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Departments of Integrative Physiology and Internal Medicine, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas 76107
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested the
hypothesis that hypotension occurred in older adults at the onset of
orthostatic challenge as a result of vagal dysfunction. Responses of
heart rate (HR) and mean arterial pressure (MAP) were compared between
10 healthy older and younger adults during onset and sustained lower
body negative pressure (LBNP). A younger group was also assessed after
blockade of the parasympathetic nervous system with the use of atropine
or glycopyrrolate and after blockade of the
1-adrenoceptor by use of metoprolol. Baseline HR (older
vs. younger: 59 ± 4 vs. 54 ± 1 beats/min) and MAP (83 ± 2 vs. 89 ± 3 mmHg) were not significantly different between the groups. During 
40 Torr, significant tachycardia occurred at the
first HR response in the younger subjects without hypotension, whereas
significant hypotension [change in MAP (
MAP) 7 ± 2 mmHg] was observed in the elderly without tachycardia. After
the parasympathetic blockade, tachycardiac responses of younger
subjects were diminished and associated with a significant hypotension
at the onset of LBNP. However, MAP was not affected after the cardiac
sympathetic blockade. We concluded that the elderly experienced
orthostatic hypotension at the onset of orthostatic challenge because
of a diminished HR response. However, an augmented
vasoconstriction helped with the maintenance of their blood pressure
during sustained LBNP.
vagal dysfunction; tachycardiac response; lower body negative pressure; atropine; glycopyrrolate; metoprolol
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ORTHOSTATIC HYPOTENSION,
DEFINED AS a decrease in systolic blood pressure of 
20 mmHg or
in diastolic blood pressure of 10 mmHg in upright posture, is
prevalent with aging (26). It has been reported that up to
30% of normotensive subjects over 65 yr of age experience a decrease
in systolic blood pressure 20 mmHg during 60° head-up tilt
(23). However, the incidence of orthostatic hypotension
observed in the elderly population is frequently complicated by
age-related pathological conditions, such as high blood pressure
(10, 14), or by medications for these conditions, such as
antihypertensive agents (20, 30). Arterial blood pressure
regulation during orthostatic challenge, elicited by standing or
simulated by lower body negative pressure (LBNP), appears to be
functional in healthy, normotensive older adults compared with their
younger counterparts (29). Although the arterial
baroreflex control of heart rate is significantly diminished with aging
(17, 29), responses of muscle sympathetic nerve activity
(12) and venous plasma norepinephrine concentrations (29) during hypotensive stimuli are not different between
younger and older adults. Because the neurally and humorally mediated vasomotor responses take longer to be effective, it remains
questionable whether elderly people exhibit a greater hypotension at
the onset of orthostatic challenge compared with their younger
counterparts. We postulated that aging contributes to the attenuated
response of arterial blood pressure regulation at the onset of
orthostatic challenge because of an impaired tachycardiac response
caused by an age-related vagal dysfunction. The purpose of this study was to determine whether orthostatic hypotension was present in older
adults at the onset of LBNP-induced central hypovolemia because of an
age-related decrease in reflex tachycardia. If the diminution of the
vagal function was the mechanism responsible for the orthostatic
hypotension in the older adults, then this aging phenomenon would be
imitated in younger subjects after administration of a muscarinic
cholinergic (MC) antagonist to block the parasympathetic influence,
thus simulating the age-related vagal dysfunction. Because the MC
antagonist atropine penetrates the blood-brain barrier and blocks both
central and peripheral MC receptors (21), we also chose
the MC antagonist glycopyrrolate, which presumably has little central
"confounding" effect (3) (24).
