Functional state of the liver during simulation of the hemodynamic effects of microgravity on the human body

Radioisotope studies of the choleresis function of the liver, ultrasonic studies of the liver and contractile function of the gallbladder and gastroduodenoscopy were carried out in eight subjects after a 24-h stay in a 12° antiorthostatic position (AOP) simulating the hemodynamic changes in the abdominal cavity caused by microgravity. The dynamically hindered venous blood outflow from the liver induced in the AOP model caused activation of choleresis on an empty stomach. This activation manifested itself as an increase in the central perfusion zone of the liver parenchyma, dilation of the biliary ductules, and contraction of the gall-bladder, as well as choleresis into the duodenum. Activation of choleresis in the liver took place against the background of a reduction of the area of radioactive marker distribution in the liver and a decrease in the hepatocyte metabolic activity and the concentration function of the biliary excretion system. The functional characteristics of the liver in the AOP model reflected the reaction caused by changes in its blood content due to the changes in the body position negative to the gravity vector. The mechanism of the changes includes the occurrence of a dynamic venous plethora in the liver; centralization of hepatic blood flow, and activation of choleresis activity against the background of peripheral blood flow depletion, as well as the reduction of metabolic activity of hepatocytes and the concentration function of the biliary excretion system.     

Short review of human prolonged horizontal bed rest studies in Japan

As many as 700,000-1,000,000 Japanese are spending a substantial part of their life in bed not being able to resume standing position due to disease and/or accident. Our objectives were urgently derived from that fact. The research project group at Faculty of Medicine, University of Tokyo, in Japan have studied effects of prolonged horizontal bed rest on humans since 1990. Financial supports from the Japanese Ministry of Education (Grant-in aide for scientific research), National Aero Space Development Agency of Japan and Japan Federation for Health Sciences have enabled us to perform five prolonged bed rest experiments for 5 years from 1990 to 1994. Many scientists in Europe, America and Russia have already made a heap of studies on this subject since the latter half of 1940s (eg. 39). However, our studies mainly focused upon the effects of inactivity on human health to determine how to bring a human from inactivity back to an unrestricted active life. This short review is going to summarize our results obtained from 1990 to 1993.     

Plasma volume restoration with salt tablets and water after bed rest prevents orthostatic hypotension and changes in supine hemodynamic and endocrine variables

Head-down bed rest changes the values of many cardiovascular and endocrine variables and also elicits significant hypovolemia. Because previous studies had not controlled for hypovolemia, it is unknown whether the reported changes were primary effects of bed rest or secondary effects of bed rest-induced hypovolemia. We hypothesized that restoring plasma volume with salt tablets and water after 12 days of head-down bed rest would result in an absence of hemodynamic and endocrine changes and a reduced incidence of orthostatic hypotension. In 10 men, we measured changes from pre-bed-rest to post-bed-rest in venous and arterial pressures; heart rate; stroke volume; cardiac output; vascular resistance; plasma norepinephrine, epinephrine, vasopressin, renin activity (PRA), and aldosterone responses to different tilt levels (0 degrees, -10 degrees, 20 degrees, 30 degrees, and 70 degrees); and plasma volume and platelet alpha2- and lymphocyte beta2-adrenoreceptor densities and affinities (0 degrees tilt only). Fluid loading at the end of bed rest restored plasma volume and resulted in the absence of post-bed-rest orthostatic hypotension and changes in supine hemodynamic and endocrine variables. Fluid loading did not prevent post-bed-rest increases in beta2-adrenoreceptor density or decreases in the aldosterone-to-PRA ratio (P = 0.05 for each). Heart rate, epinephrine, and PRA responses to upright tilt after bed rest were increased (P < 0.05), despite the fluid load. These results suggest that incidents of orthostatic hypotension and many of the changes in supine hemodynamic and endocrine variables in volume-depleted bed-rested subjects occur secondarily to the hypovolemia. Despite normovolemia after bed rest, beta2-adrenoreceptors were upregulated, and heart rate, epinephrine, and PRA responses to tilt were augmented, indicating that these changes are independent of volume depletion.     

