Summary of final report: Space Life Sciences Planning Workshop (SLSPW). June 5-7, 2000 Mont Tremblant, Quebec.

A Space Life Sciences Planning Workshop was sponsored by the Canadian Space Agency to identify key questions in the major research areas supported by the Life Sciences Program, to identify Canadian strengths and capabilities as they relate to these research areas, and to make recommendations for the future directions of the Life Sciences Program. The conclusions reached by the workshop participants have been presented to the Canadian Space Agency. This report is a summary of those conclusions.

Somatosensory evoked potentials during hypoxia and hypocapnia in conscious humans.

PURPOSE: The objective of the study was to evaluate the effects of moderate hypoxia and hypocapnia on the latency and amplitude of cortical somatosensory evoked potentials (SSEPs) in conscious human subjects. METHODS: In ten volunteers the amplitude and latency of the cortical somatosensory evoked potentials were recorded during stimulation of the left posterior tibial nerve. Measurements of SSEPs and respiratory variables were made breathing ambient air, air containing a reduced oxygen percentage (17% O2, 14% O2 (n = 6) or 11% O2 (n = 10)), and again during voluntary hyperventilation breathing ambient air (PETCO2 = 20 mmHg, n = 10). RESULTS: Hypoxia (11% O2) caused mild stimulation of ventilation (P < 0.05) but had no effects on the latency or amplitude of the SSEP. Lesser degrees of hypoxia had no effects. Hyperventilation caused a small (2-4%) decrease) in the latency of the SSEP and an increase in the amplitude of the SSEP (P < 0.05). CONCLUSIONS: These findings in conscious subjects were consistent with previous observations in anaesthetized humans and anaesthetized dogs and show that the decrease in latency of the SSEP associated with hypocapnia is not due to changes in the depth of anaesthesia. These effects of hypocapnia may contribute to small variations in the latency of the SSEP when monitoring is performed during surgery, but are unlikely to be large enough to be of clinical concern.

Diurnal changes in lumbar intervertebral distance, measured using ultrasound.

STUDY DESIGN: This study measured the distances between the tips of the transverse processes of adjacent lumbar vertebrae (L1-L4) in the same subjects after 1 day of normal activities and again the next morning. OBJECTIVES: To determine the feasibility of directly measuring the lumbar intervertebral distance using ultrasound and to determine the magnitude of the diurnal change in the intervertebral distance. SUMMARY OF BACKGROUND DATA: A diurnal variation in height results from, in part, a decrease in height of the intervertebral discs with loading of the spine during the day. Previous estimates of the diurnal changes in disc height have used radiologic, stereophotographic, and magnetic resonance imaging techniques. No previous study has used ultrasound imaging. METHODS: Ultrasound was used to measure the distance between the tips of adjacent lumbar vertebral transverse processes. Measurements were made on six occasions in each of seven subjects after 6:00 PM in the evening and again the following morning before rising. RESULTS: The distance between the tips of adjacent transverse processes could be measured, within an individual, with a reproducibility of better than +/- 7.5% coefficient of variation. Reproducibility of the measurement of the total distance between L1 and L4 was better than +/- 4%. The intervertebral distances between L1 and L4 were significantly greater in the morning than in the evening. The average diurnal change in the total intervertebral distance L1-L4 was 5.3 mm. CONCLUSIONS: The study confirms the feasibility of using ultrasound to directly measure changes in the distances between the lumbar vertebrae.

Long term stability of somatosensory evoked potentials and the effects of microgravity.

