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Department of Exercise Science, The University of Iowa, Iowa City, Iowa 52242
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Tolerance to +Gz
stress is reduced by preceding exposure to 
Gz (push-pull
effect). The mechanism(s) responsible for this effect are not
fully understood, although the arterial baroreceptor reflexes have been
implicated. We investigated the integrative response of the autonomic
nervous system by studying responses to gravitational stress before and
after autonomic function was inhibited by hexamethonium in 10 isoflurane-anesthetized male and female Sprague-Dawley rats. Animals
were restrained supine and subjected to two rotations imposed about the
x-axis: 1) a control G profile consisting of
rotation from 0 Gz (+1 Gy) to 90° head-up
tilt (+1 Gz) for 10 s and 2) a push-pull G
profile consisting of rotation from 0 Gz to 90° head-down
tilt (1 Gz) for 2 s immediately preceding 10 s
of +1 Gz stress. Eight G profiles consisting of equal
numbers of control and push-pull trials were imposed by using a
counterbalanced design. We found that hexamethonium lowered baseline
arterial pressure and abolished the push-pull effect. The lack of a
push-pull effect after autonomic blockade persisted when arterial
pressure was restored to baseline levels by phenylephrine infusion.
Lowering baseline arterial pressure by sodium nitroprusside infusion or
by hemorrhage when autonomic function was intact also abolished the
push-pull effect. We conclude that intact autonomic function and a
normal baseline arterial pressure are needed for expression of the
push-pull effect in anesthetized rats subjected to tilting.
hexamethonium; orthostatic stress; Gz; tilt; cerebral perfusion pressure; hypergravity; hypogravity; microgravity; arterial blood pressure; baroreceptor reflexes
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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BRIEF EXPOSURE to
Gz ("push") reduces eye-level blood pressure (ELBP)
during subsequent exposure to +Gz ("pull"), termed the
"push-pull effect" (3). The push-pull effect is
expressed in human subjects when this type of gravitational stress is
imposed by aerial combat maneuvering (1), tilting
(4), centrifugation (2, 3), or parabolic
flight profiles (8). It is also expressed in conscious
rats exposed to centrifugation (10) and in anesthetized
rats subjected to tilting (7, 10). The axis of rotation
appears to be an important factor in humans (4) but not in
rats (7), and gender does not appear to be a factor in
rats (7).
Although the mechanism(s) responsible for the push-pull effect is not completely understood, it has been speculated that the arterial baroreflexes play a major role (1-4, 6, 10). The thinking is that the rise in carotid distending pressure imposed during the push activates the carotid sinus baroreceptors, which in turn slow the heart and initiate peripheral vasodilation in an effort to restore carotid pressure back toward its baseline value. These blood pressure-lowering responses, initiated during the push, persist during the early phase of the subsequent pull. At this time, the mechanical reduction in carotid artery pressure produced by the alteration in acceleration is suddenly added to the pressure-reducing effects of the (slowly reversing) baroreceptor-induced bradycardia and peripheral vasodilation. This can lead to an unexpectedly large fall in cerebral perfusion pressure and loss of consciousness in extreme conditions (9). The cardiopulmonary mechanoreceptor reflexes and/or vestibular-autonomic responses may contribute to the push-pull effect as well. However, other mechanisms such as myogenic vasomotor responses could contribute to and/or cause the push-pull effect. To our knowledge, there has been no direct test of the importance of the autonomic nervous system in causing or contributing to the push-pull effect.
The purpose of the present study was to evaluate the contribution of baroreceptor reflexes to the push-pull effect. Studies were carried out before and after autonomic ganglionic neurotransmission was inhibited with hexamethonium. We hypothesized that treatment with hexamethonium would abolish the push-pull effect. Because hexamethonium inhibits autonomic effector mechanisms, this approach provides an indication of the integrated response of the cardiovascular reflexes from both the high- and low-pressure sides of the circulation as well as the vestibular-autonomic responses in determining the push-pull effect. Because hexamethonium reduces baseline arterial pressure, we also carried out studies before and after autonomic blockade when baseline arterial pressure was manipulated by infusion of vasoactive substances or hemorrhage. Studies were carried out in anesthetized rats subjected to gravitational stress by tilting.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The following procedures meet National Institutes of Health guidelines and were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Iowa.
