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2002; Volume 12(2) from Clinical Autonomic Research                                           
Send comments or suggestions about Autonomic News to: italo.biaggioni@mcmail.vanderbilt.edu

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To review the original abstract of these articles, click on the references below

More on alpha-synuclein  <<
        alpha-synuclein is a protein of unknown function normally present in presynaptic neurons and found in neuronal Lewy bodies of patients with Parkinson’s disease or Lewy body dementias.  It is not normally present in glial cells, but is found in the oligodendrocyte inclusions of multiple system atrophy.  To determine if α-synuclein can damage glial cells, Stefanova et al., transfected human wild type or C-terminus truncated α-synuclein in astrocytoma cells in vitro.  Overexpression of alpha-synuclein, particularly if truncated at the C-terminus, resulted in increased susceptibility to oxidative stress, formation of precipitates, and apoptosis.  Previous studies have shown similar alterations in neuronal cells. 
        Most of the α-synuclein present in normal brain is soluble in aqueous buffer or easily extractable in detergent.  In contrast, most of the α-synuclein in brains containing Lewy bodies is found in the detergent-insoluble fraction.  Kahle et al. confirmed these finding and also showed that brains from mice transfected with human wild-type alpha-synuclein also contained the detergent-insoluble form.  Of interest, Campbell et al., found alpha-synuclein only in the water- and detergent-soluble fractions in brains of four patients with multiple system atrophy, but not in the detergent-insoluble fraction.  Thus, several lines of evidence suggest that α-synuclein is implicated in the pathophysiology of multiple system atrophy, but the mechanism of action and differences with Lewy body diseases is not completely clear.
        Stefanova N, Klimaschewski L, Poewe W, et al. (2001) Glial cell death induced by overexpression of α-synuclein.  J Neurosci Res 65:432-438.
       
Kahle PJ, Neumann M, Ozmen L, et al.  (2001) Selective insolubility of α-synuclein in human Lewy body dieases is recapitulated in a transgenic mouse model.  Am J Pathol 159:2215-2225.
        Campbell BCV, McLean CA, Culvenor JG, et al.  (2001) The solubility of α-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease.  J Neurochem 76:87-96.

Can a vitamin improve diabetic autonomic neuropathy? <<
       
Type 2 diabetes is associated with elevated oxidative stress, which may arguably contribute to the pathophysiology of this disease.  Vitamin E is thought to have antioxidant effects and Manzella et al. treated 50 patients with 600 mg/d vitamin E or placebo for 4 months to determine if improvement in metabolism and autonomic function would be observed.  Chronic vitamin E administration was associated with improvement in glycated hemoglobin, and decreased plasma insulin, norepinephrine and epinephrine.  The high frequency component of heart rate variability was increased by vitamin E.  If confirmed, these results would indicate a novel therapeutic approach for the treatment of diabetic autonomic neuropathy.
        Manzella D, Barbieri M, Ragno E, Paolisso G (2001) Chronic administration of pharmacologic     doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes.  Am J Clin Nutr 73:1052-1057.

Cardiac sympathetic activity in heart failure; too much or too little of a good thing? <<
   
    Whole body and cardiac sympathetic nerve activity are increased in heart failure and are indicators of poor outcome.  Brunner-La Rocca et al. performed detailed cardiac catecholamine kinetics in 116 patients with heart failure, and correlated findings to subsequent mortality.  The authors concluded that the mode of death depended on the type of cardiac sympathetic abnormality.  Patients who had increased cardiac norepinephrine spillover were at greater risk of sudden death, particularly if cardiac sympathetic innervation was intact (as determine by measurements of intraneuronal metabolism of labeled norepinephrine).  Conversely, death due to progression of heart failure was associated with depletion of sympathetic nerves, particularly if norepinephrine release remained paradoxically high.  These results would suggest that reducing sympathetic activity and/or blocking β-adrenoreceptors would be beneficial in heart failure.  The non-selective beta-blocker carvediolol has been particularly useful in reducing mortality in heart failure patients, but the mechanism of action is not completely understood.  Azevedo et al. compared carvedilol to the selective beta1-selective antagonist metoprolol on systemic and cardiac sympathetic activity in 36 patients with heart failure.  Carvedilol, but not metoprolol, decreased systemic and cardiac norepinephrine spillover.  This was not a central effect reducing sympathetic outflow, because it was not accompanied by a corresponding reduction in muscle sympathetic nerve activity.  These results imply that carvedilol acts on presynaptic beta2-adrenoreceptors to decrease norepinephrine release.  It should be noted, however, that Kaye et al. (Hypertension 2001;37:1216-1221) did not observed a reduction in cardiac spillover during treatment with carvedilol (see Autonomic News, Clin Auton Res 2001;11:276).  The reasons for this discrepancy are not apparent.
       
