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Hypertension. 2008 November ; 52(5): 787–794. doi:10.1161/HYPERTENSIONAHA.108.118927.

Neural and Non-neural Mechanisms for Sex Differences in Elderly

Hypertension:
Can Exercise Training Help?

Qi Fu, MD, PhD1,2, Wanpen Vongpatanasin, MD2, and Benjamin D. Levine, MD1,2
1Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas

2The University of Texas Southwestern Medical Center at Dallas, Texas, USA

Introduction
Blood pressure (BP) increases with advancing age in humans in most industrialized societies.
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The relationship between systolic and diastolic pressures to cardiovascular events is generally
more pronounced in people aged ≥65 years.1 The Framingham Heart Study and the National
Health and Nutrition Examination Survey uniformly demonstrated a higher prevalence of
hypertension and a lower BP control rate in elderly women than men.2, 3 Specifically, only
23-28% of hypertensive women over the age of 60 achieved BP goals on treatment, whereas
36-38% of hypertensive men of the same age reached the target BP.2 Precise mechanisms for
this observation are unknown, but may be related to sex differences in the pathophysiology of
hypertension or responses to antihypertensive therapy.

It has been recognized that the pathophysiology of hypertension in the elderly is largely due
to an age-related decline in aortic distensibility resulting in progressive increases in systolic
pressure and pulse pressure and a decrease in diastolic pressure.4, 5 However, large
epidemiological studies have shown that not only systolic but also diastolic pressure is higher
in elderly women than men, suggesting that other mechanism(s) may contribute to sex
differences in BP regulation. For example, one recent study demonstrated that aging was
accompanied by a greater increase in sympathetic traffic in healthy women than men.6 It is
well known that elevated sympathetic activity plays an important role in the development of
hypertension in the young and middle-aged population.7-10 Whether a sympathetic neural
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mechanism is responsible for the high prevalence of hypertension and the poor BP control rate
in elderly women remains unclear. Additionally, whether ventricular-arterial function and
some hormonal markers are non-neural differences that may also contribute to the influence
of aging on BP control in elderly women needs to be verified.

Clarifying the specific pathophysiology of sex differences in elderly hypertension is essential

for determining optimal evidence based therapy, particularly since the risk of stroke,
myocardial infarction, or congestive heart failure remains high in these patients even with
adequate BP control;11 moreover, many patients have inadequate BP control despite medical
therapy often involving multiple drug regimens.12 A potential mechanism for both of these
problems could be persistent or even augmented sympathetic activation by the baroreflex

Corresponding author: Benjamin D. Levine, MD, Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas,
7232 Greenville Avenue, Suite 435, Dallas, Texas 75231, Phone: (214) 345-4620, Fax: (214) 345-4618, Email: E-mail:
BenjaminLevine@TexasHealth.org.
DISCLOSURES
None.
 Fu et al. Page 2

during antihypertensive drug therapy.13 One complementary non-pharmacologic therapy that

may have some promise to reduce sympathetic activation and/or arterial stiffening with limited
side effects is exercise training. However, it is unknown whether exercise training can be
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regarded as an effective therapy for elderly hypertensive patients compared with standard
pharmacologic therapies.

In this review, we highlight some previous results of neural and non-neural control in elderly
hypertensives as well as exercise training as a non-drug antihypertensive therapy in this
particularly challenging patient population. An overview of neural and non-neural
mechanisms, and the possible role of exercise training is depicted in Figure 1. The techniques
used in previous studies to assess neural and non-neural control in hypertensive patients are
summarized in Table 1.

Aging, Sex and Neural Control in Hypertension

Sympathetic neural control plays an important role in arterial pressure maintenance in humans.
14-16 Vasomotor sympathetic activity, which can be recorded as muscle sympathetic nerve
activity by the microneurographic technique,17 has been found to increase with advancing age,
while the increment is greater in women than men (Figure 2).6, 18 One recent study
demonstrated that the increase in BP per increment of muscle sympathetic nerve activity was
actually greater in women over the age of 40 years, than in similarly aged men.6 These results
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parallel epidemiological data indicating a higher prevalence of hypertension in elderly women

and suggest that a sympathetic neural mechanism may contribute importantly to the more
marked influence of aging on BP and cardiovascular disease in women.