Use of these two drugs would allow differentiation of central
modulation of MC receptors on blood pressure regulation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Ten (5 men and 5 women) younger subjects (25 ± 1 yr old) and 10 (5 men and 5 women) older subjects (64 ± 1 yr old) participated in the first study. All younger and older subjects were normotensive, without a medical history, and were taking no medications during the study. Body weight (71.1 ± 4.9 and 74.0 ± 5.0 kg, respectively) and height (173 ± 3 and 171 ± 3 cm, respectively) were similar between the younger and older subjects. The second study tested 10 (7 men and 3 women) healthy younger adults (age, 24 ± 1 yr old; weight, 71.0 ± 4.1 kg; height, 177 ± 4 cm) with and without the MC antagonists atropine and glycopyrrolate. In addition, metoprolol was used to block1-adrenoceptor in six younger
subjects. There was no gender-related difference in heart rate (see
Table 1). Arterial blood pressure tended
to be lower in young female subjects and higher in older female
subjects compared with their male counterparts, but the differences
were not statistically significant (probably because of type II or error). Heart rate and blood pressure responses to LBNP were similar in
both groups. After passing a physical examination, all subjects signed
an informed consent form, which explained the purpose and procedure of
the experiments. The experimental procedure and the consent form were
approved by the Institutional Review Board of the University of North
Texas Health Science Center at Fort Worth.
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Procedure
Before the test, each subject was oriented to the laboratory and familiarized with the experimental procedure and measurements to be used during the test. Experiments were carried out with the subjects lying supine, with the lower body in a LBNP box.Study 1.
After the box was sealed, negative pressure was preset at 15 Torr.
The subject's body was prevented from moving during LBNP by a
cushioned saddle inside the box between the subject's legs. After 30
min of supine rest, baseline pulse interval (PI) or heart rate (HR) and
systolic, diastolic, and mean arterial blood pressures were
continuously recorded by an online personal computer. Immediately after
1 min of baseline, negative pressure was established and remained for
8-10 min. Cardiovascular variables were continuously monitored
during LBNP. After 10 min of recovery from a LBNP of 15 Torr, the
baseline data were again collected, followed by the application of a
preset LBNP of 40 Torr for 8-10 min. All subjects were asked to
breathe 15 times/min during data collection.
Study 2.
The second group of younger subjects performed two LBNP tests at 40
Torr on each experimental day. Baseline HR and arterial blood pressure
were continuously collected for 1 min, followed by the application of
LBNP for 15 min, which was preset at 40 Torr. After approximately
45 min of recovery from LBNP, atropine (n = 8) was
injected at 5 µg/kg to fully block the MC receptors, i.e., there was
no further tachycardia observed after two consecutive doses, or to a
cumulative dose of 40 µg/kg wt. The cardiovascular responses to LBNP
were then assessed. After 1 wk, subjects returned to the lab to repeat
the same protocol with glycopyrrolate (n = 8) as
the MC antagonist. Glycopyrrolate was injected at 2 µg/kg until
complete blockade was achieved or to a cumulative dose of 16 µg/kg.
The dose of glycopyrrolate was determined to be equipotent to that of
atropine (2, 8, 22). The test order was randomized. In
addition, the responses of HR and arterial blood pressure to a LBNP of
40 Torr were tested in six young subjects before and after
administration of metoprolol, with a cumulative dose of 200 µg/kg wt
to selectively block 1-adrenoceptor.
Measurements
Experiments were conducted with ambient temperatures between 24 and 26°C and relative humidity between 55 and 65%. A standard lead II electrocardiogram was used to monitor HR. For study 1, arterial pressure was continuously measured by an intraradial arterial catheter (9 younger and 2 older subjects) or by a finger cuff (Finapres, Ohmeda) on the middle finger. A sterile, disposable pressure transducer (Cobe, Lakewood, CO) interfaced with the arterial catheter was monitored by a dual-pressure channel monitor (Hewlett Packard 78342A), and the reference point was set at the subject's midaxillary line. During all experiments, the pressure inside the LBNP box was continuously monitored.Data Management
Data were reported in group means ± SE. Changes in PI and systolic, diastolic, and mean arterial blood pressure during the initial 10 pulses and during the whole 1st, 2nd, 3rd, and 8th min of LBNP were calculated as the cardiovascular responses to the onset of and sustained orthostatic stresses, respectively. Two-way analysis of variance (ANOVA) was employed to determine the age and time (during LBNP) factors (in study 1) or the effects of autonomic nervous system antagonists and time in the younger group (in study 2) on these cardiovascular responses. Duncan's method was used to compare the difference of the first 10 pulse responses at the onset of LBNP. Tukey's methods were applied for post hoc analysis during LBNP if ANOVA outcome was significant for the time (in min) factor. Statistic Analysis System (SAS) software was utilized for the significance analysis. A P value
0.05 was considered
to be significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study 1
Because there was no significant difference in either baseline data or the responses of HR and arterial blood pressure between men and women in both younger and older groups (see Table 1), subjects had been merged within the age groups. All subjects' arterial blood pressures were within the normotensive range. Mean and diastolic arterial pressures tended to be higher in the older subjects (see Table 2). However, none of these differences reached a level of P0.05. HR or PI
was statistically identical in the younger and older subjects.
