifespan show a clear relationship between markers of whole body sympathetic activity and vascular resistance, such a relationship is not seen in young women. In this context, the ability of the sympathetic nerves to evoke vasoconstriction is lower in young women likely as a result of concurrent β2‐mediated vasodilation that offsets α‐adrenergic vasoconstriction. These differences reflect both central sympatho‐inhibitory effects of estrogen and also its influence on peripheral vasodilation at the level of the vascular smooth muscle and endothelium. By contrast postmenopausal women show a clear relationship between markers of whole body sympathetic traffic and vascular resistance, and sympathetic activity rises progressively in both sexes with aging. These major findings in humans are discussed in the context of differences in population‐based trends in blood pressure and orthostatic intolerance. The many areas where there is little sex‐specific data on how the autonomic nervous system participates in the regulation of the human cardiovascular system are highlighted. © 2015 American Physiological Society. Compr Physiol 5:193‐215, 2015.

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. Prevalence of hypertension from 2003 to 2006 by sex and age in the United States. These data show that blood pressure increases with age in wealthy, industrialized countries with low levels of physical activity, food abundance, and the social stresses of urbanization. The graph also shows that blood pressure is generally lower in young women than young men but that the rate of change in blood pressure is higher for women especially in the perimenopausal period. Figure adapted, with permission, from ().
Figure 2. Figure 2. The prevalence of syncope in young women (gray bars) is higher than young men (black bars) between the ages of 7 to 21 years. Figure adapted, with permission, from ().
Figure 3. Figure 3. The sites for sex differences in autonomic control of blood pressure discussed in this review. NE = norepinephrine NO = nitric oxide; β2 = β2‐adrenergic receptor.
Figure 4. Figure 4. Age‐ and sex‐related trends in blood pressure vary by cultural and environmental factors. The top panel shows blood pressure (BP) with age among isolated island Kuna Indian inhabitants and Kuna residing in the urban environment of Panama City. The bottom panel shows the prevalence of hypertension prevalence of hypertension in these communities. Note that the blood pressure trends typically observed in industrialized areas are not present in rural island dwellers, indicating that age‐related changes in blood pressure are not an obligatory feature of human biology. Figure adapted, with permission, from ref ().
Figure 5. Figure 5. The relationship between baseline muscle sympathetic nerve activity (MSNA) and plasma norepinephrine levels (PNE) is shown in panel A. Figure adapted, with permission, from (). Panel B shows the relationship between MSNA and renal norepinephrine (noradrenaline) spillover. Figure adapted, with permission, from (). These data highlight the general agreement between several commonly used indices of sympathetic activity in humans. In these studies, only a limited number or no women were included.
Figure 6. Figure 6. The autonomic support of blood pressure is estimated by the blood pressure response after ganglionic blockade, where both sympathetic and parasympathetic nerve activity is abolished. The change in mean arterial pressure (MAP) in response to ganglionic blockade is greater in young men compared with young women, indicating greater autonomic support of blood pressure in young men. Figure adapted, with permission, from ().
Figure 7. Figure 7. Mean levels of muscle sympathetic nerve activity (MSNA) are lower in young women (YW) compared with young men (YM) but rise similarly with age. Note the sex differences remain between older women (OW) and older men (OM). *P < 0.05 for pairwise comparisons. Figure adapted, with permission, from ().
Figure 8. Figure 8. The relationship between muscle sympathetic nerve activity (MSNA) and mean arterial blood pressure (MAP) in a large cohort of healthy humans is shown. All four panels show the marked variability in MSNA seen in normal humans. The top panels show that for young men and women there is no relationship between MSNA and MAP. The bottom panels show that a weak relationship emerges in men over 40 and that this relationship is stronger in women. Data adapted, with permission, from ().
Figure 9. Figure 9. Mean arterial pressure is determined by total peripheral resistance (TPR) and cardiac output (CO). The relationship between muscle sympathetic nerve activity (MSNA) and TPR or CO is only apparent in young men (left panels). The positive correlation between MSNA and TPR, and the inverse correlation between MSNA and CO in young men balances the effect of MSNA so that higher MSNA does not translate to higher MAP. However, these relationships are not present in young women which suggest that young women regulate blood pressure differently than young men. In addition, it suggests that the transduction of sympathetic activity to vasoconstrictor responses differs between young men and women. Data compiled, with permission, from several studies by our laboratory ().
