Postganglionic Parasympathetic Neurons Research Articles

Remodeling of the Intracardiac Ganglia During the Development of Cardiovascular Autonomic Dysfunction in Type 2 Diabetes: Molecular Mechanisms and Therapeutics.

Type 2 diabetes mellitus (T2DM) is one of the most significant health issues worldwide, with associated healthcare costs estimated to surpass USD 1054 billion by 2045. The leading cause of death in T2DM patients is the development of cardiovascular disease (CVD). In the early stages of T2DM, patients develop cardiovascular autonomic dysfunction due to the withdrawal of cardiac parasympathetic activity. Diminished cardiac parasympathetic tone can lead to cardiac arrhythmia-related sudden cardiac death, which accounts for 50% of CVD-related deaths in T2DM patients. Regulation of cardiovascular parasympathetic activity is integrated by neural circuitry at multiple levels including afferent, central, and efferent components. Efferent control of cardiac parasympathetic autonomic tone is mediated through the activity of preganglionic parasympathetic neurons located in the cardiac extensions of the vagus nerve that signals to postganglionic parasympathetic neurons located in the intracardiac ganglia (ICG) on the heart. Postganglionic parasympathetic neurons exert local control on the heart, independent of higher brain centers, through the release of neurotransmitters, such as acetylcholine. Structural and functional alterations in cardiac parasympathetic postganglionic neurons contribute to the withdrawal of cardiac parasympathetic tone, resulting in arrhythmogenesis and sudden cardiac death. This review provides an overview of the remodeling of parasympathetic postganglionic neurons in the ICG, and potential mechanisms contributing to the withdrawal of cardiac parasympathetic tone, ventricular arrhythmogenesis, and sudden cardiac death in T2DM. Improving cardiac parasympathetic tone could be a therapeutic avenue to reduce malignant ventricular arrhythmia and sudden cardiac death, increasing both the lifespan and improving quality of life of T2DM patients.

764 CARDIONEUROABLATION OF VAGALLY MEDIATED BRADYARRHYTHMIA: A SINGLE-CENTER EXPERIENCE

Abstract Background Cardioneuroablation (CNA) is a novel catheter-ablation technique for the treatment of vagally-mediated bradyarrhythmia including vaso-vagal syncope (VVS), functional atrioventricular block (AVB) and sinus node dysfunction (SND). CNA aims to blunt the cardioinhibitory reflex by eliminating postganglionic parasympathetic neurons in the atrial wall and ganglionated plexi (GPs). Early-phase studies have shown promising results, but clinical evidence remains limited. Purpose We present our single-center experience with CNA in the setting of VVS, symptomatic functional AVB, and SND. Methods Baseline and procedural characteristics, procedure-related complications, and clinical outcomes were collected in patients who underwent CNA from December 2018 to July 2022. The procedural workflow included an electroanatomic mapping-guided ablation strategy, which combines the bi-atrial 3D mapping with endocardial atrial bipolar electrograms (EGM), specifically targeting high-amplitude fractionated EGM. Results A total of 14 CNA procedures were performed in our center. Ablation indication was mainly VVS (57%), followed by AVB (29%) and SND (14%). Syncope was the most common symptom in our cohort (71%, burden of 7 per person-lifetime). Patients were young (43±16 years) and without structural heart disease (LVEF 58±4 ml, LAD 31±7 mm). Procedures were performed under general anesthesia, mean procedure time was 102±42 min, with minimal fluoroscopy dose (2.7±1.8 Gy/cm2). We observed 1 instance of post-ablation pericarditis and 2 sinus tachycardia which required medical treatment; no major adverse events occurred. Heart rate increased after ablation in all the patients, with a mean RR interval shortening of 28% and no further increase after atropine administration. Two patients had a recurrence at a median follow-up of 251 days (IQR: 118-536), both cases were syncopal events without documentation at loop-recorder of sinus bradycardia or atrial bradyarrhythmia. Conclusions CNA may be an alternative to pacemaker implantation in young, highly symptomatic patients, refractory to conventional therapies and without structural heart disease. Ablation is reasonably safe in experts’ hands, especially if compared with the long-life risk of device-related complications. Further large-scale randomized studies are needed to support these findings.