Brunner-La Rocca HP, Esler MD, Jennings GL, Kaye DM (2001)  Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure.  Eur Heart J 22;1136-1143.
        Azevedo ER, Kubo T, Mak S, et al (2001) Nonselective versus selective β-adrenergic receptor blockade in congestive heart failure.  Differential effects on sympathetic activity. Circulation 104:2194-2199.

Adaptation of the autonomic nervous system to microgravity and it role in orthostatic intolerance post-spaceflight.  <<
       
A major role of the autonomic nervous system (ANS) is to adapt to changes in the external environment.  On earth, the ANS is important in adaptating to changes in gravitational forces, e.g., when going from the supine to upright posture.  Heretofore, it has not been clear how the ANS adapts to microgravity during spaceflight, and if this adaptation contributes to the orthostatic intolerance seen post-flight.  This series of articles report the most detailed investigation to-date of ANS function during spaceflight and in the immediate post-flight period.  These studies were part of Neurolab, a shuttle spaceflight dedicated by NASA to neurobiology research.  Ertl et al. measured norepinephrine spillover using tritriated norepinephrine, and sympathetic nerve traffic using microneurography and found that resting sympathetic activity is increased during space flight.  This is contrary to the widely held expectation that the headward fluid shifts induced by microgravity would produce sympathoinhibition.  Furthermore, the sympathetic response to simulated upright posture, using lower body negative pressure, was preserved in space.  Cox et al. found a greater decrease in blood pressure during phase II of the Valsalva maneuver in space, most likely due to the known decrease in plasma volume that occurs in space.  This decrease in blood pressure was associated with a corresponding increase in sympathetic nerve activity, so that sympathetic “baroreflex gain” was similar on earth and in space.  Levine et al, examined the hemodynamic and autonomic response to upright tilt in the immediate post-space flight period.  Stroke volume was lower during tilt, but this was associated with an appropriate increase in muscle sympathetic nerve activity.  Of note, orthostatic intolerance did not occur in any of the five subjects examined during 60º tilt, whereas it occurs in about two thirds of astronauts during active standing.  Thus, the autonomic nervous system adapts well to the exposure to microgravity of space travel with appropriate responses in space and on earth.  It is unlikely that post-flight orthostatic intolerance is due to a primary alteration of the autonomic nervous system, but occurs when adaptive processes are overcome.
        Cox JF, Tahvanainen KUO, Kuusela TA, et al. (2002) Influence of microgravity on astronauts’ sympathetic and vagal response to Valsalva’s manoeuvre.  J Physiol 538:309-320.
        Ertl AC, Diedrich A, Biaggioni I, et al. (2002) Human muscle sympathetic nerve activity and plasma noradrenaline kinetics in space.  J Physiol 538:321-329.
        Levine BD, Pawelcyk JA, Ertl AC. (2002) Human muscle sympathetic neural and haemodynamic responses to tilt following spaceflight.  J Physiol 538:331-340.
        See also editorial about these articles by Wieling W, Halliwill JR and Karemaker JM (2002) J Physiol 538:1.

Evidence for an “otoreflex” in humans  <<
       
The autonomic nervous system plays a pivotal role in the maintenance of blood pressure during upright posture.  Sympathetic nerve traffic increases substantially on standing, resulting in a doubling of plasma norepinephrine, increased vascular resistance and cardiac function.  Activation of baroreptors constitutes a major afferent limb of this reflex response.  Unloading and activation of baroreceptors, however, occur only after venous or arterial pressures have already decreased, a classic feedback mechanism.  Kaufmann et al., report on an otolith-sympathetic reflex that may constitute a feedforward postural mechanism designed to increase sympathetic tone on standing.  The otoliths, located in the vestibular apparatus of the inner ear, are true gravity receptors and are activated as the head moves forward during standing.  Studies in animals have shown that afferents arising from the otoliths send projections, through vestibular nuclei, to brainstem centers regulating autonomic outflow (for review see Yates BJ, et al. (2000) Brain Res Bull 53:3-9).  Kaufmann used off-vertical axis steady state rotation (OVAR) around the coronal plane in normal volunteers to induce selective otolith stimulation in a sinusoidal fashion.  Muscle sympathetic nerve activity (MSNA) was monitored continuously during rotation using technology developed by NASA for the Neurolab mission (see above).  MSNA was not altered by on axis chair rotation (which does not stimulate the otoliths), but became entrained to the frequency of OVAR rotation.  Maximal MSNA activity coincided with the head up position, with a lag time of 0.4 seconds, consistent with the conduction delay of a response originating in the vestibular system.  Thus, gravireceptors, such as the otoliths, may be the initial afferent signal arising from head forward movements that signals autonomic centers to increase sympathetic tone in preparation to standing, a novel feedforward mechanism.
        Kaufmann H, Biaggioni I, Voustianiouk A, et al.  Vestibular control of sympathetic activity. An otholith-sympathetic reflex in humans.  Exp Brain Res 2002; 143:463-469. 