Figure 10. Figure 10. A significant relationship between muscle sympathetic nerve activity (MSNA) and total peripheral resistance (TPR) also exists in healthy postmenopausal women. This pattern is similar between young men (Fig. 9) and postmenopausal women, but not young women suggests a role for sex hormones in blood pressure regulation. Data adapted, with permission, from ().
Figure 11. Figure 11. Sex hormones vary throughout the ovarian cycle in young women. The change between mid‐luteal and early follicular phases in estradiol (top panel) and in the ratio of estradiol/progesterone (bottom panel) were inversely associated with the change in muscle sympathetic nerve activity (MSNA). This suggests that higher estrogen in mid‐luteal phases may be sympatho‐inhibitory. Data adapted, with permission, from ().
Figure 12. Figure 12. Sex hormones and specifically estrogen have been shown to affect sympathetic neural outflow. Administration of transdermal estrogen for 8 weeks in postmenopausal women reduces muscle sympathetic nerve activity. *P < 0.05. Data adapted, with permission, from ().
Figure 13. Figure 13. The left panel shows that the rise in MSNA is similar in young men and women during a cold pressor test. The right panel shows that the rise in calf vascular resistance is lower in the women. These data are consistent with the idea that the transduction of sympathetic activity to vascular tone is lower in young women than men. Data adapted, with permission, from ().
Figure 14. Figure 14. Effects of brachial artery administration of norepinephrine (noradrenaline, NA) on forearm vascular conductance before and after local administration of the nonselective β‐blocker propranolol (BB). In young women (panel A) increasing doses of NA did not evoke marked vasoconstriction at rest. However, marked vasoconstriction is seen after administration of propranolol. In postmenopausal women propranolol had no effect and the constriction caused by administration of NA caused more marked vasoconstriction. In men, β‐blockade has little effect on these responses (not shown). These responses indicate that concurrent β‐adrenergic vasodilation limits α‐adrenergic vasoconstriction in young women. This sex difference might explain many of the findings highlighted in Figures 7, 8, and 9. Data adapted, with permission, from ().
Figure 15. Figure 15. The is no association between muscle sympathetic nerve activity (MSNA) and total peripheral resistance (TPR) in young women, however, there is a significant positive association in young men (not shown) and in postmenopausal women (left panels). After systemic β‐blockade, where β‐adrenergic vasodilation is attenuated, a positive association between MSNA and TPR emerges in young women (right upper panel). This suggests that β‐adrenergic vasodilation blunts vascular transduction of the sympathetic nerves. Data adapted, with permission, from ().
Figure 16. Figure 16. Augmentation index (AIx%) is a pulse wave characteristic that is affected by increases in central arterial stiffness. Individuals with greater arterial stiffness typically demonstrate higher values of AIx. In young men, higher muscle sympathetic nerve activity (MSNA) is associated with greater AIx and presumably, higher arterial stiffness (left panel). However, this association is inverse in young women, highlighting another important difference in neurovascular regulation. Data adapted, with permission, from ().
Figure 17. Figure 17. An example of age differences in acute sympatho‐excitatory maneuvers. In this study, isometric handgrip was performed and then the forearm was occluded. Note the absolute change in MSNA during these maneuvers was similar in both age groups. Data adapted, with permission, from ().
Figure 18. Figure 18. Summary figure illustrating vascular transduction and how this influences sex differences in blood pressure. Specifically the effect on the vasculature appears to be dependent on estrogen, as young women are different than young men and older women. α = α‐adrenergic receptors; β = β‐adrenergic receptors; CO = cardiac output; MAP = mean arterial pressure; NA = noradrenaline; OM = older men; OW = older women; PMW = postmenopausal women; SNA = sympathetic nerve activity; TPR = total peripheral resistance; VSMC = vascular smooth muscle; YM = young men; YW = young women.
Figure 19. Figure 19. In women, both muscle sympathetic nerve activity (MSNA) and plasma norepinephrine (NE) are associated with the change in mean arterial pressure (MAP) after ganglionic blockade. Young women are shown in black squares and older women are shown in white squares. Note that older women demonstrate a greater reduction in MAP after ganglionic blockade. Figure adapted, with permission, from ().