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Arterial blood pressure during a LBNP of 15 Torr was well maintained
in both age groups (Fig. 1 and
Table 2). Baseline cardiovascular data before a LBNP of 15 and 40
Torr were not statistically different in either age group. When a LBNP
of 40 Torr was applied, a significant systemic hypotension
accompanied by an absence of tachycardiac response within the
first 10 pulses was observed in the older subjects (Fig.
2 and Table
3). In contrast, the younger group
experienced a significant tachycardiac response at the onset of LBNP
without hypotension. However, the age-related difference in the change
of arterial blood pressure was absent after 1 min of LBNP of 40 Torr,
despite a significantly diminished tachycardiac response in the older
subjects.
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Study 2
Baseline PI, arterial blood pressure, and their responses to a LBNP of40 Torr before atropine and glycopyrrolate
were not statistically different. Therefore, these baseline data were
merged into one control group. MC antagonists increased HR
(P < 0.001) but did not significantly affect arterial
blood pressure (Table 3). The effect between drugs was not
significantly different. During the control condition (i.e., before
drug), arterial blood pressure was well maintained, with a significant
tachycardiac response in the younger adults (Fig.
3 and Table 3). However, after atropine
or glycopyrrolate to block vagal influence, a systemic hypotension
occurred, associated with a significantly diminished tachycardiac
response at the onset of LBNP. This response was similar to that
observed in the older adults (Fig. 2). The changes in PI and arterial
blood pressure were similar between atropine and glycopyrrolate. During
sustained LBNP, the difference among the experimental conditions was
insignificant.
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Metoprolol tended to decrease HR (or PI) and to enhance its response
during a LBNP of 40 Torr (see Table 4
and Fig. 4). However, none of
these differences reached P 0.05, according to the post
hoc analysis. Arterial blood pressure was similar before and after
1-adrenoceptor blockade using metoprolol.
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A systemic hypotension was inversely (P < 0.05)
related to a tachycardiac response at the onset of a LBNP of 40 Torr,
indicating that a decrease in arterial pressure was associated with a
diminished tachycardiac response. This correlation tended to be less
significant in the older than in the younger subjects. However, this
correlation in the younger subject group was disassociated after
administration of either atropine or glycopyrrolate.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major finding of this study indicated that significant
hypotension in normal, healthy older adults, but not in the younger counterparts, occurred at the onset of orthostatic challenge simulated by a LBNP of 40 Torr, suggesting that aging without complication of
diseases diminished the immediate response of arterial blood pressure
regulation. The underlying mechanism appeared to be an age-related
vagal dysfunction, because a similar systemic hypotension occurred in
the younger subjects after administration of the MC antagonist atropine
or glycopyrrolate, whereas this response was not affected by blocking
the cardiac sympathetic efferent influence with metoprolol. However,
the initial orthostatic hypotension was not present during sustained
LBNP. Our data also suggested that a LBNP of 15 Torr did not
significantly decrease arterial blood pressure in either the younger or
older groups. Although baseline HR in the supine position was
relatively lower in the older than in the younger subjects, this
difference did not reach a significant level. A lower baseline HR in
the older adults may be related to a decrease in the intrinsic HR with
aging (16).
The present investigation demonstrated that the orthostatic hypotension
observed in the older adults at the onset of a LBNP of 40 Torr (Fig.
