Results for “Agonists” — Page 13

NASA NTRS2006

Hemodynamic Effects of Midodrine After Space Flight in Astronauts Without Orthostatic Hypotension

Orthostatic hypotension and presyncope are common and potentially serious risks for astronauts returning from space. Susceptible subjects fail to generate an adequate adrenergic response to upright posture. The -1 adrenergic agonist, midodrine, may be an effective countermeasure. We tested the hypothesis that midodrine would have no negative hemodynamic effect on healthy astronauts returning from space. Five male astronauts participated in preflight and postflight tilt testing on a control flight as well as on the test flights, where midodrine (10 mg, orally) was administered after landing, approximately 1 hour before testing. None of these astronauts exhibited orthostatic hypotension or presyncope before or after either flight. Midodrine did not cause any untoward reactions in these subjects before or after flight, in fact a modest beneficial effect was seen on postflight tachycardia (p=0.036). These data show that midodrine protected against post-spaceflight increases in heart rate, without having any adverse hemodynamic effects on non-presyncopal, male astronauts. Among these subjects, midodrine was a safe cardiovascular countermeasure.

Platts, Steven H.↗

NASA NTRS2017

MS Non-Pharmacological Countermeasure to Decrease Landing Sickness and Improve Functional Performance While Disorientad

Upon return from spaceflight, a majority of crewmembers experience motion sickness (MS) symptoms. The interactions between crewmembers' adaptation to a gravitational transition, the performance decrements resulting from MS and/or use of promethazine (PMZ), and the constraints imposed by mission task demands could significantly challenge and limit an astronaut's ability to perform functional tasks during gravitational transitions. No operational countermeasure currently exists to mitigate the risks associated with these sensorimotor disturbances. Stochastic resonance (SR) can be thought of simply as "noise benefit" or an increase in information transfer by a system when in the presence of a non-zero level of noise. We have shown that low levels of stochastic vestibular stimulation (SVS) improve balance and locomotor performance due to SR (Goel et al. 2015, Mulavara et al. 2011, 2015). Additionally, a study in a 6-hydroxydopamine (6-OHDA) hemi-lesioned rat model of Parkinson's disease demonstrated improvements in locomotor activity after low-level SVS delivery possibly due to an increase in nigral gamma-aminobutyric acid (GABA) release in a dopamine independent way (Samoudi et al. 2012). SVS specifically increased GABA release on the lesioned, but not the intact side. These results suggest that SVS can cause targeted alterations of GABA release to affect performance of functional tasks. Activation of the GABA pathway is important in modulating MS and promoting adaptability (Cohen 2008). Magnusson et al. (2000) supported this finding by showing that the administration of a GABAB agonist caused a reversal of the symptoms that is normally seen after unilateral labyrinthectomy. Thus, GABA could play a significant role in reducing MS and promoting adaptability. We have taken advantage of the SR mechanism as a modulator of neurotransmitters to develop a unique SVS countermeasure system to mitigate MS symptoms and improve functional performance after landing. Healthy subjects (n=20) participated in two test sessions, one in which they received +/-400 microA of SVS and one where they received no stimulation (0 microA); the study design was counterbalanced. Subjects began by performing a series of four functional tasks 3-5 times as baseline measurements of task performance. Then, to induce MS, subjects walked an obstacle course with up-down reversing prisms. If they completed the course before achieving our pre-determined level of MS, they were asked to read a poster while making large up-down head movements to a metronome while still wearing the reversing prism goggles. Subjects were stopped every two minutes and asked to report their MS symptoms. Using the Pensacola Scale for motion sickness, test operators evaluated the level of MS of each subject. Once a subject reached an 8 on this scale, which is equivalent to mild malaise, or 30 minutes had passed since the start of the MS induction, this protocol was stopped. Finally, immediately after MS induction, subjects were asked to complete the four functional tasks again. Although, 100% of our subjects experienced at least one MS symptom, only 55% of our subjects experienced stomach awareness to any degree. Without SVS, only 40% of subjects lasted the full 30-minute MS induction protocol, while 65% of subjects lasted the full 30 minutes with SVS, which is nearly a significant increase (p=0.056). In addition, subjects showed significant improvement from baseline when performing a tandem walk and a prone-to-stand test immediately after the MS induction protocol was stopped but the stimulation level was continued. The results are promising and future work includes comparing MS progression between PMZ and SVS directly in subjects that are provoked to a minimum of nausea. Low levels of SVS stimulation may serve as a non-pharmacological countermeasure to replace or reduce the PMZ dosage requirements and concurrently improve functional performance during transitions to new gravitational environments after spaceflight.

