Graded lower body negative pressure induces intraventricular negative pressures and incremental diastolic suction: a pressure-volume study in a porcine model.

Lower body negative pressure (LBNP) is a tool to study compensatory mechanisms to central hypovolemia for decades. However, the underlying hemodynamic mechanisms were mostly assessed noninvasively and remain unclear. We hypothesized that incremental LBNP reduces diastolic filling and thereby affects left ventricular (LV) diastolic suction (DS). Here, we investigated the impact of graded LBNP at three different levels of seal as well as during ß-adrenergic stimulation by invasive pressure-volume (PV) analysis. Eight Landrace pigs were instrumented closed-chest for PV assessment. LBNP was applied at three consecutive locations: I) cranial, 10 cm below xiphoid process; II) medial, half-way between cranial and caudal; III) caudal, at the iliac spine. Level III was repeated under dobutamine infusion. At each level, baseline measurements were followed by application of incremental LBNP of -15, -30, and -45 mmHg. LBNP induced varying degrees of preload-dependent hemodynamic changes, with cranial LBNP inducing more pronounced effects than caudal. According to the Frank-Starling mechanism, graded LBNP progressively reduced LV stroke volume (LV SV) following a decrease in LV end-diastolic volume. Negative intraventricular minimal pressures were observed during dobutamine-infusion as well as higher levels of LBNP. Of note, incremental LV negative pressures were accompanied by increasing DS volumes, derived by extrapolating the volume at zero transmural pressure, the so-called equilibrium volume (V0), related to LV SV. In conclusion, graded preload reduction via LBNP shifts the PV loop to smaller volumes and end-systolic volume below V0, which induces negative LV pressures and increases LV suction. Accordingly, LBNP-induced central hypovolemia is associated with increased DS.NEW & NOTEWORTHY This study examined the effects of incremental lower body negative pressure (LBNP) from -15 to -45 mmHg on hemodynamic regulation using invasive pressure-volume assessment in closed-chest pigs. Graded preload reduction via LBNP induces negative left ventricular (LV) pressures while increasing LV suction and thus allowing the ventricle to eject below the equilibrium volume at the end of systole. Accordingly, LBNP-induced central hypovolemia is associated with increased diastolic suction.

Volume regulation and renal function at high altitude across gender.

AIMS: We investigated changes in volume regulating hormones and renal function at high altitudes and across gender. METHODOLOGY: Included in this study were 28 subjects (n = 20 males; n = 8 females. ages: 19 - 65 yrs), who ascended to a height of 3440m (HA1), on the 3rd day and to 5050m (HA2), on the 14th day. Plasma and urinary creatinine and urinary osmolality as well as plasma levels of plasma renin activity (PRA), Aldosterone, antidiuretic hormone (ADH), and atrial natriuretic peptide (ANP) were measured. The plasma volume loss (PVL) was estimated from plasma density and hematocrit. Glomerular filtration rate (GFR) was measured based on nocturnal (9 hour) creatinine clearance; this was compared with various methods for estimation of GFR. RESULTS: The mean 24-hour urine production increased significantly in both sexes across the expedition. But PVL reached significance only in males. No changes in Na+ in plasma, urine or its fractional excretion were seen at both altitudes. Urinary osmolality decreased upon ascent to the higher altitudes. ADH and PRA decreased significantly at both altitudes in males but only at HA2 in females. However, no changes in aldosterone were seen across the sexes and at different altitudes. ANP increased significantly only in males during the expedition. GFR, derived from 9-h creatinine clearance (CreaCl), decreased in both sexes at HA1 but remained stable at HA2. Conventional Crea[p]-based GFR estimates (eGFR) showed only poor correlation to CreaCl. CONCLUSIONS: We report details of changes in hormonal patterns across high altitude sojourn. To our knowledge we are not aware of any study that has examined these hormones in same subjects and across gender during high altitude sojourn. Our results also suggest that depending on the estimation formula used, eGFR underestimated the observed decrease in renal function measured by CreaCl, thus opening the debate regarding the use of estimated glomerular filtration rates at high altitudes.

Effect of orthostasis on endothelial function: a gender comparative study.

