Adaptation to antiorthostasis with
modified extracellular fluid volume
This project investigated
circulatory adaptation to simulated removal of gravity (antiorthostasis:
-6 deg. head down positioning for 8 days) with three levels of extracellular
fluid volume (ECFV) as influenced by oral sodium supply. In 10 normotensive
nonobese male persons, four levels (15, 30, 45, 60 mmHg - 10 min each)
of lower body suction (LBNP)
were used to create graded central hypovolemia. We tested hormonal threshold
and response intensities with altered ECFV, and gravitational load.
Procedures, methods, protocol:
Low, medium and high oral sodium intake was provided to every test person
for 12 days each: 4 days ambulatory (A), and 8 days antiorthostatic (B)
condition. LBNP stimulus responses of arterial blood pressures, thoracic
impedance, blood volume change indices (blood plasma mass
density, hematocrit), and hormones (renin, aldosterone, vasopressin,
atrial natriuretic peptide,
norepinephrine) were determined on days 1, 5, and 13, using conventional
methods (density with the mechanical
oscillator technique). Basal (morning) values of body mass, total body
electric impedance and plasma osmolality, and 24-hr sodium excretion were
recorded every day.
sodium supply influences extracellular fluid and plasma volume, central
venous pressure, and various hormone levels. It is hypothesized that in
addition, stimulus responses within measured variables strongly depend
on extracellular volume and adaptation to antiorthostasis. In particular,
responses of adrenomedullin to altered sodium and gravity loading, and
LBNP are yet unknown and will be studied. Subjects serve as their own controls,
corresponding data from different conditions (low vs. medium vs. high sodium,
ambulatory vs. antiorthostatic) are compared to test these conjectures,
referred to as the 'sodium adaptation' and 'gravity
deprivation' hypotheses, respectively.
According to previous investigations,
one week of HDBR seems to reset cardiopulmonary receptors, with reduced
ANP and norepinephrine but increased renin and aldosteron levels. In contrast,
vasopressin was reported unchanged after up to 28 days HDBR. Recent studies
reported unchanged heart rate, blood pressure, and plasma concentration
of volume effective hormones after 2 days HDBR; decreased plasma vasopressin
after 7 days bed rest; increased basal renin and aldosterone levels after
1-2 weeks, and unchanged vasopressin during up to 4 weeks bed rest; increased
blood pressure and heart rate after 14 days; unaffected systolic blood
pressure and heart rate with 17 days HDBR. Thus, no agreement on hemodynamic
and hormonal effects of bed rest can be derived.
Results: We tested
if salt intake could explain some of the discrepancies reported earlier.
It has been shown that LBNP
tolerance decreases with HDBR. On the other hand, salt intake determines
cardiovascular function as characterized by altered cardiac preload pressures
and cardiovascular stimulus responses and has been found to reduce plasma
renin activity and aldosterone. According to existing literature, we expected
unchanged (pre-LBNP) vasopressin and possibly increased PRA and aldosterone
levels after 8 days HDBR.
basal heart rate unaltered with
8 days HDBR regardless of salt supply.
Mean arterial pressure was consistently
lower with 8 days HDBR ? also regardless of salt supply -, which is in
disagreement with previous studies that found unchanged or increased arterial
We did not find consistent HDBR-dependent
changes of cardiac index.
It is conceivable to conclude
that with LS, the volume status is already challenged to an extent that
does not allow for additional LBNP-induced increase after 8 additional
days of antiorthostatic bedrest, whereas with ‚normal’ salt diet, deconditioning
allows for further increase in aldosterone responses to graded LBNP.
Plasma renin activity and plasma
aldosterone are known to decrease with oral salt supply, and our results
confirm this. Further, our data clearly show the highest LBNP-induced aldosterone
levels in the LS group, with similar response magnitude pre- and post-HDBR,
clearly confirming our ‚sodium adaptation’ hypothesis while refuting the
‚gravity deprivation’ hypothesis.
