Mechanisms of postspaceflight orthostatic hypotension: low α₁-adrenergic receptor responses before flight and central autonomic dysregulation postflight

Abstract

Although all astronauts experience symptoms of orthostatic intolerance after short-duration spaceflight, only approximately 20% actually experience presyncope during upright posture on landing day. The presyncopal group is characterized by low vascular resistance before and after flight and low norepinephrine release during orthostatic stress on landing day. Our purpose was to determine the mechanisms of the differences between presyncopal and nonpresyncopal groups. We studied 23 astronauts 10 days before launch, on landing day, and 3 days after landing. We measured pressor responses to phenylephrine injections; norepinephrine release with tyramine injections; plasma volumes; resting plasma levels of chromogranin A (a marker of sympathetic nerve terminal release), endothelin, dihydroxyphenylglycol (DHPG, an intracellular metabolite of norepinephrine); and lymphocyte beta(2)-adrenergic receptors. We then measured hemodynamic and neurohumoral responses to upright tilt. Astronauts were separated into two groups according to their ability to complete 10 min of upright tilt on landing day. Compared with astronauts who were not presyncopal on landing day, presyncopal astronauts had 1). significantly smaller pressor responses to phenylephrine both before and after flight; 2). significantly smaller baseline norepinephrine, but significantly greater DHPG levels, on landing day; 3). significantly greater norepinephrine release with tyramine on landing day; and 4). significantly smaller norepinephrine release, but significantly greater epinephrine and arginine vasopressin release, with upright tilt on landing day. These data suggest that the etiology of orthostatic hypotension and presyncope after spaceflight includes low alpha(1)-adrenergic receptor responsiveness before flight and a remodeling of the central nervous system during spaceflight such that sympathetic responses to baroreceptor input become impaired.

Regulation of plasma vasopressin and renin activity in conscious hindlimb-unloaded rats

“…Increased circulating vasopressin may serve to compensate for blunted baroreflex regulation of sympathetic nervous activity produced by hindlimb unloading or may actually contribute to it. neurohumoral control; antidiuretic hormone; renin-angiotensin system ASTRONAUTS RETURNING FROM space, or individuals recovering from prolonged bed rest often experience symptoms of orthostatic intolerance (5,8,16,31,54,65). To delineate the possible mechanisms mediating orthostatic intolerance, individuals have been categorized as presyncopal or nonpresyncopal (17, 31, 66), finishers and nonfinishers (5), or simply, orthostatic tolerant and intolerant (54).…”

“…In addition to the activation of the sympathetic nervous system, increases in circulating vasoconstrictor agents, such as AVP and ANG II, occur in response to an orthostatic challenge, especially when prolonged, or blood pressure begins to decrease (47, 48). Therefore, the compensatory response to an orthostatic challenge uses both neural and humorally mediated vasoconstriction as a means to maintain arterial pressure.Although orthostatic intolerance and baroreflex dysfunction do not always occur after spaceflight (25) or bed rest (41), previous work does indicate a relationship between the presence of orthostatic intolerance in certain individuals and the attenuation of baroreflex control of sympathetic activity (12,17,31,54). In addition, hindlimb unloading in rats, which simulates the effect of spaceflight or bed rest (21, 36), also produces blunted baroreflex activation of the sympathetic nervous system (14,34).…”

Stimulation of brain mast cells by compound 48/80, a histamine liberator, evokes renin and vasopressin release in dogs

“…Such potentiation of the increases in ADH and NE might be due to the cardiovascular-regulating system showing compensatory or hypersensitive responses as a result of a lack of afferent inflow from the kidneys. Such enhancements in ADH and plasma NE responses have been seen in spaceflight (45) and in hindlimbunloaded animals (49,64). Indeed, mechano-and chemosensitive information transmitted from the kidneys to the paraventricular nucleus (PVN) of the hypothalamus via the renal afferent nerves has been shown to contribute to the modulation of ADH release (14,58,60).…”

Understanding post-spaceflight orthostatic intolerance - a simulation study

“…Of particular importance are perturbations to the α-sympathetically mediated reflex pathways of arteriolar resistance and venous tone, both of which depend on the peripheral neurotransmitter norepinephrine (NE). Meck and co-workers [7] have recently demonstrated that astronauts who become pre-syncopal on landing day fail to mount a significant vasoconstrictor response due to an inappropriately low release of NE in the upright posture. Our simulations suggest that in volumecompromised individuals failure to constrict arteries and veins leads to serious reductions in MAP in the upright posture.…”