Electrophysiological characterization of mouse intracardiac calbindin neurons

Neural control of the heart involves central and peripheral neurons that act interdependently to modulate cardiac parameters such as heart rate, conduction velocity or contractility. Within this cardiac neuronal regulation, the intrinsic cardiac nervous system (ICNS), which correspond to clusters of neurons found on the dorsal atrial surface of the heart, is receiving growing attention. Indeed, whereas they were initially considered as simple parasympathetic postganglionic neurons, studies conducted over the past 30 years suggested a more complex organization, involving the existence of sensory, local regulatory and motor neurons within intracardiac ganglia. Moreover, growing evidence suggest the implication of this neural network in the initiation and maintenance of cardiac arrhythmias. However, the functional organization of this intracardiac neural network, as well as its involvement in cardiac diseases have not been fully elucidated. This study aims to decipher the complexity of this intracardiac nervous system by examining the phenotypic and electrophysiological properties of mouse intracardiac neurons. Global cardiac innervation and phenotypic diversity of mouse intracardiac neurons were investigated by performing immunohistochemistry on cleared heart and on tissue sections. The patch clamp technique (current and voltage clamp) was used for the electrophysiological characterization of these neurons. Calbindin expressing neurons were specifically studied by using cre transgenic mice and targeted viral transduction strategy. We identified 6 distinct neuronal markers within mouse intracardiac neurons revealing the neurochemical diversity of this intracardiac neural network. The characterization of passive and active electrical membrane properties of these neurons gave rise to the identification of two distinct firing profiles within intracardiac neurons. The first group was classified as phasic due to its limited firing activity while the second was defined as adapting. Phasic neurons were also characterized by a higher rheobase compared to the adapting one. In addition, intracardiac neurons could also be distinguished by the presence or absence of an afterhyperpolarization. We also identified calbindin expressing neurons as a population with a distinct electrophysiological signature. This could be explained by the differential expression of several ionic channels including the N-type voltage-gated calcium channel. This study demonstrates the molecular and functional complexity of the mouse ICNS.

Сучасні наукові погляди на склад та будову автономної нервової системи (огляд літератури)

The purpose of the study was to analyze literary sources to summarize modern scientific views on the structure and possible changes in the existing classification of the autonomic nervous system. Results and discussion. According to classical views, the anatomically and functionally autonomic nervous system is divided into sympathetic and parasympathetic parts, and the last one includes cranial and sacral centers. This classification, in addition to ontogenetic, anatomical and physiological justification, has historical roots and is associated with the research of J. Langley. For more than a century, such a classification of the autonomic nervous system was considered commonplace. However, modern views on this issue emphasize the mechanisms of development and molecular mechanisms of these systems. More attention was paid to such elements as gene expression, features of embryogenesis and development, as well as the general functions of neurons localized in these parts of the autonomic nervous system. In recent years, a group of researchers Espinosa-Medina et al. determined the differential genetic features and relationships of sympathetic and parasympathetic preganglionic and postganglionic neurons. The aim of the study was to compare the relationships and genetic characteristics of lumbar and sacral preganglionic neurons with cranial (parasympathetic) and thoracic (sympathetic) neurons. In general, 15 phenotypic and ontogenetic features are given that distinguish the pre- and postganglionic neurons of the cranial part of the parasympathetic part from the sympathetic neurons of the thoracolumbar region. Each of the features, according to Espinosa-Medina et al., proves that the sacral section must be considered as part of the sympathetic, and not the parasympathetic, section of the autonomic nervous system. This assumption is based on the study on mice at 11.5, 13, 165 days of embryonic development of several transcription factors common to both sacral and thoracolumbar preganglionic neurons, but absent in cranial preganglionic neurons. When revising the existing classification, cranial vegetative nervous structures are proposed to be considered parasympathetic, and spinal – sympathetic. However, a number of researchers were critical of the proposed changes to the existing classification. They consider the interpretation of the findings controversial, point to possibly misleading conclusions due to misinterpretations of the evidence, and suggest that the phenotypes of common thoracic and sacral preganglionic neurons may simply share a common spinal identity. Conclusion. In recent years, thanks to the latest research, there has been a rethinking and possible change in the ideas that have existed for a long time about the composition and structure of the autonomic nervous system. The proposed reclassification of the autonomic nervous system involves the assignment of the sacral region to its sympathetic, not parasympathetic part. Such a simplified two-component structure offers a new concept of neurophysiology, as well as the evolution and development of the autonomic nervous system. At the same time, a number of researchers give their arguments in favor of rejecting the proposed radical changes and saving the existing classification. In this regard, further studies are highly demanded, which could finally shed light on this issue