Fasting promotes functional changes in liver mitochondria

Overnight fasting of rodents is commonly adopted in protocols to obtain isolated liver mitochondria, but the effects of fasting itself on mitochondrial function are poorly characterized. In this study we show that overnight fasting (15?h) promotes a shift in the liver mitochondrial bioenergetic profile, with a reduction in ADP-stimulated and maximal respiration, lower membrane potentials and lower resistance to Ca²⁺-induced mitochondrial permeability transition. Short term fasting (4?h) promoted similar changes, suggesting that this is a physiological shift in mitochondrial function associated with fasting, but not torpor. Our results suggest that the widely adopted liver mitochondrial isolation technique using fasted animals should be reconsidered, and also uncover physiological changes in bioenergetic function associated to nutritional status.     

Regional changes in muscle mass and strength following 20 days of bed rest, and the effects on orthostatic tolerance capacity in young subjects

To this day, many studies have suggested that prolonged bed rest (BR) affects on muscle mass and strength not only in gravity muscles but also in ungravity muscles. However, it is still unclear whether the decrease in regional muscle strength after BR is due to the alterations in the corresponding muscle mass, or not. On the other hand, if BR decreases the mass of antigravity muscles (UGM) as well as muscle strength and then increases tissue compliance of the antigravity muscles, orthostatic tolerance capacity will be decreased by the reduction in cardiac output (CO) in spite of the increase in myocardial contractility because the more decrease in venous return due to the more increase in blood pooling within the compliant tissues of the lower body. However, this is also unclear. To make these questions clear, the present study investigated the regional muscle mass and strength and orthostatic tolerance capacity before and after 20 days of bed rest in young subjects.     

Photooptical and ultrastructural changes in the microcirculatory bed of the kidney after functional vasoconstriction

In experiments on rats it was found that at the early stages (5 to 15 minutes) after vasoconstriction of the kidney caused by adrenaline solution there occurred sharp narrowing of the intraorganic arterial bed lumen, particularly that of the afferent arterioles. Ultrastructural changes in the glomerular renal capillary components observed were morphological expression of the effect of angiospasm and circulatory hypoxia. Residual phenomena of constriction of the renal microcirculatory bed still persisted at later stages--in 3, 7 days. These changes characterized the stage of peculiar mobility and contractile properties of their endothelial cells, caused by spasmogenic disturbances of microcirculation.     

Gender differences in effects of 20 days horizontal bed rest on muscle strength in young subjects

Gender differences in the effect of 20 days bed rest (BR) on muscle strength were evaluated in voluntary 11 male and 7 female students. Maximum Isometric Voluntary Contractions (MVC) of 4 right arm muscles (RAM), 5 right leg muscles (RLM), and 2 body trunk muscles were measured with an isometric dynamometer, respectively. Muscle masses (MM) of right arm and leg and body trunk were determined by dual energy X-ray absorptiometry, respectively. The maximum cross sectional area (CSAmax) of right m. quadriceps femoris was measured by magnetic resonance imaging. Elbow flexion MVC in males and all MVC of RLM except knee flexion in both males and females were decreased (p<0.05), but elbow extension MVC in females was increased (p<0.05), while all of other MVC only tended to decrease. However, the decrements in leg MVC were not correlated to the leg MM, and also the decrement in knee extension was not correlated to the CSAmax of m. quadriceps. The reduction of MVC of antigravity muscles might be caused not only by a decrease in MM but also by other factors. The greater decrements of leg MVC during BR were the higher initial level in males, but the inverse was observed in females. However, this discrepancy between males and females cannot be explained in the present study.     

Diastolic suction is impaired by bed rest: MRI tagging studies of diastolic untwisting.