Laitinen et al19 showed that during upright posture, the increase in heart rate was more
pronounced in young individuals, whereas the increase in peripheral vascular resistance was
more dramatic in the elderly, suggesting that vascular responses related to vasoactive
mechanisms and vasomotor sympathetic regulation become augmented with increasing age.
Although the study by Laitinen et al19 focused on age but not sex, it seems likely that
augmented sympathetic vasoconstriction plays a more critical role in elderly hypertensive
women. Indeed, this notion was supported by the findings of Lipsitz et al,20 showing enhanced
vasoreactivity in elderly hypertensive women. They found that elderly hypertensive women
had a much greater increase in systemic vascular resistance than elderly hypertensive men
during upright tilt, which was associated with a greater low-frequency systolic pressure
variability, a presumed marker of sympathetic vascular control.20 Since muscle sympathetic
nerve activity was not measured in this study, it is difficult to be certain whether the enhanced
vascular resistance response was due to an increase in sympathetic outflow in these patients.
21 It was shown that alpha-adrenergic vasoconstriction was blunted despite elevated
sympathetic activity in the peripheral22 and renal arteries in healthy elderly men.23
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Mechanisms underlying this observation is unknown, but a recent study in rats indicates that
aging is associated with a decline in alpha adrenergic-receptor expression and binding affinity
in male rats, but not in female rats.24 Therefore, a sex-specific, age-related difference in alpha-
adrenergic vasoconstriction may also contribute to the enhanced vasoreactivity in elderly
hypertensive women.

Previous studies have suggested that hypertension is associated with a resetting of the
cardiovagal baroreflex arc at a higher set point.25 With the spectral transfer function analysis
technique, it was found that the sensitivity of baroreflex control of heart rate did not differ
between normotensive men and women,26, 27 but hypertensive patients had lower baroreflex
sensitivity than normotensive controls; moreover, cardiovagal baroreflex sensitivity was
significantly reduced in middle-aged hypertensive women compared with age-matched
hypertensive men.27 It was proposed that sex was an important determinant of the cardiovagal

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baroreflex sensitivity and heart rate variability in hypertensive individuals.27 Conversely,

while there is nearly universal agreement that human hypertension is associated with
impairment of baroreflex control of cardiac vagal outflow, it is still not completely certain
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whether human hypertension is associated with a corresponding enhancement of sympathetic

outflow, whether baroreflex control of vasomotor sympathetic activity is impaired in
hypertensives, especially in hypertensive seniors, and whether the impairment of sympathetic
baroreflex function is age and sex dependent in hypertensive patients.

Non-neural Mechanism for Sex Differences in Elderly Hypertension

Increased ventricular-arterial stiffness is associated with hypertension and is recognized as an
important determinant of cardiovascular risk.28-30 It was found recently that advancing age
and female sex were associated with increases in vascular and ventricular stiffness even in the
absence of cardiovascular disease.31 An increased prevalence of isolated systolic hypertension
in elderly women32, 33 has been proposed to be associated with an increase in arterial stiffness.
34 One hemodynamic consequence of vascular stiffening is an increase in left ventricular
afterload.35 However, there is strong evidence that vascular resistance is not the dominant
factor in the rise in systolic pressure after the age of 60 years. For example, it was found that
total peripheral resistance was only marginally elevated in elderly patients with isolated systolic
hypertension compared with age- and sex-matched normotensive controls.36 On the other
hand, it was shown that an augmentation of aortic pressure throughout systole (large artery
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stiffness and early pulse wave reflection) predominated over increased vascular resistance in
these elderly patients.4, 37 Age and hypertension are associated with alterations in the elastic
properties of the arterial wall that cause profound changes in arterial pressure waves, while
these changes are attributed primarily to the changes in amplitude and timing of pulse wave
reflections from peripheral reflecting sites in the lower body.38