Stefanova N, Klimaschewski L, Poewe W, Wenning GK, Reindl M (2001). Glial cell death induced by overexpression of alpha-synuclein. Journal of Neuroscience Research.65:432-438.

Abstract: alpha-Synuclein is present in intracellular protein aggregates that are hallmarks of common neurodegenerative disorders including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. alpha-Synuclein is localized in neurons and presynaptic terminals. Under pathological conditions, however, it is also found in glia. The role of alpha-synuclein in glial cells and its relevance to the molecular pathology of neurodegenerative diseases is presently unclear. To investigate the consequence of alpha-synuclein overexpression in glia, we transfected U373 astrocytoma cells with vectors encoding wild-type human alpha-synuclein or C-terminally truncated synuclein fused to red fluorescent protein. alpha-synuclein immunocytochemistry of transfected astroglial cells revealed diffuse cytoplasmic labeling associated with discrete inclusions both within cell bodies and processes. Susceptibility to oxidative stress was increased in astroglial cells overexpressing alpha-synuclein, particularly in the presence of cytoplasmic inclusions. Furthermore, overexpression of alpha-synuclein induced apoptotic death of astroglial cells as shown by TUNEL staining. Our in vitro model is the first to replicate salient features of the glial pathology associated with alpha-synucleinopathies. It provides a simple testbed to further explore the cascade of events that leads to apoptotic glial cell death in some of these disorders; it may also be useful to assess the effects of therapeutic interventions including antioxidative and antiapoptotic strategies.

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Kahle PJ, Neumann M, Ozmen L et al (2002). Hyperphosphorylation and insolubility of {alpha}-synuclein in transgenic mouse oligodendrocytes. EMBO Rep.3:583-588.

Abstract: (Oligodendro)glial cytoplasmic inclusions composed of alpha-synuclein (alphaSYN) characterize multiple system atrophy (MSA). Mature oligodendrocytes (OLs) do not normally express alphaSYN, so MSA pathology may arise from aberrant expression of alphaSYN in OLs. To study pathological deposition of alphaSYN in OLs, transgenic mice were generated in which human wild-type alphaSYN was driven by a proteolipid protein promoter. Transgenic alphaSYN was detected in OLs but no other brain cell type. At the light microscopic level, the transgenic alphaSYN profiles resembled glial cytoplasmic inclusions. Strikingly, the diagnostic hyperphosphorylation at S129 of alphaSYN was reproduced in the transgenic mice. A significant proportion of the transgenic alphaSYN was detergent insoluble, as in MSA patients. The histological and biochemical abnormalities were specific for the disease-relevant alphaSYN because control green fluorescent protein was fully soluble and evenly distributed throughout OL cell bodies and processes. Thus, ectopic expression alphaSYN in OLs might initiate salient features of MSA pathology

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Campbell BC, McLean CA, Culvenor JG et al (2001). The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease. J Neurochem.76:87-96.

Abstract: Intracellular inclusions containing alpha-synuclein (alphaSN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of alphaSN, this study compared the levels, solubility and molecular weight species of alphaSN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble alphaSN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had significantly higher levels of alphaSN in the detergent-soluble fraction of brain samples from pons and white matter but detergent-insoluble alphaSN was not detected. There was an inverse correlation between buffered saline-soluble and detergent-soluble levels of alphaSN in individual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of alphaSN between grey and white matter in disease may result from different processing of alphaSN in neurons compared with oligodendrocytes. Highly insoluble alphaSN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of alphaSN are involved in the pathogenesis of other alphaSN-related diseases

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Manzella D, Barbieri M, Ragno E, Paolisso G (2001). Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. American Journal of Clinical Nutrition.73:1052-1057.