BACKGROUND: Exposure to microgravity causes a height increase of up to 70 mm that places traction on the spine and may possibly lead to spinal cord dysfunction. Somatosensory evoked potentials (SSEP) have been widely used to monitor spinal cord function. This study was carried out to determine the long-term stability of the latency of SSEP's in individual subjects and the feasibility of recording SSEP's in a microgravity environment. METHODS: Baseline values and variability of the latency of the cortical evoked potentials were established in seven subjects over periods of 1-2.5 years. These values were then compared with measurements made in six of the subjects during periods of microgravity on a KC-135 aircraft. The latency of the cortical potentials was also measured in the evening and in the morning before rising in a separate group of seven subjects, to determine whether there was any diurnal variation. RESULTS: The mean coefficient of variance of the latency of the SSEP was approximately 1.5% of the latency, and there were no changes in the latency over the period studied. There was no evidence of diurnal variation in the latency of the cortical SSEP. Satisfactory recordings of the SSEP were obtained in five of six subjects tested in microgravity. In three of these five subjects there was a significant decrease in the latency of the cortical SSEP in microgravity. CONCLUSIONS: In individual subjects the latency of the cortical SSEP varies within very small limits (1.5%) over 1-2.5 years. The results demonstrate the feasibility of recording SSEP's in the microgravity state. They show that relatively small changes (2-3 ms) in the latency of the SSEP can be detected when prior baseline values are established for each subject. The reason for the decrease in latency of the cortical SSEP in some subjects on the KC-135 is not known.

Presence and actions of vasoactive intestinal peptide in the isolated rabbit heart.

The objectives of these experiments were to localize vasoactive intestinal peptide immunoreactivity (VIP-IR) in the intracardiac ganglia of the interatrial septum of the rabbit heart and to examine the effects of vasoactive intestinal peptide (VIP) on the isolated perfused rabbit heart. Cell bodies of neurones containing VIP-IR were located in the interatrial septa of rabbit hearts by using immunocytochemistry. In addition, the effects of substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) on the isolated rabbit heart were compared with those of VIP. Bolus injections of SP, NKA, VIP, and NKB caused dose-dependent decreases in the perfusion pressure of hearts perfused at constant flow with ED50 values of 2.73 +/- 0.10 fmol (n = 6), 0.18 +/- 0.01 pmol (n = 8), 93.75 +/- 1.88 pmol (n = 6), and 75.00 +/- 3.06 pmol (n = 6), respectively. The slope of the dose-response curve of VIP was much greater than those of SP and NKA, suggesting the presence of one receptor subtype for VIP and multiple receptor subtypes for the neurokinins on rabbit coronary vessels. Differences in the slopes of the dose-response curves and potency may reflect differences in the mechanism of vasodilatation. The maximal values of vasodilatation of all of the peptides did not differ. None of the peptides produced significant changes in heart rate, left ventricular pressure, or contractility. These results suggest that VIP found in the intracardiac neurones of the rabbit heart can mediate coronary vasodilatation.

Mechanisms of release of atrial natriuretic factor in vivo.

The aim of the study was to define the relationship between the concentration of immunoreactive atrial natriuretic factor (ANF) in the plasma and atrial stretch, atrial pressure and atrial wall stress during changes in blood volume within the physiological range. Advantage was taken of the potentiation of the release of ANF, in response to blood volume expansion, in the anaesthetized rabbit, by section of the carotid sinus, aortic depressor and vagus nerves. Mean arterial pressure and right and left atrial pressures were measured. Right and left atrial dimensions were measured by sonomicrometry. Blood volume was expanded by 20% and then decreased at 1% of the blood volume per minute for 40 min, before and after section of the nerves. Plasma ANF did not change significantly in response to either the increase or decrease in blood volume in the presence of intact nerves. After the nerves were sectioned, blood volume expansion significantly increased IR-ANF (34.6 +/- 12 to 260.6 +/- 89.8 pg/ml). The relationship between ANF and the changes in left atrial dimensions (extension ratio) was exponential. A significant linear correlation was found between ANF and left atrial pressure and left atrial wall stress. Over a range of atrial pressures from 1-10 cm H2O the atrial wall was extremely distensible, but there were only minor changes in ANF. At higher atrial pressures there was little further extension of the atrial wall but there were much larger increases in plasma ANF. In response to changes in blood volume within the physiological range cardiovascular reflexes normal maintain atrial dynamic function within a narrow range and there is little stimulus for the release of ANF. In conditions in which the cardiovascular reflexes are unable to maintain atrial function constant then there will be changes in the release of ANF and there will be an exponential relationship between atrial wall stretch and plasma ANF.

