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Hypertension (Dallas, Tex. : 1979) Jul 2024The NET (norepinephrine transporter) is situated in the prejunctional plasma membrane of noradrenergic neurons. It is responsible for >90% of the norepinephrine uptake... (Review)
Review
The NET (norepinephrine transporter) is situated in the prejunctional plasma membrane of noradrenergic neurons. It is responsible for >90% of the norepinephrine uptake that is released in the autonomic neuroeffector junction. Inhibitors of this cell membrane transporter, known as norepinephrine reuptake inhibitors (NRIs), are commercially available for the treatment of depression and attention deficit hyperactivity disorder. These agents increase norepinephrine levels, potentiating its action in preganglionic and postganglionic adrenergic neurons, the latter through activation of α-1 adrenoreceptors. Previous studies found that patients with neurogenic orthostatic hypotension can improve standing blood pressure and reduce symptoms of neurogenic orthostatic hypotension after a single administration of the selective NRI atomoxetine. This effect was primarily observed in patients with impaired central autonomic pathways with otherwise normal postganglionic sympathetic fibers, known as multiple system atrophy. Likewise, patients with normal or high norepinephrine levels may benefit from NRIs. The long-term efficacy of NRIs for the treatment of neurogenic orthostatic hypotension-related symptoms is currently under investigation. In summary, an in-depth understanding of the pathophysiology of neurogenic orthostatic hypotension resulted in the discovery of a new therapeutic pathway targeted by NRI.
Topics: Humans; Hypotension, Orthostatic; Adrenergic Uptake Inhibitors; Norepinephrine; Atomoxetine Hydrochloride; Norepinephrine Plasma Membrane Transport Proteins; Blood Pressure
PubMed: 38766862
DOI: 10.1161/HYPERTENSIONAHA.124.22069 -
Journal of Neurophysiology Jun 2024Microneurographic recordings of muscle sympathetic nerve activity (MSNA) reflect postganglionic sympathetic axonal activity directed toward the skeletal muscle... (Comparative Study)
Comparative Study
Microneurographic recordings of muscle sympathetic nerve activity (MSNA) reflect postganglionic sympathetic axonal activity directed toward the skeletal muscle vasculature. Recordings are typically evaluated for spontaneous bursts of MSNA; however, the filtering and integration of raw neurograms to obtain multiunit bursts conceals the underlying c-fiber discharge behavior. The continuous wavelet transform with matched mother wavelet has permitted the assessment of action potential discharge patterns, but this approach uses a mother wavelet optimized for an amplifier that is no longer commercially available (University of Iowa Bioengineering Nerve Traffic Analysis System; Iowa NTA). The aim of this project was to determine the morphology and action potential detection performance of mother wavelets created from the commercially available NeuroAmp (ADinstruments), from distinct laboratories, compared with a mother wavelet generated from the Iowa NTA. Four optimized mother wavelets were generated in a two-phase iterative process from independent datasets, collected by separate laboratories (one Iowa NTA, three NeuroAmp). Action potential extraction performance of each mother wavelet was compared for each of the NeuroAmp-based datasets. The total number of detected action potentials was not significantly different across wavelets. However, the predictive value of action potential detection was reduced when the Iowa NTA wavelet was used to detect action potentials in NeuroAmp data, but not different across NeuroAmp wavelets. To standardize approaches, we recommend a NeuroAmp-optimized mother wavelet be used for the evaluation of sympathetic action potential discharge behavior when microneurographic data are collected with this system. The morphology of custom mother wavelets produced across laboratories using the NeuroAmp was highly similar, but distinct from the University of Iowa Bioengineering Nerve Traffic Analysis System. Although the number of action potentials detected was similar between collection systems and mother wavelets, the predictive value differed. Our data suggest action potential analysis using the continuous wavelet transform requires a mother wavelet optimized for the collection system.
Topics: Action Potentials; Animals; Wavelet Analysis; Sympathetic Nervous System; Muscle, Skeletal; Male
PubMed: 38629146
DOI: 10.1152/jn.00448.2023 -
Journal of Parkinson's Disease 2024Autonomic dysfunction is a prevalent feature of Parkinson's disease (PD), mediated by disease involvement of the autonomic nervous system. Chronotropic incompetence (CI)...
