Does long-term experimental antiorthostasis lead to cardiovascular deconditioning in the rat?

Microgravity or simulated microgravity induces acute and chronic cardiovascular responses, whose mechanism is pivotal for understanding of physiological adaptation and pathophysiological consequences. We investigated hemodynamic responses of conscious Wistar rats to 45? head-down tilt (HDT) for 7 days. Arterial blood pressure (BP) was recorded by telemetry. Heart rate (HR), spectral properties and the spontaneous baroreflex sensitivity (sBRS) were calculated. Head-up tilt (HUT) was applied for 2 h before and after HDT to assess the degree of any possible cardiovascular deconditioning. Horizontal control BP and HR were 112.5+/-2.8 mmHg and 344.7+/-10 bpm, respectively. HDT elicited an elevation in BP and HR by 8.3 % and 8.8 %, respectively, in less than 1 h. These elevations in BP and HR were maintained for 2 and 3 days, respectively, and then normalized. Heart rate variability was unchanged, while sBRS was permanently reduced from the beginning of HDT (1.01+/-0.08 vs. 0.74+/-0.05 ms/mmHg). HUT tests before and after HDT resulted in BP elevations (6.9 vs. 11.6 %) and sBRS reduction (0.44 vs. 0.37 ms/mmHg), respectively. The pressor response during the post-HDT HUT test was accompanied by tachycardia (13.7 %). In conclusion, chronic HDT does not lead to symptoms of cardiovascular deconditioning. However the depressed sBRS and tachycardic response seen during the post-HDT HUT test may indicate disturbances in cardiovascular control.     

Reduced orthostatic tolerance following 4 h head-down tilt

The cardiovascular responses to a 10-min 1.22 rad (70 degrees) head-up tilt orthostatic tolerance test (OST) was observed in eight healthy men following each of a 5-min supine baseline (control), 4 h of 0.1 rad (6 degrees) head-down tilt (HDT), or 4 h 0.52 rad (30 degrees) head-up tilt (HUT). An important clinical observation was presyncopal symptoms in six of eight subjects following 4 h HDT, but in no subjects following 4 h HUT. Immediately prior to the OST, there were no differences in heart rate, stroke volume, cardiac output, mean arterial pressure and total peripheral resistance for HDT and HUT. However, stroke volume and cardiac output were greater for the control group. Mean arterial pressure for the control group was less than HDT but not HUT. Over the full 10-min period of OST, the mean arterial pressure was not different between groups. Heart rate increased to the same level for all three treatments. Stroke volume decreased across the full time period for control and HDT, but only at 3 and 9 min for HUT. There was a higher total peripheral resistance in the HDT group than control or HUT. The pre-ejection period to left ventricular ejection time ratio was less in HDT than for control or HUT groups. These data indicate a rapid adaptation of the cardiovascular system to 4 h HDT that appears to be inappropriate on reapplication of a head to foot gravity vector. We speculate that the cause of the impaired orthostatic tolerance is decreased tone in venous capacitance vessels so that venous return is inadequate.     

Rat cardiovascular responses to whole body suspension: head-down and non-head-down tilt.

The rat whole body suspension technique mimics responses seen during exposure to microgravity and was evaluated as a model for cardiovascular responses with two series of experiments. In one series, changes were monitored in chronically catheterized rats during 7 days of head-down tilt (HDT) or non-head-down tilt (N-HDT) and after several hours of recovery. Elevations of mean arterial (MAP), systolic, and diastolic pressures of approximately 20% (P < 0.05) in HDT rats began as early as day 1 and were maintained for the duration of suspension. Pulse pressures were relatively unaffected, but heart rates were elevated approximately 10%. During postsuspension (2-7 h), most cardiovascular parameters returned to presuspension levels. N-HDT rats exhibited elevations chiefly on days 3 and 7. In the second series, blood pressure was monitored in 1- and 3-day HDT and N-HDT rats to evaluate responses to rapid head-up tilt. MAP, systolic and diastolic pressures, and HR were elevated (P < 0.05) in HDT and N-HDT rats during head-up tilt after 1 day of suspension, while pulse pressures remained unchanged. HDT rats exhibited elevated pretilt MAP and failed to respond to rapid head-up tilt with further increase of MAP on day 3, indicating some degree of deconditioning. The whole body suspended rat may be useful as a model to better understand responses of rats exposed to microgravity.     