Multicolor labeling of airway neurons and analysis of parasympathetic heterogeneity

We report subpopulations of airway parasympathetic neurons expressing substance P, neuronal nitric oxide synthase, and tyrosine hydroxylase, highlighting unexplored heterogeneity in this population. These neurotransmitter-specific subpopulations did not form intraganglionic interneurons, but rather, extended outside the ganglia, into the airways, to distant innervation targets. Our experiments demonstrate the utility of multicolor labeling to characterize airway innervation, allowing us to confirm the extensive heterogeneity of postganglionic parasympathetic neurons. These methods will facilitate future investigations of neurophysiology and neural contributions to airway disease.

Electrophysiological characterization of mouse intracardiac calbindin neurons

Neural control of the heart involves central and peripheral neurons that act interdependently to modulate cardiac parameters such as heart rate, conduction velocity or contractility. Within this cardiac neuronal regulation, the intrinsic cardiac nervous system, which correspond to clusters of neurons found on the dorsal atrial surface of the heart, is receiving growing attention. Indeed, whereas they were initially considered as simple parasympathetic postganglionic neurons, studies conducted over the past 30 years suggested a more complex organization, involving the existence of sensory, local regulatory and motor neurons within intracardiac ganglia.

Frey's Syndrome: A Review of Aetiology and Treatment.

First described by Polish Neurologist Łucja Frey in 1923, Frey’s syndrome (FS), or auriculotemporal syndrome, is a rare condition characterised by gustatory sweating, typically encountered as sequelae following invasive head and neck surgery. The pathophysiology of FS can be described by aberrant reinnervation of postganglionic parasympathetic neurons to the surrounding denervated sweat glands and cutaneous blood vessels.Multiple invasive procedures have been associated with FS ranging from salivary gland surgery to burn reconstruction and thoracoscopic sympathectomies. Rarely, FS can be secondary to trauma or non-surgical aetiologies, including diabetes and infection.Physical symptoms vary based on the severity and surface area affected by FS and range from mild symptoms to severe psychosocial morbidity for patients. Surgeons operating in the head and neck, including otolaryngologists, maxillofacial surgeons, and plastic surgeons, should be aware of this potential complication and be up to date with diagnosis and treatment strategies for FS.This review article summarises the literature relating to FS focusing on its aetiologies, symptomatology, prevention, and available treatments, aiming to provide an up-to-date review of this condition for surgeons operating in the head and neck region. Although various treatment options have been suggested, these are often limited to topical agents that require life-long administration for symptom control. Further research is recommended to identify the optimal treatment for this condition and the role of surgery as a treatment for severe or refractory cases.

Endurance training increases ventricular refractoriness and wavelength of the cardiac impulse without participation of parasympathetic postganglionic neurons. A study in isolated rabbit heart

Abstract Background Endurance physical training plays a protective role in against ventricular fibrillation (VF), but the exact underlying mechanisms are not completely understood. It is well-known that modifications in myocardial ventricular properties such as refractoriness, conduction velocity and wavelength are key in the initiation and maintenance of VF; furthermore, vagus nerve stimulation has prophylactic effects on malignant arrhythmias and VF. On the other hand, parasympathetic nervous system activity is increased in trained individuals, which in turn affects different ventricular electrophysiological properties. We hypothesized that physical training increases conduction velocity and wavelength, and that these changes are mediated by myocardial cholinergic neurons. Methods To test this hypothesis, ten rabbits were submitted to a six-week endurance training protocol and twenty controls were not trained (divided in control group, n=10 and sham group n=10). After training, rabbits were euthanized and their hearts excised, isolated and perfused in a Langendorff system. A pacing electrode and a plaque with 240 recoding electrodes acquiring at 1 KHz were positioned on the left ventricle (LV). Extraestimulus test using four different pacing cycle lengths (90% basal cycle length, 250, 200 and 150 ms) was performed before and after atropine (1μM, control and trained groups) or vehicle (tyrode, sham group) infusion. We studied 1) LV effective refractory period (ERP), 2) LV functional refractory period (FRP), 3) LV conduction velocity (CV), and 4) LV wavelength, determined as LV FRP x CV. Factorial ANOVA (mixed model) was used for statistical analysis (p<0.05). Results Before parasympathetic blockade, LV FRP increased in trained animals (Figure, B) whereas no difference was found in LV CV between trained and control animals at any pacing cycle length (Figure, A). In consequence, LV wavelength increased in trained animals (Figure, C). There were no changes in LV ERP, FRP, CV and wavelength when comparisons were made within groups before and after atropine infusion. In sham animals, vehicle infusion or time-course of the experiment did not modify LV FRP, ERP, CV and wavelength. Conclusion Physical training increases LV wavelength, which can be one electrophysiological mechanism by which endurance training could protect against VF. Since modifications of ventricular refractoriness and wavelength do not seem dependent of intrinsic parasympathetic nervous system activity, other intrinsic mechanisms could be implied and warrant further research. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Generalitat Valenciana