Surgical preparation. Eight Sprague-Dawley rats (5 female, 3 male; 270-390 g) were anesthetized with isoflurane and restrained supine on a homeothermically controlled table. The animal's body temperature was maintained at 37°C. A catheter was implanted in the right carotid artery for arterial pressure measurement and either the left jugular or femoral vein for drug infusion with a syringe pump.
Experimental procedures.
For all rotations, the tilt table was oriented such that Earth's
gravity vector was applied across the animal's y-axis so that Gz gravitational stress could be imposed by manually
rotating the table and thus the animal ±90° about the animal's
x-axis (roll rotation). The starting position was 0 Gz (+1 Gy). Control gravitational stress
consisted of rotating the animal 90° head-up (+1 Gz) for 10 s. Push-pull treatment consisted of 10 s of head-up tilt
that was immediately preceded by 2 s of 90° head-down tilt (1
Gz). The animal recovered for 50 s in the horizontal
(0 Gz) position between tilts. Eight G profiles were
imposed under each condition in a counterbalanced design to minimize
possible time effects of repeated exposure to gravitational stress. A
schematic illustration of the experimental protocol is shown in Fig.
1A.
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Data collection. The arterial catheter was connected to a pressure transducer (PE10 EZ, Ohmeda, Madison, WI) secured at eye level. A length of water-filled tubing connected to a similar pressure transducer was mounted on the table to measure tilt.
Signals were digitized at 1 kHz and stored on the fixed disk of a laboratory microcomputer for subsequent analysis (PONEMAH Physiology Platform, P3, Gould Instruments, Valley View, OH).Data analysis.
Data analysis was performed on 1-s averages of the digitized data.
Baseline ELBP was established by calculating the average pressure over
the 5 s immediately preceding tilt onset. The magnitude of the
ELBP response to the brief Gz gravitational stress
(
Push) was calculated as the difference between the peak pressure
during the 1 Gz (taken at a time when the animal was
stationary) and baseline pressure. The magnitude of the ELBP response
to the +1 Gz gravitational stress (Pull) for both the
control and push-pull G profiles was calculated as the difference
between baseline pressure and the pressure observed at second
3 after the onset of head-up tilt. This measure (Pull) was used
to determine whether a push-pull effect was present or not. The extent
of recovery of pressure during the 10 s of head-up tilt
(Recovery) was calculated as the difference in arterial pressure
between second 3 and second 9 and was used to
indicate autonomic reflex compensation during the head-up tilt.
Positive Recovery numbers denote restoration of pressure, whereas
negative numbers denote deterioration of arterial pressure from
second 3 to second 9. The manner in which these
variables were derived is shown schematically in Fig. 1B.
Statistical analysis.
The Pull value between control and push-pull treatments within each
condition (no drug, phenylephrine, sodium nitroprusside, etc.) was
compared statistically by performing a paired t-test. Single
sample t-tests were performed to determine whether the Push and Recovery values were different from zero. Statistical significance was deemed to exist when P was <0.05. Data are
reported as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ELBP during +1 Gz (control) gravitational stress in a
single rat is shown in Fig. 3A,
top. Pressure initially falls from 109 mmHg at baseline to 71 mmHg
at second 3 and then is partially restored to 94 mmHg at
second 9 after the onset of tilt. ELBP during push-pull
gravitational stress in the same rat is shown in Fig. 3B.
From 108 mmHg at baseline, ELBP rises to 119 mmHg during the 2 s
of 1 Gz stress and then falls during the subsequent +1
Gz stress to a value (66 mmHg), 4 mmHg lower than seen
during control +1 Gz gravitational stress (Fig.
