Lower Body Negative Pressure: Physiological Effects, Applications, and Implementation.

This review presents lower body negative pressure (LBNP) as a unique tool to investigate the physiology of integrated systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia in humans. An early review published in Physiological Reviews over 40 yr ago (Wolthuis et al. Physiol Rev 54: 566-595, 1974) focused on the use of LBNP as a tool to study effects of central hypovolemia, while more than a decade ago a review appeared that focused on LBNP as a model of hemorrhagic shock (Cooke et al. J Appl Physiol (1985) 96: 1249-1261, 2004). Since then there has been a great deal of new research that has applied LBNP to investigate complex physiological responses to a variety of challenges including orthostasis, hemorrhage, and other important stressors seen in humans such as microgravity encountered during spaceflight. The LBNP stimulus has provided novel insights into the physiology underlying areas such as intolerance to reduced central blood volume, sex differences concerning blood pressure regulation, autonomic dysfunctions, adaptations to exercise training, and effects of space flight. Furthermore, approaching cardiovascular assessment using prediction models for orthostatic capacity in healthy populations, derived from LBNP tolerance protocols, has provided important insights into the mechanisms of orthostatic hypotension and central hypovolemia, especially in some patient populations as well as in healthy subjects. This review also presents a concise discussion of mathematical modeling regarding compensatory responses induced by LBNP. Given the diverse applications of LBNP, it is to be expected that new and innovative applications of LBNP will be developed to explore the complex physiological mechanisms that underline health and disease.

Effect of novel short-arm human centrifugation-induced gravitational gradients upon cardiovascular responses, cerebral perfusion and g-tolerance.

KEY POINTS: The aim of this study was to determine the effect of rotational axis position (RAP and thus g-gradient) during short-arm human centrifugation (SAHC) upon cardiovascular responses, cerebral perfusion and g-tolerance. In 10 male and 10 female participants, 10 min passive SAHC runs were performed with the RAP above the head (P1), at the apex of the head (P2), or at heart level (P3), with foot-level Gz at 1.0 g, 1.7 g and 2.4 g. We hypothesized that movement of the RAP from above the head (the conventional position) towards the heart might reduce central hypovolaemia, limit cardiovascular responses, aid cerebral perfusion, and thus promote g-tolerance. Moving the RAP footward towards the heart decreased the cerebral tissue saturation index, calf circumference and heart rate responses to SAHC, thereby promoting g-tolerance. Our results also suggest that RAP, and thus g-gradient, warrants further investigation as it may support use as a holistic spaceflight countermeasure. ABSTRACT: Artificial gravity (AG) through short-arm human centrifugation (SAHC) has been proposed as a holistic spaceflight countermeasure. Movement of the rotational axis position (RAP) from above the head towards the heart may reduce central hypovolaemia, aid cerebral perfusion, and thus promote g-tolerance. This study determined the effect of RAP upon cardiovascular responses, peripheral blood displacement (i.e. central hypovolaemia), cerebral perfusion and g-tolerance, and their inter-relationships. Twenty (10 male) healthy participants (26.2 ± 4.0 years) underwent nine (following a familiarization run) randomized 10 min passive SAHC runs with RAP set above the head (P1), at the apex of the head (P2), or at heart level (P3) with foot-level Gz at 1.0 g, 1.7 g and 2.4 g. Cerebral tissue saturation index (cTSI, cerebral perfusion surrogate), calf circumference (CC, central hypovolaemia), heart rate (HR) and digital heart-level mean arterial blood pressure (MAP) were continuously recorded, in addition to incidence of pre-syncopal symptoms (PSS). ΔCC and ΔHR increases were attenuated from P1 to P3 (ΔCC: 5.46 ± 0.54 mm to 2.23 ± 0.42 mm; ΔHR: 50 ± 4 bpm to 8 ± 2 bpm, P < 0.05). In addition, ΔcTSI decrements were also attenuated (ΔcTSI: -2.85 ± 0.48% to -0.95 ± 0.34%, P < 0.05) and PSS incidence lower in P3 than P1 (P < 0.05). A positive linear relationship was observed between ΔCC and ΔHR with increasing +Gz, and a negative relationship between ΔCC and ΔcTSI, both independent of RAP. Our data suggest that movement of RAP towards the heart (reduced g-gradient), independent of foot-level Gz, leads to improved g-tolerance. Further investigations are required to assess the effect of differential baroreceptor feedback (i.e. aortic-carotid g-gradient).

