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1
-adrenoceptor blockade using metoprolol.
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 arte-
rial pressure was associated with a diminished tachy-
cardiac response. This correlation tended to be less
signicant in the older than in the younger subjects.
However, this correlation in the younger subject group
was disassociated after administration of either atro-
pine or glycopyrrolate.
DISCUSSION
The major nding of this study indicated that signif-
icant 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, be-
cause a similar systemic hypotension occurred in the
younger subjects after administration of the MC antag-
onist atropine or glycopyrrolate, whereas this response
was not affected by blocking the cardiac sympathetic
efferent inuence with metoprolol. However, the initial
orthostatic hypotension was not present during sus-
tained LBNP. Our data also suggested that a LBNP of
15 Torr did not signicantly decrease arterial blood
pressure in either the younger or older groups. Al-
though baseline HR in the supine position was rela-
tively lower in the older than in the younger subjects,
this difference did not reach a signicant 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 or-
thostatic 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 reex response in muscle sympathetic nerve activ-
ity (12) or venous plasma norepinephrine concentra-
tion (29) during hypotensive stimuli appears unaffected
by age. Consequently, the increases in peripheral vascu-
lar resistance during steady-state LBNP, observed to
be similar between healthy older and younger subjects,
conrm our earlier ndings (27). Recent data implied
Fig. 2. Responses of pulse interval (PI) and systolic arterial pres-
sure (SBP) within the rst 10 pulses at the onset of LBNP and
during min 1, min 2, min 3, and min 8 of 40 Torr LBNP. Baseline
PI and SBP before 40 Torr LBNP are similar between the younger
(n 10; 1,081 58 ms and 122 4 mmHg, respectively) and older
(n 10; 1,112 35 ms and 129 6 mmHg, respectively) subjects.
Orthostatic hypotension is observed in the older subjects at the onset
of LBNP only. The SBP was not different between the groups from
min 2 LBNP, although tachycardia is still less in the older subjects.
*Signicant change from baseline. #Signicant change from baseline
plus min 1 data.
Table 3. Blood pressure responses of younger subjects during 40 Torr LBNP with
and without MC antagonists
Variable B P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 M1 M2 M3 M8
MAP, mmHg
C 862 22 22 32 22 12 02 12 02 12 02 01 11 21 31
A 883 82* 92* 103* 113* 103* 113* 123* 133* 133* 123* 52 32 42 42
G 945 101* 112* 122* 132* 143* 153* 163* 164* 155* 155* 54 24 13 45
P value 0.164 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.003 0.006 0.299 0.884 0.661 0.990
DBP, mmHg
C 671 11 22 21 11 12 12 02 12 02 12 01 01 01 21
A 712 83 103* 113* 113* 113* 114* 133* 143* 133* 133* 42 12 22 22
G 765 92* 102* 112* 132* 143* 153* 164* 164* 154* 145* 35 04 14 25
P value 0.111 0.002 0.001 0.001 0.001 0.001 0.001 0.002 0.002 0.005 0.006 0.484 0.899 0.727 0.992
Values are means SE. C, before drug (n 10); A, atropine (n 8); G, glycopyrrolate (n 8); MC, muscarinic cholinergic.
H1551 AGING AND ORTHOSTATIC HYPOTENSION
that a reex 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. How-
ever, the age-related difference in the vasomotor re-
sponse could not be responsible for the initial ortho-
static 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 reex tachycardiac response can be caused by
vagal withdrawal or sympathetic activation. The
present data conrm 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 reex tachycar-
diac 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 inuence with the
1
-adrenoceptor antag-
onist metoprolol. However, after the administration of
MC antagonists in the younger adults, the tachycar-
diac responses were signicantly diminished, which
was associated with a signicant systemic hypoten-
sion. However, the difference in systemic hypotension
before and after MC receptor antagonists became sim-
ilar 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 insignicant,
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 ortho-
static 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 vaso-
motor response predominates in the maintenance of
Fig. 3. Responses of pulse interval (PI) and systolic
arterial pressure (SBP) of younger subjects at the
onset of LBNP and during min 1, min 2, min 3, and min
8 of 40 Torr LBNP with and without muscarinic
cholinergic antagonists. PI is signicantly decreased
(from 1,028 51 ms) to 604 22 and 567 19 ms after
atropine and glycopyrrolate blockade, respectively.