There is increasing evidence to support the concept that the age-related increase in aortic
stiffness is significantly greater in women than men (Figure 3).39 A recent study by Berry et
al40 found that elderly systolic hypertensive women had stiffer large arteries, greater central
wave reflection, and higher pulse pressure than elderly hypertensive men, and they thereby
concluded that stiffer large arteries likely contributed to the greater prevalence of systolic
hypertension in elderly women and may partly explain the acceleration in postmenopausal
cerebrovascular and cardiac complications. However, the Third National Health and Nutrition
Examination Survey showed that not only systolic but also diastolic pressure was higher in
elderly women compared with elderly men.41 Whether the greater prevalence of diastolic
hypertension and/or combined systolic-diastolic hypertension in elderly women can also be
explained by impaired ventricular-arterial function alone or whether other mechanisms play
an additional role remains unclear.
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It has been shown that menopause is associated with increased susceptibility to salt-induced
rise in BP.42, 43 Schulman et al44 demonstrated that salt sensitivity of BP increased
significantly 4 months after surgical menopause in middle-aged women, which could be related
to increased angiotensin receptor subtype 1 expression in the kidney.45 Salt-sensitive
hypertensive patients have a higher incidence of left ventricular hypertrophy,46, 47, endothelial
dysfunction,48, insulin resistance,49 and hyperlipidemia50 compared with salt-resistant
hypertensive patients. Thus decreases in sex hormones and increased sensitivity to sodium may
be important factors in the genesis of postmenopausal hyperteniosn.51

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Effects of Exercise Training on Neural and Non-neural Control in Elderly

Hypertension
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Aging generally leads to reductions in physical activity in both humans and animals. A
sedentary lifestyle increases the risk of hypertension, while increased physical activity or
exercise training is associated with lower levels of BP.52, 53 We found that a sedentary lifestyle
during normal aging led to cardiac atrophy and an increase in arterial elastance/stiffness, while
very prolonged exercise training prevented ventricular-arterial stiffening (Figure 4).54
Recently, we demonstrated that three to six months of endurance training in initially sedentary
seniors reduced both systolic and diastolic pressures effectively.55 Training-induced reduction
in BP has been proposed to be associated with an increased release of nitric oxide, resulting
from an increase in vascular shear stress during exercise.56 Chronic increases in shear stresses
lead to function and histological alterations of vascular endothelium, causing enhanced
vascular structure and function.57

Exercise training was found to improve arterial compliance in healthy middle-aged individuals,
58 but it was reported that short-term (i.e., 8 weeks) training did not modify large-artery
compliance and left ventricular mass or function in elderly patients with isolated systolic
hypertension.59 However, one recent study showed that although arterial compliance remained
unchanged, flow-mediated endothelium-dependent vasodilation increased after 12 weeks of
training in elderly hypertensives, indicating improved endothelial function.60 Rinder et al61
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found that long-term (i.e., 6 months) training not only decreased BP but also induced regression
of left ventricular hypertrophy in elderly hypertensive patients. Recently, Westhoff et al62
demonstrated in elderly hypertensives that 12 weeks of training evoked comparable reductions
in BP and improvements of endothelial function in the presence and absence of beta-blockades,
suggesting that drug therapy provided no additive benefit to and did not prevent the
antihypertensive effects of exercise training. These results are consistent with some previous
reports with both selective and non-selective beta-blockade as well as calcium-channel
blockers.63-68

Grassi et al69 showed in young hypertensive men that the BP reduction after training was
mediated by a neural mechanism, since vasomotor sympathetic activity decreased after 10
weeks of training. Similar results were obtained in middle-aged and elderly hypertensives after
4 and 6 months of training,70, 71 indicating that suppression of sympathetic activity may play
a role in the reduction in arterial pressure. Additionally, the sympathetic baroreflex function
was improved after training in middle-aged hypertensive patients.70 Elevated sympathetic
activity was found to be associated with an increase in arterial wall thickening72 and left
ventricular mass.73 Thus, training-induced decreases in sympathetic activity may be beneficial
in preventing arterial stiffening in hypertension.
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Exercise training could elicit adaptations in the adrenergic system, since the sympathetic
nervous system is activated during each bout of exercise and repeated activation of the
sympathetic nervous system may result in an attenuation of sympathetic activity.74 Animal
studies suggested that nitric oxide decreased overall sympathetic excitability within the
brainstem and possibly through actions in higher brain regions (i.e., hypothalamus).75, 76 Due
to the inevitable experimental restrictions, it is unclear whether the increased release of nitric
oxide during exercise training has a central sympathoinhibitory effect in humans. It is also
unclear whether training reduces salt sensitivity in elderly women. Previous studies
demonstrated that hyperinsulinemia and insulin resistance were associated with hypertension
and sympathetic activation,77, 78 while training could improve insulin sensitivity in
normotensive and hypertensive individuals.79, 80 Training-induced muscle adaptations also
appear to be important in attenuating insulin mediated sympathetic activation. Additionally,
exercise training has been shown to improve aerobic capacity, vascular conductance, and lower