Blood pressure and heart rate responses to sudden change of posture during 20 days of simulated microgravity (-6 degrees head-down tilt)

The cardiovascular function buffering the disturbance of blood pressure caused by postural changes may be deconditioned after exposure to microgravity (microG). However, total picture of the deconditioning including its longitudinal process is still unknown. The aim of this study was to determine time-dependent changes in the feedback regulation system of blood pressure as exposed to simulated microG (-6 degrees head-down tilt (HDT)) for 20 days.     

Cardiorespiratory responses of animals to passive orthostasis after intermittent hypoxia during head-down tilt

Cardiorespiratory responses induced by upright tilt before and after intermittent hypoxia during head-down tilt, were investigated in rabbits. Arterial blood pressure, heart rate, central venous pressure, transmural filling pressure of the heart (calculated as the product of esophageal and central venous pressure), breathing frequency, esophageal pressure were measured in supine (baseline), head-down and upright posture. Our results indicate a reduction in orthostatic responses in cardiovascular system after intermittent hypoxia.     

Structural and functional characteristics of the aortic nerve in the rabbit raised in head-down tilt posture

When human returns to the earth from space, the reverse shift of body fluid to the shift caused by microgravity. The physical phenomenon produces probably cardiovascular deconditioning due to a disturbance of the baroreflex for regulating blood pressure. To clarify the disturbance, the nervous control mechanisms of cardiovascular system in mammals exposed to microgravity should be investigated. Head-down tilt (HDT) is one of the methods to simulate the headward shift of the body fluid. To understand the effect of microgravity on the cardiovascular nervous control system, we studied effects of headward shift of the body fluid on structural and functional development of the aortic nerve and the aortic baroreflex in the young rabbit raised in a head-down and tail-up posture.     

Alterations in glomerular and tubular dynamics at 1 and 14 days simulated microgravity and after acute return to orthostasis

Head-down tilt (HDT) is utilized to simulate microgravity and produces a cephalad fluid shift, which results in alterations in fluid and electrolyte balance. These changes in volume homeostasis are due, in part, to alterations in multiple volume control mechanisms in which renal function is a major participant. We have previously demonstrated that glomerular filtration rate increases early in HDT and eventually returns to values not different from non-tilt measurements. This early increase in glomerular filtration rate was also demonstrated during days 2 and 8 of the SLS-1 mission. However, urine flow and electrolyte excretion does not parallel the alterations in glomerular filtration rate and the site of this change in nephron fluid reabsorption pattern has not been previously examined. Through determination of the location of alterations in tubular fluid reabsorption within the nephron, a more detailed hypothesis can be forwarded as to which specific neuro-humoral agents participating in control of renal function in microgravity conditions. The importance of this type of examination is that measurements in circulating neuro-humoral agents and urinary excretion patterns alone are not accurate predictors of how renal functional response may alter to head-down tilt or other models of simulated weightlessness. To examine this issue, renal micropuncture techniques were utilized in Munich-Wistar rats submitted 24 hours and 14 day head-down tilt, measuring all the determinants of glomerular ultrafiltration and obtaining data regarding segmental tubular fluid reabsorption. Following these measurements, the rats were returned to an orthostatic position and after 60 min, the measurements were repeated.     