However, baseline SBP was not signicantly affected
by drugs (control, 123 3 mmHg, n 10; atropine,
126 3 mmHg, n 8; and glycopyrrolate, 128 5
mmHg, n 8). A signicant systemic hypotension is
observed in the younger subjects after vagal blockade
with the use of either atropine or glycopyrrolate, asso-
ciated with a substantially blunted tachycardiac re-
sponse at the onset of LBNP. During sustained LBNP,
the difference among 3 conditions is insignicant. *Sig-
nicant change from baseline.
Table 4. Blood pressure responses of younger subjects during 40 Torr LBNP with and without metoprolol
Variable B P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 M1 M2 M3 M8
MAP,
mmHg
C 864 12 02 12 02 02 11 11 11 11 22 01 21 32 22
M 865 22 32 22 02 32 31 41 41 21 11 21 11 22 32
DBP,
mmHg
C 693 12 12 12 12 01 01 11 11 21 11 01 01 02 01
M 684 22 22 22 02 31 31 11 31 21 21 01 01 01 21
Values are means SE; n 8 under both experimental conditions. C, before drug; M, after metoprolol treatment to block
1
-adrenoceptor.
H1552 AGING AND ORTHOSTATIC HYPOTENSION
arterial blood pressure during sustained orthostatic
challenge, and that this presence of an augmented
vasomotor mechanism in the healthy elderly compen-
sates for the age-related diminution of the tachycar-
diac response. Because the response of sympathetic
nerve activation was not signicantly different be-
tween 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 compensa-
tion, however, the initial orthostatic hypotension
would lead to orthostatic intolerance or syncope, de-
spite the presence of a persistent tachycardiac re-
sponse during the orthostatic hypotension.
It has been known that a signicant central hypovo-
lemia can be developed by a LBNP of 15 Torr (15, 32),
yet there was no signicant hypotension in either the
younger or the older group of subjects in the present
study. It is generally accepted that a central hypovole-
mia during LBNP 20 Torr unloads both cardiopul-
monary 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 ves-
tibular apparatus during head-down neck exion (28).
Degenerative changes in the peripheral vestibular ap-
paratus (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 ortho-
static challenge compared with head-up tilt test, be-
cause the tilt challenges a collective response mediated
by both the baroreex and vestibulosympathetic reex.
However, the inuence of the vestibular interaction
with the age-related vagal dysfunction on the cardio-
vascular 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 reex vaso-
constriction is able to compensate for the preload-
induced reduction in stroke volume, this response re-
quires 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 rst few
heartbeats probably did not substantially alter stroke
volume. Thus the response of stroke volume as it con-
tributes to the regulation of arterial blood pressure at
the onset of orthostatic challenge is likely similar be-
tween the two age groups. It is generally accepted that
the ventricles are sparsely innervated by the parasym-
pathetic nerve bers, and the left ventricular contrac-
tility 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 dur-
ing orthostatic challenge. Therefore, our postulation
was that the contribution of stroke volume to the reg-
ulation of arterial blood pressure at the onset of LBNP
was not signicantly different between the older and
younger subject groups. Rather, the diminished tachy-
cardiac 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 ac-
Fig. 4. Responses of pulse interval (PI) and systolic arterial pres-
sure (SBP) of younger subjects at the onset of LBNP and during
min 1, min 2, min 3, and min 8 of 40 Torr LBNP with and without
1
-adrenoceptor antagonist metoprolol. Baseline PI shows the ten-
dency to increase with metoprolol (P 0.11), from 1,030 56 to
1,213 87 ms, and SBP is similar between two conditions, i.e., 121
4 vs. 119 4 mmHg (n 8). *Signicant change from baseline.
H1553 AGING AND ORTHOSTATIC HYPOTENSION
tivities of daily life. The underlying mechanism ap-
peared to be an age-related diminution of tachycardiac
response, probably due to vagal dysfunction. However,
an augmented vasoconstrictor response compensated
for the diminished reex tachycardia and maintained
arterial blood pressure during a steady-state ortho-
static challenge, if human aging was not complicated
with disease. We concluded that an orthostatic hypo-
tension was present in older adults during orthostatic
challenge, but an augmented vasomotor response pre-
vented syncope in healthy elderly individuals.
We are indebted to Dr. Peter B. Raven for continued support. We
also sincerely thank all our subjects for cheerful cooperation during
the experiment.
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 fulllment of the require-
ments 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.
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