2) was related to a diminished tachycardiac response. Clearly the onset
of orthostatic hypotension could not be attributed to a decreased
vasomotor response in the elderly, because the reflex response in
muscle sympathetic nerve activity (12) or venous plasma
norepinephrine concentration (29) during hypotensive
stimuli appears unaffected by age. Consequently, the increases in
peripheral vascular resistance during steady-state LBNP, observed to be
similar between healthy older and younger subjects, confirm our earlier
findings (27). Recent data implied that a reflex increase
in forearm vascular resistance was less in the older subjects in terms
of unit increase in muscle sympathetic nerve activity
(11), probably because of a desensitization of 
-adrenoceptor. However, the age-related difference in the vasomotor response could not be responsible for the initial orthostatic hypotension observed in the older subjects, because the contribution of
vasomotor tone to arterial blood pressure regulation takes longer to be
effective (19). Our data indicate that the tachycardiac response plays a crucial role in the maintenance of arterial blood pressure at the onset of orthostatic challenge.
The reflex tachycardiac response can be caused by vagal withdrawal or
sympathetic activation. The present data confirm that vagal withdrawal
was the dominant factor for the rapid tachycardiac response in the
maintenance of hemodynamic homeostasis at the onset of orthostatic
stress, because the reflex tachycardiac and arterial blood pressure
responses to the onset of LBNP at 40 Torr in younger subjects were
not different before and after selective blockade of cardiac
sympathetic influence with the 1-adrenoceptor antagonist
metoprolol. However, after the administration of MC antagonists in the
younger adults, the tachycardiac responses were significantly
diminished, which was associated with a significant systemic
hypotension. However, the difference in systemic hypotension before and
after MC receptor antagonists became similar during sustained LBNP. The
increases in HR (in terms of beat/min) with MC receptor antagonists
tended to be greater after 1 min of LBNP, suggesting a slower but an
augmented cardiac sympathetic activity. The difference in hemodynamic
responses observed between atropine and glycopyrrolate was
insignificant, although it has been noticed that a low dose of atropine
decelerates HR (21) as a result of the central mediated
antagonism (13). These data implied that the effect of
blocking central MC receptors with a high dose of atropine was minor on
the systemic hypotension that occurred at the onset of the
LBNP-simulated orthostatic challenge. The altered response of
the end organ (i.e., heart) mediated by peripheral MC receptors was the
underlying mechanism for the initial orthostatic hypotension.
Despite the presence of a systemic hypotension in the older group at
the onset of a LBNP of 40 Torr and a persistent attenuation in the
tachycardiac response in the older subjects during a sustained LBNP of
40 Torr, there was no age-related difference in the change of
arterial blood pressure after 1 min of LBNP. These data suggest that a
neurohormonally mediated vasomotor response predominates in the
maintenance of arterial blood pressure during sustained orthostatic
challenge, and that this presence of an augmented vasomotor mechanism
in the healthy elderly compensates for the age-related diminution of
the tachycardiac response. Because the response of sympathetic nerve
activation was not significantly different between the younger and the
older adults (12, 29), this augmented vasomotor response
is likely mediated by vasoactive hormones, such as angiotensin II, in
the older subjects. Without the vasoconstrictor compensation, however,
the initial orthostatic hypotension would lead to orthostatic
intolerance or syncope, despite the presence of a persistent
tachycardiac response during the orthostatic hypotension.
It has been known that a significant central hypovolemia can be
developed by a LBNP of 15 Torr (15, 32), yet there was no significant hypotension in either the younger or the older group of
subjects in the present study. It is generally accepted that a central
hypovolemia during LBNP > 20 Torr unloads both cardiopulmonary
and arterial baroreceptors (1, 15, 32) and that the
eliciting of orthostatic stress by LBNP of 50 Torr is similar to
passive standing or head-up tilt at +70°, as assessed by the
changes in HR and blood pressure (9, 31). It has been reported that muscle sympathetic nerve activity can be activated by
disturbing the vestibular apparatus during head-down neck flexion (28). Degenerative changes in the peripheral vestibular
apparatus (6) and vestibular nucleus (4)
occur with aging, and the vestibular function appears to diminish in
the elderly (5, 7). The performance of the older subject
might be overestimated by LBNP-simulated orthostatic challenge compared
with head-up tilt test, because the tilt challenges a collective
response mediated by both the baroreflex and vestibulosympathetic
reflex. However, the influence of the vestibular interaction with the
age-related vagal dysfunction on the cardiovascular responses remains
to be elucidated during the onset and the sustained orthostatic challenges.