Regulation of plasma vasopressin by plasma osmolality and carotid sinus pressure in anesthetized rabbits.

The purpose of the experiments was to investigate the effect of changes in carotid sinus baroreceptor stimulation on plasma vasopressin (AVP) at different plasma osmolalities in the anesthetized artificially ventilated rabbit. Both carotid sinuses were isolated and perfused with blood at servo-controlled pressures. The vagus and aortic depressor nerves were sectioned bilaterally to eliminate input from atrial and aortic arch baroreceptors. Saline (0.3%, wt/vol) was infused to lower plasma osmolality, and 5% saline was infused to raise plasma osmolality. At three plasma osmolalities, the carotid sinus pressure (CSP) was changed from 100 mmHg to 40 and 140 mmHg and returned to 100 mmHg. There were no changes in plasma AVP in response to changes in CSP at low plasma osmolality (289 mosmol/kgH2O), but at medium (309 mosmol/kgH2O) and high (323 mosmol/kgH2O) osmolality, plasma AVP was higher at 40 than at 140 mmHg CSP. The relationship between plasma AVP and plasma osmolality was expressed as a linear regression at each CSP. Changes in CSP changed the sensitivity but not the threshold of the osmotic control of AVP release.

Plasma atrial natriuretic factor and atrial wall stress in hypertensive and normotensive rabbits after pacing and volume expansion.

Atrial natriuretic factor (ANF) is present in high concentration in atria but in very low concentration in the ventricles. Under conditions of haemodynamic overload ventricular gene expression may become activated, but it is not clear if ventricular ANF can be released through a regulated or constitutive pathway. The purpose of this study was to determine whether basal and stimulated release of ANF are increased in perinephritic rabbits with mild hypertension. Six rabbits were rendered hypertensive by wrapping both kidneys in cellophane, and six sham-operated rabbits were used as controls. Eight weeks after renal wrapping, mean arterial pressure was approximately 20 mmHg higher in the experimental group. After anaesthesia, the renal-wrapped group had a higher vascular resistance. Right and left atrial wall stress was measured using sonomicrometry. Volume expansion by 30% of blood volume, using donor blood, caused a small increase in right and left atrial diastolic and systolic wall stress but did not significantly increase plasma ANF. Pacing the heart at 6 Hz caused increases in systolic but not diastolic wall stress and caused a significant increase in plasma ANF; the increase was larger after volume expansion. There were no significant differences between the responses of the experimental and control groups. It is concluded that mild hypertension, in the rabbit, does not lead to changes in atrial wall stress or either basal or stimulated release of ANF.

Atrial dynamics and release of atrial natriuretic factor in vivo.

In anaesthetized rabbits blood volume was altered by infusion and withdrawal of donor blood over the range of +60 to -40% of the blood volume. Right and left atrial pressures were measured and it was shown that sonomicrometry allowed adequate measurement of phasic changes in atrial dimensions. Plasma immunoreactive atrial natriuretic peptide concentration changed in a nonlinear fashion with changes in blood volume, and was linearly related to both peak systolic and peak diastolic right and left atrial wall stress. It was not possible to make the distinction between distension (diastolic stress) or tension (systolic stress) as the major determinant of ANF release in response to changes in blood volume.

Atrial dynamics, atrial natriuretic factor, tachycardia, and blood volume in anesthetized rabbits.

