Download Mechanisms of increase in cardiac output during acute

J Appl Physiol 111: 407–411, 2011.
First published June 2, 2011; doi:10.1152/japplphysiol.01188.2010.
Mechanisms of increase in cardiac output during acute weightlessness
in humans
Lonnie G. Petersen,1 Morten Damgaard,2 Johan C. G. Petersen,1 and Peter Norsk1
1
Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen; and 2Department
of Clinical Physiology and Nuclear Medicine, Hvidovre University Hospital, Hvidovre, Denmark
Submitted 8 October 2010; accepted in final form 2 June 2011
regional blood flow; blood pressure; vascular resistance; gravity
GRAVITY CONSTANTLY STRESSES the cardiovascular system in
upright humans by diminishing venous return. It decreases
stroke volume (SV) and thus cardiac output (CO) and, through
the baroreflex system, induces arteriolar constriction and an
increase in heart rate (HR) to counteract a fall in blood pressure
(4, 21, 30). Compared with the upright 1-G position, sudden
entry into weightlessness (0 G) causes a redistribution of blood
from the lower vascular beds to the central circulation (4, 29),
leading to an increase in venous return, and thus in SV and CO,
and, through stimulation of the baroreflexes, to arteriolar vasodilatation and a decrease in HR (18, 21, 23, 29).
Our laboratory has previously observed that, in upright
seated humans, short-term 0 G created by parabolic airplane
flights increases CO by as much as 1.8 l/min, which corresponds to some 0.6 liters over the 20-s period of 0 G (21).
Bailliart et al. (2) estimated that, in standing humans, some 165
ml of fluid disappeared from each leg during 20 s of 0 G. These
and our observations collectively suggest that the contribution
of blood from the legs to the acute 0-G-induced increase in CO
amounts to some 50%. In another study from our laboratory,
Address for reprint requests and other correspondence: L. G. Petersen, Dept. of
Biomedical Sciences, Faculty of Health Sciences, Univ. of Copenhagen,
Blegdamsvej 3, DK-2200 Copenhagen, Denmark (e-mail: [email protected]).
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we have, however, observed that water immersion in humans,
which is used to simulate the effects of 0 G, increases the
diameter of the left atrium to the same degree, whether or not
the leg venous vasculature is separated from the rest of the
circulation by arterial or venous occlusion (13, 14). This
indicates that the majority of the blood translocated from the
peripheral to the central circulation during immersion originates from the vascular beds above the legs.
In this study, we, therefore, tested the hypothesis that, in
upright seated humans, most of the blood redistributed from
the lower to the central circulation by 0 G originates from
vascular beds above the legs, such as the splanchnic. We also
tested the hypothesis that 0 G would increase SV and CO to
levels above those of the 1-G supine position, because we have
previously observed an increase in transmural central venous
pressure in supine subjects, who are suddenly exposed to 0 G
(29). Thus we expected 0 G to further increase SV and CO
through the Frank-Starling mechanism because of abolishment
of the 1-G-induced front to back compression of the thoracic
cage (⫹1 Gx).
SUBJECTS AND METHODS
The protocol was approved by the medical board of the European
Space Agency (ESA) and considered acceptable and in compliance
with the declaration of Helsinki by the Ethics Committee of Copenhagen (KF 07, 09/26/2006).
Eight healthy volunteers [age ⫽ 35 yr (range 26 – 48 yr); weight ⫽
75 kg (range 52–94 kg); height ⫽ 179 cm (range 156 –192 cm); and
male-to-female ratio ⫽ 5/3] participated in the study. All fulfilled the
general health criteria required to obtain a Joint Aviation Administration class II physical medical flight certificate and had given their
written, informed consent. Subjects with any disease or abnormality
were excluded.
On the day of flight, the test subject had a light breakfast 1.5–2 h
before the experiment was carried out. No medication against motion
sickness was administered. All of the subjects had participated in at
least one previous parabolic flight campaign.
