Autonomic Neuroscience-Basic & Clinical最新文献

Dopamine (DA) is a catecholamine regulatory molecule with potential role in physiology and physiopathology of the intestinal tract. Various cellular sources of DA have been indicated as enteric neurons, immune cells, intestinal flora and gastrointestinal epithelium. Moreover, DA is produced by nutritional tyrosine. All the five DA receptors, actually described, are present throughout the gut. Current knowledge of DA in this area is reviewed, focusing on gastrointestinal function in health and during inflammation. Research on animal models and humans are reported. A major obstacle to understanding the physiologic and/or pharmacological roles of enteric DA is represented by the multiplicity of receptors involved in the responses together with many signalling pathways related to each receptor subtype. It is mandatory to map precisely the distributions of DA receptors, to determine the relevance of a receptor in a specific location in order to explore novel therapies directed to dopaminergic targets that may be useful in the control of intestinal inflammation.

Background

The superior cervical ganglion (SCG) plays critical roles in the regulation of blood pressure and cardiac output. Metabotropic glutamate receptors (mGluRs) in the SCG are not clearly elucidated yet. Most studies on the expression and functions of mGluRs in the SCG focused on the cultured SCG neurons, and yet little information has been reported in the SCG tissue. Chronic intermittent hypoxia (CIH), one of the major clinical features of obstructive sleep apnea (OSA) patients, is a critical pathological cause of secondary hypertension in OSA patients, but its impact on the level of mGluRs in the SCG is unknown.

Objective

To explore the expression and localization of mGluR2/3 and the effect of CIH on mGluR2/3 level in rat SCG tissue.

Methods

RT-PCR and immunostaining were conducted to examine the mRNA and protein expression of mGluR2/3 in rat SCG. Immunofluorescence staining was conducted to examine the distribution of mGluR2/3. Rats were divided into control and CIH group which the rats were exposed to CIH for 6 weeks. Western blots were performed to examine the level of mGluR2/3 in rat SCG.

Results

mRNAs of mGluR2/3 expressed in rat SCG. mGluR2 distributed in principal neurons and small intensely fluorescent cells but not in satellite glial cells, nerve fibers, and vascular endothelial cells; mGluR3 was detected in nerve fibers rather than in the cells mentioned above. CIH exposure reduced the protein level of mGluR2/3 in rat SCG.

Conclusion

mGluR2/3 exists in rat SCG with diverse distribution patterns, and may be involved in CIH-induced hypertension.

Purpose

Chronic psychological stress aggravates painful bladder syndrome symptoms. Previous studies suggest roles of 5-HT₃ receptors in regulating micturition and bladder hypersensitivity. This study aimed to investigate the roles of 5-HT₃ receptors in modulating voiding patterns and spontaneous bladder contractile properties in water avoidance stress-induced mice.

Materials and methods

Voiding patterns in sham stress (SS), water avoidance stress (WS), and water avoidance stress with daily oral gavage of ondansetron (1 mg/kg BW) (WA) groups were analyzed after exposure to repeated water avoidance stress for 10 days. Changes in contractile activity of isolated bladder in response to KCl, carbachol, and 5-hydroxytryptamine were determined. Bladder mast cell quantification was examined using toluidine blue staining.

Results

Urine voided area was significantly decreased in WS group after exposure to 10 days of the stress protocol, which was reversed in the WA group. The WS group had a higher number of urine spots than the SS group. Increased mast cell degranulation was observed in the stressed mice. Bladder strips of the WS group showed higher tonic and amplitude of spontaneous contraction than the SS group, which were normalized by ondansetron administration. Increased response to carbachol-induced bladder contraction was observed in the bladder of stressed mice, which was attenuated with ondansetron pre-incubation.

Conclusions

Water avoidance stress-induced mice exhibited changes in voiding pattern, which was reversed by oral administration with a 5-HT₃ receptor antagonist (ondansetron). Enhanced contractile response to cholinergic stimulation in the urinary bladder of the psychological stress-induced bladder overactivity was mediated through 5-HT₃ receptors.

Objective

Cardiovascular autonomic neuropathy is a known complication in type 2 diabetes (T2D). However, the extent of sympathetic dysfunction and its relation to blood pressure (BP) dysregulation is insufficiently studied. We therefore assessed the cardiovascular sympathetic function using a standardized autonomic test-battery.

