FWF-Project 13451-MED

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, adrenomedullin, 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.

Hypotheses: Dietary 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. We found

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. 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.
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.
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.
Plasma volume and central venous pressure depend on oral sodium intake: A 250 mM/d sodium diet resulted in higher (7.10.6) CVP than 20-mM/d DSS (4.20.5 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.