Figure 1. Prevalence of hypertension from 2003 to 2006 by sex and age in the United States. These data show that blood pressure increases with age in wealthy, industrialized countries with low levels of physical activity, food abundance, and the social stresses of urbanization. The graph also shows that blood pressure is generally lower in young women than young men but that the rate of change in blood pressure is higher for women especially in the perimenopausal period. Figure adapted, with permission, from ().


Figure 2. The prevalence of syncope in young women (gray bars) is higher than young men (black bars) between the ages of 7 to 21 years. Figure adapted, with permission, from ().


Figure 3. The sites for sex differences in autonomic control of blood pressure discussed in this review. NE = norepinephrine NO = nitric oxide; β2 = β2‐adrenergic receptor.


Figure 4. Age‐ and sex‐related trends in blood pressure vary by cultural and environmental factors. The top panel shows blood pressure (BP) with age among isolated island Kuna Indian inhabitants and Kuna residing in the urban environment of Panama City. The bottom panel shows the prevalence of hypertension prevalence of hypertension in these communities. Note that the blood pressure trends typically observed in industrialized areas are not present in rural island dwellers, indicating that age‐related changes in blood pressure are not an obligatory feature of human biology. Figure adapted, with permission, from ref ().


Figure 5. The relationship between baseline muscle sympathetic nerve activity (MSNA) and plasma norepinephrine levels (PNE) is shown in panel A. Figure adapted, with permission, from (). Panel B shows the relationship between MSNA and renal norepinephrine (noradrenaline) spillover. Figure adapted, with permission, from (). These data highlight the general agreement between several commonly used indices of sympathetic activity in humans. In these studies, only a limited number or no women were included.


Figure 6. The autonomic support of blood pressure is estimated by the blood pressure response after ganglionic blockade, where both sympathetic and parasympathetic nerve activity is abolished. The change in mean arterial pressure (MAP) in response to ganglionic blockade is greater in young men compared with young women, indicating greater autonomic support of blood pressure in young men. Figure adapted, with permission, from ().


Figure 7. Mean levels of muscle sympathetic nerve activity (MSNA) are lower in young women (YW) compared with young men (YM) but rise similarly with age. Note the sex differences remain between older women (OW) and older men (OM). *P < 0.05 for pairwise comparisons. Figure adapted, with permission, from ().


Figure 8. The relationship between muscle sympathetic nerve activity (MSNA) and mean arterial blood pressure (MAP) in a large cohort of healthy humans is shown. All four panels show the marked variability in MSNA seen in normal humans. The top panels show that for young men and women there is no relationship between MSNA and MAP. The bottom panels show that a weak relationship emerges in men over 40 and that this relationship is stronger in women. Data adapted, with permission, from ().


Figure 9. Mean arterial pressure is determined by total peripheral resistance (TPR) and cardiac output (CO). The relationship between muscle sympathetic nerve activity (MSNA) and TPR or CO is only apparent in young men (left panels). The positive correlation between MSNA and TPR, and the inverse correlation between MSNA and CO in young men balances the effect of MSNA so that higher MSNA does not translate to higher MAP. However, these relationships are not present in young women which suggest that young women regulate blood pressure differently than young men. In addition, it suggests that the transduction of sympathetic activity to vasoconstrictor responses differs between young men and women. Data compiled, with permission, from several studies by our laboratory ().


Figure 10. A significant relationship between muscle sympathetic nerve activity (MSNA) and total peripheral resistance (TPR) also exists in healthy postmenopausal women. This pattern is similar between young men (Fig. 9) and postmenopausal women, but not young women suggests a role for sex hormones in blood pressure regulation. Data adapted, with permission, from ().


Figure 11. Sex hormones vary throughout the ovarian cycle in young women. The change between mid‐luteal and early follicular phases in estradiol (top panel) and in the ratio of estradiol/progesterone (bottom panel) were inversely associated with the change in muscle sympathetic nerve activity (MSNA). This suggests that higher estrogen in mid‐luteal phases may be sympatho‐inhibitory. Data adapted, with permission, from ().


Figure 12. Sex hormones and specifically estrogen have been shown to affect sympathetic neural outflow. Administration of transdermal estrogen for 8 weeks in postmenopausal women reduces muscle sympathetic nerve activity. *P < 0.05. Data adapted, with permission, from ().


Figure 13. The left panel shows that the rise in MSNA is similar in young men and women during a cold pressor test. The right panel shows that the rise in calf vascular resistance is lower in the women. These data are consistent with the idea that the transduction of sympathetic activity to vascular tone is lower in young women than men. Data adapted, with permission, from ().


Figure 14. Effects of brachial artery administration of norepinephrine (noradrenaline, NA) on forearm vascular conductance before and after local administration of the nonselective β‐blocker propranolol (BB). In young women (panel A) increasing doses of NA did not evoke marked vasoconstriction at rest. However, marked vasoconstriction is seen after administration of propranolol. In postmenopausal women propranolol had no effect and the constriction caused by administration of NA caused more marked vasoconstriction. In men, β‐blockade has little effect on these responses (not shown). These responses indicate that concurrent β‐adrenergic vasodilation limits α‐adrenergic vasoconstriction in young women. This sex difference might explain many of the findings highlighted in Figures 7, 8, and 9. Data adapted, with permission, from ().


Figure 15. The is no association between muscle sympathetic nerve activity (MSNA) and total peripheral resistance (TPR) in young women, however, there is a significant positive association in young men (not shown) and in postmenopausal women (left panels). After systemic β‐blockade, where β‐adrenergic vasodilation is attenuated, a positive association between MSNA and TPR emerges in young women (right upper panel). This suggests that β‐adrenergic vasodilation blunts vascular transduction of the sympathetic nerves. Data adapted, with permission, from ().


Figure 16. Augmentation index (AIx%) is a pulse wave characteristic that is affected by increases in central arterial stiffness. Individuals with greater arterial stiffness typically demonstrate higher values of AIx. In young men, higher muscle sympathetic nerve activity (MSNA) is associated with greater AIx and presumably, higher arterial stiffness (left panel). However, this association is inverse in young women, highlighting another important difference in neurovascular regulation. Data adapted, with permission, from ().