Autonomic dysfunction is a prevalent feature of Parkinson's disease (PD), mediated by disease involvement of the autonomic nervous system. Chronotropic incompetence (CI) refers to inadequate increase of heart rate in response to elevated metabolic demand, partly dependent on postganglionic sympathetic tone. In a retrospective study, PD patients with/without CI were identified. We show that PD with CI was associated with a higher levodopa equivalent daily dose and Hoehn and Yahr stage, 5±2 years after motor onset. Our data support a putative role of CI as a clinical marker of a more severe disease phenotype, possibly reflecting more widespread alpha-synuclein pathology.
Topics: Humans; Parkinson Disease; Male; Female; Aged; Middle Aged; Phenotype; Retrospective Studies; Heart Rate; Autonomic Nervous System Diseases; Severity of Illness Index; Levodopa; Biomarkers
PubMed: 38517804
DOI: 10.3233/JPD-230256 -
Clinical Autonomic Research : Official... Feb 2024We have re-evaluated the anatomical arguments that underlie the division of the spinal visceral outflow into sympathetic and parasympathetic divisions. (Review)
Review
PURPOSE
We have re-evaluated the anatomical arguments that underlie the division of the spinal visceral outflow into sympathetic and parasympathetic divisions.
METHODOLOGY
Using a systematic literature search, we mapped the location of catecholaminergic neurons throughout the mammalian peripheral nervous system. Subsequently, a narrative method was employed to characterize segment-dependent differences in the location of preganglionic cell bodies and the composition of white and gray rami communicantes.
RESULTS AND CONCLUSION
One hundred seventy studies were included in the systematic review, providing information on 389 anatomical structures. Catecholaminergic nerve fibers are present in most spinal and all cranial nerves and ganglia, including those that are known for their parasympathetic function. Along the entire spinal autonomic outflow pathways, proximal and distal catecholaminergic cell bodies are common in the head, thoracic, and abdominal and pelvic region, which invalidates the "short-versus-long preganglionic neuron" argument. Contrary to the classically confined outflow levels T1-L2 and S2-S4, preganglionic neurons have been found in the resulting lumbar gap. Preganglionic cell bodies that are located in the intermediolateral zone of the thoracolumbar spinal cord gradually nest more ventrally within the ventral motor nuclei at the lumbar and sacral levels, and their fibers bypass the white ramus communicans and sympathetic trunk to emerge directly from the spinal roots. Bypassing the sympathetic trunk, therefore, is not exclusive for the sacral outflow. We conclude that the autonomic outflow displays a conserved architecture along the entire spinal axis, and that the perceived differences in the anatomy of the autonomic thoracolumbar and sacral outflow are quantitative.
Topics: Animals; Humans; Neurons; Sympathetic Nervous System; Ganglia, Sympathetic; Spinal Cord; Sacrum; Mammals
PubMed: 38403748
DOI: 10.1007/s10286-024-01023-6 -
American Journal of Physiology.... Apr 2024To investigate noxious stimulation-responsive neural circuits that could influence the gut, we recorded from intestinally directed (efferent) nerve filaments dissected...
To investigate noxious stimulation-responsive neural circuits that could influence the gut, we recorded from intestinally directed (efferent) nerve filaments dissected from mesenteric nerves close to the small intestine in anesthetized rats. These exhibited baseline multiunit activity that was almost unaffected by vagotomy (VagX) and reduced only slightly by cutting the splanchnic nerves. The activity was halved by hexamethonium (Hex) treatment. When an adjacent gut segment received an intraluminal stimulus 2,4,6-trinitrobenzenesulfonate (TNBS) in 30% ethanol, mesenteric efferent nerve activity increased for more than 1 h. The increased activity was almost unaffected by bilateral vagotomy or splanchnic nerve section, indicating a lack of central nervous involvement, but it was 60% reduced by hexamethonium. Spike sorting discriminated efferent single and predominantly single-unit spike trains that responded to TNBS, were unaffected by splachnectomy but were silenced by hexamethonium. After noxious stimulation of one segment, the adjacent segment showed no evidence of suppression of gut motility or vasoconstriction. We conclude that luminal application of a noxious stimulus to the small intestine activates an entirely peripheral, intestinointestinal reflex pathway. This pathway involves enteric intestinofugal neurons that excite postganglionic sympathetic neurons via a nicotinic synapse. We suggest that the final sympathetic efferent neurons that respond to a tissue damaging stimulus are distinct from vasoconstrictor, secretomotor, and motility inhibiting neurons. An intraluminal noxious chemical stimulus applied to one segment of small intestine increased mesenteric efferent nerve activity to an adjacent segment. This was identified as a peripheral ganglionic reflex that did not require vagal or spinal connections. Hexamethonium blocked most, but not all, ongoing and reflex mesenteric efferent activity. The prevertebral sympathetic efferent neurons that are activated likely affect inflammatory and immune functions of other gut segments.