Novel findings on ultrastructural protection of skeletal muscle fibers during hibernation of Daurian ground squirrels: Mitochondria, nuclei, cytoskeleton, glycogen.

We examined ultrastructure protective phenomena and mechanisms of slow and fast muscles in hibernating Daurian ground squirrels (Spermophilus dauricus). Some degenerative changes such as slightly decreased sarcomere length and vacuolization occurred in hibernation, but periaxonal capsular borders in intrafusal fibers remained distinct and the arrangement of extrafusal fibers and Z-lines unscathed. In soleus samples, the number of glycogenosomes more than tripled during hibernation. The expression of phosphorylated glycogen synthase remained unaltered while that of glycogen phosphorylase decreased during hibernation. The number of extensor digitorum longus glycogenosomes decreased and the expression of phosphorylated glycogen synthase decreased, while glycogen phosphorylase expression remained unaltered. The nuclei number remained unchanged. Kinesin and desmin, preventors of nuclear loss and damage, were maintained or just slightly reduced in hibernation. The single-fiber mitochondrial concentration and sub-sarcolemmal mitochondrial number increased in both muscle types. The expression of vimentin, which anchors mitochondria and maintains Z-line integrity, was increased during and after hibernation. Also, dynamin-related protein 1, mitochondrial fission factor, and adenosine triphosphate synthase were elevated in both muscle types. These findings confirm a remarkable ultrastructure preservation and show an unexpected increase in mitochondrial capacity in hibernating squirrels.

Adrenomedullin and galanin responses to orthostasis in older persons.

BACKGROUND: Neuroendocrine responses to orthostasis may be critical in the maintenance of mean arterial pressure in healthy individuals. A greater reduction in orthostatic tolerance with age may relate to modulation of hormonal responses such as adrenomedullin and galanin. Thus, we investigated (i) whether adrenomedullin and galanin concentrations increase during orthostatic challenge in older subjects, (ii) whether adrenomedullin and galanin concentrations are higher in older females compared with older males when seated and during orthostatic challenge, and (iii) whether postural changes in plasma concentrations of galanin are correlated with levels of adrenomedullin in either older females or males. MATERIALS AND METHODS: Subjects (n = 18; 12 ♀; 55-80 years old) performed a sit-to-stand test in a 25°C sensory-minimised environment, with blood samples collected after 4 min of being seated and then when standing. Plasma adrenomedullin and galanin concentrations were determined. RESULTS: Baseline plasma concentration of adrenomedullin (5·35 ± 0·74 (n = 12, females) vs. 7·40 ± 1·06 pg/mL (n = 5, males)) and galanin (64·07 ± 9·05 vs. 98·99 ± 16·90 pg/mL, respectively) did not significantly differ between genders. Furthermore, plasma adrenomedullin and galanin concentrations were not significantly affected by adoption of the upright posture in either gender and were not correlated in females or males. CONCLUSIONS: Adrenomedullin and galanin concentrations were similar between genders and did not change following adoption of the standing posture. To further clarify the roles, these hormones play in orthostatic intolerance, adrenomedullin and galanin concentrations should be assessed in participants who show presyncopal symptoms during an orthostatic challenge.

Bed rest does not induce hypercoagulability.