Figure 17. An example of age differences in acute sympatho‐excitatory maneuvers. In this study, isometric handgrip was performed and then the forearm was occluded. Note the absolute change in MSNA during these maneuvers was similar in both age groups. Data adapted, with permission, from ().


Figure 18. Summary figure illustrating vascular transduction and how this influences sex differences in blood pressure. Specifically the effect on the vasculature appears to be dependent on estrogen, as young women are different than young men and older women. α = α‐adrenergic receptors; β = β‐adrenergic receptors; CO = cardiac output; MAP = mean arterial pressure; NA = noradrenaline; OM = older men; OW = older women; PMW = postmenopausal women; SNA = sympathetic nerve activity; TPR = total peripheral resistance; VSMC = vascular smooth muscle; YM = young men; YW = young women.


Figure 19. In women, both muscle sympathetic nerve activity (MSNA) and plasma norepinephrine (NE) are associated with the change in mean arterial pressure (MAP) after ganglionic blockade. Young women are shown in black squares and older women are shown in white squares. Note that older women demonstrate a greater reduction in MAP after ganglionic blockade. Figure adapted, with permission, from ().
References
 1.Alecu C, Gueguen R, Aubry C, Salvi P, Perret‐Guillaume C, Ducrocq X, Vespignani H, Benetos A. Determinants of arterial stiffness in an apparently healthy population over 60 years. J Hum Hypertens 20: 749‐756, 2006.
 2.Alghatrif M, Strait JB, Morrell CH, Canepa M, Wright J, Elango P, Scuteri A, Najjar SS, Ferrucci L, Lakatta EG. Longitudinal trajectories of arterial stiffness and the role of blood pressure: The Baltimore Longitudinal Study of Aging. Hypertension 62: 934‐941, 2013.
 3.Ali YS, Daamen N, Jacob G, Jordan J, Shannon JR, Biaggioni I, Robertson D. Orthostatic intolerance: A disorder of young women. Obstet Gynecol Surv 55: 251‐259, 2000.
 4.Barnes JN, Hart EC, Curry TB, Nicholson WT, Eisenach JH, Wallin BG, Charkoudian N, Joyner MJ. Aging enhances autonomic support of blood pressure in women. Hypertension 63: 303‐308, 2014.
 5.Barnes JN, Matzek LJ, Charkoudian N, Joyner MJ, Curry TB, Hart EC. Association of cardiac baroreflex sensitivity with blood pressure transients: Influence of sex and menopausal status. Frontiers Physiol 3: 187, 2012.
 6.Behnke ARW, Wilmore JH. Evaluation and Regulation of Body Build and Composition. Englewood Cliffs, New Jersey: Prentice‐Hall, Inc., 1974.
 7.Beilin LJ, Burke V, Cox KL, Hodgson JM, Mori TA, Puddey IB. Non pharmacologic therapy and lifestyle factors in hypertension. Blood Pressure 10: 352‐365, 2001.
 8.Berntson GG, Bigger JT, Jr., Eckberg DL, Grossman P, Kaufmann PG, Malik M, Nagaraja HN, Porges SW, Saul JP, Stone PH, van der Molen MW. Heart rate variability: Origins, methods, and interpretive caveats. Psychophysiology 34: 623‐648, 1997.
 9.Bogert LW, van Lieshout JJ. Non‐invasive pulsatile arterial pressure and stroke volume changes from the human finger. Exp Physiol 90: 437‐446, 2005.
 10.Brodde OE. Beta 1‐ and beta 2‐adrenoceptors in the human heart: Properties, function, and alterations in chronic heart failure. Pharmacol Rev 43: 203‐242, 1991.
 11.Brown GO. Henry Darcy and the making of a law. Water Resour Res 38, 2002.
 12.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.
 13.Carter JR, Fu Q, Minson CT, Joyner MJ. Ovarian cycle and sympathoexcitation in premenopausal women. Hypertension 61: 395‐399, 2013.
 14.Carter JR, Ray CA. Sympathetic neural responses to mental stress: Responders, nonresponders and sex differences. Am J Physiol Heart Circ Physiol 296: H847‐H853, 2009.
 15.Carter JR, Ray CA. Sympathetic responses to vestibular activation in humans. Am J Physiol Regul Integr Comp Physiol 294: R681‐R688, 2008.
 16.Casey DP, Curry TB, Joyner MJ, Charkoudian N, Hart EC. Relationship between muscle sympathetic nerve activity and aortic wave reflection characteristics in young men and women. Hypertension 57: 421‐427, 2011.
 17.Charkoudian N, Hart EC, Barnes JN, Joyner MJ. Comments on Point:Counterpoint: The dominant contributor to systemic hypertension: Chronic activation of the sympathetic nervous system vs. Activation of the intrarenal renin‐angiotensin system. The role of the sympathetic nervous system–influences of sex and aging. J Appl Physiol (1985) 109: 2005, 2010.
