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PubMed2004

Influence of simulated weightlessness on the pharmacokinetics of acetaminophen administered by the oral route: a study in the rat.

During space flights, the human body is submitted to weightlessness which induces physiological variations that could modify drug disposition during space missions. Since space experiments are infrequent and difficult to perform, in order to evaluate pharmacokinetic modifications, simulation experiments of weightlessness have to be carried out on earth, using animal-models such as the Morey-Holton model. In this model, rats are suspended by the tail with their front paws on the ground. We studied the effects of simulated weightlessness on drug absorption and on gastric emptying, using acetaminophen as a probe. Three periods of suspension (1, 2 and 5 days) were compared with two control groups (free and attached rats). The attached group was used to evaluate a possible 'stress effect' caused by the suspension device. Each group was composed of 36 rats (12 sampling times and three rats per time). An oral dose of acetaminophen (100 mg/kg) was administered and blood samples were collected before and up to 12 h after administration. Plasma assays were performed using an high-performance liquid chromatography method with UV detection. The calculated population pharmacokinetic parameters were Ka, Kel (first order absorption and elimination constants) and Vd/F (apparent volume of distribution). The statistical interpretation of the population pharmacokinetic parameters indicated that 2 days of suspension significantly decreased the Vd/F by 83% and the Ka by 125%. The increase in the Ka was probably because of an increased acceleration of the gastric emptying and/or to a decrease in the total peripheral resistance which increased intestinal blood flow.

Acetaminophen↗
PubMed1995

Estimations of changes in plasma volume during simulated weightlessness.

Results of previous investigations on the effects of simulated microgravity (thermoneutral (34.5 degrees C) head-out water immersion, WI) have indicated that plasma volume (PV) increases initially and thereafter decreases to attain values below the pre-immersion level. In these cases, changes in hematocrit (Hct) and hemoglobin concentration (Hgb) were used as indicators of relative changes in PV. In order to test whether changes in Hct and Hgb are accurate measures of changes in PV during simulated microgravity, direct measurements of PV were performed with a modified Evans blue dye dilution technique before, during, and after a 12 h WI experiment. Furthermore, PV was determined with the same technique before, during, and after acute 6 degrees head-down tilt (HDT). Changes in PV were then compared with changes calculated from changes in Hct and Hgb.

Dye Dilution Technique↗
PubMed1980

Effect of simulated weightlessness on the immune system in rats.

Rats suspended in a model system designed to simulate many aspects of weightlessness were immunized with sheep red blood cells. Parameters measured on these and control rats included titers of anti-sheep red blood cell antibodies, serum immunoglobulin levels, spleen and thymus weights, hematocrits, and leukocyte differential counts on peripheral blood. No significant differences were found between test and weight-bearing, harnessed controls; however, the thymuses of animals in both these groups were significantly smaller than untreated cage controls. The lack of an effect of simulated weightlessness on the immune system is an interesting result, and its significance is discussed.

Animals↗
PubMed1987

Body volume changes during simulated weightlessness: an overview.

It has been hypothesized that many of the adaptive processes that occur in man during exposure to space involve the rapid headward shift of tissue fluids, blood, and other fluids during the first few hours of spaceflight. A total of 53 men and women between the ages of 22 and 55 years were tested during four bed rest studies lasting between 4 h and 7 d to define the segmental volume changes that took place during simulated weightlessness. Impedance plethysmography can be used to measure baseline resistance (Ro) changes of the calf, thigh, total leg, pelvic, torso, and arm segments before, during, and after each bed rest exposure. Records of Ro were analyzed to determine the fluid volume and volume change of each segment during each test sequence.

Adaptation, Physiological↗
PubMed1982

Skeletal abnormalities in rats induced by simulated weightlessness.

A hypokinetic model has been developed which attempts to simulate the weightlessness experienced during space flight. Male rats (approximately 130 g) were suspended from the model with a head-down tilt for a two-week period. Total mechanical unloading of the hind limbs and partial unloading of the fore limbs occurred. In comparison to pair-fed control rats, the skeletal alterations in the proximal tibial and humeral metaphyses of suspended rats were determined to be a diminished rate of longitudinal bone growth, a reduced mass of mineralized tissue, and an accumulation of marrow fat. Also, suspended rats exhibited decreased numbers of osteoblasts and increased numbers of osteoclasts immediately adjacent to the growth plate-metaphyseal junction at both skeletal sites. Although the reduction in mineralized tissue and the fat accumulation were more marked in the tibia, the skeletal changes in the proximal tibial and humeral metaphyses were generally comparable. The observed abnormalities may be due to mechanical unloading and/or a hypersecretion of corticosteroids.