As the vascular endothelium has multiple functions, including regulation of vascular tone, it may play a role in the pathophysiology of orthostatic intolerance. We investigated the effect of orthostasis on endothelial function using EndoPAT®, a non-invasive and user-independent method, and across gender. As sex steroid hormones are known to affect endothelial function, this study examined the potential effect of these hormones on the endothelial response to orthostasis by including females at different phases of the menstrual cycle (follicular and luteal-where the hormone balance differs), and females taking an oral contraceptive. A total of 31 subjects took part in this study (11 males, 11 females having normal menstrual cycles and 9 females taking oral contraceptive). Each subject made two visits for testing; in the case of females having normal menstrual cycles the first session was conducted either 1-7 (follicular) or 14-21 days (luteal) after the start of menstruation, and the second session two weeks later, i.e., during the other phase, respectively. Endothelial function was assessed at baseline and following a 20-min orthostatic challenge (active standing). The EndoPAT® index increased from 1.71 ± 0.09 (mean ± SEM) at baseline to 2.07 ± 0.09 following orthostasis in females (p<0.001). In males, the index increased from 1.60 ± 0.08 to 1.94 ± 0.13 following orthostasis (p<0.001). There were no significant differences, however, in the endothelial response to orthostasis between females and males, menstrual cycle phases and the usage of oral contraceptive. Our results suggest an increased vasodilatatory endothelial response following orthostasis in both females and males. The effect of gender and sex hormones on the endothelial response to orthostasis appears limited. Further studies are needed to determine the potential role of this post orthostasis endothelial response in the pathophysiology of orthostatic intolerance.

Maximizing information from space data resources: a case for expanding integration across research disciplines.

Regulatory systems are affected in space by exposure to weightlessness, high-energy radiation or other spaceflight-induced changes. The impact of spaceflight occurs across multiple scales and systems. Exploring such interactions and interdependencies via an integrative approach provides new opportunities for elucidating these complex responses. This paper argues the case for increased emphasis on integration, systematically archiving, and the coordination of past, present and future space and ground-based analogue experiments. We also discuss possible mechanisms for such integration across disciplines and missions. This article then introduces several discipline-specific reviews that show how such integration can be implemented. Areas explored include: adaptation of the central nervous system to space; cerebral autoregulation and weightlessness; modelling of the cardiovascular system in space exploration; human metabolic response to spaceflight; and exercise, artificial gravity, and physiologic countermeasures for spaceflight. In summary, spaceflight physiology research needs a conceptual framework that extends problem solving beyond disciplinary barriers. Administrative commitment and a high degree of cooperation among investigators are needed to further such a process. Well-designed interdisciplinary research can expand opportunities for broad interpretation of results across multiple physiological systems, which may have applications on Earth.

Ligustrazine and the contractile properties of soleus muscle in hindlimb-unloaded rats.

BACKGROUND: In this study we investigated the effects of different dosages of ligustrazine (tetramethylpyrazine, Tmp) on soleus function and sarco(endo)plasmatic reticulum Ca(2+)-ATPase (SERCA) activity in 14-d hindlimb-unloaded (HU) rats. METHODS: Female Sprague-Dawley rats were randomly divided into 4 groups (8 rats in each group): synchronous control (CON); HU plus intragastric water instillation (HU-W); HU plus different dosages of instilled Tmp (high: 42.53 mg x kg(-1), HU-TmpH; low: 21.15 mg x kg(-1), HU-TmpL). Muscle contraction force was examined in the soleus muscle. SERCA activity was assayed according to the released inorganic phosphate content. RESULTS: As expected, in HU-W, soleus peak twitch tension (Pt), peak tetanic tension (P0), time to 50% peak tension (TP50), time to peak tension (TPT), time from peak tension to 50% relaxation (RT50), and SERCA activity decreased, all compared with CON. HU-TmpH Pt and P0 values were 179% and 90% above HU-W, and 187% and 124% above HU-W in HU-TmpL, respectively. TP50 and TPT values were 148% and 80% slower than HU-W with HU-TmpH and 95% and 32% in the HU-TmpL group, respectively. RT50 was slower than HU-W by 21% in HU-TmpH; SERCA activity elevated by 56% with HU-TmpH and by 72% with HU-TmpL. CONCLUSIONS: Ligustrazine may alleviate the decrease of muscle contractile force and increase of shortening velocity in atrophied soleus, possibly by means of elevated sarcoplasmic reticulum Ca(2+)-ATPase activity.

Skeletal muscle is protected from disuse in hibernating dauria ground squirrels.