Research design and methods

Forty T2D patients (mean age and duration of diabetes ±SD, 65.5 ± 7.3 and 9.5 ± 4.2 years) and 40 age- and gender-matched controls were examined through autonomic testing, assessing cardiovascular responses to deep breathing, Valsalva maneuver and tilt-table testing. Additionally, 24-hour oscillometric BP and self-reported autonomic symptoms on COMPASS-31 questionnaire was recorded.

Results

Patients with T2D had reduced parasympathetic activity with reduced deep breathing inspiratory:expiratory-ratio (median [IQR] T2D 1.11 [1.08–1.18] vs. controls 1.18 [1.11–1.25] (p = 0.01)), and reduced heart rate variability (p < 0.05). We found no differences in cardiovascular sympathetic function measured through BP responses during the Valsalva maneuver (p > 0.05). 24-hour-BP detected reduced night-time systolic BP drop in T2D (9.8 % ± 8.8 vs. controls 15.8 % ± 7.7 (p < 0.01)) with more patients having reverse dipping. Patients with T2D reported more symptoms of orthostatic intolerance on the COMPASS-31 (p = 0.04).

Conclusions

Patients with T2D showed reduced parasympathetic activity but preserved short-term cardiovascular sympathetic function, compared to controls, indicating autonomic dysfunction with predominantly parasympathetic impairment. Despite this, T2D patients reported more symptoms of orthostatic intolerance in COMPASS-31 and had reduced nocturnal BP dipping, indicating that these are not a consequence of cardiovascular sympathetic dysfunction.

Invasive cervical vagus nerve stimulation (VNS) is approved for the treatment of epilepsies, depression, obesity, and for stroke-rehabilitation. The procedure requires surgery, has side-effects, is expensive and not readily available. Consequently, transcutaneous VNS (tVNS) has been developed 20 years ago as non-invasive, less expensive, and easily applicable alternative. Since the vagus nerve reaches the skin at the outer acoustic canal and ear, and reflex-responses such as the ear-cough-reflex or the auriculo-cardiac reflex have been observed upon auricular stimulation, the ear seems well suited for tVNS. However, several sensory nerves with variable fiber-density and significant overlap innervate the outer ear: the auricular branch of the vagus nerve (ABVN), the auriculotemporal nerve, greater auricular nerve, and to some extent the lesser occipital nerve. VNS requires activation of Aβ-fibers which are far less present in the ABVN than the cervical vagus nerve. Thus, optimal stimulation sites and parameters, and tVNS-algorithms need to be further explored. Unravelling central pathways and structures that mediate tVNS-effects is another challenge. tVNS impulses reach the nucleus of the solitary tract and activate the locus-coeruleus-norepinephrine system. However, many more brain areas are activated or deactivated upon VNS, including structures of the central autonomic network and the limbic system. Still, the realm of therapeutic tVNS applications grows rapidly and includes medication-refractory epilepsies, depressive mood disorders, headaches including migraine, pain, heart failure, gastrointestinal inflammatory diseases and many more. tVNS might become a standard tool to enhance autonomic balance and function in various autonomic, neurological, psychiatric, rheumatologic, as well as other diseases.

Purpose

Acute head-down-tilt (HDT) simulates short duration hemodynamic impact of microgravity. We sought to determine whether an increase in ICP caused by acute HDT affects sympathetic nervous system activity and cerebral blood flow velocities (CBFV) in healthy male volunteers.

Methods

HDT protocol was established as follows: basal condition immediately followed by gradual negative angles (−10°, −20° and −30°) lasting 10mn and then a return to basal condition. Velocities in the MCA (CBFV) were monitored using TCD. Sympathetic activity was assessed using MSNA. Baroreflex sensitivity (BRS) was measured using the sequence method. ICP changes were assessed using ultrasonography of the optic nerve sheath diameter (ONSD). Cerebral autoregulation (CA) was evaluated by transfer function and the autoregulatory index (Mxa).

Results

Twelve male volunteers (age: 35 ± 2 years) were included. Neither blood pressure nor heart rate was significantly modified during HDT. ONSD increased significantly at each step of HDT and remained elevated during Recovery. MSNA burst incidence increased at −30°. A positive correlation between variations in ONSD and variations in MSNA burst incidence was observed at −20°. CBFV were significantly diminished at −20° and −30. In the LF band, the transfer function coherence was reduced at −30° and the transfer function phase was increased at −30° and during Recovery.