Adipose Tissue↗
PubMed1997

Haematocrit, plasma volume and noradrenaline in humans during simulated weightlessness for 42 days.

Previous results from our laboratory demonstrate that changes in haematocrit (Hct) and haemoglobin concentration (Hb) underestimate the relative (%) change in plasma volume (PV) in seated subjects during simulation of weightlessness by water immersion. Therefore, we examined whether changes in Hct and Hb would accurately reflect the changes in PV in seven subjects during simulation of weightlessness by another model, 6 degrees head-down tilted bed rest (HDBR), for 42 days. Since we have previously observed unexpectedly high plasma levels of noradrenaline (NA) in astronauts during space flight, we also took the opportunity to measure this variable. The measurements were compared with those of the supine horizontal position before and after HDBR. During HDBR, PV measured by the Evans blue dye dilution technique decreased by 6.1 +/- 2.8% (P < 0.05) on day 2 and 9.6 +/- 2.2% (P < 0.05) on the 42nd day compared with that of the supine, horizontal position. Based on changes in Hct and Hb, PV decreased similarly by 8.3 +/- 2.8 and 10.2 +/- 3.2% (P < 0.05) respectively. There were no differences comparing the results of the two methods (P > 0.05). Forearm venous plasma NA was unchanged during the whole course of HDBR compared with that of the pre-HDBR supine position. It is concluded that changes in Hct and Hb reliably reflect the changes in PV comparing prolonged HDBR with the pre- and post-HDBR horizontal, supine position. Thus, changes in Hct and Hb might accurately reflect the change in PV during weightlessness in humans provided that the horizontal supine position is used as the ground-based reference. Furthermore, the results of this study, as well as of previous studies from space, confirm that NA release is unchanged or even increased during weightlessness.

Adult↗
PubMed2000

An upper arm model for simulated weightlessness.

This investigation examined the effects of 4 weeks of non-dominant arm unloading on the functional and structural characteristics of the triceps brachii muscle of six normo-active college-age males (age: 23 +/- 1 years, height: 176 +/- 4 cm, weight: 76 +/- 6 kg). The primary intention of this study was to determine if arm unloading is an effective analogue for simulating the effects of weightlessness on human skeletal muscle. Subjects were tested 2-3 days preceding unloading in a standard arm sling and following removal of the sling. The sling was worn during waking hours to unload the arm. Subjects were allowed to remove the sling during sleep and bathing. Torque production (Nm) during maximal isometric extension at 90 degrees significantly declined (P < 0.05) in response to unloading (53.93 +/- 5.07 to 47.90 +/- 5.92; 12%). There was no significant change (P > 0.05) in the force-velocity attributes of the triceps over the other measured velocities (1.05, 1.57, 2.09, 3.14, 4.19, 5.24 rad.s-1). Cross-sectional muscle area (CSA) of the upper arm was smaller (44.3 +/- 2.7 to 42.4 +/- 2.5 cm2; 4%) following 4 weeks of unloading (P < 0.05). Histochemical analysis of individual muscle fibres demonstrated reductions in fibre CSA of 27 and 18% for type I and type II fibres, respectively. However, these changes were not statistically significant. Electrophoretic analysis of muscle samples revealed a significant increase (40 +/- 7 to 58 +/- 4%, pre- and post-, respectively) in myosin heavy chain (MHC) type II isoforms following unloading. Reductions in type I MHC isoform composition failed to reach statistical significance (P < 0.08). Amplitude of the integrated electromyographic (IEMG) signal during maximal isometric contraction of the long head of the triceps decreased by 21% in response to the 4-week unloading period (P < 0.05). The changes in triceps, muscle structure and function found with arm unloading are similar in magnitude and direction to data obtained from humans following exposure to real and simulated weightlessness. These findings demonstrate that arm unloading produces some of the effects seen in response to weightlessness in muscles of the upper arm and provides potential for an additional model to simulate the effects of microgravity on human skeletal muscle.