BACKGROUND: Although there is no direct evidence, it is generally believed that bed rest shifts the haemostatic system towards hypercoagulability; thus, immobilized patients are commonly treated with anticoagulants. We therefore aimed to investigate whether long-term bed rest actually leads to an elevated risk for thromboembolic events. MATERIALS AND METHODS: Eleven healthy men were enrolled in our study (bed rest campaign in MEDES Clinique d'Investigation, Toulouse, France). Besides various standard laboratory methods, we used calibrated automated thrombography (CAT) and thrombelastometry (TEM). Activation of samples with minute amounts of relipidated tissue factor allowed sensitive detection of hyper- or hypocoagulable states. RESULTS: CAT and TEM values were not indicative of bed rest-induced hypercoagulability. On the contrary, several parameters were indicative of a tendency towards a hypocoagulable state. Peak and thrombin formation velocity (VELINDEX) were significantly decreased during bed rest compared to baseline. Coagulation times were significantly increased and alpha angles were significantly decreased, indicating attenuated clot formation. Moreover, F1 + 2 and thrombin/antithrombin complex (TAT) values were significantly decreased during bed rest, indicating suppressed coagulation activation. FVII plasma levels were also significantly decreased during the first week of bed rest. CONCLUSIONS: Our data indicate that the re-ambulation period is associated with a tendency towards hypercoagulability: ttPeak and StartTail were significantly shorter, Peak and VELINDEX were significantly higher compared to baseline. Moreover, plasma levels of F1 + 2, TAT, FVII and FVIII were significantly higher compared to baseline. The results from our study suggest that bed rest by itself is not associated with hypercoagulable states in healthy subjects.

Influence of bed rest on plasma galanin and adrenomedullin at presyncope.

BACKGROUND: The role of hormones in reduced orthostatic tolerance following long-term immobilization remains uncertain. We have previously shown that plasma concentrations of adrenomedullin and galanin, two peptides with vasodepressor properties, rise significantly during orthostatic challenge. We tested the hypothesis that bedrest immobilization increases the rise in adrenomedullin and galanin during orthostatic challenge leading to presyncope. MATERIALS AND METHODS: We measured baseline (supine), presyncope and recovery (10 min postpresyncope, supine) levels of adrenomedullin and galanin in 8 healthy men, before and after 21 days of -6° head-down bed rest (HDBR). Presyncope was elicited using a combined head-up tilt and graded lower body negative pressure protocol. Orthostatic tolerance was defined as the time taken from the commencement of head-up tilt to the development of presyncope. RESULTS: Orthostatic tolerance time after HDBR reduced by 8·36 ± 5·39 min (P = 0·0032). HDBR increased plasma adrenomedullin concentration to orthostatic challenge (P = 0·0367). Compared to pre-HDBR, a significant rise in post-HDBR presyncopal (P < 0·001) and recovery adrenomedullin concentration (P < 0·01) was demonstrated. In contrast, we observed no change in pre- and post-HDBR galanin levels to orthostatic challenge. CONCLUSIONS: Bedrest immobilization appears to affect adrenomedullin levels in that greater increases in adrenomedullin occur at presyncope following bedrest immobilization. Due to its peripheral vasculature hypotensive effect, the greater levels of adrenomedullin at presyncope following bedrest immobilization may have contributed to the reduced orthostatic capacity postbedrest.

Short-arm human centrifugation with 0.4g at eye and 0.75g at heart level provides similar cerebrovascular and cardiovascular responses to standing.

BACKGROUND AND PURPOSE: Orthostatic intolerance continues to be a problem with astronauts upon return to Earth as a result of cerebral and cardiovascular adaptations to weightlessness. We tested the hypothesis that artificial gravity from a short-arm human centrifuge (SAHC) could provide cerebral and cardiovascular stimuli similar to upright posture and thereby serve as a suitable countermeasure. METHODS: We compared cardiovascular and cerebrovascular responses before, during, and after exposure to hyper-G with that of standing in healthy young participants. The head was positioned such that the middle cerebral artery (MCA) was 0.46 m from the center of rotation. Two levels of hyper-G that provided 1g and 2g at foot level were investigated. Continuous blood pressure, heart rate, calf blood volume, MCA mean blood flow velocity (MFV) and end-tidal CO2 were measured. RESULTS: Blood pressure at the level of the MCA (BP-MCA) and MFV was reduced during stand and at 2g. The relationship between MFV and BP-MCA at 2g was different from supine and similar to standing, while 1g centrifugation was not different from supine. The cardiovascular system was also not different from supine at 1g but was similarly challenged in 2g compared to stand. CONCLUSIONS: Our data suggest that short-arm centrifugation 2g at the feet, with the head offset 0.5 m from the center, provides similar cardiovascular and cerebral responses to standing. This supports the hypothesis that passive 2g SAHC exposure at the feet could be used as a countermeasure for in-flight cardiovascular and cerebrovascular deconditioning.