The effects of tachycardia and a slow (1%/min) 20% reduction and elevation of blood volume (BV) on right atrial pressure (RAP), right atrial dimension (RAD), and plasma immunoreactive atrial natriuretic factor (IR-ANF) were examined in anesthetized rabbits. Plasma IR-ANF was significantly increased during pacing at 6 Hz in the presence of high BV but not at low BV. Mean RAP increased with expansion of BV, but this change was not associated with significant changes in IR-ANF. There were no statistically significant changes in systolic or diastolic RAD with alterations in BV or with tachycardia. Tachycardia had no effect on left atrial dimension. Diastolic right atrial wall stress (DRAS) and minute DRAS increased with a 20% increase in BV, but changes in BV did not affect systolic right atrial wall stress (SRAS) or minute SRAS. Tachycardia decreased DRAS at high BV and significantly increased SRAS and minute SRAS. The increases in SRAS and minute SRAS were greater during tachycardia at high BV, suggesting that an interaction between BV and tachycardia results in potentiation of SRAS and minute SRAS. The results suggest that systolic RAS is a significant factor in ANF release during tachycardia at high BV.

The effect of isoproterenol on right and left atrial dynamics and plasma atrial natriuretic factor in anesthetized rabbits.

The effect of isoproterenol on mean right and left atrial pressures (RAP, LAP) and dimensions (RAD, LAD), and plasma immunoreactive atrial natriuretic factor (IR-ANF) was investigated in anesthetized rabbits. Infusion of isoproterenol (10 micrograms.kg-1.min-1 for 10 min) significantly increased plasma IR-ANF and heart rate. There were no significant changes in mean RAP or LAP following isoproterenol. Neither mean RAD, systolic RAD and diastolic RAD nor mean LAD, systolic LAD or diastolic LAD changed significantly. Systolic right and left atrial wall stress and diastolic right and left atrial wall stress did not change significantly during the infusion of isoproterenol. Since atrial dimensions did not increase, it is unlikely that the release of IR-ANF in response to isoproterenol is mediated by atrial stretch. These results suggest that the release of IR-ANF in response to this dose of isoproterenol is mediated by factors other than stretch or changes in atrial dynamics.

The effect of tachycardia on right atrial dynamics and plasma atrial natriuretic factor in anaesthetized rabbits.

1. The effect of tachycardia on right atrial pressure (RAP) and dimensions (RAD) and plasma immunoreactive atrial natriuretic factor (IR-ANF) was examined in anaesthetized rabbits before and after the administration of atenolol. 2. Small increases in plasma IR-ANF occurred during pacing at 6 Hz and after the administration of atenolol (0.4 mg kg-1). A significantly greater increase in IR-ANF occurred during pacing in the presence of atenolol. 3. Despite a significant rise in mean RAP, systolic RAD (SRAD) and diastolic RAD (DRAD) did not change during tachycardia. Systolic RAD increased after the administration of atenolol while both SRAD and DRAD increased during pacing in the presence of atenolol. 4. Systolic right atrial wall stress (SRAS) increased during tachycardia, did not change after the administration of atenolol, and increased during pacing in the presence of atenolol. Minute SRAS followed a similar pattern of changes except that it decreased after atenolol. 5. Diastolic right atrial wall stress (DRAS) did not change during tachycardia, and increased both after atenolol and after pacing in the presence of atenolol. Tachycardia led to an increase in minute DRAS; a significantly greater increase in minute DRAS occurred during tachycardia in the presence of atenolol. 6. The absence of alterations in RAD during tachycardia suggests that the release of ANF in response to tachycardia is not due to simple mechanical stretch of the atria. Both systolic and diastolic atrial wall stress may be determinants of ANF release: the influence of systolic factors appears to predominate during tachycardia while diastolic factors appear to be the major determinants of the effects of atenolol.

Carotid sinus pressure, blood volume, and vasopressin in the anaesthetized rabbit.

Experiments were carried out on anaesthetized rabbits to determine the influence of carotid sinus pressure (CSP) on the changes in the plasma concentration of arginine vasopressin (AVP) that occurred in response to changing blood volume. The aortic depressor nerves were sectioned in all experiments and the vagus nerves remained intact. Both carotid sinuses were perfused at constant controlled pressure. Blood volume was increased (n = 10) or decreased (n = 10) by 10 and 20% of the estimated blood volume. Plasma immunoreactive arginine vasopressin concentration (IR-AVP) was significantly higher at a CSP of 60 mmHg (1 mmHg = 133.322 Pa) than it was at a CSP of 120 mmHg in both groups of animals. Increasing blood volume did not cause any significant change in IR-AVP at either carotid sinus pressure. Haemorrhage of 10% of the blood volume did not change IR-AVP. Haemorrhage of 20% of the blood volume significantly increased IR-AVP at both CSPs; the magnitude of the increase in IR-AVP was not altered by changing the CSP. No interaction was demonstrated between the effects of CSP and blood volume on plasma IR-AVP.