Reduced Cell Excitability of Cardiac Postganglionic Parasympathetic Neurons Correlates With Myocardial Infarction-Induced Fatal Ventricular Arrhythmias in Type 2 Diabetes Mellitus

ObjectiveWithdrawal of cardiac vagal activity is considered as one of the important triggers for acute myocardial infarction (MI)-induced ventricular arrhythmias in type 2 diabetes mellitus (T2DM). Our previous study demonstrated that cell excitability of cardiac parasympathetic postganglionic (CPP) neurons was reduced in T2DM rats. This study investigated whether cell excitability of CPP neurons is associated with cardiac vagal activity and MI-induced ventricular arrhythmias in T2DM rats.MethodsRat T2DM was induced by a high-fat diet plus streptozotocin injection. MI-evoked ventricular arrhythmia was achieved by surgical ligation of the left anterior descending coronary artery. Twenty-four-hour, continuous ECG recording was used to quantify ventricular arrhythmic events and heart rate variability (HRV) in conscious rats. The power spectral analysis of HRV was used to evaluate autonomic function. Cell excitability of CPP neurons was measured by the whole-cell patch-clamp technique.ResultsTwenty-four-hour ECG data demonstrated that MI-evoked fatal ventricular arrhythmias are more severe in T2DM rats than that in sham rats. In addition, the Kaplan-Meier analysis demonstrated that the survival rate over 2 weeks after MI is significantly lower in T2DM rats (15% in T2DM+MI) compared to sham rats (75% in sham+MI). The susceptibility to ventricular tachyarrhythmia elicited by programmed electrical stimulation was higher in anesthetized T2DM+MI rats than that in rats with MI or T2DM alone (7.0 ± 0.58 in T2DM+MI group vs. 3.5 ± 0.76 in sham+MI). Moreover, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of increase of left ventricular pressure (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in T2DM rats. Furthermore, T2DM increased heterogeneity of ventricular electrical activities and reduced cardiac parasympathetic activity and cell excitability of CPP neurons (current threshold-inducing action potentials being 62 ± 3.3 pA in T2DM rats without MI vs. 27 ± 1.9 pA in sham rats without MI). However, MI did not alter vagal control of the ventricular function and CPP neuronal excitability, although it also induced cardiac autonomic dysfunction and enhanced heterogeneity of ventricular electrical activities.ConclusionThe reduction of CPP neuron excitability is involved in decreased cardiac vagal function, including cardiac parasympathetic activity and vagal control of ventricular function, which is associated with MI-induced high mortality and malignant ventricular arrhythmias in T2DM.

S2024 Don’t Sweat the Swallowed Stuff: A Case of Frey’s Syndrome After Surgical Correction of Dysphagia Lusoria

INTRODUCTION: Dysphagia is a fairly common patient presentation, but dysphagia lusoria is not a common etiology. Fortunately, it is a correctable problem, but sometimes complications can arise from the treatment. CASE DESCRIPTION/METHODS: A 67-year-old white male with past medical history of gastroesophageal reflux disorder (GERD), paranoid schizophrenia, Barrett’s esophagus, lung cancer, and chronic obstructive pulmonary disease (COPD) was referred to Gastroenterology Clinic for dysphagia. He reported that symptoms developed gradually and worsened to the point that he experienced weight loss because of decreased oral intake. Previous EGDs by the local surgery service showed no evidence of strictures, rings, or other abnormalities to explain his dysphagia. Patient then underwent a barium esophagram which showed extrinsic compression upon the posterior esophagus from an aberrant right subclavian artery. At this point, he was diagnosed with Dysphagia Lusoria, a “rare embryologic defect of the aortic arch vasculature characterized by an aberrant retro-esophageal course of the right subclavian artery (RSA), comprising a vascular sling.”1 He underwent a successful right subclavian to right common carotid artery bypass which resulted in complete resolution of dysphagia. However, on return to clinic, he complained of sweating on the right side of his face whenever he chews while eating. DISCUSSION: In the setting of previous neck surgery, he was diagnosed with Frey’s Syndrome, an “aberrant reinnervation of postganglionic parasympathetic neurons to nearby denervated sweat glands and cutaneous blood vessels. Consequently, this results in flushing and sweating in the sympathetically void skin in response to mastication and salivation.”2 Although usually in the setting of parotid gland surgery, it has been reported to occur after neck dissection surgeries. He is currently utilizing topical antiperspirant applied to the face with a plan for Botox injection by Otolaryngology if there is no improvement with antiperspirant use.Figure 1.: Barium esophagram images showing external compression in upper mediastinum.Figure 2.: CT Chest showing an aberrant right subclavian artery causing compression on the posterior esophagus.

Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation.

Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM (db/db). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice, and the kinetics of pacing-induced Ca2+ transients (recorded from isolated cardiomyocytes) were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control.NEW & NOTEWORTHY Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after β-sympathetic blockade.

Postganglionic Parasympathetic but Not Postganglionic Sympathetic Neuron Derived Exosomes Inhibit Hyperglycemia Induced Apoptosis in H9c2 Cells

Diabetic cardiomyopathy involves the two main types of cell death: apoptosis and necrosis. It is unclear, however, on whether apoptosis induced by hyperglycemia in a cell culture model can be inhibited by postganglionic parasympathetic neuron derived exosomes (PPN‐Exos). Postganglionic parasympathetic and postganglionic sympathetic neurons were isolated, cell cultured, and exosomes were isolated. H9c2 cells were utilized to induce apoptosis via hyperglycemia, which were then divided into 4 groups: 1. Control, 2. H9c2 + Glucose, 3. H9c2 + Glucose + PPN‐Exos, 4. H9c2 + Glucose + postganglionic sympathetic neuron‐derived exosomes (PSN‐Exos). An MTT assay kit was utilized to determine cell proliferation and viability, while apoptosis was determined using TUNEL staining and cell death detection (CDD) ELISA kit. The H9c2 cells that were exposed to glucose displayed significantly (p<0.05) reduced cell viability, and a significant (p<0.05) increase in TUNEL staining and CDD ELISA was present in hyperglycemic H9c2 cells compared to controls and this reduced cell viability and increased apoptosis was reversed with PPN‐Exos but not with PSN‐Exos, suggesting a cell protecting components are present in these PPN‐Exos. Our data on pro‐apoptotic gene expression of caspase‐3 and BAX was significantly (p<0.05) increased in glucose treated H9c2 cells compared with control. These pro‐apoptotic genes were attenuated with PPN‐Exos treatment. Anti‐apoptotic protein Bcl‐2 levels were significantly (p<0.05) reduced in hyperglycemia group and this decrease in Bcl‐2 was improved following PPN‐Exos treatment. In conclusion, our data demonstrate that apoptosis is present in hyperglycemic H9c2 cells mediated through caspase‐3 and BAX pathway is inhibited with PPN‐Exos but not with PSN‐Exos. Our data also suggest that PPN‐Exos must be containing a unique set of protective factors that needs further investigation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Correlation of Ventricular Arrhythmogenesis with Neuronal Remodeling of Cardiac Postganglionic Parasympathetic Neurons in the Late Stage of Heart Failure after Myocardial Infarction.

Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with ventricular arrhythmogenesis in CHF rats.Methods and Results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-h continuous radiotelemetry ECG recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 3 and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of left ventricular pressure rise (LV dP/dtmax) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3 or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF.Conclusion: Malignant ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of ventricular arrhythmias in the late stage of CHF.