 18.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.
 19.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.
 20.Christou DD, Jones PP, Jordan J, Diedrich A, Robertson D, Seals DR. Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men. Circulation 111: 494‐498, 2005.
 21.Ciriello J, Roder S. 17beta‐Estradiol alters the response of subfornical organ neurons that project to supraoptic nucleus to plasma angiotensin II and hypernatremia. Brain Res 1526: 54‐64, 2013.
 22.Convertino VA. Gender differences in autonomic functions associated with blood pressure regulation. Am J Physiol 275: R1909‐1920, 1998.
 23.Coutinho T, Borlaug BA, Pellikka PA, Turner ST, Kullo IJ. Sex differences in arterial stiffness and ventricular‐arterial interactions. J Amer Coll Cardiol 61: 96‐103, 2013.
 24.Dias AR Jr, de Mello NR, Eluf Gebara OC, Nussbacher A, Wajngarten M, Petti DA. Conjugated equine estrogen, raloxifene and arterial stiffness in postmenopausal women. Climacteric 11: 390‐396, 2008.
 25.Dinenno FA, Dietz NM, Joyner MJ. Aging and forearm postjunctional alpha‐adrenergic vasoconstriction in healthy men. Circulation 106: 1349‐1354, 2002.
 26.Dinenno FA, Eisenach JH, Dietz NM, Joyner MJ. Post‐junctional alpha‐adrenoceptors and basal limb vascular tone in healthy men. J Physiol 540: 1103‐1110, 2002.
 27.Dinenno FA, Jones PP, Seals DR, Tanaka H. Age‐associated arterial wall thickening is related to elevations in sympathetic activity in healthy humans. Am J Physiol Heart Circ Physiol 278: H1205‐H1210, 2000.
 28.Dinenno FA, Joyner MJ. Alpha‐adrenergic control of skeletal muscle circulation at rest and during exercise in aging humans. Microcirculation 13: 329‐341, 2006.
 29.Eckberg DL. Sympathovagal balance: A critical appraisal. Circulation 96: 3224‐3232, 1997.
 30.Edgerton VR, Gardner GW, Ohira Y, Gunawardena KA, Senewiratne B. Iron‐deficiency anaemia and its effect on worker productivity and activity patterns. Br Med J 2: 1546‐1549, 1979.
 31.Eisenach JH, Clark ES, Charkoudian N, Dinenno FA, Atkinson JL, Fealey RD, Dietz NM, Joyner MJ. Effects of chronic sympathectomy on vascular function in the human forearm. J Appl Physiol (1985) 92: 2019‐2025, 2002.
 32.Eisenach JH, Gullixson LR, Kost SL, Joyner MJ, Turner ST, Nicholson WT. Sex differences in salt sensitivity to nitric oxide dependent vasodilation in healthy young adults. J Appl Physiol (1985) 112: 1049‐1053, 2012.
 33.Esler M. Clinical application of noradrenaline spillover methodology: Delineation of regional human sympathetic nervous responses. Pharmacol Toxicol 73: 243‐253, 1993.
 34.Esler M, Jennings G, Korner P, Blombery P, Sacharias N, Leonard P. Measurement of total and organ‐specific norepinephrine kinetics in humans. Am J Physiol 247: E21‐28, 1984.
 35.Ferrer M, Meyer M, Osol G. Estrogen replacement increases beta‐adrenoceptor‐mediated relaxation of rat mesenteric arteries. J Vasc Res 33: 124‐131, 1996.
 36.Fleenor BS. Large elastic artery stiffness with aging: Novel translational mechanisms and interventions. Aging Dis 4: 76‐83, 2013.
 37.Franke WD, Johnson CP, Steinkamp JA, Wang R, Halliwill JR. Cardiovascular and autonomic responses to lower body negative pressure: Do not explain gender differences in orthostatic tolerance. Clin Auton Res 13: 36‐44, 2003.
 38.Fu Q. Microneurographic research in women. Frontiers Physiol 3: 278, 2012.
 39.Fu Q, Arbab‐Zadeh A, Perhonen MA, Zhang R, Zuckerman JH, Levine BD. Hemodynamics of orthostatic intolerance: Implications for gender differences. Am J Physiol Heart Circ Physiol 286: H449‐H457, 2004.
 40.Fu Q, Levine BD. Autonomic circulatory control during pregnancy in humans. Semin Reprod Med 27: 330‐337, 2009.
 41.Fu Q, Witkowski S, Okazaki K, Levine BD. Effects of gender and hypovolemia on sympathetic neural responses to orthostatic stress. Am J Physiol Reg Integ Comp Physiol 289: R109‐R116, 2005.
 42.Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and triggers of syncope in medical students. Am J Cardiol 91: 1006‐1008, A1008, 2003.
 43.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.
 44.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.