The study was carried out in connection with two ESA parabolic
flight campaigns: nos. 42 and 44 in Bordeaux, France. The parabolic
maneuvers were conducted in a modified Airbus A-300. Each campaign consisted of 3 consecutive days of flight, and, on each day, 30
parabolic flight maneuvers were carried out in series of 5, leaving a
few minutes of 1 G in between each parabolic maneuver and 5–15 min
of 1 G in between each series of 5 parabolas. Each parabolic maneuver
consisted of three 20-s phases by following a parabolic trajectory: an
acceleration phase, where the G force gradually increased from 1.0 to
1.8; a weightless phase (0 G), where the aircraft suddenly entered a
free-fall condition, and finally a deceleration phase, where the G force
abruptly reached 1.8 and thereafter gradually faded back to 1.0.
Experimental procedure. In the airplane, ambient temperature varied between 19 and 23°C and humidity between 12 and 17% at a cabin
pressure of 850 millibars.
8750-7587/11 Copyright © 2011 the American Physiological Society
407
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Petersen LG, Damgaard M, Petersen JCG, Norsk P. Mechanisms of increase in cardiac output during acute weightlessness in
humans. J Appl Physiol 111: 407– 411, 2011. First published June 2,
2011; doi:10.1152/japplphysiol.01188.2010.—Based on previous water immersion results, we tested the hypothesis that the acute 0-Ginduced increase in cardiac output (CO) is primarily caused by
redistribution of blood from the vasculature above the legs to the
cardiopulmonary circulation. In seated subjects (n ⫽ 8), 20 s of 0 G
induced by parabolic flight increased CO by 1.7 ⫾ 0.4 l/min (P ⬍
0.001). This increase was diminished to 0.8 ⫾ 0.4 l/min (P ⫽ 0.028),
when venous return from the legs was prevented by bilateral venous
thigh-cuff inflation (CI) of 60 mmHg. Because the increase in stroke
volume during 0 G was unaffected by CI, the lesser increase in CO
during 0 G ⫹ CI was entirely caused by a lower heart rate (HR). Thus
blood from vascular beds above the legs in seated subjects can alone
account for some 50% of the increase in CO during acute 0 G. The
remaining increase in CO is caused by a higher HR, of which the
origin of blood is unresolved. In supine subjects, CO increased from 7.1
⫾ 0.7 to 7.9 ⫾ 0.8 l/min (P ⫽ 0.037) when entering 0 G, which was
solely caused by an increase in HR, because stroke volume was
unaffected. In conclusion, blood originating from vascular beds above
the legs can alone account for one-half of the increase in CO during
acute 0 G in seated humans. A Bainbridge-like reflex could be the
mechanism for the HR-induced increase in CO during 0 G in particular in supine subjects.
408
ACUTE WEIGHTLESSNESS AND VENOUS RETURN
piece from and into a bag containing 1.5 liters of gas mixture of 1%
freon-22 (blood-soluble tracer gas), 1% sulfur hexafluoride (SF6,
blood-insoluble tracer gas), and 35% oxygen in nitrogen. The
fraction of the gases was measured by an infrared photoacoustic
gas analyzer in sampled inspired and expired air through a tube
connected to the mouthpiece (6). From the disappearance rate of
end-expiratory freon-22, pulmonary blood flow was calculated,
which is equal to CO (6, 10). SF6 was used to correct for
inadequate mixing of air in the lungs with the gas mixture from the
rebreathing bag and for estimating changes in breathing volume.
At least 5 min passed between each rebreathing in each subject to
ensure adequate clearance of tracer gases from the blood (8).
Breathing was timed so that the subjects exhaled, held their breath
very shortly, and, on entering 0 G, pushed a switch to commence
rebreathing. By afterwards comparing the temporal profiles of the
changes in G and the disappearance rate of freon-22, care was
taken to ensure that rebreathing had, in fact, taken place only
during the desired G phase.
MAP and HR were measured continuously by an infrared photoplethysmographic technique (Portapress) in an index finger, and the
presented values are averages of the full 20 s at each level of G, with
(1 G or 0 G) or without (1.8 G) simultaneous rebreathing. The
hydrostatic reference level for MAP measurements during 1 G and 1.8
G was chosen at the fourth intercostal space, when the subjects were
seated, and at the midaxillary line, when they were supine. A height
sensor between the Portapress cuff on the finger and the reference
point was used for this purpose.