Bed rest deconditioning leads to physiological cardiac atrophy, which may compromise left ventricular (LV) filling during orthostatic stress by reducing diastolic untwisting and suction. To test this hypothesis, myocardial-tagged magnetic resonance imaging (MRI) was performed, and maximal untwisting rates of the endocardium, midwall, and epicardium were calculated by Harmonic Phase Analysis (HARP) before and after -6 degrees head-down tilt bed rest for 18 days with (n = 14) and without exercise training (n = 10). LV mass and LV end-diastolic volume were measured using cine MRI. Exercise subjects cycled on a supine ergometer for 30 min, three times per day at 75% maximal heart rate (HR). After sedentary bed rest, there was a significant reduction in maximal untwisting rates of the midwall (-46.8 +/- 14.3 to -35.4 +/- 12.4 degrees /s; P = 0.04) where untwisting is most reliably measured, and to a lesser degree of certainty in the endocardium (-50.3 +/- 13.8 to -40.1 +/- 18.5 degrees /s; P = 0.09); the epicardium was unchanged. In contrast, when exercise was performed in bed, untwisting rates were enhanced at the endocardium (-48.4 +/- 20.8 to -72.3 +/- 22.3 degrees /ms; P = 0.05) and midwall (-39.2 +/- 12.2 to -59.0 +/- 19.6 degrees /s; P = 0.03). The differential response was significant between groups at the endocardium (interaction P = 0.02) and the midwall (interaction P = 0.004). LV mass decreased in the sedentary group (156.4 +/- 30.3 to 149.5 +/- 27.9 g; P = 0.07), but it increased slightly in the exercise-trained subjects (156.4 +/- 34.3 to 162.3 +/- 40.5 g; P = 0.16); (interaction P = 0.03). We conclude that diastolic untwisting is impaired following sedentary bed rest. However, exercise training in bed can prevent the physiological cardiac remodeling associated with bed rest and preserve or even enhance diastolic suction.     

Daily short-period gravitation can prevent functional and structural changes in arteries of simulated microgravity rats.

This study was designed to clarify whether simulated microgravity-induced differential adaptational changes in cerebral and hindlimb arteries could be prevented by daily short-period restoration of the normal distribution of transmural pressure across arterial vasculature by either dorsoventral or footward gravitational loading. Tail suspension (Sus) for 28 days was used to simulate cardiovascular deconditioning due to microgravity. Daily standing (STD) for 1, 2, or 4 h, or +45 degrees head-up tilt (HUT) for 2 or 4 h was used to provide short-period dorsoventral or footward gravitational loading as countermeasure. Functional studies showed that Sus alone induced an enhancement and depression in vasoconstrictor responsiveness of basilar and femoral arterial rings, respectively, as previously reported. These differential functional alterations can be prevented by either of the two kinds of daily gravitational loading treatments. Surprisingly, daily STD for as short as 1 h was sufficient to prevent the differential functional changes that might occur due to Sus alone. In morphological studies, the effectiveness of daily 4-h HUT or 1-h STD in preventing the differential remodeling changes in the structure of basilar and anterior tibial arteries induced by Sus alone was examined by histomorphometry. The results showed that both the hypertrophic and atrophic changes that might occur, respectively, in cerebral and hindlimb arteries due to Sus alone were prevented not only by daily HUT for 4 h but also by daily STD even for 1 h. These data indicate that daily gravitational loading by STD for as short as 1 h is sufficient to prevent differential adaptational changes in function and structure of vessels in different anatomic regions induced by a medium-term simulated microgravity.     

Electrolyte changes in plasma and urine of athletes during acute and rigorous bed rest and ambulatory conditions

Rigorous bed rest (RBR) induces significant electrolyte changes, but little it is not known about the effect of acute bed rest (ABR) (i.e., abrupt confinement to a RBR). The aim of this study was to measure urinary and plasma electrolyte changes during ABR and RBR conditions. The studies were done during 3 d of a pre-bed-rest (BR) period and during 7 d of an ABR and RBR period. Thirty male trained athletes aged, 24.4 ± 6.6 yr were chosen as subjects. They were divided equally into three groups: unrestricted ambulatory control subjects (UACS), acute-bed-rested subjects (ABRS), and rigorous-bed-rested subjects (RBRS). The UACS group experienced no changes in professional training and daily activities. The ABRS were submitted abruptly to a RBR regimen and without having any prior knowledge of the exact date and time when they would be subjected to an RBR regimen. The RBRS were subjected to an RBR regime on a predetermined date and time known to them from the beginning of the study. Sodium (Na), potassium (K), magnesium (Mg), calcium (Ca), and phosphate (P) in plasma and urine, plasma renin activity (PRA) and plasma aldosterone (PA), physical characteristics, peak oxygen uptake, and food and water intakes were measured. Urinary Na, K, Ca, Mg, and P excretion and plasma Na, K, Mg, Ca, and P concentration, PRA, and PA concentration increased significantly (p ≤ 0.01), whereas body weight, peak oxygen uptake, and food and water intakes decreased significantly in the ABRS and RBRS groups when compared with the UACS group. However, urinary and plasma Na, K, Mg, P, and Ca, PRA, and PA values increased much faster and were much greater in the ABRS group than in the RBRS group. Plasma and urinary Na, K, Ca, Mg, and P, PRA and PA levels, food and water intakes, body weight, and peak oxygen uptake did not change significantly in the UACS group when compared with its baseline control values. It was shown that RBR and ABR conditions induce significant increases in urinary and plasma electrolytes; however, urinary and plasma electrolyte changes appeared much faster and were much greater in the ABRS group than the RBRS group. It was concluded that the more abruptly motor activity is ended, the faster and the greater the urinary and plasma electrolyte change.     