Abstract: BACKGROUND: Type 2 diabetes is associated with elevated oxidative stress and declines in antioxidant defense. The disease is also characterized by an imbalance in the ratio of cardiac sympathetic to parasympathetic tone. Antioxidants, vitamin E in particular, may have beneficial effects on the cardiac autonomic nervous system through a decline in oxidative stress. OBJECTIVE: We investigated the possible effects of vitamin E on the cardiac autonomic nervous system, as assessed by analysis of heart rate variability, in patients with type 2 diabetes and cardiac autonomic neuropathy. DESIGN: In a double-blind randomized controlled trial, 50 patients with type 2 diabetes were assigned to treatment with vitamin E (600 mg/d) or placebo for 4 mo. RESULTS: The anthropometric characteristics of the patients remained unchanged throughout the study. Chronic vitamin E administration was associated with decreases in concentrations of glycated hemoglobin (P < 0.05), plasma insulin (P < 0.05), norepinephrine (P < 0.03), and epinephrine (P < 0.02); a lower homeostasis model assessment index (P < 0.05); and improved indexes of oxidative stress. Furthermore, vitamin E administration was associated with increases in the R-R interval (P < 0.05), total power (P < 0.05), and the high-frequency component of heart rate variability (HF; P < 0.05) and decreases in the low-frequency component (LF; P < 0.05) and the ratio of LF to HF (P < 0.05). Finally, change in the plasma vitamin E concentration was correlated with change in the LF-HF ratio (r = -0.43, P < 0.04) independently of changes in the homeostasis model assessment index and plasma catecholamines concentrations. CONCLUSIONS: Chronic vitamin E administration improves the ratio of cardiac sympathetic to parasympathetic tone in patients with type 2 diabetes. Such an effect might be mediated by a decline in oxidative stress

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Brunner-La Rocca HP, Esler MD, Jennings GL, Kaye DM (2001). Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure. [see comments.]. European Heart Journal.22:1136-1143.

Abstract: AIMS: To investigate whether strong cardiac sympathetic activity contributes primarily to sudden death or to worsening heart failure, and to determine the relationship of the size of cardiac noradrenaline stores to the mode of death. METHODS AND RESULTS: The study population comprised 116 patients with congestive heart failure (ejection fraction 19+/-7%) and a mean follow-up of 18+/-19 months. Cardiac sympathetic nervous function was measured using coronary sinus blood sampling and noradrenaline isotope dilution methodology. Cardiac sympathetic activity was estimated from cardiac noradrenaline spillover, and noradrenaline stores from the overflow of the tritiated noradrenaline metabolite [(3)H]dihydroxyphenylglycol, which is produced by monoamine oxidase inside nerve endings. Small cardiac noradrenaline stores (below median) predicted death from worsening heart failure (hazard ratio=4.18, P<0.05), particularly if cardiac noradrenaline spillover was elevated (hazard ratio=2.36 per tertile, P<0.01), indicating progression of disease associated with defective sympathetic innervation. In contrast, large stores (hazard ratio=2.81, P<0.05), especially if coupled with increased noradrenaline spillover (hazard ratio=1.64 per tertile, P<0.05), were related to sudden death. CONCLUSION: High cardiac sympathetic activity is a risk factor for sudden death, particularly in the presence of intact cardiac sympathetic innervation. Conversely, progression of myocardial disease and heart failure is closely associated with depletion of sympathetic nerves in the heart, especially if rates of noradrenaline release paradoxically remain high. Copyright 2001 The European Society of Cardiology

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Azevedo ER, Kubo T, Mak S et al (2001). Nonselective versus selective beta-adrenergic receptor blockade in congestive heart failure: differential effects on sympathetic activity. Circulation.104:2194-2199.

Abstract: BACKGROUND: Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective beta-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional beta(2)-adrenergic receptors. METHODS AND RESULTS: Thirty-six patients with chronic heart failure were randomized to the nonselective beta-blocker carvedilol or the selective beta-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (n=17), there were significant reductions in both total body (-1.7+/-0.5 nmol/min, P<0.01) and cardiac norepinephrine spillover (-87+/-29 pmol/min, P<0.01). By contrast, in the metoprolol group (n=14), there were no significant changes in total body or cardiac norepinephrine spillover. Responses in the carvedilol group were significantly different from those observed in the metoprolol group (P<0.05). Both agents caused a reduction in heart rate and increases in pulse pressure, although mean arterial pressure did not change. Importantly, microneurographic measures of sympathetic nerve traffic to skeletal muscle did not change in either group. CONCLUSIONS: Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective beta-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional beta-adrenergic receptors

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Cox JF, Tahvanainen KU, Kuusela TA et al (2002). Influence of microgravity on astronauts' sympathetic and vagal responses to Valsalva's manoeuvre. [see comments.]. Journal of Physiology.538:1-20.