Data analysis and statistics. SV was calculated by dividing CO by
HR, and total peripheral vascular resistance (TPR) by dividing MAP
by CO. All data are presented as means ⫾ SE. A one-way ANOVA
(SigmaStat 2.03) for repeated measurements was performed to evaluate the effects of each intervention on each variable. Statistical
significant differences between selected mean values (P ⬍ 0.05) were
Fig. 1. Schematic drawing of the parabolic
trajectory in combination with the experimental protocol, with emphasis on cuff inflation (CI) and measurements of cardiac
output, mean arterial pressure, and heart rate
during the different phases of the flight. CR,
cuff release. Shaded bar, CI; striped bar,
rebreathing; solid bar, mean arterial pressure
and heart rate.
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On each day of flight, two subjects were investigated, spending the
first 20 parabolic maneuvers in the seated and the last 10 in the supine
position. Mean arterial pressure (MAP) and HR were recorded continuously, and CO measurements were performed during 20-s periods,
during either 1 G or 0 G, and alternating between the two subjects,
thus maximizing the total number of measurements performed in each
of the subjects and allowing them to rest during every other parabola.
Measurements were performed during the following conditions (Fig. 1):
seated in between the series of parabolic maneuvers while flying
straight and level at 1 G, with or without bilateral thigh-cuff inflation
(CI) of 60 mmHg, and allowing for at least 5 min of rest following the
previous parabolic maneuver. We also performed the measurements
during 0 G, with and without CI, inflating the cuffs immediately
before the 1.8-G parabolic phase and maintaining cuff pressure and
venous occlusion throughout 0 G (0 G ⫹ CI). Furthermore, we also
released the cuff pressure (CR ⫽ cuff release) immediately upon
entering 0 G (0 G ⫹ CR). The sequence of the procedures (1 G, 0 G,
0 G ⫹ CI, and 0 G ⫹ CR) was randomized between the subjects and
performed once, twice, or three times in each subject, and the data
thereafter were averaged for each procedure. Finally, with the subjects
supine throughout the parabolic maneuver, we likewise measured
MAP and HR continuously and CO during 1 and 0 G.
CI was achieved by manual inflation of a standard cuff of appropriate size (21 ⫻ 53 cm) around each upper thigh to 60 mmHg above
ambient pressure. This pressure was chosen as the best compromise
between ensuring occlusion of leg venous return while causing minimal disruption of arterial flow both during 1 G and when the
hydrostatic pressure gradients were augmented during 1.8 G (11). The
cuff pressure during CI was registered electronically by a transducer
and was 59.0 ⫾ 0.3 mmHg.
Measurements. CO was measured by a noninvasive rebreathing
technique (Pulmonary Function System, ESA), described in detail
elsewhere (6, 8, 10). Measurements were performed by having the
subject breathe at a rate of 18 ⫾ 3 breaths/min through a mouth-
ACUTE WEIGHTLESSNESS AND VENOUS RETURN
evaluated by a post hoc multiple-range test (Newman-Keuls) or a
paired, two-sided t-test.
RESULTS
Seated. In the seated position, 0 G increased CO by 1.7 ⫾
0.4 l/min from a 1-G value of 7.3 ⫾ 0.7 l/min to a 0-G value
of 9.0 ⫾ 0.9 l/min (P ⬍ 0.001, Fig. 2). This increase was
attenuated during 0 G ⫹ CI, where CO only increased by 0.8 ⫾ 0.4
l/min from a 1-G ⫹ CI value of 7.0 ⫾ 0.7 l/min (n ⫽ 8) to a
0-G ⫹ CI value of 8.3 ⫾ 1.0 l/min (n ⫽ 7) (P ⫽ 0.026), which
was significantly less than when the cuffs were not inflated
(P ⫽ 0.028, Fig. 2). Releasing the 60-mmHg cuff pressure
upon entering 0 G (0 G ⫹ CR) did not increase CO further
compared with when the cuff pressure was maintained
409
DISCUSSION
Fig. 2. Cardiac output, stroke volume, and heart rate in seated subjects during
1 G, 0 G, 1 G ⫹ CI (venous CI of 60 mmHg), 0 G ⫹ CI, and 0 G ⫹ CR (venous
CI during 1.8 G, followed by cuff pressure release on initiation of 0 G). bpm,
Beats/min. The bars represent means ⫾ SE of n ⫽ 8, except for during 0 G ⫹
CI, where n ⫽ 7. *Significant difference compared with 1 G, if not otherwise
indicated.