Comparison of cardiovascular response to passive tilt in young and elderly men

To test the hypothesis that altered hemodynamic responses to postural changes are associated with aging, cardiovascular responses to head-up tilt (HUT) and head-down tilt (HDT) were examined in 12 healthy young (average age, 24.6 +/- 1.7 years) and 12 healthy elderly (average age, 68.6 +/- 2.2 years) men. Subjects were passively tilted from supine to 30 degrees, 60 degrees, and 90 degrees HUT and HDT. Responses to these perturbations were determined 5 min after tilting with measures of heart rate (HR), blood pressure (SBP, DBP), and echocardiographically determined left ventricular diameter in systole and diastole (LVIDs, LVIDd). In HUT there were no significant age effects. In both young and elderly, SBP decreased significantly (p less than 0.05), and DBP and HR increased significantly. Ejection fraction (EF), mean arterial blood pressure (MABP), and rate-pressure product (RPP) were unchanged in both groups. In HDT, the hemodynamic responses of the young and elderly were in opposite directions and significant age effects were found for SBP, DBP, HR, LVIDs, EF, MABP, and RPP. In HDT, the young appear to increase cardiac output primarily due to an increase in EF and end-diastolic volume (LVIDd), while HR is unchanged and SBP is decreased. MABP is unchanged, suggesting a small decrease in total peripheral resistance. The elderly may increase cardiac output slightly, owing to an increase in LVIDd with no change in EF, and a large increase in HR. Afterload increased markedly, therefore attenuating any increase in cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of acute cardiovascular responses to water immersion and head-down tilt in humans.

The hypothesis was tested that acute water immersion to the neck (WI) compared with 6 degrees head-down tilt (HDT) induces a more pronounced distension of the heart and lower plasma levels of vasoconstrictor hormones. Ten healthy males underwent 30 min of HDT, WI, and a seated control (randomized). During WI, left atrial diameter and stroke volume increased to the same extent as during HDT. Cardiac output increased by 1 l/min more during WI than during HDT. (P < 0.05). Plasma atrial natriuretic peptide increased during WI (P < 0.05) but not during HDT, whereas plasma norepinephrine, vasopressin, and renin activity were suppressed similarly. Mean arterial pressure decreased by 9 mmHg (P < 0.05) during HDT and was unchanged during WI, and heart rate decreased more during HDT (P < 0.05). Arterial pulse pressure increased considerably more during HDT than during WI. In conclusion, the hypothesis was not confirmed because the cardiac atria were similarly distended by acute HDT and WI and the release of vasoconstrictor hormones were suppressed to the same extent.     

Effects of hindlimb suspension training on the central and regional hemodynamic responses during 24 hours antiorthostatic hypokinesia in the awake rat

To date the hindlimb suspension model utilizing rats has a wide application to simulate weightlessness. In our previous study we have examined the cardiovascular responses in the tail suspension model using the radiolabeled microspheres technique. We have reported increases of cardiac output (CO) and decreases of total peripheral vascular resistance (TPVR) after 24 hours of head-down tilt (HDT). However, there is no comparison of arterial and venous systems parameters with blood flow changes in organs and tissues. Apart from the preliminary HDT training influence on these parameters is unknown. Thus we aimed to evaluate the role of HDT training in central circulation responses, venous tone and regional blood flow.     

Transcapillary fluid shifts in tissues of the head and neck during and after simulated microgravity.

To understand the mechanism, magnitude, and time course of facial puffiness that occurs in microgravity, seven male subjects were tilted 6 degrees head-down for 8 h, and all four Starling transcapillary pressures were directly measured before, during, and after tilt. Head-down tilt (HDT) caused facial edema and a significant elevation of microvascular pressures measured in the lower lip: capillary pressures increased from 27.7 +/- 1.5 mmHg (mean +/- SE) pre-HDT to 33.9 +/- 1.7 mmHg by the end of tilt. Subcutaneous and intramuscular interstitial fluid pressures in the neck also increased as a result of HDT, whereas interstitial fluid colloid osmotic pressures remained unchanged. Plasma colloid osmotic pressure dropped significantly by 4 h of HDT (21.5 +/- 1.5 mmHg pre-HDT to 18.2 +/- 1.9 mmHg), suggesting a transition from fluid filtration to absorption in capillary beds between the heart and feet during HDT. After 4 h of seated recovery from HDT, microvascular pressures in the lip (capillary and venule pressures) remained significantly elevated by 5-8 mmHg above baseline values. During HDT, urine output was 126.5 ml/h compared with 46.7 ml/h during the control baseline period. These results suggest that facial edema resulting from HDT is caused primarily by elevated capillary pressures and decreased plasma colloid osmotic pressures. The negativity of interstitial fluid pressures above heart level also has implications for maintenance of tissue fluid balance in upright posture.     