3A). ELBP undergoes restoration to 92 mmHg at second
9. Responses from the same rat after autonomic inhibition are
shown in Fig. 3, C and D. During +1
Gz (control) gravitational stress (Fig. 3C),
pressure initially falls as when autonomic function is intact but then
continues to deteriorate during the 10 s of gravitational stress.
During push-pull gravitational stress (Fig. 3D), ELBP rises
during the push phase, drops during the initial pull phase, and then
continues to deteriorate throughout the 10 s of +1 Gz
gravitational stress. Group mean values of ELBP at baseline and at
second 3 and second 9 after the onset of +1 Gz gravitational stress are provided in Table
1 for all conditions. Also provided in
Table 1 are values representing the magnitude of the rise in ELBP
during 1 Gz stress (Push) and the magnitude of the
fall in pressure during the initial phase of +1 Gz
gravitational stress (Pull). Finally, the extent of recovery (or
deterioration) of pressure from second 3 to second
9 during +1 Gz gravitational stress (Recovery) for
all conditions is provided in Table 1.
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Figure 4A shows the group mean
response of ELBP during control and push-pull gravitational stress when
autonomic function was intact. There was a statistically significant
push-pull effect in that the magnitude of the fall in ELBP from
baseline (Pull) was significantly greater (P < 0.05) during push-pull stress than during control stress (Table 1).
Note also that ELBP was partially restored toward baseline during the
10 s of 1 Gz stress in both the control and push-pull
treatments. The Recovery pressures for both stresses were
significantly greater than zero (P < 0.05, Table 1).
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Before hexamethonium administration, phenylephrine was infused to raise arterial pressure above control levels. No push-pull effect was seen under this condition (Fig. 4B). Arterial pressure appears to fall throughout the 10 s of +1 Gz gravitational stress in both the control and push-pull conditions, but these changes did not achieve statistical significance (P < ~0.08).
Also, before hexamethonium administration, baseline arterial pressure was reduced to the level later caused by autonomic blockade by nitroprusside infusion and by hemorrhage. As shown in Fig. 4, C and D, the effects of these two interventions were similar in that both abolished the push-pull effect and the partial recovery of pressure normally seen during +1 Gz gravitational stress.
The effects of treatment with hexamethonium are shown in Fig.
5A. Inhibition of autonomic
function lowered baseline ELBP by ~25 mmHg. Hexamethonium abolished
the push-pull effect in that the responses of ELBP during 10 s of
+1 Gz gravitational stress for the control and push-pull
conditions are essentially superimposed. Hexamethonium also abolished
the partial restoration of pressure normally seen over the 10 s of
+1 Gz stress. In fact, the Recovery values were
significantly less than zero (P < 0.05, Table 1), indicating that pressure further deteriorated over this period.
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Phenylephrine was infused after hexamethonium administration to restore baseline arterial pressure to control levels. No push-pull effect was seen under these conditions (Fig. 5B), and pressure deteriorated throughout the 10 s of +1 Gz gravitational stress.
Finally, phenylephrine was infused at a higher rate after hexamethonium
administration to raise arterial pressure to the levels achieved by
this drug before hexamethonium (Fig. 5C). There was no
push-pull effect inasmuch as the magnitudes of the decreases in
pressure (Pull) were not different. Arterial pressure was stable
from second 3 to second 9 during +1
Gz gravitational stress.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major findings of this study are twofold. First, the push-pull effect is abolished when autonomic ganglionic neurotransmission is inhibited by hexamethonium. Arterial baroreceptor reflexes are often suggested to contribute to or cause the push-pull effect, and our findings support this supposition. However, because hexamethonium inhibits all autonomic reflexes, it is possible that the cardiopulmonary mechanoreceptor reflexes and/or vestibular-autonomic responses contribute as well. Second, substantially lowering or raising baseline arterial blood pressure also abolishes the push-pull effect, probably by disrupting baroreflex function.
