Neural control of the circulation: how sex and age differences interact in humans

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.

Figures

Figure 1

Prevalence of hypertension from 2003–2006 by sex and age in the United States. These data shows that blood pressure increases with age in wealthy, industrialized countries with low levels of physical activity, food abundance, and the social stresses of urbanization. It 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 from ref NCHS, (73).

Figure 2

The prevalence of syncope in young women (grey bars) is higher than young men (black bars) between the ages of 7–21 years. Figure adapted from (42).

Figure 3

This illustrates 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 amount these communities. Note that the blood pressure trends typically observed in industrialized areas is not present in rural island dweller, indicating that age-related changes in blood pressure are not an obligatory feature of human biology. Figure adapted from ref (48).

Figure 5

The relationship between baseline muscle sympathetic nerve activity (MSNA) and plasma norepinephrine levels (PNE) is shown in panel A (Figure adapted from) (74). Panel B shows the relationship between MSNA and renal norepinephrine (noradrenaline) spillover. Figure adapted from (1097). 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 from (20).

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

Figure 8

The relationship between muscle sympathetic nerve activity (MSNA) and mean arterial blood pressure (MAP) in 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 from (72).

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 from several studies from our laboratory (, –45).

Figure 10

The 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 (Figure 9) and postmenopausal women, but not young women suggests a role for sex hormones in blood pressure regulation. Data from (43).

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 estradiol/progesterone (bottom panel) was 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 from (13).

Figure 12

Sex hormones and specifically estrogen has been shown to affect neural outflow. Administration of transdermal estrogen for 8 weeks in postmenopausal women reduces muscle sympathetic nerve activity. *p

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 from (48).

Figure 14

Effects of brachial artery administration of norepinephrine (noradrenaline, NA) on forearm vascular conductance before and after local administration of the non-selective 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). The 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 from (43).

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 panel). This suggests that β-adrenergic vasodilation blunts vascular transduction of the sympathetic nerves. Data from (43).

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 the important differences in neurovascular regulation. Data from (16).

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 from. (75).

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) is 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 from (4).