Abstract: When astronauts return to Earth and stand, their heart rates may speed inordinately, their blood pressures may fall, and some may experience frank syncope. We studied brief autonomic and haemodynamic transients provoked by graded Valsalva manoeuvres in astronauts on Earth and in space, and tested the hypothesis that exposure to microgravity impairs sympathetic as well as vagal baroreflex responses. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, respiration and peroneal nerve muscle sympathetic activity in four healthy male astronauts (aged 38-44 years) before, during and after the 16 day Neurolab space shuttle mission. Astronauts performed two 15 s Valsalva manoeuvres at each pressure, 15 and 30 mmHg, in random order. Although no astronaut experienced presyncope after the mission, microgravity provoked major changes. For example, the average systolic pressure reduction during 30 mmHg straining was 27 mmHg pre-flight and 49 mmHg in flight. Increases in muscle sympathetic nerve activity during straining were also much greater in space than on Earth. For example, mean normalized sympathetic activity increased 445% during 30 mmHg straining on earth and 792% in space. However, sympathetic baroreflex gain, taken as the integrated sympathetic response divided by the maximum diastolic pressure reduction during straining, was the same in space and on Earth. In contrast, vagal baroreflex gain, particularly during arterial pressure reductions, was diminished in space. This and earlier research suggest that exposure of healthy humans to microgravity augments arterial pressure and sympathetic responses to Valsalva straining and differentially reduces vagal, but not sympathetic baroreflex gain

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Ertl AC, Diedrich A, Biaggioni I et al (2002). Human muscle sympathetic nerve activity and plasma noradrenaline kinetics in space. [see comments.]. Journal of Physiology.538:1-9.

Abstract: Astronauts returning from space have reduced red blood cell masses, hypovolaemia and orthostatic intolerance, marked by greater cardio-acceleration during standing than before spaceflight, and in some, orthostatic hypotension and presyncope. Adaptation of the sympathetic nervous system occurring during spaceflight may be responsible for these postflight alterations. We tested the hypotheses that exposure to microgravity reduces sympathetic neural outflow and impairs sympathetic neural responses to orthostatic stress. We measured heart rate, photoplethysmographic finger arterial pressure, peroneal nerve muscle sympathetic activity and plasma noradrenaline spillover and clearance, in male astronauts before, during (flight day 12 or 13) and after the 16 day Neurolab space shuttle mission. Measurements were made during supine rest and orthostatic stress, as simulated on Earth and in space by 7 min periods of 15 and 30 mmHg lower body suction. Mean (+/- S.E.M.) heart rates before lower body suction were similar pre-flight and in flight. Heart rate responses to -30 mmHg were greater in flight (from 56 +/- 4 to 72 +/- 4 beats min(-1)) than pre-flight (from 56 +/- 4 at rest to 62 +/- 4 beats min(-1), P < 0.05). Noradrenaline spillover and clearance were increased from pre-flight levels during baseline periods and during lower body suction, both in flight (n = 3) and on post-flight days 1 or 2 (n = 5, P < 0.05). In-flight baseline sympathetic nerve activity was increased above pre-flight levels (by 10-33 %) in the same three subjects in whom noradrenaline spillover and clearance were increased. The sympathetic response to 30 mmHg lower body suction was at pre-flight levels or higher in each subject (35 pre-flight vs. 40 bursts min(-1) in flight). No astronaut experienced presyncope during lower body suction in space (or during upright tilt following the Neurolab mission). We conclude that in space, baseline sympathetic neural outflow is increased moderately and sympathetic responses to lower body suction are exaggerated. Therefore, notwithstanding hypovolaemia, astronauts respond normally to simulated orthostatic stress and are able to maintain their arterial pressures at normal levels

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Levine BD, Pawelczyk JA, Ertl AC et al (2002). Human muscle sympathetic neural and haemodynamic responses to tilt following spaceflight. [see comments.]. Journal of Physiology.538:1-40.