The major limitation of this study is the lack of stroke volume data,
which could be different between the younger and older subjects,
affecting the arterial blood pressure response. Arterial blood pressure
is regulated by both vasomotor tone and cardiac output, the latter of
which is the product of HR and stroke volume. The left ventricular
contractility, preload, and afterload modify stroke volume. The
arterial blood pressure before LBNP was not statistically different
between the older and younger subject groups, nor was it statistically
different before and after the blockade of MC receptors in the younger
subjects. Thus changes in afterload could not be responsible for the
different responses of arterial blood pressure or stroke volume at the
onset of LBNP of 40 Torr. Although reflex vasoconstriction is able to
compensate for the preload-induced reduction in stroke volume, this
response requires time to become fully effective. The absence of
systemic hypotension in both the older and younger subjects at the
immediate onset of LBNP of 15 Torr indicated that the reduced preload
in the first few heartbeats probably did not substantially alter stroke
volume. Thus the response of stroke volume as it contributes to the
regulation of arterial blood pressure at the onset of orthostatic challenge is likely similar between the two age groups. It is generally
accepted that the ventricles are sparsely innervated by the
parasympathetic nerve fibers, and the left ventricular contractility is
primarily mediated by 1-adrenoceptor of the sympathetic
nerve system (25). Downregulation of
1-adrenoceptor and adenylate cyclase activity
(18) has been observed with aging. However, neither
arterial blood pressure nor tachycardiac response was affected by the
blockade of cardiac 1-adrenoceptors with the use of
metoprolol in the younger subjects, whereas a systemic hypotension
associated with the diminished tachycardiac response after vagal
blockade occurred at the onset of a LBNP of 40 Torr. These data
suggested that the age-related difference in the sympathetically mediated contractility could not be a determinant in the immediate response of arterial blood pressure during orthostatic challenge. Therefore, our postulation was that the contribution of stroke volume
to the regulation of arterial blood pressure at the onset of LBNP was
not significantly different between the older and younger subject
groups. Rather, the diminished tachycardiac response was responsible
for the orthostatic hypotension observed both in the older subjects and
in the MC-blocked younger subjects.
In summary, the present investigation indicated that the orthostatic
hypotension was present in healthy older adults at the onset of LBNP of
40 Torr. This systemic hypotension may explain why elderly people
experience more syncopal symptoms during postural transitions to
upright position during the activities of daily life. The underlying
mechanism appeared to be an age-related diminution of tachycardiac
response, probably due to vagal dysfunction. However, an augmented
vasoconstrictor response compensated for the diminished reflex
tachycardia and maintained arterial blood pressure during a
steady-state orthostatic challenge, if human aging was not complicated with disease. We concluded that an orthostatic hypotension was present
in older adults during orthostatic challenge, but an augmented vasomotor response prevented syncope in healthy elderly individuals.
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ACKNOWLEDGEMENTS |
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We are indebted to Dr. Peter B. Raven for continued support. We also sincerely thank all our subjects for cheerful cooperation during the experiment.
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FOOTNOTES |
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This study was supported by National Institute on Aging Grant AG-14219, National Heart, Lung, and Blood Institute Grant HL-45547, and the University of North Texas Health Science Center Faculty Research grants.
This work was submitted in partial fulfillment of the requirements for the degree of Master of Science for D. W. Wray, as submitted to the Graduate School of Biomedical Science, University of North Texas Health Science Center at Fort Worth.
Address for reprint requests and other correspondence: X. Shi, Dept. of Integrative Physiology, Univ. of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107 (E-mail: xshi{at}hsc.unt.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 11 November 1999; accepted in final form 1 May 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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