Baroreceptor-mediated suppression of osmotically stimulated vasopressin in normal humans

Increases in central venous pressure and arterial pressure have been reported to have variable effects on normal arginine vasopressin (AVP) levels in healthy humans. To test the hypothesis that baroreceptor suppression of AVP secretion might be more likely if AVP were subjected to a prior osmotic stimulus, we investigated the response of plasma AVP to increased central venous pressure and mean arterial pressure after hypertonic saline in six normal volunteers. Plasma AVP, serum osmolality, heart rate, central venous pressure, mean arterial pressure, and pulse pressure were assessed before and after a 0.06 ml.kg-1.min-1-infusion of 5% saline give over 90 min and then after 10 min of 30 degrees head-down tilt and 10 min of head-down tilt plus lower-body positive pressure. Hypertonic saline increased plasma AVP. After head-down tilt, which did not change heart rate, pulse pressure, or mean arterial pressure but did increase central venous pressure, plasma AVP fell. Heart rate, pulse pressure, and central venous pressure were unchanged from head-down tilt values during lower-body positive pressure, whereas mean arterial pressure increased. Plasma AVP during lower-body positive pressure was not different from that during tilt. Osmolality increased during the saline infusion but was stable throughout the remainder of the study. These data therefore suggest that an osmotically stimulated plasma AVP level can be suppressed by baroreflex activation. Either the low-pressure cardiopulmonary receptors (subjected to a rise in central venous pressure during head-down tilt) or the sinoaortic baroreceptors (subjected to hydrostatic effects during head-down tilt) could have been responsible for the suppression of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of lower body negative pressure on orthostatic tolerance and cardiac function during 21 days head-down tilt bed rest

The purpose of the present study was to investigate the changes of orthostatic tolerance and cardiac function during 21 d head-down tilt (HDT) bed rest and effect of lower body negative pressure in the first and the last week in humans. Twelve healthy male volunteers were exposed to -6 degrees HDT bed rest for 21 d. Six subjects received -30 mmHg LBNP sessions for 1 h per day from the 1st to the 7th day and from the 15th to the 21st day of the HDT, and six others served as control. Orthostatic tolerance was assessed by means of standard tilt test. Stroke volume (SV), cardiac output (CO), preejection period (PEP) and left ventricular ejection time (LVET) were measured before and during HDT. Before HDT, all the subjects in the two groups completed the tilt tests. After 10 d and 21 d of HDT, all the subjects of the control group and one subject of the LBNP group could not complete the tilt test due to presyncopal or syncopal symptoms. The mean upright time in the control group (15.0 +/- 3.2 min) was significantly shorter than those in the LBNP group (19.7 +/- 0.9 min). SV and CO decreased significantly in the control group on days 3 and 10 of HDT, but remained unchanged throughout HDT in the LBNP group. A significant increase in PEP/LVET was observed on days 3 and 14 of HDT in both groups. The PEP/LVET in the LBNP group was significantly lower on day 3 of HDT, while LVET in the LBNP group was significantly higher on days 3, 7 and 14 of HDT than those in the control group. The results of this study suggest that brief daily LBNP sessions used in the first and the last weeks of 21 d HDT bed rest were effective in diminished the effect of head-down tilt on orthostatic tolerance, and LBNP might partially improve cardiac pumping function and cardiac systole function.     

Development of osteoporosis in primates in hypokinesia with head-down tilt

It has been shown earlier that 7-19 day exposure of monkeys to hypokinesia with head-down tilt (HDT) produces osteopenia in their load-bearing bones. The present work continued the investigations of osteopenia dynamics in monkeys which had been under the HDT conditions for 15 and 30 days.     