Plasma vasopressin and atrial natriuretic factor during haemorrhage: influence of cardiac and aortic receptors.

1. The changes in plasma concentrations of immunoreactive vasopressin (iVP) and atrial natriuretic factor (iANF) in response to haemorrhage (10-30% blood volume) were measured in 10 anaesthetized rabbits before and after cardiac receptor denervation (vagal nerve section). Carotid sinus pressure was maintained constant (60 mmHg) to eliminate any changing input from carotid baroreceptors. 2. Haemorrhage increased iVP before and after vagal nerve section indicating that withdrawal of input from aortic baroreceptors may have contributed to the increase in iVP. 3. Section of the vagus nerves attenuated the iVP response to haemorrhage. 4. There was no correlation between release of iVP and iANF. 5. Haemorrhage decreased iAF before and after vagal nerve section. Section of the vagus nerves increased iANF. Plasma iANF was highly correlated with atrial pressure and mean arterial pressure suggesting iANF release was secondary to changes in cardiac haemodynamics.

Plasma vasopressin and atrial natriuretic factor in response to blood volume changes in the anaesthetized rabbit.

The influence of aortic baroreceptors and vagal afferent nerves on the release of immunoreactive vasopressin (iVP) and immunoreactive atrial natriuretic factor (iANF) was examined in anaesthetized rabbits. Changes in plasma concentrations of iVP and iANF, heart rate, mean arterial pressure, and right atrial pressure were measured in response to blood volume changes (+20, +10, -10, -20%). Carotid sinus pressure was maintained at 100 mmHg (1 mmHg = 133.3 Pa), and blood volume changes were performed before and after bilateral vagotomy (VNX) in all experiments. Two experimental groups were studied: rabbits with aortic depressor nerves intact (ADNI) and those with aortic depressor nerves sectioned (ADNX). Mean arterial and right atrial pressures decreased during haemorrhage and increased in response to volume expansion. Plasma iVP concentrations increased with haemorrhage and decreased with volume expansion in the ADNI group. Plasma iANF, however, decreased with haemorrhage and increased during volume expansion in both ADNI and ADNX groups. Vagotomy caused an increase in baseline plasma iANF in the ADNX group. The responses of iANF to blood volume changes were augmented after VNX and ADNX. The results show that neither the aortic baroreceptor nor the vagal afferent input are needed for the iANF response to changes in blood volume, over the range of +/- 20%. In contrast, intact aortic baroreceptors are essential for changes in circulating iVP in this preparation.

The influence of carotid sinus pressure on plasma atrial natriuretic peptide in anaesthetized rabbits.

The effect of changes in carotid sinus perfusion pressure on plasma immunoreactive atrial natriuretic peptide (IR-ANP) was examined in anaesthetized rabbits, and the role of arterial pressure in mediating the changes in IR-ANP was assessed. Plasma IR-ANP was significantly greater (101.7 +/- 24.3 pg ml-1) when carotid sinus pressure was 60 mmHg than when it was 160 mmHg (27.1 +/- 8.6 pg ml-1). Mean arterial pressure (MAP) was significantly greater when carotid sinus pressure was controlled at 60 mmHg compared to when it was 160 mmHg, but right atrial pressure (RAP) was not significantly different at the two carotid sinus pressures. The administration of hexamethonium attenuated the changes in MAP and heart rate (HR) which occurred in response to alterations in carotid sinus pressure, and abolished the change in plasma IR-ANP. The results suggest that an inverse relationship exists between carotid sinus pressure and plasma IR-ANP, and that the release of ANP in response to a reduction of carotid sinus pressure is mediated by the associated haemodynamic changes.