Correlation of ventricular arrhythmogenesis with neuronal remodeling in cardiac postganglionic parasympathetic neurons during the progression of heart failure after myocardial infarction

Lethal ventricular arrhythmia has been a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Autonomic dysfunction has been defined as a negative prognostic indicator for high mortality associated with lethal ventricular arrhythmia during the progression of CHF. Our previous study has demonstrated that expression and ion currents of N‐type Ca2+ channels in cardiac postganglionic parasympathetic (CPP) neurons located in intracardiac ganglia (ICG) are decreased in late stage of CHF rats. However, it is unclear whether electrical remodeling in CPP neurons contributes to ventricular arrhythmogenesis during the development of CHF. Here, we investigated relationship between ventricular arrhythmogenesis and neuronal remodeling in CPP neurons in coronary arterial ligation‐induced CHF rats. ECG data obtained from continuous telemetry recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 1–3 and 12–14 weeks after coronary arterial ligation (60 % and 80%, respectively), whereas VT/VF did not occurred in 6–8 weeks after coronary arterial ligation. Additionally, as an index of ventricular vagal tone, the change of left ventricular pressure in response to vagal efferent nerve stimulation was blunted in 12 –14 weeks but not 1–3 weeks or 6–8 weeks after coronary arterial ligation. More importantly, the results from whole‐cell patch clamp recording demonstrated that N‐type Ca2+ currents in CPP neurons began to decrease in 6–8 weeks after coronary arterial ligation, and had a significant decrease in 12–14 weeks after coronary arterial ligation. Based on above results, we concluded that lethal ventricular arrhythmia mainly occurred in both early stage and late stage of CHF after myocardial infarction. Electrical remodeling in CPP neurons highly correlated with the occurrence of fatal ventricular arrhythmia in late stage of CHF. However, lethal ventricular arrhythmia in early stage of CHF was not attributed to N‐type Ca2+ currents in CPP neurons. These new findings suggest that improving ventricular vagal tone at late stage of CHF might be a potential therapeutic target for prevention of fatal ventricular arrhythmia and sudden cardiac death in patients with CHF.Support or Funding InformationThis study was supported by AHA Grant‐in‐Aid (15GRANT24970002)

Human presynaptic receptors.

Presynaptic receptors are sites at which transmitters, locally formed mediators or hormones inhibit or facilitate the release of a given transmitter from its axon terminals. The interest in the identification of presynaptic receptors has faded in recent years and it may therefore be justified to give an overview of their occurrence in the autonomic and central nervous system; this review will focus on presynaptic receptors in human tissues. Autoreceptors are presynaptic receptors at which a given transmitter restrains its further release, though in some instances may also increase its release. Inhibitory autoreceptors represent a typical example of a negative feedback; they are tonically activated by the respective endogenous transmitter and/or are constitutively active. Autoreceptors also play a role under pathophysiological conditions, e.g. by limiting the massive noradrenaline release occurring during congestive heart failure. They can be used for therapeutic purposes; e.g., the α2-adrenoceptor antagonist mirtazapine is used as an antidepressant and the inverse histamine H3 receptor agonist pitolisant has been marketed as a new drug for the treatment of narcolepsy in 2016. Heteroreceptors are presynaptic receptors at which transmitters from adjacent neurons, locally formed mediators (e.g. endocannabinoids) or hormones (e.g. adrenaline) can inhibit or facilitate transmitter release; they may be subject to an endogenous tone. The constipating effect of the sympathetic nervous system or of the antihypertensive drug clonidine is related to the activation of inhibitory α2-adrenoceptors on postganglionic parasympathetic neurons. Part of the stimulating effect of adrenaline on the sympathetic nervous system during stress is related to its facilitatory effect on noradrenaline release via β2-adrenoceptors.

Identification of autonomic neuronal chains innervating gingiva and lip.

The major goals of this present study were 1) to further clarify which parasympathetic ganglion sends postganglionic fibers to the lower gingiva and lip that may be involved in the inflammatory processes besides the local factors; 2) to separately examine the central pathways regulating sympathetic and parasympathetic innervation; and 3) to examine the distribution of central premotor neurons on both sides. A retrogradely transported green fluorescent protein conjugated pseudorabies virus was injected into the lower gingiva and lip of intact and sympathectomized adult female rats. Some animals received virus in the adrenal medulla which receive only preganglionic sympathetic fibers to separately clarify the sympathetic nature of premotor neurons. After 72-120h of survival and perfusion, the corresponding thoracic part of the spinal cord, brainstem, hypothalamus, cervical, otic, submandibular and trigeminal ganglia were harvested. Frozen sections were investigated under a confocal microscope. Green fluorescence indicated the presence of the virus. The postganglionic sympathetic neurons related to both organs are located in the three cervical ganglia, the preganglionic neurons in the lateral horn of the spinal cord on ipsilateral side; premotor neurons were found in the ventrolateral medulla, locus ceruleus, gigantocellular and paraventricular nucleus and perifornical region in nearly the same number on both sides. The parasympathetic postganglionic neurons related to the gingiva are present in the otic and related to the lip are present in the otic and submandibular ganglia and the preganglionic neurons are in the salivatory nuclei. Third order neurons were found in the gigantocellular reticular and hypothalamic paraventricular nuclei and perifornical area.