The purpose of this study is to test the hypothesis that muscle fibers are protected from undue atrophy in hibernating dauria ground squirrels (Spermophilus dauricus, Brandt). Muscle mass, fiber cross sectional area (CSA, video analysis) and fiber type distribution (m-ATPase staining) were determined in extensor digitorum longus (EDL) muscle from non-hibernating control animals (Pre-H), from animals who hibernated for one (H1) or two (H2) months, and from animals 2-4days after arousal (Post-H; N=8 each). Muscle wet weight decreased less than body weight in hibernating animals, resulting in a steady increase in muscle-to-body mass ratio (+37% in Post-H compared to Pre-H, p<0.001). In the Pre-H group, Type I (6.3±2.0%) and II (93.7±2.0%) fiber CSAs were 1719±201 and 2261±287µm(2), respectively. There was a tendency (n.s.) of larger CSA of type I in hibernators compared to pre-H. In the Post-H group, fiber CSA and type distribution were not different from Pre-H. We are the first to report data on EDL fiber type distribution and confirm a protective effect that prevents muscle atrophy in spite of prolonged disuse during hibernation in dauria ground squirrels.

Heart rate and stroke volume response patterns to augmented orthostatic stress.

AIMS: Combined head up tilt (HUT) and lower body negative pressure (LBNP) can be used to exploit the full spectrum of cardiovascular control mechanisms and to reveal characteristics of individual blood pressure control. We studied whether the response to combined HUT and LBNP was reproducible within subjects and whether characteristic response patterns could be distinguished between different subjects. MATERIALS AND METHODS: Ten healthy young males were subjected to combined HUT and graded LBNP to achieve a presyncopal end point in four tests, each separated by more than 2 weeks. Heart rate, blood pressure and thoracic impedance were monitored, cardiac output and peripheral vascular resistance were computed. RESULTS: From supine control to presyncope, heart rate, mean arterial blood pressure, pulse pressure and stroke index changed as expected. The time courses of heart rate and stroke volume as well as orthostatic tolerance times (15 +/- 6 to 18 +/- 7 minutes, n.s) appeared reproducible between trials within subjects but different between different subjects. CONCLUSION: LBNP-tilt approach was repeatable in time and pattern. Furthermore, differences observed between subjects indicated preferred activation of selected pathways of blood pressure control in different individuals while at the same time, reproducibility measured within the same subject showed that preferential mechanisms were highly conserved within the same individual. These characteristics are a prerequisite to use the combined graded orthostatic paradigm for hemodynamic testing and identification.

Reactive hyperemia in the human liver.

We tested whether hepatic blood flow is altered following central hypovolemia caused by simulated orthostatic stress. After 30 min of supine rest, hemodynamic, plasma density, and indocyanine green (ICG) clearance responses were determined during and after release of a 15-min 40 mmHg lower body negative pressure (LBNP) stimulus. Plasma density shifts and the time course of plasma ICG concentration were used to assess intravascular volume and hepatic perfusion changes. Plasma volume decreased during LBNP (-10%) as did cardiac output (-15%), whereas heart rate (+14%) and peripheral resistance (+17%) increased, as expected. On the basis of ICG elimination, hepatic perfusion decreased from 1.67 +/- 0.32 (pre-LBNP control) to 1.29 +/- 0.26 l/min (-22%) during LBNP. Immediately after LBNP release, we found hepatic perfusion 25% above control levels (to 2.08 +/- 0.48 l/min, P = 0.0001). Hepatic vascular conductance after LBNP was also significantly higher than during pre-LBNP control (21.4 +/- 5.4 vs. 17.1 +/- 3.1 ml.min(-1).mmHg(-1), P < 0.0001). This indicates autoregulatory vasodilatation in response to relative ischemia during a stimulus that has cardiovascular effects similar to normal orthostasis. We present evidence for physiological post-LBNP reactive hyperemia in the human liver. Further studies are needed to quantify the intensity of this response in relation to stimulus duration and magnitude, and clarify its mechanism.

Radix astragali and orthostatic response: a double-masked crossover study.