J Appl Physiol • VOL
The main findings of this study are that vascular beds above
those of the legs can alone account for the 0-G induced increase
in SV and for some 50% of the increase in CO, because, during
0 G ⫹ CI, SV was increased to its maximum, corresponding to the
flat portion of the Starling curve. Thus reestablishing venous
return from the legs during 0 G did not cause any further increase
in SV, but did surprisingly cause an increase in HR, leading to a
significant 50% further increase in CO.
Hence, we suggest that the increase in CO during acute 0 G in
seated humans consists of two factors, which are both induced by
hydrostatic redistribution of blood from the more peripheral,
caudad vasculature to the central circulation: 1) an increase in SV
to the flat portion of the Starling curve, which can be obtained
solely by translocation of blood from the splanchnic to the
cardiopulmonary circulation; and 2) an additional increase in HR,
which causes the remaining increase in CO and could be explained by a Bainbridge-like reflex, because HR was higher
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throughout the parabolic maneuver (8.4 ⫾ 0.9 vs. 8.3 ⫾ 1.0
l/min, Fig. 2).
0 G increased SV to a similar extent independently of
whether the cuffs were inflated or not, from a 1-G value of 96 ⫾ 15
ml to a 0-G value of 110 ⫾ 15 ml (P ⬍ 0.001), and from a 1-G ⫹
CI value of 93 ⫾ 14 ml to a 0-G ⫹ CI value of 111 ⫾ 16 ml (P ⬍
0.001), and finally from a 1-G value of 96 ⫾ 15 ml to a 0-G ⫹
CR value of 106 ⫾ 15 ml (P ⬍ 0.001, Fig. 2). Thus the
attenuated increase in CO during 0 G ⫹ CI compared with
when the thigh cuffs were not inflated was entirely caused by
a lower HR (Fig. 2). The lower CO during 0 G ⫹ CR vs. during
0 G was caused by a combination of a slightly lower SV and
HR, which, however, were not statistically significant.
During 1.8 G, HR increased from 80 ⫾ 6 to 89 ⫾ 4 beats/min
(P ⫽ 0.017). This increase was abolished by CI (83 ⫾ 4 beats/min,
Table 1), and, during the subsequent 0 G ⫹ CI, HR decreased
to 76 ⫾ 6 beats/min, which was significantly lower than when
CI was not applied during the preceding 1.8 G (Fig. 2). During
0 G ⫹ CR, inflation of the cuffs again abolished the 1.8-G
induced increase in HR (Fig. 2, Table 1). However, when the
cuff pressure was released upon entering 0 G (0 G ⫹ CR), HR
was not decreased and was significantly higher compared with
0 G ⫹ CI (P ⫽ 0.03, Fig. 2).
MAP decreased during 0 G from a 1-G seated value of 99 ⫾
6 to 95 ⫾ 6 mmHg (P ⬍ 0.05). This decrease was still present
during 0 G ⫹ CI and 0 G ⫹ CR (Table 1). Because MAP
decreased during 0 G, while CO increased, TPR decreased
from 14.2 ⫾ 1.1 to 11.2 ⫾ 1.1 mmHg·l⫺1·min (P ⬍ 0.001,
Table 1). 0 G ⫹ CI still caused a decrease in TPR to 12.3 ⫾ 1.4
mmHg·l⫺1·min (P ⬍ 0.001, Table 1), which, however, was
significantly less compared with when the venous return from
the legs was intact (P ⬍ 0.017).
The intervention of 40 s of CI without variations in G (1 G
vs. 1 G ⫹ CI) showed a decrease in MAP from 99 ⫾ 6 to 96 ⫾
5 mmHg (P ⬍ 0.05), whereas no other cardiovascular variables
were affected (Table 1, Fig. 2).
Supine. In the supine position, 0 G increased CO by 0.8 ⫾
0.3 l/min, from 7.1 ⫾ 0.7 to 7.9 ⫾ 0.8 l/min (P ⫽ 0.037,
Table 2). This was caused entirely by an increase in HR from
73 ⫾ 5 to 79 ⫾ 5 beats/min (P ⬍ 0.001, Table 2), leaving SV
unchanged.