Academic Goal Orientation and Cardiovascular Reactivity in a Performance Situation.

The present study investigated whether students' academic goal orientation (learning goals, performance goals, work avoidance) and their individual competence beliefs (their academic self-concept) can predict motivation-related cardiovascular activation patterns in a demanding performance situation. A sample of seventy-two undergraduate students rated their academic goal orientation as well as their competence beliefs and completed a mental arithmetic task. Heart rate (HR), blood pressure, pre-ejection period (PEP) as well as cardiac output (CO) and total peripheral resistance were monitored continuously during rest and task exposure. Students scoring higher on work avoidance showed smaller increases in HR and CO, and a smaller shortening of the PEP. A lower academic self-concept was associated with attenuated CO reactivity and a smaller shortening of the PEP. Learning and performance goals were unrelated to cardiovascular activity. The attenuated cardiac activity observed for work avoidance and competence beliefs was interpreted in terms of reduced task engagement resulting from lower success importance.

Cardiovascular effects of acute positive emotional arousal.

Since there are several popular beliefs about putative health benefits of amusement which are empirically substantiated poorly about putative health benefits of amusement, the immediate cardiovascular effects of amusement were studied in detail. Cardiovascular activity was studied while participants were viewing humorous films, relative to a control condition involving no amusement. High-resolution measures of heart rate, heart rate variability, continuous blood pressure, and respiration were recorded, and the phase synchronization among the variables was analyzed, which provides information on the coordinated behavior of response systems. Viewing humorous films had cardiovascular effects indicating heightened sympathetic arousal, if they elicited intense amusement. No effects were observed for variables indicating parasympathetic input to the heart. The observed effects associated with amusement were not driven by changes in the respiration. The suppression of positive affect expressions did not produce any additional activation. The transient cardiovascular effects of amusement do not correspond to beneficial correlates of a habitual positive affect disposition reported in the literature, demonstrating that it would be erroneous to argue from the long-term effects of a positive affect disposition to the effects of a single amusing event.

Increased anxiety induced by listening to unpleasant music during stress exposure is associated with reduced blood pressure and ACTH responses in healthy men.

The relationship between anxiety and the neuroendocrine response to stress stimuli is still not fully understood. The aim of this study was to evaluate the contribution of an acute increase in state anxiety to neuroendocrine activation under stress conditions. To do so, it was necessary to find a stress condition of the same character and intensity with and without a rise in state anxiety. We decided to examine the effects of listening to music on anxiety and to apply a new methodological approach. A group of 14 healthy volunteers participated in a counterbalanced crossover design study. The stress procedure consisted of mental (Stroop test, mental arithmetic) and physical (handgrip exercise) tasks combined with listening to music played forward (pleasant) or backwards (unpleasant). The results confirmed our hypothesis, namely the condition with listening to unpleasant music was anxiogenic, while the other was not. In case of increased state anxiety, the rise in ACTH concentrations in response to mental challenge and the increase in systolic blood pressure induced by handgrip exercise was reduced compared to the situation with unchanged anxiety. Concentrations of testosterone, oxytocin, vasopressin and aldosterone were slightly increased in response to the stress paradigm accompanied with increased anxiety. In conclusion, the present data demonstrate that an acute increase in state anxiety contributes to neuroendocrine activation under stress conditions. Moreover, the results show that listening to music may both positively and negatively influence the perception of stress and the level of anxiety, which might have functional consequences.

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.

Blood volume redistribution during hypovolemia.

