Capsaicin-Sensitive Sensory Nerves Indirectly Modulate Motor Function of the Urinary Bladder / 대한배뇨장애요실금학회지

PURPOSE: The urinary bladder (UB) is innervated by both sensory and autonomic nerves. Recent studies have shown that sensory neuropeptides induced contractions in the detrusor muscle. Therefore, in a mouse model, we investigated the presence of interactions between the submucosal sensory nerves and the autonomic nerves that regulate the motor function of the detrusor muscle. METHODS: UB samples from male C57BL/6 mice were isolated, cut into strips, and mounted in an organ bath. Dose-response curves to norepinephrine and phenylephrine were studied in UB strips with and without mucosa, and the effects of preincubation with a receptor antagonist and various drugs on relaxation were also studied using tissue bath myography. RESULTS: Phenylephrine-induced relaxation of the UB strips showed concentration-related effects. This relaxation appeared in both mucosa-intact and mucosa-denuded UB strips, and was significantly inhibited by lidocaine, silodosin, and guanethidine (an adrenergic neuronal blocker). Meanwhile, phenylephrine-induced relaxation was inhibited by pretreatment with propranolol and calcitonin gene-related peptide (CGRP)–depletory capsaicin in UB strips with and without mucosa. CONCLUSIONS: The present study suggests that phenylephrine activates the α-1A adrenergic receptor (AR) of the sensory nerve, and then activates capsaicin-sensitive sensory nerves to release an unknown substance that facilitates the release of norepinephrine from adrenergic nerves. Subsequently, norepinephrine stimulates β-ARs in the detrusor muscle in mice, leading to neurogenic relaxation of the UB. Further animal and human studies are required to prove this concept and to validate its clinical usefulness.

Three Gaseous Neurotransmitters, Nitric oxide, Carbon Monoxide, and Hydrogen Sulfide, Are Involved in the Neurogenic Relaxation Responses of the Porcine Internal Anal Sphincter

BACKGROUND/AIMS: The internal anal sphincter (IAS) plays an important role in maintaining continence and a number of neurotransmitters are known to regulate IAS tone. The aim of this study was to determine the relative importance of the neurotransmitters involved in the relaxant and contractile responses of the porcine IAS. METHODS: Responses of isolated strips of IAS to electrical field stimulation (EFS) were obtained in the absence and presence of inhibitors of neurotransmitter systems. RESULTS: Contractile responses of the sphincter to EFS were unaffected by the muscarinic receptor antagonist, atropine (1 muM), but were almost completely abolished by the adrenergic neuron blocker guanethidine (10 muM). Contractile responses were also reduced (by 45% at 5 Hz, P carbon monoxide > hydrogen sulfide.

Central chemoreceptors and neural mechanisms of cardiorespiratory control

The arterial partial pressure (P CO2) of carbon dioxide is virtually constant because of the close match between the metabolic production of this gas and its excretion via breathing. Blood gas homeostasis does not rely solely on changes in lung ventilation, but also to a considerable extent on circulatory adjustments that regulate the transport of CO2 from its sites of production to the lungs. The neural mechanisms that coordinate circulatory and ventilatory changes to achieve blood gas homeostasis are the subject of this review. Emphasis will be placed on the control of sympathetic outflow by central chemoreceptors. High levels of CO2 exert an excitatory effect on sympathetic outflow that is mediated by specialized chemoreceptors such as the neurons located in the retrotrapezoid region. In addition, high CO2 causes an aversive awareness in conscious animals, activating wake-promoting pathways such as the noradrenergic neurons. These neuronal groups, which may also be directly activated by brain acidification, have projections that contribute to the CO2-induced rise in breathing and sympathetic outflow. However, since the level of activity of the retrotrapezoid nucleus is regulated by converging inputs from wake-promoting systems, behavior-specific inputs from higher centers and by chemical drive, the main focus of the present manuscript is to review the contribution of central chemoreceptors to the control of autonomic and respiratory mechanisms.