Indirect evidence for the contribution of baroreceptor reflexes in
eliciting the push-pull effect is provided in a number of studies. For
example, the bradycardia that attends the push occurs more quickly than
does the tachycardia that eventually accompanies the subsequent pull
(8). As a consequence, heart rate is "too low" early
on during +Gz stress when the +Gz stress is
preceded by exposure to Gz (1). Also, Doe et
al. (5) imposed rapid, brief alterations in isolated
carotid sinus pressure in anesthetized dogs and measured vasomotor
responses. They found that the reductions in vascular resistance
elicited by increases in carotid sinus pressure were faster and more
profound than the vasoconstriction induced by decreases in sinus
pressure (5). The relative sluggishness of vasoconstrictor
responses could contribute to the exaggerated hypotension early on
during +Gz gravitational stress when it follows
Gz stress. Again, these blood pressure-lowering responses, initiated during the push, persist during the early phase of
the subsequent pull. At this time, the mechanical reduction in carotid
artery pressure produced by gravity is suddenly added to the
pressure-reducing effects of the (slowly reversing)
baroreceptor-induced bradycardia and peripheral vasodilation. This
leads to an unexpectedly large fall in ELBP. Our results indicate that
inhibition of autonomic function with hexamethonium likely abolishes
the pressure-lowering adjustments initiated during brief
Gz stress and thereby normalizes the fall in arterial
pressure that attends +Gz gravitational stress independent
of the recent G history. For example, if head-down tilt produced the
push-pull effect by altering the mechanical loading of the ventricles
or by altering myogenic stimuli, we would expect the push-pull effect
to persist across the conditions studied, and this was not the case.
Responses to +1 Gz gravitational stress. When autonomic function is intact, arterial pressure initially falls and then undergoes partial restoration from second 3 to second 9 after the onset of +1 Gz gravitational stress under both the control and push-pull conditions. Treatment with hexamethonium reversed this normal recovery of pressure; in fact, pressure falls further from second 3 to second 9. This observation indicates both the efficacy of autonomic inhibition induced by hexamethonium and the importance of the autonomic system in producing this recovery. As expected, this lack of recovery persisted when baseline arterial pressure was manipulated with phenylephrine infusion after treatment with hexamethonium. A lack of recovery of pressure was also observed in the three conditions in which we altered baseline arterial pressure before hexamethonium. This lack of recovery of pressure despite intact ganglionic transmission likely stems from the baroreflex-suppressing effects of these interventions as discussed below.
The response of ELBP from second 3 to second 9 of +1 Gz gravitational stress followed one of three basic patterns. First, as noted above, pressure was partially restored toward baseline when autonomic function was intact and no further manipulations were performed. Second, ELBP remained stable over this period, or third, ELBP fell over this period. By and large, a consistent finding was that when ELBP fell below ~60 mmHg during head-up tilt, ELBP remained relatively stable throughout the 10 s of +1 Gz gravitational stress (Fig. 4, C and D), suggesting a possible lower limit to arterial pressure for the conditions under which these studies were carried out. In contrast, when above this level, ELBP underwent deterioration over this period (Figs. 4B and 5, A and B). The one exception was during the higher dose of phenylephrine after hexamethonium (Fig. 5C); here, pressure was stable over this period despite being far above 60 mmHg.Push-pull gravitational stress.
Under control conditions, we found a statistically significant
push-pull effect in that Pull (second 3 ELBP less
baseline ELBP) was significantly greater for push-pull vs. control
gravitational stress. The direction and magnitude of the changes
observed are comparable to previously reported values for this species
(7, 10) and are in line with human values (2-4,
6, 8) given the fivefold greater heart-to-eye distance in humans.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-46314.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. D. Sheriff, Exercise Science, 518 Field House, Iowa City, IA 52242.
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.
10.1152/japplphysiol.00554.2002
Received 25 June 2002; accepted in final form 12 October 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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