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ACUTE WEIGHTLESSNESS AND VENOUS RETURN
Table 1. CO, SV, HR, MAP, and TPR during same conditions as described in Fig. 2 and additionally during 1.8 G,
1.8 G ⫹ CI, and 1.8 G ⫹ CR
CI
Seated
1G
CO, l/min
SV, ml
HR, beats/min
MAP, mmHg
TPR, mmHg 䡠 l⫺1 䡠 min
7.3 ⫾ 0.7
96 ⫾ 15
80 ⫾ 6
99 ⫾ 6
14.2 ⫾ 1.1
1.8 G
89 ⫾ 4
95 ⫾ 5
0G
1G
9.0 ⫾ 0.9*
110 ⫾ 15*
84 ⫾ 6
95 ⫾ 6*
11.2 ⫾ 1.1*
7.0 ⫾ 0.7
93 ⫾ 14
79 ⫾ 6
96 ⫾ 5*
14.4 ⫾ 1.3
1.8 G
83 ⫾ 4
94 ⫾ 5
CR
0G
1G
8.3 ⫾ 1.0*
111 ⫾ 16*
76 ⫾ 6†
95 ⫾ 7*
12.3 ⫾ 1.4*†
7.3 ⫾ 0.7
96 ⫾ 15
80 ⫾ 6
99 ⫾ 6
14.2 ⫾ 1.1
1.8 G
85 ⫾ 4
96 ⫾ 5
0G
8.4 ⫾ 0.9*
106 ⫾ 15*
82 ⫾ 5†
91 ⫾ 5*
11.6 ⫾ 1.2*
Values are means ⫾ SE; n ⫽ 8 subjects except for 0 G ⫹ CI, which is based on n ⫽ 7. CO, cardiac output; SV, stroke volume; HR, heart rate; MAP, mean
arterial pressure; TPR, total peripheral vascular resistance; 1.8 G ⫹ CI, 1.8 G combined with venous thigh cuff inflation; 1.8 G ⫹ CR, 1.8 G followed by release
of the cuff inflation immediately after completion of 1.8 G. Significant difference compared with *1 G during the same intervention, and †0 G without cuffs:
P ⬍ 0.05.
Table 2. CO, SV, HR, MAP, and TPR during 1.8 G, 1.8 G,
and 0 G in the supine position
Supine
1G
CO, l/min
SV, ml
HR, beats/min
MAP, mmHg
TPR, mmHg 䡠 l⫺1 䡠 min
7.1 ⫾ 0.7
101 ⫾ 15
73 ⫾ 5
91 ⫾ 5
13.5 ⫾ 1.2
1.8 G
71 ⫾ 5†
92 ⫾ 4
0G
7.9 ⫾ 0.8*
104 ⫾ 15
79 ⫾ 5*
92 ⫾ 4
12.5 ⫾ 1.3
Values are mean ⫾ SE; n ⫽ 8 subjects. Significant difference compared with
*1 G and †0 G: P ⬍ 0.05.
J Appl Physiol • VOL
Because, however, the effect of the 1.8-G phase was abolished during both 0 G ⫹ CI and 0 G ⫹ CR, thus ensuring
identical pre-0-G conditions, the higher HR in the latter condition may be explained by an additional venous return from
the legs to the central circulation, activating a Bainbridge-like
reflex. The notion of a Bainbridge-like reflex is supported by
our observations, when the subjects were supine, where the
increase in CO during 0 G was purely a result of an unexpected
increase in HR of 6 ⫾ 5 beats/min. This increase might
theoretically have been initiated by a Bainbridge-like reflex, as
previously suggested in studies concerning acute central volume loading by head-down tilt (5, 28), or by intravenous
infusion (3, 22), and/or by mechanisms intrinsic to the heart,
such as direct stretch of the sinus node (25), because our
laboratory has previously shown that the transmural central
venous pressure increases during 0 G in supine humans (29).
This is also in accordance with previous water immersion
observations by our laboratory (17), where HR was more
suppressed during immersion to the midchest than to the neck,
despite that central transmural filling pressures were higher
during neck immersion.