Remodeling in the ischemic heart: the stepwise progression for heart

Abstract Coronary artery disease is the leading cause of death in the developed world and in developing countries. Acute mortality from acute myocardial infarction (MI) has decreased in the last decades. However, the incidence of heart failure (HF) in patients with healed infarcted areas is increasing. Therefore, HF prevention is a major challenge to the health system in order to reduce healthcare costs and to provide a better quality of life. Animal models of ischemia and infarction have been essential in providing precise information regarding cardiac remodeling. Several of these changes are maladaptive, and they progressively lead to ventricular dilatation and predispose to the development of arrhythmias, HF and death. These events depend on cell death due to necrosis and apoptosis and on activation of the inflammatory response soon after MI. Systemic and local neurohumoral activation has also been associated with maladaptive cardiac remodeling, predisposing to HF. In this review, we provide a timely description of the cardiovascular alterations that occur after MI at the cellular, neurohumoral and electrical level and discuss the repercussions of these alterations on electrical, mechanical and structural dysfunction of the heart. We also identify several areas where insufficient knowledge limits the adoption of better strategies to prevent HF development in chronically infarcted individuals.

Gender-Specific Association of the Brain-Derived Neurotrophic Factor Gene with Attention-Deficit/Hyperactivity Disorder

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder with a strong genetic component. Brain-derived neurotrophic factor (BDNF), which participates in the differentiation and survival of dopaminergic and noradrenergic neurons, could play a role in ADHD development. We aimed to explore the relationships between ADHD and BDNF gene polymorphism. METHODS: We conducted a case-control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test on 151 trios, and compared the results of a continuous performance test (CPT) according to the genotype of the three single nucleotide polymorphisms (rs11030101, rs6265, rs16917204) in the BDNF gene. RESULTS: In the case-control analysis, the AA genotype of the BDNF rs11030101 polymorphism was significantly associated with ADHD only in girls (p=0.024, odds ratio=3.00). The T-G-G haplotype was significantly less frequent (p=0.005) and A-G-G was more frequent (p=0.048) in girls with ADHD than in control girls (global p=0.027). A multivariate analysis of variance for commission errors on the CPT showed a significant main effect for the rs11030101 genotype (p=0.026) and an interaction effect of the rs11030101 genotype and gender (p=0.032) in ADHD probands. CONCLUSION: These results provide preliminary evidence for a gender-specific association between BDNF and ADHD in the Korean population.

Evaluation of recombinant adenovirus-mediated gene delivery for expression of tracer genes in catecholaminergic neurons / 대한해부학회지

Selective labeling of small populations of neurons of a given phenotype for conventional neuronal tracing is difficult because tracers can be taken up by all neurons at the injection site, resulting in nonspecific labeling of unrelated pathways. To overcome these problems, genetic approaches have been developed that introduce tracer proteins as transgenes under the control of cell-type-specific promoter elements for visualization of specific neuronal pathways. The aim of this study was to explore the use of tracer gene expression for neuroanatomical tracing to chart the complex interconnections of the central nervous system. Genetic tracing methods allow for expression of tracer molecules using cell-type-specific promoters to facilitate neuronal tracing. In this study, the rat tyrosine hydroxylase (TH) promoter and an adenoviral delivery system were used to express tracers specifically in dopaminergic and noradrenergic neurons. Region-specific expression of the transgenes was then analyzed. Initially, we characterized cell-type-specific expression of GFP or RFP in cultured cell lines. We then injected an adenovirus carrying the tracer transgene into several brain regions using a stereotaxic apparatus. Three days after injection, strong GFP expression was observed in the injected site of the brain. RFP and WGA were expressed in a cell-type-specific manner in the cerebellum, locus coeruleus, and ventral tegmental regions. Our results demonstrate that selective tracing of catecholaminergic neuronal circuits is possible in the rat brain using the TH promoter and adenoviral expression.

Effect of Fluoxetine on Calcium or Potassium Channels in the Neuron of Rat Major Pelvic Ganglia / 대한비뇨기과학회지

PURPOSE: The major pelvic ganglia (MPG) provide the majority of the innervations to the lower urinary tract. The pelvic ganglia are unique autonomic ganglia that contain both sympathetic and parasympathetic neurons. It has been known that the low-threshold voltage-gated (T-type) Ca2 channels are only expressed only in the sympathetic neurons, whereas these channels are absent in parasympathetic neurons. In the present study, we examined the effect of fluoxetine, a world-wide used antidepressant, on the voltage-dependent Ca2 and K currents in the adrenergic neurons of the MPG. MATERIALS AND METHODS: The effect of fluoxetine on the voltage-dependent Ca2 and K currents in the adrenergic neurons of the MPG were examined using the whole-cell patch-clamp technique. RESULTS: Fluoxetine inhibited the voltage-activated Ca2 currents in the adrenergic neurons of the MPG. Both high-threshold (HVA) and low- threshold (LVA, T-type) Ca2 currents were inhibited by fluoxetine with an IC50 of 5.3 and 10.8microM, respectively. Fluoxetine also decreased the both the peak amplitude and the plateau of the outward K currents. The inhibition of the peak K currents by fluoxetine was concentration- dependent with an IC50 of 3.2microM. The inhibitions of the Ca2 and K currents were quickly reversible upon washout of the fluoxetine. CONCLUSIONS: These results provide evidence for the direct inhibition of the voltage dependant Ca2 and K currents by fluoxetine and these inhibitory effects could modify the synaptic transmission in adrenergic neurons of the MPG.