Abstract: Orthostatic intolerance is common when astronauts return to Earth: after brief spaceflight, up to two-thirds are unable to remain standing for 10 min. Previous research suggests that susceptible individuals are unable to increase their systemic vascular resistance and plasma noradrenaline concentrations above pre-flight upright levels. In this study, we tested the hypothesis that adaptation to the microgravity of space impairs sympathetic neural responses to upright posture on Earth. We studied six astronauts approximately 72 and 23 days before and on landing day after the 16 day Neurolab space shuttle mission. We measured heart rate, arterial pressure and cardiac output, and calculated stroke volume and total peripheral resistance, during supine rest and 10 min of 60 deg upright tilt. Muscle sympathetic nerve activity was recorded in five subjects, as a direct measure of sympathetic nervous system responses. As in previous studies, mean (+/- S.E.M.) stroke volume was lower (46 +/- 5 vs. 76 +/- 3 ml, P = 0.017) and heart rate was higher (93 +/- 1 vs. 74 +/- 4 beats min(-1), P = 0.002) during tilt after spaceflight than before spaceflight. Total peripheral resistance during tilt post flight was higher in some, but not all astronauts (1674 +/- 256 vs. 1372 +/- 62 dynes s cm(-5), P = 0.32). No crew member exhibited orthostatic hypotension or presyncopal symptoms during the 10 min of postflight tilting. Muscle sympathetic nerve activity was higher post flight in all subjects, in supine (27 +/- 4 vs. 17 +/- 2 bursts min(-1), P = 0.04) and tilted (46 +/- 4 vs. 38 +/- 3 bursts min(-1), P = 0.01) positions. A strong (r(2) = 0.91-1.00) linear correlation between left ventricular stroke volume and muscle sympathetic nerve activity suggested that sympathetic responses were appropriate for the haemodynamic challenge of upright tilt and were unaffected by spaceflight. We conclude that after 16 days of spaceflight, muscle sympathetic nerve responses to upright tilt are normal

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Wieling W, Halliwill JR, Karemaker JM (2002). Orthostatic intolerance after space flight. [letter; comment.]. Journal of Physiology.538:1.

Abstract: Physiologists have always been challenged by the adjustments of the human body to hostile environments. The set of papers in this issue of The Journal of Physiology (Cox et al. 2002; Ertl et al. 2002; Levine et al. 2002) fits into the tradition of the study of human responses to extreme physical circumstances. The Neurolab project represents a huge undertaking that required major contributions from many different collaborators, and the coordination of efforts at different institutions. The studies succeeded because of the dedication and years of work of the astronauts involved. The manuscripts present the fundamental findings from the first direct recordings of sympathetic vasoconstrictor nerves and noradrenaline kinetics in humans during microgravity. Despite the difficulties of performing such measurements on the space shuttle and the small numbers of astronauts involved, unique data are set forth that represent a major advance in our understanding of the physiology of space flight

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Kaufmann H, Biaggioni I, Voustianiouk A et al (2002). Vestibular control of sympathetic activity. An otolith-sympathetic reflex in humans. Experimental Brain Research.143:463-469.

Abstract: It has been proposed that a vestibular reflex originating in the otolith organs and other body graviceptors modulates sympathetic activity during changes in posture with regard to gravity. To test this hypothesis, we selectively stimulated otolith and body graviceptors sinusoidally along different head axes in the coronal plane with off-vertical axis rotation (OVAR) and recorded sympathetic efferent activity in the peroneal nerve (muscle sympathetic nerve activity, MSNA), blood pressure, heart rate, and respiratory rate. All parameters were entrained during OVAR at the frequency of rotation, with MSNA increasing in nose-up positions during forward linear acceleration and decreasing when nose-down. MSNA was correlated closely with blood pressure when subjects were within +/-90 degrees of nose-down positions with a delay of 1.4 s, the normal latency of baroreflex-driven changes in MSNA. Thus, in the nose-down position, MSNA was probably driven by baroreflex afferents. In contrast, when subjects were within +/-45 degrees of the nose-up position, i.e., when positive linear acceleration was maximal along the naso-ocipital axis, MSNA was closely related to gravitational acceleration at a latency of 0.4 s. This delay is too short for MSNA changes to be mediated by the baroreflex, but it is compatible with the delay of a response originating in the vestibular system. We postulate that a vestibulosympathetic reflex, probably originating mainly in the otolith organs, contributes to blood pressure maintenance during forward linear acceleration. Because of its short latency, this reflex may be one of the earliest mechanisms to sustain blood pressure upon standing

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