It may be argued that hyperventilation during the rebreathing
maneuver, which was performed at 1 G and 0 G, but not during
1.8 G, may have affected the cardiovascular parameters (1, 12).
However, active hyperventilation has not been shown to have
a significant effect on MAP (16), nor does breathing rate or
breathing volume change CO (8, 15, 16, 19). Furthermore, it
has been reported that HR does not change during short-term
hyperventilation (7, 19, 27). Thus existing evidence does not
support that cardiovascular variables are significantly affected
by the rebreathing maneuver itself.
The unchanged SV during 0 G, when the subjects were
supine, was also somewhat unexpected because of our laboratory’s previously observed increase in cardiac distension pressures (29), which, through the Frank-Starling mechanism,
should have increased SV. Apparently this was not the case.
One explanation could be that, in the 1-G supine position, the
relationship between SV and preload is on the upper flat
portion of the Starling curve, so that an increase in cardiac
preload has no further effect on SV.
Conclusion. Our results indicate that vascular areas above
those of the legs in seated humans can alone account for some
50% of the increase in CO during acute 0 G induced by
parabolic flights. Furthermore, our results surprisingly indicate
that the remaining increase in CO during 0 G is caused by an
accelerated HR for which the origin of blood cannot be
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during 0 G and 0 G ⫹ CR than during 0 G ⫹ CI. Whether this
suggestion is correct remains, however, to be further explored.
In the supine position, the increase in CO during 0 G is
caused by a higher HR leaving SV unchanged. Thus an
increase in transmural central venous pressure and preload (29)
induced by abolishment of the front to back thoracic compression is probably the cause for an augmented venous return and
a Bainbridge-like increase in HR.
Possible mechanisms. Whether the cardiac preload during 0
G was diminished by occlusion of venous return from the legs
cannot be deducted from this study with certainty. Regardless,
however, of whether cardiac preload was affected or not by CI,
SV increased to the same extent during 0 G, with or without
occlusion. Thus blood from the leg vasculature was not a
necessity for increasing SV during 0 G.
Acute weightlessness did not decrease HR to below the 1-G
control value, as expected compared with effects of simulation
experiments, such as an upright-to-supine body posture
change, head-down tilt, or head-out water immersion (4, 9, 13,
14, 17, 26, 28, 29). One might speculate that a possible
mechanism for the lack of a decrease in HR during 0 G could
be that the preceding 1.8 G stimulated HR by activation of the
sympathetic nervous system through inhibition of the baroreflexes, and that this activation counteracted the effects of the
subsequent short-term 0-G phase. Support for this view is the
fact that 1.8 G ⫹ CI did not increase HR (Table 1) and that it
was lower during the subsequent 0 G ⫹ CI (Fig. 2 and Table
1). The thigh cuffs in this way could have acted as a modified
anti-G suit, shifting the venous hydrostatic indifference point
cranially, thus counteracting a decrease in preload. This
view is supported by results of Montmerle and Linnarsson
(20), who found that 70 mmHg of lower body positive
pressure during centrifugation of 2 G was sufficient to
prevent a decrease in SV.
ACUTE WEIGHTLESSNESS AND VENOUS RETURN
ACKNOWLEDGMENTS
We are grateful to the European Space Agency, in particular Vladimir
Pletser and supporting staff, the company Novespace, and all of the subjects
who supported and participated in our study.
GRANTS
This study was supported by Grants 2105-04-0006 and 272-07-0614 from
the Danish Research Councils.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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determined from the results of this study. We suggest that a
Bainbridge-like reflex exists in humans, which accounts for
some 50% of the increase in CO during acute 0 G. This is
supported by our observation that, in supine humans, the
increase in CO during 0 G compared with 1 G is only
secondary to an increase in HR.
Perspectives. It is of fundamental interest in physiology to
investigate whether the human cardiovascular system possesses a Bainbridge-like reflex or other intrinsic mechanisms
that regulate HR during acute changes in G stress. According
to Rowell (24), humans do not possess a Bainbridge reflex, or,
at least, it is very weak. This is probably very true, when
central filling pressures vary between those in the upright and
supine body position, whereas when central filling exceeds that
of supine, a Bainbridge or similar reflex may play a role in
humans. The results in this study indicate so. Thus acute 0 G
during parabolic flights, in particular in supine humans, might
be a unique way of studying the existence of such a fundamental mechanism, because cardiac distension can be created
without intervening hydrostatic gradients.
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