 45.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.
 46.Hedman AE, Hartikainen JE, Tahvanainen KU, Hakumaki MO. The high frequency component of heart rate variability reflects cardiac parasympathetic modulation rather than parasympathetic ‘tone’. Acta Physiol Scand 155: 267‐273, 1995.
 47.Hogarth AJ, Mackintosh AF, Mary DA. Gender‐related differences in the sympathetic vasoconstrictor drive of normal subjects. Clin Sci 112: 353‐361, 2007.
 48.Hollenberg NK, Martinez G, McCullough M, Meinking T, Passan D, Preston M, Rivera A, Taplin D, Vicaria‐Clement M. Aging, acculturation, salt intake, and hypertension in the Kuna of Panama. Hypertension 29: 171‐176, 1997.
 49.Jensen K, Johansen L, Secher NH. Influence of body mass on maximal oxygen uptake: Effect of sample size. Eur J Appl Physiol 84: 201‐205, 2001.
 50.Johnson BD, Beck KC, Proctor DN, Miller J, Dietz NM, Joyner MJ. Cardiac output during exercise by the open circuit acetylene washin method: Comparison with direct Fick. J Appl Physiol (1985) 88: 1650‐1658, 2000.
 51.Jonason T, Henrikssen E, Kangro T, Nilsson H, Vessby B, Ringqvist I. Stiffness of the common carotid artery in healthy 50‐year‐old subjects. Clin Physiol 17: 569‐577, 1997.
 52.Jones JM, W.; Daniels, K. Current Contraceptive Use in the United States, 2006‐2010, and Changes in Patterns of Use Since 1995. In: National Health Statistics Report. Hyattsville, MD: United States Department of Health and Human Services, 2012, p. 26.
 53.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.
 54.Joyner MJ, Charkoudian N, Wallin BG. A sympathetic view of the sympathetic nervous system and human blood pressure regulation. Exp Physiol 93: 715‐724, 2008.
 55.Joyner MJ, Charkoudian N, Wallin BG. Sympathetic nervous system and blood pressure in humans: individualized patterns of regulation and their implications. Hypertension 56: 10‐16, 2010.
 56.Joyner MJ, Dietz NM. Sympathetic vasodilation in human muscle. Acta Physiol Scand 177: 329‐336, 2003.
 57.Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, Benjamin EJ, Vasan RS, Mitchell GF. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA 308: 875‐881, 2012.
 58.Kimmerly DS, Wong S, Menon R, Shoemaker JK. Forebrain neural patterns associated with sex differences in autonomic and cardiovascular function during baroreceptor unloading. Am J Physiol Reg Integ Comp Physiol 292: R715‐R722, 2007.
 59.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.
 60.Korner PI, Shaw J, Uther JB, West MJ, McRitchie RJ, Richards JG. Autonomic and non‐autonomic circulatory components in essential hypertension in man. Circulation 48: 107‐117, 1973.
 61.Leonetti P, Audat F, Girard A, Laude D, Lefrere F, Elghozi JL. Stroke volume monitored by modeling flow from finger arterial pressure waves mirrors blood volume withdrawn by phlebotomy. Clin Auton Res 14: 176‐181, 2004.
 62.Liu Z, Hesse C, Curry TB, Pike TL, Issa A, Bernal M, Charkoudian N, Joyner MJ, Eisenach JH. Ambulatory arterial stiffness index is not correlated with the pressor response to laboratory stressors in normotensive humans. J Hypertens 27: 763‐768, 2009.
 63.Lohmeier TE, Hildebrandt DA, Dwyer TM, Iliescu R, Irwin ED, Cates AW, Rossing MA. Prolonged activation of the baroreflex decreases arterial pressure even during chronic adrenergic blockade. Hypertension 53: 833‐838, 2009.
 64.MacDougall JD, Tuxen D, Sale DG, Moroz JR, Sutton JR. Arterial blood pressure response to heavy resistance exercise. J Appl Physiol (1985) 58: 785‐790, 1985.
 65.Mackerras D, Singh G. The prevalence of anaemia depends on the definition: An example from the Aboriginal Birth Cohort Study. Eur J Clin Nutrit 61: 135‐139, 2007.
 66.Matsukawa K. Central command: Control of cardiac sympathetic and vagal efferent nerve activity and the arterial baroreflex during spontaneous motor behaviour in animals. Exp Physiol 97: 20‐28, 2012.
 67.Matthews KA, Katholi CR, McCreath H, Whooley MA, Williams DR, Zhu S, Markovitz JH. Blood pressure reactivity to psychological stress predicts hypertension in the CARDIA study. Circulation 110: 74‐78, 2004.
 68.Millar‐Craig MW, Bishop CN, Raftery EB. Circadian variation of blood‐pressure. Lancet 1: 795‐797, 1978.