Adult↗
PubMed2000

Bone changes during simulated weightlessness in rats.

Weightless environment due to prolonged Space mission results in decreased mineralisation of the weight bearing bones. Hind limb unweighting (HU) in rats by tail suspension was used to simulate the effect of weightlessness on tibia. Adult male albino rats were divided into two groups as (i) Control (CON, n = 12) and (ii) HU for 15 days (HU, n = 18). After 15 days of HU tibia from all the animals were removed and subsequently dried and ashed. The calcium content of these bones were then determined. HU resulted in atrophic changes in the weight bearing bone, tibia, due to the reductions of water content (-35.8%), organic matrix (-12.2%) and calcium content (-33.4%). The reduction in the dry wt of tibia (-13.5%) was due to proportionate reductions in the organic matrix and total mineral content of the bone. The reduction in the mineral content was solely due to the reduction in calcium content of the bone.

Animals↗
PubMed2006

Protein nitration increased by simulated weightlessness and decreased by melatonin and quercetin in PC12 cells.

A variety of experiments suggest that space flight is associated with an increase in oxidative stress in organism. To explore the effects of oxidative stress on neuronal cells during microgravity, we used rat pheochromocytoma (PC12) cells as a neuronal cell model, cultured in a clinostat, which could simulate microgravity, to investigate the effects of reactive nitrogen species on protein nitration in PC12 cells during clinorotation. The effects of melatonin and quercetin on protein nitration in PC12 cells were also assayed to evaluate the possible protective role of melatonin or quercetin as an antioxidant. The results of immunological staining showed that after the 3 days' clinorotation the protein expressions of neuronal nitric oxide synthase and inducible nitric oxide synthesis were up-regulated. Our data also reflected that the concentrations of nitric oxide and nitrotyrosine were significantly increased after clinorotation, and they were reduced markedly in cells that were treated with 50 micromol/L melatonin or 0.5 micromol/L quercetin during simulated microgravity, when compared to those of control cells. These results suggest that clinorotation-induced weightlessness increases oxidative stress responses in PC12 cells, and melatonin or quercetin was shown to protect PC12 cells from oxidative damage during simulated weightlessness.

Animals↗
PubMed1991

Neural and humoral controlling mechanisms of cardiovascular functions in man under weightlessness simulated by water immersion.

To clarify how neural and humoral mechanisms operate to control cardiovascular functions in man under weightlessness, the response of sympathetic nerve activity was observed in healthy human subjects by means of microneurographic technique with the changes of several hemodynamic parameters and hormonal responses during thermoneural head-out water immersion. Muscle sympathetic nerve activity was markedly suppressed by head-out immersion, concomitantly with a reduction of the leg volume, an increase of the stroke volume and a reduction of total peripheral resistance. At the same time, plasma level of norepinephrine, vasopressive and antidiuretic hormones (ADH, aldosterone, renin activity, angiotensin I-II) were reduced, while vasodepressive and diuretic hormone (ANP) was markedly increased. The systemic blood pressure was maintained almost unchanged during head-out water immersion. The suppressive response of sympathetic nerve activity seemed to be age-dependent. This response was less prominent in the elderly than in young subjects. It is concluded that the suppressive response of muscle sympathetic activity plays an important role to maintain hemodynamic homeostasis under weightlessness to compensate for the cephalad fluid shift and the resultant increase of the stroke volume in cooperation with the hormonal responses.

Adolescent↗
PubMed1997

[Effects of simulated weightlessness and overweight on the growth of osteoblast cultured in vitro].

A special rotator designed for this experiment was used to simulate the gravitational conditions. 3 groups of osteoblast cells were cultured under simulated hypogravity, normal (1 g) or hypergravity acceleratively (3 g) for 7 d. Changes of cell shape and speed of cell division were observed. The results showed that cells cultured under simulated hypogravity became round and cells divided slowly as compared with 1g group. While cells cultured under 3 g divided more actively and many growth spots appeared in the culture bottle.

Biophysical Phenomena↗
PubMed1997

Weightlessness simulations for cardiovascular and muscle systems: validity of rat models.