Short-term variability of blood pressure: effects of lower-body negative pressure and long-duration bed rest

Mild lower-body negative pressure (LBNP) has been utilized to selectively unload cardiopulmonary baroreceptors, but there is evidence that arterial baroreceptors can be transiently unloaded after the onset of mild LBNP. In this paper, a black box mathematical model for the prediction of diastolic blood pressure (DBP) variability from multiple inputs (systolic blood pressure, R-R interval duration, and central venous pressure) was applied to interpret the dynamics of blood pressure maintenance under the challenge of LBNP and in long-duration, head-down bed rest (HDBR). Hemodynamic recordings from seven participants in the WISE (Women's International Space Simulation for Exploration) Study collected during an experiment of incremental LBNP (-10 mmHg, -20 mmHg, -30 mmHg) were analyzed before and on day 50 of a 60-day-long HDBR campaign. Autoregressive spectral analysis focused on low-frequency (LF, ~0.1 Hz) oscillations of DBP, which are related to fluctuations in vascular resistance due to sympathetic and baroreflex regulation of vasomotor tone. The arterial baroreflex-related component explained 49 ± 13% of LF variability of DBP in spontaneous conditions, and 89 ± 9% (P < 0.05) on day 50 of HDBR, while the cardiopulmonary baroreflex component explained 17 ± 9% and 12 ± 4%, respectively. The arterial baroreflex-related variability was significantly increased in bed rest also for LBNP equal to -20 and -30 mmHg. The proposed technique provided a model interpretation of the proportional effect of arterial baroreflex vs. cardiopulmonary baroreflex-mediated components of blood pressure control and showed that arterial baroreflex was the main player in the mediation of DBP variability. Data during bed rest suggested that cardiopulmonary baroreflex-related effects are blunted and that blood pressure maintenance in the presence of an orthostatic stimulus relies mostly on arterial control.     

Structural changes and hemodynamic relations in the microcirculatory bed of the mesentery of the white rat during the period of sexual maturation

Structural changes and hemodynamic relations have been studied in the microcirculatory bed of the white rat small intestine mesentery during sex maturation (from the 3d up to the 10th week of the postnatal development). All calculations are performed regarding the mesenteric segment limited with two intestinal arteries, which is considered as an elementary microvascular module. Complication of the microcirculatory bed construction takes place at the expense of increasing number (nearly five-fold) of microvessels in the segment and increase of the capillary network density. The hemodynamic factor plays a certain role for stimulating the process of the capillary growth. The definitive structure of the mesenteric microcirculatory bed is completed by the 7th week. The main rearrangement of the microcirculatory system during the developmental process from a simple arterio-venular loop up to a complex microcirculatory bed with a branching capillary network is performed within the limits of the mesenteric segment.     

The effects of 20 days bed rest on serum lipids and lipoprotein concentrations in healthy young subjects

The effects of 20 days bed rest (BR) on serum lipids and lipoprotein concentrations were investigated in 23 healthy young subjects (13 males and 10 females, aged 19 to 25 yr.). After 20 days BR, VO2max was reduced in both genders, but body composition did not change. The ratio of glucose area to insulin area during an oral glucose tolerance test decreased gradually throughout BR, which suggested a decrease in insulin sensitivity. Estimated changes in plasma volume from the beginning of BR were largest at day 3 of BR (-9.1% in females and -3.4% in males) and seemed to return the initial level at the end of BR in both genders. The increase in serum triglycerides and the decrease in high density lipoprotein (HDL) cholesterol, and apolipoprotein AI were observed in both genders during BR. In a smaller study of 4 males and 5 females, 20 days BR was associated with a decrease in HDL, cholesterol, a decrease in apolipoprotein AI and apolipoprotein AII, decrease in a plasma postheparin lipoprotein lipase activity and an increase in very low density lipoprotein triglyceride. Overall, the data suggested that the decrease in lipoprotein lipase activity and insulin sensitivity may contribute to the impairment in HDL metabolism.     