Rosenberg, M. J. F.↗

NASA NTRSDate not supplied

Role of PIEZO1 in T Cell Activation Under Simulated Microgravity

True and simulated microgravity conditions have been well documented to cause the inhibition of T cell activation by mitogens. Although several studies aimed at exploring the mechanisms for such a phenomenon have been published, how this is occurring remains unresolved. PIEZO1 is a known mechanosensing gene and has been shown to be critically involved in human T cell activation. In our analysis of transcriptomics changes in peripheral mononuclear cells (PBMC) collected from the ISS crewmembers in space, the expression of PIEZO1 was downregulated. To investigate the role of the PIEZO1 gene in T cell activation in microgravity, we used rotating wall vessels (RWV), which simulate microgravity on the ground and are known to inhibit T cell activation. In this pilot study, PBMC cultured in RWV and in the static 1g condition were stimulated with Human T-Activator CD3/CD28 beads. The cells were also treated with and without Yoda1, a chemical agonist that activates PIEZO1 independent of mechanical cues or any other cellular component. After culturing for 24 hours, the cells were stained for activation markers and the PIEZO1 antibody, then were analyzed by flow cytometry. Our results indicate reduced T cell activation with mitogen under simulated microgravity, but no changes of the PIEZO1 signals were detected. In addition, the reduced activation was not restored in cells cultured with Yoda1. Taken together, our results suggest that PIEZO1 may play a minimal role in the inhibition of T cell activation in space.

Honglu Wu↗

NASA NTRSDate not supplied

Role of PIEZO1 in T Cell Activation Under Simulated Microgravity

True and simulated microgravity conditions have been well documented to cause the inhibition of T cell activation by mitogens. Although several studies aimed at exploring the mechanisms for such a phenomenon have been published, how this is occurring remains unresolved. PIEZO1 is a known mechanosensing gene and has been shown to be critically involved in human T cell activation. In our analysis of transcriptomics changes in peripheral mononuclear cells (PBMC) collected from the ISS crewmembers in space, the expression of PIEZO1 was downregulated. To investigate the role of the PIEZO1 gene in T cell activation in microgravity, we used rotating wall vessels (RWV), which simulate microgravity on the ground and are known to inhibit T cell activation. In this pilot study, PBMC cultured in RWV and in the static 1g condition were stimulated with Human T-Activator CD3/CD28 beads. The cells were also treated with and without Yoda1, a chemical agonist that activates PIEZO1 independent of mechanical cues or any other cellular component. After culturing for 24 hours, the cells were stained for activation markers and the PIEZO1 antibody, then were analyzed by flow cytometry. Our results indicate reduced T cell activation with mitogen under simulated microgravity, but no changes of the PIEZO1 signals were detected. In addition, the reduced activation was not restored in cells cultured with Yoda1. Taken together, our results suggest that PIEZO1 may play a minimal role in the inhibition of T cell activation in space.

Honglu Wu↗

NASA NTRSDate not supplied

Role of PIEZO1 in T Cell Activation Under Simulated Microgravity

True and simulated microgravity conditions have been well documented to cause the inhibition of T cell activation by mitogens. Although several studies aimed at exploring the mechanisms for such a phenomenon have been published, how this is occurring remains unresolved. PIEZO1 is a known mechanosensing gene and has been shown to be critically involved in human T cell activation. In our analysis of transcriptomics changes in peripheral mononuclear cells (PBMC) collected from the ISS crewmembers in space, the expression of PIEZO1 was downregulated. To investigate the role of the PIEZO1 gene in T cell activation in microgravity, we used rotating wall vessels (RWV), which simulate microgravity on the ground and are known to inhibit T cell activation. In this pilot study, PBMC cultured in RWV and in the static 1g condition were stimulated with Human T-Activator CD3/CD28 beads. The cells were also treated with and without Yoda1, a chemical agonist that activates PIEZO1 independent of mechanical cues or any other cellular component. After culturing for 24 hours, the cells were stained for activation markers and the PIEZO1 antibody, then were analyzed by flow cytometry. Our results indicate reduced T cell activation with mitogen under simulated microgravity, but no changes of the PIEZO1 signals were detected. In addition, the reduced activation was not restored in cells cultured with Yoda1. Taken together, our results suggest that PIEZO1 may play a minimal role in the inhibition of T cell activation in space.