Pharmacokinetics of vasopressin and atrial natriuretic peptide in anesthetized rabbits.

The elimination from plasma of the peptide hormones vasopressin (VP) and atrial natriuretic peptide (ANP) as well as the time course of release and elimination of these hormones after a physiological stimulus were studied in anesthetized rabbits. As an inverse relationship was found to exist between carotid sinus pressure and plasma IR-ANP, a decrease in carotid sinus pressure to 60 mm Hg was used to stimulate ANP as well as VP release. The elimination of VP after iv injection involved a rapid initial phase and a slow late component, with corresponding half-life (t1/2) values of 0.9 and 5.4 min, respectively. After reduction of carotid sinus pressure to 60 mm Hg, plasma VP increased significantly within 1 min and reached a maximum at 10 min. When carotid sinus pressure was increased to 160 mm Hg to inhibit VP release, the t1/2 of VP was 1.3 min. The t1/2 of immunoreactive (IR) ANP after iv infusion was 1.2 min. Plasma IR-ANP was significantly increased 2 min after carotid sinus pressure was decreased, and a maximum was observed at 10 min. The t1/2 of IR-ANP after elevation of carotid sinus pressure to 160 mm Hg was 3.2 min. These studies indicate that both VP and IR-ANP are rapidly eliminated in the anesthetized rabbit.

Carotid sinus pressure and plasma vasopressin in anesthetized rabbits.

The arterial baroreceptors are known to influence the release of vasopressin, but the quantitative relationship between baroreceptor stimulation and plasma vasopressin concentration has not been defined. These experiments examine the effect of stepwise changes in carotid sinus pressure (40-160 mmHg) on the plasma concentration of vasopressin in chloralose-urethan anesthetized rabbits. Plasma vasopressin concentration (9.2 +/- 1.2 pg/ml, n = 27) did not change in response to changes in carotid sinus pressure when the aortic depressor nerves were intact. These results were unaltered by bilateral cervical vagotomy. However, after aortic depressor nerve section, decreases in carotid sinus pressure were associated with increases in plasma vasopressin concentration. There appeared to be a greater redundancy in the baroreceptor control of plasma vasopressin than in the baroreceptor control of arterial pressure or heart rate. The results provided no evidence that receptors with vagal afferents have a tonic influence on the baroreceptor control of vasopressin release in the anesthetized rabbit.

Ventilatory muscle training in kyphoscoliosis.

Cardiorespiratory failure is the usual cause of death in severe kyphoscoliosis. The pathophysiology of this mechanism will be reviewed. Ventilatory muscle training (VMT), a relatively new respiratory technique, has been shown to improve the strength and endurance of the ventilatory muscles. It is known that stronger, endurance trained ventilatory muscles will guard against ventilatory muscle fatigue which may lead to respiratory failure. The actual technique is described with documentation of two representative cases. Case 1 showed a 63% increase in maximum inspiratory mouth pressure (PiMax) and an increased ability to walk and climb stairs with comfort. Case 2 used VMT as an adjunct to her weaning protocol from a portable ventilator. She progressed from full-time to nocturnal ventilator assistance in 1 month.

Extracted and nonextracted atrial natriuretic peptide in rabbits during tachycardia.

The time course of changes in the plasma concentration of immunoreactive atrial natriuretic peptide (iANP) accompanying tachycardia was measured in anesthetized rabbits. In contrast to the hemodynamic changes, which occurred within the 1st min of tachycardia, the plasma iANP increased gradually and did not reach significantly elevated levels until 10 min into the stimulation period. After 20 min of tachycardia iANP was almost 200 pg/ml. Immunoreactive ANP was measured prior to and following extraction. Although the basal levels of iANP were higher in the unextracted than in extracted plasma (62 vs. 22 pg/ml), the time course of changes in iANP was identical in both. The gradual increase in iANP suggests that the release of iANP in this model may not simply be a consequence of the increase in atrial pressure.