BACKGROUND: The goal of this study was to investigate the contribution of splanchnic volume redistribution and lower limb vasoconstriction in the maintenance of blood pressure during progressive central hypovolemia induced by graded lower body negative pressure (LBNP). It was hypothesized that splanchnic blood volume loss during LBNP would buffer decreases in thoracic blood volume. METHODS: There were 15 healthy subjects (8 men, 7 women) who participated in the study. We used LBNP of -10, -20, -30, and -40 mmHg with segmental impedance analysis to determine central and splanchnic volume changes, and near infrared spectroscopy (NIRS) to assess calf venous volume changes and vasoconstrictor tone. RESULTS: In relation to baseline, LBNP to -40 mmHg resulted in a 57% increase in deoxygenated blood in the calf, indicating venous pooling in the lower limbs. These events led to a decrease in venous return and a 28% decline in cardiac output. Total upper body impedance increased by 6.6% with a 2.4% change in thoracic and a 13.1% increase in splanchnic impedance with progressive LBNP. Splanchnic blood volume contributed to more than 50% of the volume redistribution to the thoracic compartment during hypovolemia. Both men and women increased their heart rate, but only men vasoconstricted (4.4%) with increasing LBNP. The net result of these events was the maintenance of mean arterial blood pressure with no presyncopal symptoms in these subjects. DISCUSSION: Our results suggest that splanchnic blood volume redistribution--rather than leg vasoconstriction--plays an important role in blood pressure regulation during central hypovolemia.

Paradoxical clearance of hyaluronan fragments during haemodialysis and haemodiafiltration.

BACKGROUND: The physiological clearance of hyaluronic acid (HA), a mortality marker in end-stage kidney disease (ESKD) patients, occurs in the liver and in the kidneys and depends on its molecular mass. The aim of this study was to examine the effect of different modes of renal replacement therapy on levels of low- and high-molecular-mass HA (LMWHA and HMWHA, respectively). METHODS: Levels of total plasma HA as well as LMWHA and HMWHA fractions were measured before and after haemodialysis (HD) and haemodiafliltration (HDF) treatments and compared with those in normal controls. Plasma ß2-microglobulin was determined to be an independent inflammation marker. The isolated effect of the extracorporeal system on HMWHA fractions was investigated in a separate in vitro study. RESULTS: In 150 ESKD patients, LMWHA (135 ng/mL) and HMWHA fractions (386 ng/mL) were elevated (P < 0.01), compared with those in 80 healthy persons. The LMWHA fraction remained unchanged both during HD and HDF, whereas the fraction of HMWHA, which is incapable of passing through dialysis membranes, decreased by about 40% (P < 0.05). The concentration of plasma ß2-microglobulin correlated with the pro-inflammatory LMWHA (P < 0.0001; r = 0.67) but not with total HA. In vitro dialysis runs suggested that this decrease was not caused by degradation or adsorption of HMWHA fragments. CONCLUSIONS: Our data suggest that the decrease in the high-mass HA level during HD and HDF mirrors a physiological clearance initiated by HD and HDF rather than by physical elimination in the extracorporeal circulation.

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.

Assessing formal teaching of ethics in physiology: an empirical survey, patterns, and recommendations.

Ethics should be an important component of physiological education. In this report, we examined to what extent teaching of ethics is formally being incorporated into the physiology curriculum. We carried out an e-mail survey in which we asked the e-mail recipients whether their institution offered a course or lecture on ethics as part of the physiology teaching process at their institution, using the following query: "We are now doing an online survey in which we would like to know whether you offer a course or a lecture on ethics as part of your physiology teaching curriculum." The response rate was 53.3%: we received 104 responses of a total of 195 sent out. Our responses came from 45 countries. While all of our responders confirmed that there was a need for ethics during medical education and scientific training, the degree of inclusion of formal ethics in the physiology curriculum varied widely. Our survey showed that, in most cases (69%), including at our Medical University of Graz, ethics in physiology is not incorporated into the physiology curriculum. Given this result, we suggest specific topics related to ethics and ethical considerations that could be integrated into the physiology curriculum. We present here a template example of a lecture "Teaching Ethics in Physiology" (structure, content, examples, and references), which was based on guidelines and case reports provided by experts in this area (e.g., Benos DJ. Ethics revisited. Adv Physiol Educ 25: 189-190, 2001). This lecture, which we are presently using in Graz, could be used as a base that could lead to greater awareness of important ethical issues in students at an early point in the educational process.