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body fat, each of which could also contribute to a reduction in BP.81-85 The improved vascular
conductance in athletes and with training is not endothelial mediated, and probably reflects
structural adaptations required to accommodate a high muscle blood flow.84, 85
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Sex differences in training-induced BP reduction in elderly hypertensives have not been

investigated extensively. It was found in a Japanese population that elderly hypertensives
experienced smaller reductions in BP than younger counterparts after 8 weeks of training, while
sex did not affect the efficacy of physical activity for lowering elevated BP.86 Brown et
al71 showed similar results, but sex was not investigated in their study. These observations
cannot be explained by a suboptimal training stimulus, since maximal oxygen uptake increased
similarly (i.e., 14-16%) in young and elderly patients after training in both studies. Rather,
persistent sympathetic activation and ventricular-arterial stiffening may be potential
mechanisms underlying the attenuated training-induced BP reduction in hypertensive seniors.
Unfortunately, comparisons of training effects on neural and non-neural control in elderly
hypertensive men and women have never been made in the same study, although two previous
investigations have looked extensively at the effects of training in hypertensive women,87,
88 without direct measurements of muscle sympathetic nerve activity. Whether exercise
training can be regarded as an effective therapy for elderly hypertensive patients needs to be
clarified. Table 2 shows the effects of training on neural and non-neural control of BP in
hypertensive patients from previous studies.
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Significance
It is important to note that approximately two-thirds of elderly hypertensive women, who are
most at risk for stroke and cardiovascular events, do not have their BP adequately controlled,
either because they are not on drug treatment or because in spite of taking antihypertensive
drugs, their BP is still above recommended levels. The questions of which drug classes offer
the most benefit for these patients, whether antihypertensive drug treatment should be the same
or different for elderly men and women, and whether non-pharmacologic therapy, such as
exercise training is effective for elderly hypertensive women are as yet unanswered. If a
heightened level of sympathetic activity coupled with elevated arterial stiffness is the
fundamental mechanism of hypertension in elderly women which cannot be reversed by most
antihypertensive agents, exercise training may be an integral strategy to achieve BP control in
this patient population by reducing both sympathoexcitation and arterial stiffness. If this is the
case, formal exercise training should be incorporated as an essential part of hypertension
treatment in elderly hypertensive women in addition to BP medications.

Acknowledgments
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SOURCES OF FUNDING

Some of the work included in this review was supported by grants from the National Institutes of Health (AG17479
and HL075283) and the American Heart Association Texas Affiliate Beginning Grant-In-Aid (0060024Y).

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Figure 1.
A schematic overview of neural and non-neural mechanisms for sex differences in elderly
hypertension, and the effects of exercise training on hypertension in seniors. Advancing age
and female sex seem to be associated with a marked increase in sympathetic activity and a
dramatic decrease in ventricular-arterial function, both of which may be responsible for the
high prevalence of hypertension in elderly women. Increased sympathetic activity could also
decrease ventricular-arterial function. On the other hand, exercise training increases the release
of nitric oxide through shear stress, which may decrease sympathetic activity and improve
ventricular-arterial function, and therefore, decrease blood pressure in elderly hypertensives.
SNA, sympathetic nerve activity; V-A, ventricular-arterial.
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Figure 2.
Supine resting muscle sympathetic nerve activity increased with advancing age, and the
increment was greater in women than men. Adapted with permission from Reference 18.
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Figure 3.
Comparisons of the ventricular-arterial function in men (open circle) and women (filled circle)
in the young, middle-age, and older populations. Data presented as mean±SEM. Significant
difference between sexes within each age group; *P < 0.05, **P < 0.01, ***P < 0.001. Adapted
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with permission from Reference 39.