Nicotinic Acetylcholine Receptors and Cardiac Vagal activity in Rats with Type 2 Diabetes

Reduced cardiac parasympathetic activity is involved in sudden cardiac death and is responsible for high mortality in patients with type 2 diabetes mellitus (T2DM). Nicotinic acetylcholine receptors (nAChRs) mediate synaptic transmission in the intracardiac ganglia (ICG) and regulate the excitability of postganglionic parasympathetic neurons. We hypothesized that changes in the functional responsiveness of postsynaptic nAChRs to nicotine (a nAChR agonist) might be involved in attenuated cardiac parasympathetic (vagal) activity in type 2 diabetic rats. A rat model of T2DM was induced by a combination of both high-fat diet and injection of low-dose streptozotocin (30 mg/kg, i.p.). As an index of cardiac vagal function, changes of heart rate in response to graded vagal efferent nerve stimulation were blunted in T2DM rats, compared to sham rats. In isolated Langendorff-perfused hearts, there was no significant difference on sensitivity of the heart to acetylcholine in sham and T2DM rats. Whole-cell patch-clamp data showed that T2DM decreased nAChR currents and sensitivity of the nAChR channel to nicotine in ICG neurons. However, the data from immunofluorescence staining showed that there is no significant difference in the protein expression of ?3 and ?4 nAChR subunits in ICG neurons of sham and T2DM rats. These results suggest that the low sensitivity of nAChR channels to nicotine might contribute to impairment of the cardiac vagal activity in T2DM.

Recent advances in research on nitrergic nerve-mediated vasodilatation.

Cerebral vascular resistance and blood flow were widely considered to be regulated solely by tonic innervation of vasoconstrictor adrenergic nerves. However, pieces of evidence suggesting that parasympathetic nitrergic nerve activation elicits vasodilatation in dog and monkey cerebral arteries were found in 1990. Nitric oxide (NO) as a neurotransmitter liberated from parasympathetic postganglionic neurons decreases cerebral vascular tone and resistance and increases cerebral blood flow, which overcome vasoconstrictor responses to norepinephrine liberated from adrenergic nerves. Functional roles of nitrergic vasodilator nerves are found also in peripheral vasculature, including pulmonary, renal, mesenteric, hepatic, ocular, uterine, nasal, skeletal muscle, and cutaneous arteries and veins; however, adrenergic nerve-induced vasoconstriction is evidently greater than nitrergic vasodilatation in these vasculatures. In coronary arteries, neurogenic NO-mediated vasodilatation is not clearly noted; however, vasodilatation is induced by norepinephrine released from adrenergic nerves that activates β1-adrenoceptors. Impaired actions of NO liberated from the endothelium and nitrergic neurons are suggested to participate in cerebral hypoperfusion, leading to brain dysfunction, like that in Alzheimer's disease. Nitrergic neural dysfunction participates in impaired circulation in peripheral organs and tissues and also in systemic blood pressure increase. NO and vasodilator peptides, as sensory neuromediators, are involved in neurogenic vasodilatation in the skin. Functioning of nitrergic vasodilator nerves is evidenced not only in a variety of mammals, including humans and monkeys, but also in non-mammals. The present review article includes recent advances in research on the functional importance of nitrergic nerves concerning the control of cerebral blood flow, as well as other regions, and vascular resistance. Although information is still insufficient, the nitrergic nerve histology and function in vasculatures of non-mammals are also summarized.

Neural development: finding the source of parasympathetic neurons.

Studies show that postganglionic parasympathetic neurons originate from nerve-associated Schwann cell precursors.

Equine grass sickness in the Czech Republic a case report

Equine grass sickness (EGS) is a degenerative polyneuropathy affecting postganglionic parasympathetic and sympathetic neurons. The major clinical signs relate to dysfunction of the gastrointestinal tract and the condition is frequently fatal. EGS has been reported in different parts of the world including Europe. This paper describes the first case of equine dysautonomia in the Czech Republic. The ante mortem diagnosis was based on typical clinical signs and a positive phenylephrine eye-drop test and was confirmed at necropsy following observation of pathognomic histopathological lesions in the enteric neural system of the ileum.