Bridging different perspectives of the physiological and mathematical disciplines.

The goal of this report is to discuss educational approaches for bridging the different perspectives of the physiological and mathematical disciplines. These approaches can enhance the learning experience for physiology, medical, and mathematics students and simultaneously act to stimulate mathematical/physiological/clinical interdisciplinary research. While physiology education incorporates mathematics, via equations and formulas, it does not typically provide a foundation for interdisciplinary research linking mathematics and physiology. Here, we provide insights and ideas derived from interdisciplinary seminars involving mathematicians and physiologists that have been conducted over the last decade. The approaches described here can be used as templates for giving physiology and medical students insights into how sophisticated tools from mathematics can be applied and how the disciplines of mathematics and physiology can be integrated in research, thereby fostering a foundation for interdisciplinary collaboration. These templates are equally applicable to linking mathematical methods with other life and health sciences in the educational process.

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.

Impact of Increasing Lower Body Negative Pressure and Its Abrupt Release on Left Ventricular Hemodynamics in Anesthetized Pigs.

Lower body negative pressure (LBNP) has been implemented as a tool to simulate systemic effects of hypovolemia, understand orthostatic challenges and study G load stress in humans. However, the exact hemodynamic mechanisms of graded LBNP followed by its abrupt release have not been characterized in detail, limiting its potential applications in humans. Here, we set out to investigate the immediate hemodynamic alterations occurring during LBNP in healthy Landrace pigs. Invasive cardiac monitoring via extensive pressure volume loop analysis was carried out during application of incremental LBNP up to life threatening levels from -15 to -45 mmHg as well as during its abrupt release. Three different sealing positions were evaluated. Incremental LBNP consistently induced a preload dependent depression of systemic hemodynamics according to the Frank-Starling mechanism. Overall, the pressure-volume loop progressively shifted leftwards and downwards with increasing LBNP intensity. The abrupt release of LBNP reverted the above-described hemodynamic changes to baseline values within only three respiratory cycles. These data provide quantitative translational insights into hemodynamic mechanisms of incremental and very high levels of LBNP, levels of seal and effect of abrupt release for future human applications, such as countermeasure development for long spaceflight.

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 regulating hormone responses to repeated head-up tilt and lower body negative pressure.

BACKGROUND: We hypothesized the existence of different hormonal response patterns to repeated lower body negative pressure (LBNP) and head-up tilt (HUT) in healthy males. We compared hormonal, cardiovascular and plasma volume changes from rest to stress within- and between-LBNP and HUT applications. Hormones investigated included adrenocorticotropic hormone (ACTH), aldosterone, plasma renin activity (PRA), atrial natriuretic peptide (ANP) and arginine vasopressin (AVP). MATERIALS AND METHODS: Three sequential 30-min bouts of LBNP at -55mmHg (n=14) or 70° HUT (n=9) were preceded by 30-min supine rest, and a 60-min supine rest followed the 3rd stimulus. RESULTS: Plasma renin activity increases above baseline, in relation to aldosterone, were larger with LBNP than with HUT. The 3rd HUT application resulted in a greater increase in aldosterone compared to LBNP. Mean arterial blood pressure was elevated significantly during 1st and 3rd HUT application. ACTH responses were highly correlated with those of aldosterone in both LBNP and HUT (r(2) =0·96). AVP responses, in contrast to ANP, to the three consecutive stress situations were not significantly different, both with LBNP and HUT. CONCLUSIONS: We speculate that the observed differences in blood pressure and hormonal responses to LBNP and HUT are caused by divergent effects of blood pooling in the splanchnic region, despite similar reductions in splanchnic perfusion. Apparently with repeated central hypovolaemia, especially by the 3rd application of stress, plasma aldosterone levels rise (along with ACTH), conceivably increasing its volume-guarding effect.