Discussion

We found that an acute though modest increase in ICP induced by HDT was associated with an increase of sympathetic activity as assessed by MSNA, and with a reduction of CBFV with preserved CA.

Background

Among autonomic seizures apnea still represent a challenge for physicians, and it might constitute the only isolated sign of neurological disorder. The aim of this review is to describe ictal apnea (IA) and its treatment options.

Methods

MeSH and keywords were combined: “neonatal seizures”, “ictal neonatal apnea”, “apneic seizures”. All identified papers were screened for neonatal seizures titles and abstracts; case reports describing patients with IA as an isolated manifestation of neonatal seizures were included.

Results

Eight studies including a total of 13 patients were identified. Among 13 patients, 9 were full-term and 4 were preterm neonates. All patients developed IA within twenty-one days from birth. Etiologies of seizures included: temporal lobe hemorrhage (3 pt), occipital stroke (1 pt), hypoxic-ischemic encephalopathy (HIE) (1 pt), parasagittal injury (1 pt), 18 trisomy (2 pt). Five patients showed no structural CNS alterations. Ten patients had the ictal focus localized in the temporal lobe; the occipital lobe was the second most involved site. Phenobarbital was administered in 76 % of cases with IA (10 pt), and showed efficacy in 74 % of them; 2 required a second anti-epileptic drug (AED) to reach seizure control. Levetiracetam was given to 11 % (2 pt) successfully. Only one was treated with midazolam and one did not require any anticonvulsant.

Conclusions

Not homogeneous data and paucity of isolated IA currently reported in literature limits agreement about definition, management and treatment of entity, however an ever-growing attention is needed, and EEG/aEEG, despite their possible controversies in the diagnosis, should be performed to investigate unexplained forms of apnea.

There are many reports that, through pre- and post-junctional mechanisms, sympathetic and parasympathetic (vagal) nerves can interact in the control of heart rate. The predominant interaction is accentuated antagonism (AA), where the bradycardia produced by vagal stimulation (VNS) is amplified when heart rate has been increased by sympathetic stimulation (SNS) or beta-adrenergic agonists. The acetylcholine-activated potassium current (I_K,Ach), is the primary driver of vagal bradycardia. To examine the participation of I_K,Ach in AA, a series of experiments was performed on isolated, double innervated, guinea-pig atrial preparations. Vagal bradycardia was elicited by 10-s trains (1, 2, 5 and 7.5 Hz) or single bursts of VNS (3 stimuli at 50 Hz) before and during acceleration of HR by either SNS (1–3 Hz) or isoprenaline (ISO), in both absence and presence of tertiapin-Q (TQ–I_K,Ach blocker). When expressed as an absolute change in HR (beats/min), bradycardia produced by VNS trains was amplified (AA) at all frequencies of VNS in ISO, and at 5 and 7.5 Hz during SNS. Bradycardia in response to 1 and 2 Hz VNS was reduced during SNS. In TQ, only the bradycardia produced by 5 and 7.5 Hz VNS in ISO was amplified. The bradycardia produced by a single burst of VNS was amplified in both ISO and SNS. After TQ the bradycardia in response to a VNS burst was unchanged in ISO, while it was reduced during SNS. When these data were adjusted to account for the increase in baseline HR brought about by SNS and ISO, there was no longer evidence of AA. Diminished responses to low frequencies of VNS (1 and 2 Hz) persisted, and were also seen during I_K,Ach block by TQ. We applied the same adjustment to data from 20 published studies. In 8 studies all data indicated AA; 3 studies provided no evidence for AA, and in 9 studies evidence was mixed. There is no doubt that AA can occur in the control of heart rhythm during simultaneous SNS and VNS, but conditions which determine its occurrence, and the mechanisms involved in this interaction remain unclear.

Vagus nerve stimulation (VNS) is an established treatment option for patients with treatment resistant epilepsy and depression. However, the procedure is invasive and has side-effects. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive alternative. Particularly transcutaneous stimulation at the outer ear is gaining increasing interest. While the scope of therapeutic tVNS applications is expanding, there are still questions regarding the optimal stimulation parameters and site as well as the physiology and pathways of auricular tVNS. This Special Issue of Autonomic Neuroscience: Basic & Clinical provides an introduction and overview on basic aspects as well as special topics of tVNS.