Honglu Wu↗

DOE OSTI2024

Methods for promoting myelination and for treating demyelinating diseases

This invention provides novel methods for treating or ameliorating symptoms of demyelinating diseases such as multiple sclerosis. The methods involve administering to subjects in need of treatment a pharmaceutical composition that contains a therapeutically effective amount of taurine and also a compound that induces oligodendrocyte precursor cell (OPC) differentiation (e.g., T3, benztropine, clemastine or miconazole). Some of the methods additionally involve administration to the subject a known agent for treating demyelinating diseases (e.g., SIP receptor agonists) or a known disease modifying drug. The invention also provides methods for increasing myelination and methods for promoting OPC differentiation into oligodendrocytes. These methods entail contacting a population of OPCs with a combination of taurine and a known OPC differentiation-inducing agent such as T3, clemastine, benztropine or miconazole.

Lairson, Luke↗

NASA NTRS2002

Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity

Idiopathic orthostatic intolerance (OI) is characterized by adrenergic symptoms with standing. Changes in central sympathetic tone or in adrenoreceptor sensitivity could contribute to this syndrome. In OI patients and control subjects, we determined heart rate (HR) and systolic blood pressure (SBP) changes after incremental bolus doses of isoproterenol and phenylephrine before and during ganglionic blockade with trimethaphan. SBP decreased by 17+/-1.6 mm Hg in patients and 3.9+/-3.8 mm Hg in control subjects (P<0.01) with trimethaphan. Patients with a larger decrease (28+/-3.8 mm Hg, n=7) in SBP with trimethaphan had greater supine SBP and supine and upright plasma norepinephrine levels than did patients with a lesser decrease (3.0+/-3.0 mm Hg, n=7) in SBP. Supine and orthostatic HRs were similar for the groups. The majority of patients had a normal HR response to isoproterenol before and during ganglionic blockade. Phenylephrine increased SBP similarly in patients and control subjects before and during blockade. Sympathetic support is increased in a subgroup of OI patients. Hyperadrenergic and nonhyperadrenergic subgroups have similar degrees of orthostatic tachycardia. Our findings suggest that the hyperadrenergic features of OI cannot be completely explained by systemic hypersensitivity of postsynaptic alpha(1)- and beta-adrenoreceptors but rather originates in enhanced sympathetic activation.

Non-NASA Center↗

NASA NTRS2000

Dissociation between neural and vascular responses to sympathetic stimulation : contribution of local adrenergic receptor function

Sympathetic activation produced by various stimuli, eg, mental stress or handgrip, evokes regional vascular responses that are often nonhomogeneous. This phenomenon is believed to be the consequence of the recruitment of differential central neural pathways or of a sympathetically mediated vasodilation. The purpose of this study was to determine whether a similar heterogeneous response occurs with cold pressor stimulation and to test the hypothesis that local differences in adrenergic receptor function could be in part responsible for this diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow were measured in arms and legs at baseline and during sympathetic stimulation induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor stimulation. At baseline, legs had higher vascular resistance (27+/-5 versus 17+/-2 U, P=0.05) despite lower norepinephrine spillover (0.28+/-0.04 versus 0.4+/-0.05 mg. min(-1). dL(-1), P=0.03). Norepinephrine spillover increased similarly in both arms and legs during nitroprusside infusion and cold pressor stimulation. On the other hand, during cold stimulation, vascular resistance increased in arms but not in legs (20+/-9% versus -7+/-4%, P=0.03). Increasing doses of isoproterenol and phenylephrine were infused intra-arterially in arms and legs to estimate beta-mediated vasodilation and alpha-induced vasoconstriction, respectively. beta-Mediated vasodilation was significantly lower in legs compared with arms. Thus, we report a dissociation between norepinephrine spillover and vascular responses to cold stress in lower limbs characterized by a paradoxical decrease in local resistance despite increases in sympathetic activity. The differences observed in adrenergic receptor responses cannot explain this phenomenon.