 69.Mitchell GF. Effects of central arterial aging on the structure and function of the peripheral vasculature: Implications for end‐organ damage. J Appl Physiol (1985) 105: 1652‐1660, 2008.
 70.Molinari C, Battaglia A, Grossini E, Mary DA, Surico N, Vacca G. The role of beta 2‐adrenergic vascular receptors in the peripheral vasodilation caused by 17 beta‐estradiol in anesthetized pigs. Life Sci 65: 1545‐1552, 1999.
 71.Monahan KD, Dinenno FA, Seals DR, Clevenger CM, Desouza CA, Tanaka H. Age‐associated changes in cardiovagal baroreflex sensitivity are related to central arterial compliance. Am J Physiol Heart Circ Physiol 281: H284‐H289, 2001.
 72.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.
 73.NCHS. Health, United States, 2009: With Special Feature on Medical Technology. Hyattsville (MD), 2010.
 74.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.
 75.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: H344‐353, 1994.
 76.Okada Y, Galbreath MM, Shibata S, Jarvis SS, VanGundy TB, Meier RL, Vongpatanasin W, Levine BD, Fu Q. Relationship between sympathetic baroreflex sensitivity and arterial stiffness in elderly men and women. Hypertension 59: 98‐104, 2012.
 77.O'Neill SM, Liu J, O'Rourke MF, Khoo SK. The menopausal transition does not appear to accelerate age‐related increases in arterial stiffness. Climacteric 16: 62‐69, 2013.
 78.Pate RR, Sparling PB, Wilson GE, Cureton KJ, Miller BJ. Cardiorespiratory and metabolic responses to submaximal and maximal exercise in elite women distance runners. Int J Sports Med 8(Suppl 2): 91‐95, 1987.
 79.Pearson AC, Guo R, Orsinelli DA, Binkley PF, Pasierski TJ. Transesophageal echocardiographic assessment of the effects of age, gender, and hypertension on thoracic aortic wall size, thickness, and stiffness. Am Heart J 128: 344‐351, 1994.
 80.Pettersen KH, Bugenhagen SM, Nauman J, Beard DA, Omholt SW. Arterial stiffening provides sufficient explanation for primary hypertension. PLoS Comput Biol 10: e1003634, 2014.
 81.Ping P, Johnson PC. Role of myogenic response in enhancing autoregulation of flow during sympathetic nerve stimulation. Am J Physiol 263: H1177‐H1184, 1992.
 82.Raaijmakers E, Faes TJ, Scholten RJ, Goovaerts HG, Heethaar RM. A meta‐analysis of published studies concerning the validity of thoracic impedance cardiography. Ann NY Acad Sci 873: 121‐127, 1999.
 83.Ray CA. Effect of gender on vestibular sympathoexcitation. Am J Physiol Regul Integ Comp Physiol 279: R1330‐R1333, 2000.
 84.Ray CA, Monahan KD. Aging attenuates the vestibulosympathetic reflex in humans. Circulation 105: 956‐961.
 85.Rea RF, Wallin BG. Sympathetic nerve activity in arm and leg muscles during lower body negative pressure in humans. J Appl Physiol (1985) 66: 2778‐2781, 1989.
 86.Rowell LB. Human Circulation Regulation During Physical Stress. New York, NY: Oxford University Press, Inc., 1986.
 87.Rowell LB, Brengelmann GL, Blackmon JR, Bruce RA, Murray JA. Disparities between aortic and peripheral pulse pressures induced by upright exercise and vasomotor changes in man. Circulation 37: 954‐964, 1968.
 88.Russo C, Jin Z, Palmieri V, Homma S, Rundek T, Elkind MS, Sacco RL, Di Tullio MR. Arterial stiffness and wave reflection: Sex differences and relationship with left ventricular diastolic function. Hypertension 60: 362‐368, 2012.
 89.Saleh MC, Connell BJ, Saleh TM. Autonomic and cardiovascular reflex responses to central estrogen injection in ovariectomized female rats. Brain Res 879: 105‐114, 2000.
 90.Schmitt JA, Joyner MJ, Charkoudian N, Wallin BG, Hart EC. Sex differences in alpha‐adrenergic support of blood pressure. Clin Auton Res 20: 271‐275, 2010.
 91.Seals DR, Victor RG, Mark AL. Plasma norepinephrine and muscle sympathetic discharge during rhythmic exercise in humans. J Appl Physiol (1985) 65: 940‐944, 1988.
 92.Segers P, Rietzschel ER, De Buyzere ML, Vermeersch SJ, De Bacquer D, Van Bortel LM, De Backer G, Gillebert TC, Verdonck PR. Noninvasive (input) impedance, pulse wave velocity, and wave reflection in healthy middle‐aged men and women. Hypertension 49: 1248‐1255, 2007.
 93.Shoemaker JK, Hogeman CS, Khan M, Kimmerly DS, Sinoway LI. Gender affects sympathetic and hemodynamic response to postural stress. Am J Physiol Heart Circ Physiol 281: H2028‐H2035, 2001.
 94.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.