AIM: Recent results from animal experiments have shown that radix astragali (RA), a traditional Chinese herbal tonic, alleviates muscle atrophy under simulated weightlessness conditions, rendering RA a candidate for human use as a countermeasure against muscular atrophy. Possible cardiovascular side effects have not yet been investigated. We analyzed the effects of RA on the orthostatic stability of healthy men. METHODS: There were 10 test subjects who were assigned to a double-blinded, randomized crossover design using RA or placebo (PL) for 14 d each, respectively. Test runs were separated by a 14-d 'washout' interval. At the beginning and the end of every 14-d test run, graded orthostatic stress (GOS) consisting of head-up tilt (HUT) combined with lower body negative pressure (LBNP) was used to achieve a presyncopal endpoint. Orthostatic effects on cardiac and vascular function were continuously monitored. RESULTS: There were no significant differences between the RA vs. PL groups: mean arterial blood pressure dropped by 13 vs. 17%, pulse pressure 46 vs. 35%, heart rate increased 108 vs. 117%, and stroke volume index decreased 54 vs. 49% from supine control to presyncope. Neither did RA influence standing time compared to PL (18 +/- 7 vs. 17 +/- 6 min), nor did progression from the first to the fourth trial (15 +/- 6 to 18 +/- 7 min). CONCLUSION: RA does not influence resting cardiovascular variables and orthostatic capacity in humans. It can be expected that human studies of RA's musculo-skeletal countermeasure potential will not be compromised by any cardiovascular side effects at the dosage employed in this study.

Muscle composition after 14-day hindlimb unloading in rats: effects of two herbal compounds.

AIM: We studied the potential of two herbal compounds (HC-1 and HC-2) in different dosages (HC-1, containing ligustrazine; HC-2, containing radix astragali) as a countermeasure against muscle atrophy in a hindlimb unloading rat model. Soleus muscle weight, fiber type distribution, cross-sectional area (CSA), and myosin ATPase activity were measured. METHODS: Six rats each were assigned to a nine-group design: Control (CON); hindlimb unloading only (HLU); hindlimb unloading plus intragastric water instillation (HLU-W); and hindlimb unloading plus different dosages of instilled HC-1 (HLU-HC-1l, HLU-HC-1m, HLU-HC-1h) or HC-2 (HLU-HC-2l, HLU-HC-2m, HLU-HC-2h). RESULTS: As expected, in HLU and HLU-W, soleus muscle-to-body weight ratio and CSA of type I and II fiber went down, and myosin ATPase activity and the percentage of type II fibers went up, all compared with CON. Compared to untreated rats, high-dose HC-1 enhanced type I and II fiber CSA by 77% and 55%, respectively; myosin ATPase activity (type II fiber percentage) were lower, but soleus muscle-to-body weight ratio did not change. High-dose HC-2 enhanced soleus muscle-to-body weight ratio by 33%; and type I / type II fiber CSA by 143% and 83% above HLU-W values, respectively, and resulted in a slower myosin ATPase activity (corresponding to a lower type II fiber percentage). Low- to mid-dose HC-1 and HC-2 showed some preventive effects as well. CONCLUSION: HC-1 and HC-2 in proper dosages diminished muscle atrophy that otherwise occurs in simulated weightlessness.

Circulatory galanin levels increase severalfold with intense orthostatic challenge in healthy humans.

The purpose of this study was to test the hypothesis that plasma galanin concentration (pGal) is regularly increased in healthy humans with extensive orthostatic stress. Twenty-six test persons (14 men, 12 women) were brought to an orthostatic end point via a progressive cardiovascular stress (PCS) protocol consisting of 70 degrees head-up tilt plus increasing levels of lower body negative pressure until either hemodynamically defined presyncope or other signs of orthostatic intolerance occurred (nausea, clammy skin, excessive sweating, pallor of the skin). We further tested for possible gender, gravitational, and muscular training influences on plasma pGal responses: PCS was applied before and after 3 wk of daily vertical acceleration exposure training on a Human Powered Centrifuge. Test persons were randomly assigned to active (with bicycle work) or passive (without work) groups (seven men, six women in each group). Resting pGal was 26+/-3 pg/ml in men and 39+/-15 pg/ml in women (not significant); women had higher galanin responses (4.9-fold increase) than men (3.5-fold, P=0.017) to PCS exposure. Overall, PCS increased pGal to 186+/-5 pg/ml (P=0.0003), without significant differences between presyncope vs. orthostatic intolerance, pre- vs. postcentrifuge, or active vs. passive gravitational training. Increases in pGal were poorly related to synchronous elevations in plasma vasopressin. We conclude that galanin is regularly increased in healthy humans under conditions of presyncopal orthostatic stress, the response being independent of gravity training but larger in women than in men.

[The possible role of adrenomedullin in adaption to high altitude]. / Adrenomedullin--ein möglicher Regulationsfaktor der Höhenadaptation?