Urinary and plasma calcium changes in endurance trained volunteers during exposure to acute and rigorous bed rest conditions

The purpose of the present study was to evaluate the effect of acute (abrupt restriction of muscular activity) and rigorous bed-rest conditions on urinary and plasma calcium changes in endurance trained volunteers. The studies were performed on 30 long distance runners ages 23–25 who had a peak oxygen uptake of 66.0 mL/min/kg and had run 14.0 km/d on the average prior to their participation in the study. The volunteers were divided into three groups: The volunteers in the first group were under normal ambulatory conditions (control subjects), the second group was subjected to an acute bed-rest regime (acute bedrested subjects), and the third group was submitted to a rigorous bed-rest regime (rigorous bedrested subjects). The second and third groups of volunteers were kept under a rigorous bed rest regime for 7 d. During the pre-bed-rest period and during the actual bed-rest periods (acute and rigorous bed-rest periods), urinary excretion of calcium and plasma calcium and parathyroid hormone (PTH) concentrations were determined. During the 1st d of acute and rigorous bed-rest periods, urinary excretion and plasma concentration of calcium increased significantly (P≤0.05), while plasma parathyroid hormone content decreased significantly (P≤0.05). On the 3rd d of the experimental period, urinary excretion and plasma calcium concentration decreased somewhat, during the 7th d, calcium in urine and plasma increased further, while parathyroid hormone content in plasma increased somewhat on the 3rd d and decreased again on the 7th d of the experimental period. The changes were more pronounced in the volunteers who were subjected to acute bed-rest conditions than in the volunteers who were submitted to rigorous bed-rest conditions. It was concluded that exposure to acute bed-rest conditions induces significantly greater urinary and serum calcium changes than rigorous bed-rest conditions in endurance trained volunteers.     

Functional changes in the snail statocyst system elicited by microgravity

Background

The mollusk statocyst is a mechanosensing organ detecting the animal''s orientation with respect to gravity. This system has clear similarities to its vertebrate counterparts: a weight-lending mass, an epithelial layer containing small supporting cells and the large sensory hair cells, and an output eliciting compensatory body reflexes to perturbations.

Methodology/Principal Findings

In terrestrial gastropod snail we studied the impact of 16- (Foton M-2) and 12-day (Foton M-3) exposure to microgravity in unmanned orbital missions on: (i) the whole animal behavior (Helix lucorum L.), (ii) the statoreceptor responses to tilt in an isolated neural preparation (Helix lucorum L.), and (iii) the differential expression of the Helix pedal peptide (HPep) and the tetrapeptide FMRFamide genes in neural structures (Helix aspersa L.). Experiments were performed 13–42 hours after return to Earth. Latency of body re-orientation to sudden 90° head-down pitch was significantly reduced in postflight snails indicating an enhanced negative gravitaxis response. Statoreceptor responses to tilt in postflight snails were independent of motion direction, in contrast to a directional preference observed in control animals. Positive relation between tilt velocity and firing rate was observed in both control and postflight snails, but the response magnitude was significantly larger in postflight snails indicating an enhanced sensitivity to acceleration. A significant increase in mRNA expression of the gene encoding HPep, a peptide linked to ciliary beating, in statoreceptors was observed in postflight snails; no differential expression of the gene encoding FMRFamide, a possible neurotransmission modulator, was observed.

Conclusions/Significance

Upregulation of statocyst function in snails following microgravity exposure parallels that observed in vertebrates suggesting fundamental principles underlie gravi-sensing and the organism''s ability to adapt to gravity changes. This simple animal model offers the possibility to describe general subcellular mechanisms of nervous system''s response to conditions on Earth and in space.