It was unclear how sodium
loading would influence basal vasopressin levels in humans with circumstances
as chosen for this study.
Thoracic electrical impedance
(TI) is an index of central blood volume; its decrease (usually paralleled
by a CVP decrease) causes TI to rise. Adaptation to clamped salt intake
was repeatedly reported to take =4 days to assume full effect, therefore
we chose 4 days for ambulatory pre-HDBR. We expected that saline ingestion
influences extracellular and/or plasma volume. A recent study however (Heer
et al. 2000) showed that changing sodium supply in a range between
50 and 660 mM/d did not have an effect on total body water. Rather, fluid
seemed to been shifted from the interstitial to the intravascular compartment
with high salt load, increasing plasma volume. It has been hypothesized
that extra sodium might be stored in the interstitial space during low-salt
conditions. A recent human investigation of 135 days sodium balance indeed
(Titze et al. 2002) suggests the existence of a reservoir able to store
sodium in an osmotically inactive form, resulting in fluid retention in
spite of sodium depletion, and consequently ECV stabilization. The results
of our study add credibility to this hypothesis because there was no significant
difference between the ECV effect of HDBR with high vs. low salt intake.
Basal AVP was consistently higher
in the LS as compared to the HS group. Thus, LS conditions seem to be sufficient
to raise morning AVP levels, which would be consistent to the hypothesis
of a challenges volume status with low sodium supply. During the course
of HDBR, there was no significant AVP increase, confirming most earlier
Whole body electrical impedance
(Imp) is influenced by tissue fluid content. Given appropriate model assumptions,
Imp as determined under standard conditions allows to assess extracellular
hydration but the method has certain limitations.
It has been suggested that after
an initial fluid loss, adaptation to HDBR leads to a new steady state within
=24 hours while eliciting antinatriuretic endocrine signals, resulting
in decreased plasma and ECV. It has been suggested that total body water
stays unchanged despite diminished ECV during bed rest, which could be
explained by a fluid shift from extra- to intracellular compartments. Although
this dispute has not yet been resolved, HDBR-induced ECV loss ? as confirmed
by our data - is a well established effect.
We performed in-depth analyses
and error estimations and found that HDBR reduces extracellular volume
as early as after 2 days together with a =10% plasma volume loss which
is the same level of hemoconcentration as observed after 10 days HDBR.
Plasma volume and central
venous pressure depend on oral sodium intake: A 250 mM/d sodium diet resulted
in higher (7.1±0.6) CVP than 20-mM/d DSS (4.2±0.5 mmHg).
Another study chose 75 vs. 300 mM/d sodium, whithout significant effects
on CVP. From this it seems that rather drastic alterations within salt
supply are required to get significant preload changes. Indeed, resting
heart rate was shown to be higher with very low (19 mM/d) as compared to
normal (‘high’: 215 mM/d) sodium input.
Conclusions and outlook:
Our results suggest that
The results from this study
add evidence to the potential influence of sodium status for the design
of cardiovascular ‚deconditioning’ (HDBR) experiments. For instance, they
do not support the notion of changed ECV with oral sodium supply in the
range chosen. Heart rate responses to orthostatic (LBNP) challenge was
much increased after HDBR as expected, but did not respond to salt loading.
impedance spectroscopy reliably
reveals ECV changes in supine or slightly head-down positioned persons
over a time course of several days, and that the impedance-ECV transformation
is not significantly influenced by clamping oral sodium input between =3
and =10 g/d. This is in agreement with a recent investigation of others
(Heer et al. 2000);
while decreasing arterial blood
and pulse pressure, PRA and aldosterone levels during graded simulated
orthostatic challenge, HS did neither ameliorate HDBR-induced ECV decrease
nor alter LBNP-induced heart rate and filtration responses;
HS was able to increase arterial
blood and pulse pressure and reduced PRA and aldosterone levels during
graded simulated orthostatic challenge, but did neither ameliorate HDBR
- induced ECV decrease nor alter LBNP-induced filtration and heart rate