Diuresis and natriuresis are well-known responses to acute hypoxic exposure. Even though there have been many studies on the hormonal regulation of the hypoxic diuretic response (HDR), most of the fluid-regulating hormones showed no consistent correlation to HDR. The pathophysiology of high altitude related syndromes was often seen to be linked to an impairment of volume regulating processes. Adrenomedullin (AM) is a recently discovered polypeptide with diuretic, natriuretic and vasodilatory properties whose production is basically mediated by hypoxia. As yet, little is known about the action of AM under hypoxic conditions in vivo. We present evidence that AM may play a role in the physiology and pathophysiology of human adaption to high altitude.

Sodium intake does not influence bioimpedance-derived extracellular volume loss in head-down rest.

INTRODUCTION: There is disagreement regarding the impact of dietary sodium on alterations in extracellular volume during head-down bed rest (HDBR). The primary purpose of this study was to assess the effects of salt intake on extracellular volume (ECV) during HDBR. METHODS: We performed whole-body bioimpedance spectroscopy with controlled sodium intake during 4 d of ambulation and 8 d of -6 degrees HDBR in 10 normotensive men. Each subject performed an initial 12-d familiarization run with moderate sodium (246 +/- 12 mmol x L(-1) x d(-1) excreted) during which no measurements were made. They then participated in treatment runs involving low sodium (LS: 143 +/- 10 mmol x L(-1) x d(-1) Na+ excreted) and high sodium (HS: 434 +/- 17 mmol x L(-1) x d(-1) Na+ excreted). The different treatments were separated by > or =1 mo and the order of LS and HS was balanced among the subjects. These treatments were based on controlled food and drink supplies as prepared by a dietitian. We monitored sodium output and measured aldosterone, plasma renin activity (PRA), and vasopressin. Bioimpedance was measured every second day in supine position using tetrapolar electrodes. RESULTS: Based on exponential data fitting, we calculated an ECV decrease of 0.79 +/- 0.32 L (-5.8%; p = 0.018) in LS, and 1.21 +/- 0.31 L (-4.0%; p = 0.002) in HS during HDBR. LS and HS were not different (p > 0.1); 4 d pre-HDBR sodium adjustment produced a fall in ECV in the LS group only (-3.7%, p = 0.023). Hormone levels were not changed by HDBR. Plasma aldosterone was lower in HS (69 +/- 7 pg x ml(-1)) than in LS (180 +/- 24 pg x ml(-1)). DISCUSSION: Our bioimpedance data confirm that low sodium intake decreases ECV in ambulatory conditions and indicate that 8 d of HDBR produce a loss of ECV of about 5% (p < 0.05). The loss did not seem to be influenced by sodium intake between approximately 3 and approximately 10 g x d(-1).

Bed rest immobilization with various oral sodium supply: plasma hormones and body fluids.

OBJECTIVE: To answer the question if plasma hormone concentrations (plasma renin activity--PRA, vasopressin--pAVP, and aldosterone concentration) due to antiorthostatic immobilization (8 days -6 degree head-down tilt bed rest--HDBR) are altered by oral salt load, we provided constant sodium supply during 4 days ambulatory conditions followed by 8 days HDBR in 10 normotensive men. METHODS: A low' (LS: 143 10 mM) and high' (HS: 434+/-17 mM Na+/d excreted) sodium treatment were provided in randomized order, separated > or = 1 mo. Before and at the end of HDBR, hemodynamic variables and thoracic impedance were determined, and blood was taken for aldosterone and PRA, venous hematocrit, and plasma mass density. Extracellular fluid volume and pAVP were determined every second day. Whole body electrical impedance spectroscopy was employed to assess changes in extracellular volume, hormone determinations were done with radioimmunoassay, mass density measurements with the mechanical oscillator technique. RESULTS: Extracellular volume decreased with HDBR (LS: -4.0%, p=0.002; HS: -5.8%, p=0.018) without significant difference between salt treatments. Resting hormone levels were not altered by HDBR, but pAVP was lower (5.5+/-0.1 pg/ml) in HS than in LS (7.2+/-0.3 pg/ml) as was plasma aldosterone (HS: 69+/-7 pg/ml, LS: 180+/-24 pg/ml). On the other hand, HDBR reduced extracellular volume by ?5% irrespective of dietary sodium supply. CONCLUSIONS: Our data support the hypothesis that hormonal activities are more affected by oral salt load than by simulated short-term space flight, and suggest that the reduction of extracellular fluid volume due to head down bed rest is not influenced by moderate changes of dietary sodium supply.