24-hr blood pressure in HDT-bed rest and short-lasting space flight

In 2 ESA-cosmonauts we compared the 24-hr profiles in blood pressure (BP) and heart rate (HR) to those that we had observed in an earlier head-down tilted (HDT) bed rest study. In view of the lack of gravitational stress, an attenuated profile was expected, as in HDT. To obtain a full profile we measured automatic upper-arm cuff measurements in 2 cosmonauts, combined with PortapresTM recordings in one. Unlike HDT, actual microgravity did not result in attenuated circadian profiles. The levels of systolic and diastolic pressures tended to be slightly lower in flight. Only nighttime heart rate was significantly lower in Space.     

Low-magnitude whole body vibration with resistive exercise as a countermeasure against cardiovascular deconditioning after 60 days of head-down bed rest

Whole body vibration with resistive exercise is a promising countermeasure against some weightlessness-induced dysfunctions. Our objective was to study whether the combination of low-magnitude whole body vibration with a resistive exercise can prevent the cardiovascular deconditioning induced by a nonstrict 60-day head-down bed rest (Earth Star International Bed Rest Experiment Project). Fourteen healthy men participated in this study. We recorded electrocardiograms and blood pressure waves by means of a noninvasive beat-by-beat measurement system (Cardiospace, integrated by Centre National d'Etudes Spatiales and Astronaut Center of China) during an orthostatic test (20 min of 75-degree head-up tilt test) before and immediately after bed rest. We estimated heart rate, blood pressure, cardiac output, stroke volume, total peripheral resistance, baroreflex sensitivity, and heart rate variability. Low-magnitude whole body vibration with resistive exercise prevented an increase of the sympathetic index (reflecting the sympathovagal balance of cardiac autonomic control) and limited the decrease of the spontaneous baroreflex sensitivity induced by 60 days of head-down bed rest. However, this countermeasure had very little effect on cardiac hemodynamics and did not improve the orthostatic tolerance. This combined countermeasure did not efficiently prevent orthostatic intolerance but prevents changes in the autonomic nervous system associated with cardiovascular deconditioning. The underlying mechanisms remain hypothetical but might involve cutaneous and muscular mechanoreceptors.     

Effect of posture on arterial baroreflex control of heart rate in humans

Altered baroreflex function may contribute to the cardiovascular changes associated with weightlessness. Since central blood volume (CBV) increases during simulated weightlessness we have examined the possibility that acute changes in CBV may modify baroreceptor function. We used graded head-up tilt (HUT) and head-down tilt (HDT) to induce changes in CBV, and neck suction to stimulate carotid baroreceptors, in 6 subjects. The increase in pulse interval induced by a negative pressure of 8.2 kPa (62 mm Hg) imposed for 10 s while supine was compared with the increase while tilted for 8 min at +/- 15 degrees, +/- 30 degrees and +/- 45 degrees. During HDT at 15 degrees the pulse interval over the first 5 cardiac cycles following suction onset was 51 +/- (SEM) 18 ms longer (p less than 0.05), at 30 degrees it was 61 +/- 20 ms longer (p less than 0.05), and at 45 degrees it was 74 +/- 35 ms longer (p less than 0.01), compared with supine. During HUT at 15 degrees the pulse interval was 25 +/- 9 ms shorter (p less than 0.05) than when supine, but was not significantly different at 30 degrees and 45 degrees. These responses occurred independently of changes in brachial blood pressure. Attenuation was also observed after 5 min (56 +/- 17 ms; less than 0.05), and after 40 min (25 +/- 9 ms; p less than 0.05) of 60 degrees HUT compared with supine. We conclude that posture does modify arterial baroreflex control of heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular and hormonal response during a 4-week head-down tilt with and without exercise and LBNP countermeasures