NASA Discipline Regulatory Physiology↗

DOE OSTI2022

GPCR-FEX: A Fluoride-Based Selection System for Rapid GPCR Screening and Engineering

Not Available

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2023

Optical Control of Dopamine D2-like Receptors with Cell-Specific Fast-Relaxing Photoswitches

Dopamine D2-like receptors (D2R, D3R, and D4R) control diverse physiological and behavioral functions and are important targets for the treatment of a variety of neuropsychiatric disorders. Their complex distribution and activation kinetics in the brain make it difficult to target specific receptor populations with sufficient precision. We describe a new toolkit of light-activatable, fast-relaxing, covalently taggable chemical photoswitches that fully activate, partially activate, or block D2-like receptors. This technology combines the spatiotemporal precision of a photoswitchable ligand (P) with cell type and spatial specificity of a genetically encoded membrane anchoring protein (M) to which the P tethers. These tools set the stage for targeting endogenous D2-like receptor signaling with molecular, cellular, and spatiotemporal precision using only one wavelength of light.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

This dataset contains a subset of raw diffraction images for the serial femtosecond crystallography data of S1P5-ONO-5430608 complex. The diffraction data contain a strong systematic background as described in Lyapina et al. No additional background subtraction was applied to the data. In order to avoid its effects, the background subtraction implemented in CrystFEL, was applied (--rings-grad subtraction). The final stream, supplemented with this dataset, was obtained with: indexamajig 0.8.0 Respectively, the hkl file was obtained with: partialator 0.8.0

Human sphingosine-1-phosphate receptor 5 (S1P5) in↗

NASA NTRS2004

Mechanisms of postspaceflight orthostatic hypotension: low alpha1-adrenergic receptor responses before flight and central autonomic dysregulation postflight

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.

Clinical Trial↗

NASA NTRS2002

Regulation of period 1 expression in cultured rat pineal

The aim of the present study was to investigate the in vitro expression of Period 1 (Per1), Period 2 (Per2) and arylalkylamine N-acetyltransferase (AA-NAT) genes in the rat pineal gland to understand the mechanism(s) regulating the expression of these genes in this organ. Pineals, when maintained in vitro for 5 days, did not show circadian rhythmicity in the expression of any of the three genes monitored. Norepinephrine (NE) induced AA-NAT and Per1, whereas its effect on Per2 was negligible. Contrary to what was observed in other systems, NE stimulation did not induce circadian expression of Per1. The effect of NE on Per1 level was dose- and receptor subtype-dependent, and both cAMP and cGMP induced Per1. Per1 was not induced by repeated NE - or forskolin - stimulation. Protein synthesis was not necessary for NE-induced Per1, but it was for reduction of Per1 following NE stimulation. Per1 transcription in pinealocytes was activated by BMAL1/CLOCK. Our results indicate that important differences are present in the regulation of these genes in the mammalian pineal. Copyright 2002 S. Karger AG, Basel.

NASA Discipline Space Human Factors↗

NASA NTRS2002

Baroreflex buffering and susceptibility to vasoactive drugs

BACKGROUND: The overall effect of vasoactive drugs on blood pressure is determined by a combination of the direct effect on vascular tone and an indirect baroreflex-mediated effect, a baroreflex buffering of blood pressure. Differences in baroreflex function affect the responsiveness to vasoactive medications, particularly baroreflex buffering of blood pressure; however, the magnitude is not known. METHODS AND RESULTS: We characterized baroreflex function and responses to vasoactive drugs in patients with idiopathic orthostatic intolerance, patients with essential hypertension, patients with monogenic hypertension and brachydactyly, patients with multiple system atrophy, and control subjects. We used phenylephrine sensitivity during ganglionic blockade as a measure of baroreflex buffering. Phenylephrine (25 microg) increased systolic blood pressure 6+/-1.6 mm Hg in control subjects, 6+/-1.1 mm Hg in orthostatic intolerance patients, 18+/-3.9 mm Hg in patients with essential hypertension, 31+/-3.4 mm Hg in patients with monogenic hypertension, and 25+/-3.4 mm Hg in patients with multiple system atrophy. Similar differences in sensitivities between groups were observed with nitroprusside. The sensitivity to vasoactive drugs was highly correlated with baroreflex buffering function and to a lesser degree with baroreflex control of heart rate. In control subjects, sensitivities to nitroprusside and phenylephrine infusions were correlated with baroreflex heart rate control and sympathetic nerve traffic. CONCLUSIONS: Our findings are consistent with an important effect of baroreflex blood pressure buffering on the sensitivity to vasoactive drugs. They suggest that even moderate changes in baroreflex function may have a substantial effect on the sensitivity to vasoactive medications.