Animal models are widely used to evoke responses comparable to those obtained during weightlessness. Two models are reviewed; one examines cardiovascular responses and cephalad fluid shifts in head down tilting (HDT), and the other examines atrophy in load bearing muscles by unloading the hind limbs. Cephalad fluid shifts result in diuresis, natriuresis, and kaliuresis. Reversals are rapid, within one week. Reports of cardiovascular responses are not similar among various laboratories, probably due to variations in protocols. Blood pressures (MAP, SP and DP) and heart rates measured with direct aorta cannulations become elevated as early as one and three days of HDT; recovery occurs within several hours; the response is a transient hypertension. The role of central and peripheral sympathetic nervous activity in flight and suspended rats is examined. Rats show little or no evidence of cardiac deconditioning. Direct blood pressures have not been made in flight rats, precluding direct comparisons with earth side experiments. Muscle atrophy and load bearing (slow twitch fibers) and non-load bearing (fast twitch fibers) muscle responses with hind limb unloading and recovery are compared with flight animal responses. Soleus muscle in response to whole body suspension (WBS), tail suspension (TS) or flight exposure consistently shows significant weight loss. In contrast, the extensor digitorum longus and vastus medialis show less marked responses. More specifically, slow twitch fibers in all these muscles show the greatest loss in mass (e.g. cross sectional areas). The conclusion is that both WBS or TS systems are useful in predicting and comparing changes due to weightless flight.

Animals↗
PubMedDate not supplied

Correlation between vestibular sensitization and leg muscle relaxation under weightlessness simulated by water immersion.

The experiments were designed to determine the contribution of the leg muscle relaxation to the sensitization of the vestibular function under weightlessness, The neuromuscular unit (NMU) discharges were continuously recorded with microelectrodes from the anti-gravitational soleus muscle and its antagonist, the tibialis anterior, of a man standing first upright on the level floor of a dry water tank, and then gradually being immersed in water till it reached his neck; while he was buoyed with an airtube placed under his armpit. In each of the successive states, the caloric nystagmus was evoked, analyzed and compared with the NMU discharge as well as with subjective symptoms associated with the nystagmus. The results indicate that the nystagmogenic activity had a significant correlation with the appearance of the active NMU in the soleus, and they also suggest that the reduction of ascending signals from the antigravity muscles might be one of the causes of atypical vestibular responses occuring in weightlessness.

Adult↗
PubMed1990

Cardiovascular deconditioning during weightlessness simulation and the use of lower body negative pressure as a countermeasure to orthostatic intolerance.

The cardiovascular function is one of the main disturbed by weightlessness: it is particularly affected by the astronaut's return to Earth, where symptoms linked to the cardiovascular deconditioning syndrom appear in the following forms: (1) orthostatic intolerance with its risk of syncope: (2) higher submaximal oxygen consumption for an equivalent work load. Lower Body Negative Pressure (LBNP) is intended to stimulate the venous system of the lower limbs; however, the specific effects of periodical LBNP sessions on the orthostatic intolerance have never been studied. With this objective in mind, 5 volunteers took part in two recent antiorthostatic bedrest experiments for 30 days. In the first experiment 3 subjects were submitted to several sessions of LBNP experiment per day and 2 others were controls; in the second experiment the LBNP group of the 1st one became controls and vice-versa. Two orthostatic investigations were performed: (1) 5 days before the bedrest; (2) at the end of the 30 day bedrest period. The results showed: (1) when the subjects were control, a high orthostatic intolerance post bedrest with 3 syncopes and one presyncopal state during the first minutes of the tilt test; (2) when the subjects were submitted to LBNP sessions, no orthostatic intolerance.

Adult↗
PubMed1979

Exercise response to simulated weightlessness.

Two bed rest analog studies of space flight were performed; one 14 d and the other 28 d in duration. Exercise response was studied in detail during the 28 d study and following both the 14 d and 28 d studies. This paper relates the results of these studies to physiologic changes noted during and following space flight. The most consistent change noted after both bed rest and space flight is an elevated heart rate during exercise. A second consistent finding is a postflight or postbed rest reduction in cardiac stroke volume. Cardiac output changes were variable. The inability to simulate inflight activity levels and personal exercise makes a direct comparison between bed rest and the results from specific space flights difficult.

Adult↗