 95.Smith EG, Voyles WF, Kirby BS, Markwald RR, Dinenno FA. Ageing and leg postjunctional alpha‐adrenergic vasoconstrictor responsiveness in healthy men. J Physiol 582: 63‐71, 2007.
 96.Smulyan H, Asmar RG, Rudnicki A, London GM, Safar ME. Comparative effects of aging in men and women on the properties of the arterial tree. J Am Coll Cardiol 37: 1374‐1380, 2001.
 97.Sonesson B, Lanne T, Vernersson E, Hansen F. Sex difference in the mechanical properties of the abdominal aorta in human beings. J Vasc Surg 20: 959‐969, 1994.
 98.Sonesson B, Vernersson E, Hansen F, Lanne T. Influence of sympathetic stimulation on the mechanical properties of the aorta in humans. Acta Physiol Scand 159: 139‐145, 1997.
 99.Sudhir K, Elser MD, Jennings GL, Komesaroff PA. Estrogen supplementation decreases norepinephrine‐induced vasoconstriction and total body norepinephrine spillover in perimenopausal women. Hypertension 30: 1538‐1543, 1997.
 100.Sundlof G, Wallin BG. The variability of muscle nerve sympathetic activity in resting recumbent man. J Physiol 272: 383‐397, 1977.
 101.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 (1985) 96: 1262‐1269, 2004.
 102.Vongpatanasin W, Tuncel M, Mansour Y, Arbique D, Victor RG. Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation 103: 2903‐2908, 2001.
 103.Waddell TK, Dart AM, Gatzka CD, Cameron JD, Kingwell BA. Women exhibit a greater age‐related increase in proximal aortic stiffness than men. J Hypertens 19: 2205‐2212, 2001.
 104.Wallin BG, Charkoudian N. Sympathetic neural control of integrated cardiovascular function: Insights from measurement of human sympathetic nerve activity. Muscle Nerve 36: 595‐614, 2007.
 105.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.
 106.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.
 107.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.
 108.Weisbrod CJ, Minson CT, Joyner MJ, Halliwill JR. Effects of regional phentolamine on hypoxic vasodilatation in healthy humans. J Physiol 537: 613‐621, 2001.
 109.Weiskopf RB, Viele MK, Feiner J, Kelley S, Lieberman J, Noorani M, Leung JM, Fisher DM, Murray WR, Toy P, Moore MA. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 279: 217‐221, 1998.
 110.Weitz G, Elam M, Born J, Fehm HL, Dodt C. Postmenopausal estrogen administration suppresses muscle sympathetic nerve activity. J Clin Endocrinol Metab 86: 344‐348, 2001.
 111.Wenner MM, Haddadin AS, Taylor HS, Stachenfeld NS. Mechanisms contributing to low orthostatic tolerance in women: The influence of oestradiol. J Physiol 591: 2345‐2355, 2013.
 112.Wenner MM, Stachenfeld NS. Blood pressure and water regulation: Understanding sex hormone effects within and between men and women. J Physiol 590: 5949‐5961, 2012.
 113.Wesseling KH, Jansen JR, Settels JJ, Schreuder JJ. Computation of aortic flow from pressure in humans using a nonlinear, three‐element model. J Appl Physiol (1985) 74: 2566‐2573, 1993.
 114.Xue B, Johnson AK, Hay M. Sex differences in angiotensin II‐ and aldosterone‐induced hypertension: The central protective effects of estrogen. Am J Physiol: Reg Integ Com Physiol 305: R459‐R463, 2013.
 115.Xue B, Singh M, Guo F, Hay M, Johnson AK. Protective actions of estrogen on angiotensin II‐induced hypertension: Role of central nitric oxide. Am J Physiol Heart Circ Physiol 297: H1638‐H1646, 2009.
 116.Yang H, Cooke WH, Reed KS, Carter JR. Sex differences in hemodynamic and sympathetic neural firing patterns during orthostatic challenge in humans. J Appl Physiol (1985) 112: 1744‐1751, 2012.
 117.Yang H, Drummer TD, Carter JR. Sex differences in sympathetic neural and limb vascular reactivity to mental stress in humans. Am J Physiol Heart Circ Physiol 304: H436‐443, 2013.
 118.Yasmin Brown MJ. Similarities and differences between augmentation index and pulse wave velocity in the assessment of arterial stiffness. QJM 92: 595‐600, 1999.

Related Articles:

Sex Differences

Contact Editor

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

* Required Field

How to Cite

Michael J. Joyner, Jill N. Barnes, Emma C. Hart, B. Gunnar Wallin, Nisha Charkoudian. Neural Control of the Circulation: How Sex and Age Differences Interact in Humans. Compr Physiol 2014, 5: 193-215. doi: 10.1002/cphy.c140005