NASA Discipline Regulatory Physiology↗

NASA NTRS1994

Mechanisms of post-flight orthostatic intolerance

Post-flight orthostatic intolerance is a dramatic physiological consequence of human adaptation to microgravity made inappropriate by a sudden return to 1-G. The immediate mechanism is almost always a failure to maintain adequate tissue perfusion, specifically perfusion of the central nervous system, but vestibular dysfunction may occasionally be the primary cause. Orthostatic intolerance is present in a wide range of clinical disorders of the nervous and cardiovascular systems. The intolerance that is produced by spaceflight and 1-G analogs (bed rest, head-down tilt at a moderate angle, water immersion) is different from its clinical counterparts by being only transiently present in subjects who otherwise have normal cardiovascular and regulatory systems. However, the same set of basic pathophysiological elements should be considered in the analysis of any form of orthostatic intolerance.

Non-NASA Center↗

NASA NTRS2002

Effect of hindlimb suspension and clenbuterol treatment on polyamine levels in skeletal muscle

Polyamines are unbiquitous, naturally occurring small aliphatic, polycationic, endogenous compounds. They are involved in many cellular processes and may serve as secondary or tertiary messengers to hormonal regulation. The relationship of polyamines and skeletal muscle mass of adductor longus, extensor digitorum longus, and gastrocnemius under unloading (hindlimb suspension) conditions was investigated. Unloading significantly affected skeletal muscle polyamine levels in a fiber-type-specific fashion. Under loading conditions, clenbuterol treatment increased all polyamine levels, whereas under unloading conditions, only the spermidine levels were consistently increased. Unloading attenuated the anabolic effects of clenbuterol in predominately slow-twitch muscles (adductor longus), but had little impact on clenbuterol's action as a countermeasure in fast- twitch muscles such as the extensor digitorum longus. Spermidine appeared to be the primary polyamine involved in skeletal muscle atrophy/hypertrophy. Copyright 2002 S. Karger AG, Basel.

NASA Discipline Musculoskeletal↗

NASA NTRS2000

Hindbrain serotonin and the rapid induction of sodium appetite

Both systemically administered furosemide and isoproterenol produce water intake (i.e., thirst). Curiously, however, in light of the endocrine and hemodynamic effects produced by these treatments, they are remarkably ineffective in eliciting intake of hypertonic saline solutions (i.e., operationally defined as sodium appetite). Recent work indicates that bilateral injections of the serotonin receptor antagonist methysergide into the lateral parabrachial nuclei (LPBN) markedly enhance a preexisting sodium appetite. The present studies establish that a de novo sodium appetite can be induced with LPBN-methysergide treatment under experimental conditions in which only water is typically ingested. The effects of bilateral LPBN injections of methysergide were studied on the intake of water and 0. 3 M NaCl following acute (beginning 1 h after treatment) diuretic (furosemide)-induced sodium and water depletion and following subcutaneous isoproterenol treatment. With vehicle injected into the LPBN, furosemide treatment and isoproterenol injection both caused water drinking but essentially no intake of hypertonic saline. In contrast, bilateral treatment of the LPBN with methysergide induced the intake of 0.3 M NaCl after subcutaneous furosemide and isoproterenol. Water intake induced by subcutaneous furosemide or isoproterenol was not changed by LPBN-methysergide injections. The results indicate that blockade of LPBN-serotonin receptors produces a marked intake of hypertonic NaCl (i.e., a de novo sodium appetite) after furosemide treatment as well as subcutaneous isoproterenol.

Non-NASA Center↗

NASA NTRS2000

Effect of electrical stimulation on beta-adrenergic receptor population and cyclic amp production in chicken and rat skeletal muscle cell cultures

Expression of the beta-adrenergic receptor (betaAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the betaAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the betaAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the betaAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

Muscle, Skeletal/cytology↗