The aim of this proposal is to determine the effect of microgravity on the autonomic nervous system, combining physiologic, biochemical, and pharmacological approaches. The hypothesis of this proposal is that altered autonomic nervous system function occurs in weightlessness and is responsible for many of the physiologic response to microgravity. The proposal has specific aims as follows: 1) To determine if human subjects adapt to microgravity with a reduction in sympathetic activity. 2) To determine the role of afferent/central mechanisms in the adaptation of the autonomic nervous system to microgravity. 3) To determine if the decrease in plasma norepinephrine produced by microgravity is due to inhibition of norepinephrine release or enhanced norepinephrine clearance. 4) To determine the effect of microgravity on postsynaptic adrenoreceptor sensitivity. 5) To determine the autonomic neuropharmacology of promethazine, which is often used as anti-nausea in space flight. In the ground-based, preflight, and the Neurolab mission, plasma and urinary catecholamines and their metabolites will be assayed using HPLC with electrochemical detection, to define circulating levels of norepinephrine, epinephrine and dopamine, their response to exercise, and their intra- and extra-neural metabolism. Tracer doses of tritiated norepinephrine will be administered to assess norepinephrine spillover and determine whether alterations in clearance or release are responsible for the decreased plasma levels seen during space flight. Sympathetic nerve traffic will be directly measured with microneurography and compare the response of efferent sympathetic activity to physiologic stimuli such as carotid baroreflex, loading and unloading with a neck chamber and skeletal muscle afferent stimulation with isometric and isotonic forearm exercise. Sympathetic baroreflex function will be tested with pharmacologic stimuli (phenylephrine and nitroprusside). The number of affinity of beta-adrenergic receptors on lymphocytes and alpha 2- adrenergic receptors on platelet will be also measured before and during exposure to microgravity. Isoproterenol and phenylephrine will be used to quantitated the sensitivity of alpha 1 and beta-adrenergic receptors function. Finally, the effect of promethazine will be defined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS033460-03
Application #
2445826
Study Section
Special Emphasis Panel (SSS (S6))
Program Officer
Heetderks, William J
Project Start
1995-09-20
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Moore, Steven T; Diedrich, Andre; Biaggioni, Italo et al. (2005) Artificial gravity: a possible countermeasure for post-flight orthostatic intolerance. Acta Astronaut 56:867-76
Oeltmann, Timothy; Carson, Robert; Shannon, John R et al. (2004) Assessment of O-methylated catecholamine levels in plasma and urine for diagnosis of autonomic disorders. Auton Neurosci 116:1-10
Eckberg, D L; Neurolab Autonomic Nervous System Team (2003) Bursting into space: alterations of sympathetic control by space travel. Acta Physiol Scand 177:299-311
Parikh, Samir M; Diedrich, Andre; Biaggioni, Italo et al. (2002) The nature of the autonomic dysfunction in multiple system atrophy. J Neurol Sci 200:1-10
Shannon, John R; Diedrich, Andre; Biaggioni, Italo et al. (2002) Water drinking as a treatment for orthostatic syndromes. Am J Med 112:355-60
Diedrich, Andre; Jordan, Jens; Shannon, John R et al. (2002) Modulation of QT interval during autonomic nervous system blockade in humans. Circulation 106:2238-43
Jordan, Jens; Shannon, John R; Diedrich, Andre et al. (2002) Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity. Hypertension 39:173-8
Ertl, Andrew C; Diedrich, Andre; Biaggioni, Italo et al. (2002) Human muscle sympathetic nerve activity and plasma noradrenaline kinetics in space. J Physiol 538:321-9
Kim, Chun-Hyung; Zabetian, Cyrus P; Cubells, Joseph F et al. (2002) Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency. Am J Med Genet 108:140-7
Ketch, Terry; Biaggioni, Italo; Robertson, RoseMarie et al. (2002) Four faces of baroreflex failure: hypertensive crisis, volatile hypertension, orthostatic tachycardia, and malignant vagotonia. Circulation 105:2518-23

Showing the most recent 10 out of 39 publications