Topics: Rats; Animals; Hexamethonium; Reflex; Splanchnic Nerves; Vagotomy; Vagus Nerve; Sympathetic Nervous System
PubMed: 38226653
DOI: 10.1152/ajpgi.00145.2023 -
Revue Neurologique 2024Autonomic failure is frequently encountered in synucleinopathies such as multiple system atrophy (MSA), Parkinson's disease (PD), Lewy body disease, and pure autonomic... (Review)
Review
Autonomic failure is frequently encountered in synucleinopathies such as multiple system atrophy (MSA), Parkinson's disease (PD), Lewy body disease, and pure autonomic failure (PAF). Cardiovascular autonomic failure affects quality of life and can be life threatening due to the risk of falls and the increased incidence of myocardial infarction, stroke, and heart failure. In PD and PAF, pathogenic involvement is mainly post-ganglionic, while in MSA, the involvement is mainly pre-ganglionic. Cardiovascular tests exploring the autonomic nervous system (ANS) are based on the analysis of continuous, non-invasive recordings of heart rate and digital blood pressure (BP). They assess facets of sympathetic and parasympathetic activities and provide indications on the integrity of the baroreflex arc. The tilt test is widely used in clinical practice. It can be combined with catecholamine level measurement and analysis of baroreflex activity and cardiac variability for a detailed analysis of cardiovascular damage. MIBG myocardial scintigraphy is the most sensitive test for early detection of autonomic dysfunction. It provides a useful measure of post-ganglionic sympathetic fiber integrity and function and is therefore an effective tool for distinguishing PD from other parkinsonian syndromes such as MSA. Autonomic cardiovascular investigations differentiate between certain parkinsonian syndromes that would otherwise be difficult to segregate, particularly in the early stages of the disease. Exploring autonomic failure by gathering information about residual sympathetic tone, low plasma norepinephrine levels, and supine hypertension can guide therapeutic management of orthostatic hypotension (OH).
Topics: Humans; Pure Autonomic Failure; Synucleinopathies; Quality of Life; Autonomic Nervous System Diseases; Multiple System Atrophy; Parkinson Disease
PubMed: 38216420
DOI: 10.1016/j.neurol.2023.12.004 -
Advanced Biology Mar 2024Neuromodulation-related intervertebral disc degeneration (IVDD) is a novel IVDD pattern and are proposed recently. However, the mechanistic basis of neuromodulation and...
Neuromodulation-related intervertebral disc degeneration (IVDD) is a novel IVDD pattern and are proposed recently. However, the mechanistic basis of neuromodulation and intervertebral disc (IVD) homeostasis remains unclear. Here, this study aimed to investigate the expression of postganglionic sympathetic nerve fiber-derived vasoactive intestinal peptide (VIP) system in human IVD tissue, and to assess the role of VIP-related neuromodulation in IVDD. Patient samples and in vitro cell experiments showed that the expression of receptors for VIP is negatively correlated with the severity of IVDD, and the administration of exogenous VIP can ameliorate interleukin 1β-induced nucleus pulposus (NP) cell apoptosis and inflammation. Further mRNA-seq analysis revealed that fibroblast growth factor 18- (FGF18)-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway is involved in the protective effects of VIP on inflammation-induced NP cell degeneration. Further analysis identified VIP via its receptor vasoactive intestinal peptide receptor 2 can directly result in decreased expression of miR-15a-5p, which targeted FGF18. Finally, in vivo mice lumbar IVDD model confirmed that focally exogenous administration of VIP can effectively ameliorated the progression of IVDD, as shown by the radiological and histological analysis. In conclusion, these results indicated that sympathetic neurotransmitter, VIP, delayed IVDD via FGF18/FGFR2-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway, which will broaden the horizon concerning how the neuromodulation correlates with IVDD and shed new light on novel therapeutical alternatives to IVDD.
Topics: Humans; Mice; Animals; Intervertebral Disc Degeneration; Vasoactive Intestinal Peptide; Proto-Oncogene Proteins c-akt; Thymoma; Signal Transduction; Carrier Proteins; Thymus Neoplasms; Inflammation; Receptor, Fibroblast Growth Factor, Type 2; Fibroblast Growth Factors
PubMed: 38047500
DOI: 10.1002/adbi.202300250