To determine whether exercise and Lower Body Negative Pressure (LBNP) during 28 days of -6 degrees head-down tilt (HDT) would modify orthostatic tolerance and blood volume regulating hormones, twelve healthy men were assigned to either a no- countermeasure (No-CM, n=6), or a countermeasure (CM, n=6) group. LBNP sessions consisted of 15 minutes exposure to -30 mm Hg, on days 16, 18, 20 and 22-28 of HDT. Muscular exercise began on day 8 and consisted of combined graded dynamic and isometric resistance bilateral leg exercise on a specially designed supine ergometer, in two sessions of 15-20 min. each, every day, 6 days per week. A tilt test was performed before and at the end of HDT. Changes in resting plasma volume from control day (D-5) to HDT day 24 were -11.2% for No-CM and -2.2% for CM. After HDT three among the 6 subjects of the No-CM group presented presyncopal or syncopal symptoms, no tilt test was interrupted in CM group. Atrial Natriuretic Peptide (ANP) decreased at day 7 for the two groups and remained low during all the HDT period for No-CM group only. Plasma Renin Activity and Aldosterone increased at day 7 and remained elevated for the two groups. Norepinephrine and epinephrine were unchanged. Elevated diuresis and natriuresis were evident during the first day of HDT. However, renal excretory patterns were different between the two groups: indeed, a decrease of Na+, ANP and cGMP was observed only in No-CM at Day 13 during HDT. Our data showed that the subjects of the No-CM group experienced a greater increase in heart rate and a decrease in systolic blood pressure during tilt tests after HDT; nevertheless, after HDT, blood pressure was better maintained in CM group during the tilt test. The plasma volume decrease measured at the end of HDT was significantly lower in CM group, in contrast, these countermeasures were ineffective in preventing at least certain changes in blood volume regulating hormones.     

Computer simulation of the effect of dDAVP with saline loading on fluid balance after 24-hour head-down tilt

Fluid loading (FL) before Shuttle reentry is a countermeasure currently in use by NASA to improve the orthostatic tolerance of astronauts during reentry and postflight. The fluid load consists of water and salt tablets equivalent to 32 oz (946 ml) of isotonic saline. However, the effectiveness of this countermeasure has been observed to decrease with the duration of spaceflight. The countermeasure's effectiveness may be improved by enhancing fluid retention using analogs of vasopressin such as lypressin (LVP) and desmopressin (dDAVP). In a computer simulation study reported previously, we attempted to assess the improvement in fluid retention obtained by the use of LVP administered before FL. The present study is concerned with the use of dDAVP. In a recent 24-hour, 6 degree head-down tilt (HDT) study involving seven men, dDAVP was found to improve orthostatic tolerance as assessed by both lower body negative pressure (LBNP) and stand tests. The treatment restored Luft's cumulative stress index (cumulative product of magnitude and duration of LBNP) to nearly pre-bedrest level. The heart rate was lower and stroke volume was marginally higher at the same LBNP levels with administration of dDAVP compared to placebo. Lower heart rates were also observed with dDAVP during stand test, despite the lower level of cardiovascular stress. These improvements were seen with only a small but significant increase in plasma volume of approximately 3 percent. This paper presents a computer simulation analysis of some of the results of this HDT study.     

Influences of prostanoids and nitric oxide on post-suspension hypotension in female Sprague-Dawley rats

Impairment in cardiovascular functions sometimes manifested in astronauts during standing postflight, may be related to the diminished autonomic function and/or excessive production of endothelium-dependent relaxing factors. In the present study, using the 30 degrees head-down tilt (HDT) model, we compared the cardiovascular and biochemical effects of 7 days of suspension and a subsequent 6-h post-suspension period between suspended and non-suspended conscious female Sprague-Dawley rats. Mean arterial pressure (MAP) and heart rate were measured prior to suspension (basal), daily thereafter, and every 2h post-suspension. Following 7 days of suspension, MAP was not different from their basal values, however, upon release from suspension, MAP was significantly reduced compared to the non-suspended rats. Nitric oxide levels were elevated while thromboxane A(2) levels declined significantly in both plasma and tissue samples following post-suspension. The levels of prostacyclin following post-suspension remained unaltered in plasma and aortic rings but was significantly elevated in carotid arterial rings. Therefore, the post-suspension reduction in mean arterial pressure is due mostly to overproduction of nitric oxide and to a lesser extent prostacyclin.