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 Fu et al. Page 14
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Figure 4.
Effects of normal aging and physical activity on left ventricular mass and arterial elastance in
healthy humans. Derived with permission from Reference 54.
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 Fu et al.
Techniques used to assess neural and non-neural controls in hypertensive patients
Mechanisms Techniques
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Neural
Non-neural
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Table 1
Measurements Authors, Year, Reference
High-performance liquid chromatography Plasma catecholamines Goldstein, 19837
Goldstein, 19818
Goldstein, 19839
Fu et al, 200513
Laitinen et al, 199826
The radiotracer technique Norepinephrine spillover Esler et al, 198089
Extravascular norepinephrine release rate Brown et al, 200271
Supiano et al, 199990
The microneurographic technique Muscle sympathetic nerve activity Fu et al, 200513
Laterza et al, 200770
Spectral and transfer function analysis Baroreflex gain Lipsitz et al, 200620
Sevre et al, 200127
The modified Oxford method Baroreflex gain Korner et al, 197425
Laitinen et al, 199826
Doppler ultrasound technique Arterial stiffness/compliance van Popele et al, 200128
Tonometry Boutouyrie et al, 200229
Waddell et al, 200139
Berry et al, 200440
Ferrier et al, 200159
Echocardiography Left ventricular size and geometry and function Rinder et al, 200461
Turner et al, 200091
Acetylene rebreathing technique Arterial afterload Fu et al, 200513
Magnetic resonance imaging Left ventricular size and geometry and function Burns et al, 200773
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Table 2
Effects of endurance exercise training on neural and non-neural mechanisms in hypertensive patients

Mechanism Authors, Year, Reference Patients’ Characteristics Measured Variables Training Program Training Effects

Neural Brown et al, 200271 Mild hypertensives (18 NE2 (an index of SNA) Walking/jogging/cycling at 70% of No change in BP
women, 12 men, mean age 63
Fu et al.

HRpeak, 3 times/wk, 40 min/time for 6 No change in NE2

yr) mo

Laterza et al, 200770 Mild hypertensives (7 MSNA Cycling at 70% of VO2peak, plus strength Decreased BP
women, 7 men, mean age 44 Sympathetic baroreflex function training, 60 min/time, 3 times/wk for 4 Normalized MSNA
yr) mo Restored baroreflex function

Kouame et al, 199592 Mild to moderate Baroreflex control of limb vascular resistance Cycling at 50% and 70% of VO2peak, 3 Attenuated baroreflex control
hypertensives (1 woman, 8 times/wk, 45 min/time for 10 wk each No change in BP with high
men, mean age 43 yr) intensity training

Kohno et al, 200080 Mild to moderate Baroreflex function (systolic BP and R-R interval Cycling at 75% of VO2peak, 4 times/d, 6 Decreased BP
hypertensives (12 women, 17 relation) min/time for 3 wk Improved baroreflex function
men, mean age 43 yr)

Non-neural Ferrier et al, 200159 Mild isolated systolic Large-artery compliance Cycling at 65% of HRpeak, 3 times/wk, No change in BP
hypertensives (5 women, 5 Left ventricular mass or function 40 min/time for 8 wk No change in arterial
men, mean age 64 yr) mechanical properties or left
ventricular mass and function

Rinder et al, 200461 Mild to moderate Left ventricular geometry and mass and function Walking/jogging/cycling at 60-70% of Decreased BP
hypertensives (3 women, 13 HRpeak, ≥3 times/wk, 40-50 min/time for Regression of left ventricular
men, mean age 66 yr) 6 mo hypertrophy

Westhoff et al, 200762 Mild to moderate Endothelial function assessed by flow-mediated Interval training (treadmill walking, Decreased BP
hypertensives (13 women, 12 dilation with or without beta-blockades), 30-40 Improved endothelial function
men, mean age 68 yr) min/time, 3 times/wk for 12 wk in all patients

Higashi et al, 199993 Mild hypertensives (4 Endothelium-dependent forearm vasorelaxation Brisk walking at 50-60% of VO2peak, 30 Decreased BP
women, 13 men, mean age 47 min/time, 5-7 times/wk for 12 wk Improved endothelium-
yr) dependent vasorelaxation

Turner et al, 200091 Mild to moderate Left ventricular size and geometry and function Walking/jogging/cycling at 60-80% of Decreased BP
hypertensives (2 women, 9 HRpeak, 30-50 min/time, 4 times/wk for Partial regression of left
men, mean age 65 yr) 7 mo ventricle
NE2, extravascular norepinephrine release rate; SNA, sympathetic nerve activity; BP, blood pressure; MSNA, muscle sympathetic nerve activity; VO2peak and HRpeak; peak oxygen uptake and

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peak heart rate during maximal exercise test.
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