Clinical Application of I-123 MIBG Cardiac Imaging / 대한핵의학회잡지

Cardiac neurotransmission imaging allows in vivo assessment of presynaptic reuptake, neurotransmitter storage and postsynaptic receptors. Among the various neurotransmitter, I-123 MIBG is most available and relatively well- established. Metaiodobenzylguanidine (MIBG) is an analogue of the false neurotransmitter guanethidine. It is taken up to adrenergic neurons by uptake-1 mechanism as same as norepinephrine. As tagged with I-123, it can be used to image sympathetic function in various organs including heart with planar or SPECT techniques. I-123 MIBG imaging has a unique advantage to evaluate myocardial neuronal activity in which the heart has no significant structural abnormality or even no functional derangement measured with other conventional examination. In patients with cardiomyopathy and heart failure, this imaging has most sensitive technique to predict prognosis and treatment response of betablocker or ACE inhibitor. In diabetic patients, it allow very early detection of autonomic neuropathy. In patients with dangerous arrhythmia such as ventricular tachycardia or fibrillation, MIBG imaging may be only an abnormal result among various exams. In patients with ischemic heart disease, sympathetic derangement may be used as the method of risk stratification. In heart transplanted patients, sympathetic reinnervation is well evaluated. Adriamycin-induced cardiotoxicity is detected earlier than ventricular dysfunction with sympathetic dysfunction. Neurodegenerative disorder such as Parkinson's disease or dementia with Lewy bodies has also cardiac sympathetic dysfunction. Noninvasive assessment of cardiac sympathetic nerve activity with I-123 MIBG imaging may be improve understanding of the pathophysiology of cardiac disease and make a contribution to predict survival and therapy efficacy.

The study of dopaminergic immunoreactive cell change in mesencephalon and pons of mongolian gerbil by water deprived day / 대한해부학회지

Mongolian gerbil (Meriones unguiculatus) has been as an model animal for studing the neurologic disease because of the long-term survival in the condition of water-deprived desert condition. In order to accomplish the this research, first of all another divided the laboratory animals 10groups. In this study of the long term water deprived condition investigated catecholamine synthetic enzymes, tyrosine hydroxylase(TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine-N- methyltransferase(PNMT) in the brain by using immunohistochemical stain. The results obtained in this study were summarized as following. 1. It were observed TH-IR cells in substantia nigra pars compacta, ventral tegmental area and substantia nigra pars reticular of Midbrian. Most of them were presented in pars compacta and ventral tegmental area, but a few in pars reticular. TH-IR cell decreased until the 5th water-deprived day, increased from the 10th water-deprived day to the 15th water-deprived day and redecreased in the 20th water-deprived day 2. In locus ceruleus and rubrospinal tract were observed TH-IR cells and a few DBH-IR cell. Therefore there was composed of dopaminergic neuron and noradrenergic neuron. 3. The quantity of dopamin in serum were decreased until the 4th water-deprived day, increased from the 5th water-deprived day, redecreased on the 15th water-deprived day and reincreased from the 20th water-deprived day.

Tyrosine Hydroxylase, Dopamine-beta-Hydroxylase and Phenylethanolamine-N-Methyltransferase Immunoreactive Neurons of the Medulla Oblongata in the Apodemus agrarius / 대한해부학회지

The distributions and morphological characteristics of neurons displaying immunoreactivity to the catecholamine synthetic enzymes tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT) were examined in the adjacent sections of the whole brain in the Striped Field Mouse (Apodemus agrarius coreae) The medulla oblongata were divided into 3 parts (rostral medulla oblongata, area postrema portion of medulla oblongata and caudal medulla oblongata) in this study. In the rostral medulla oblongata, adrenergic (TH-, DBH- and PNMT-positive) neurons were found in dorsal motor nucleus of vagus, nucleus tractus solitarius, dorsal strip and medial longitudinal fasciculus. In the ventrolateral medullary tegmentum of rostral medulla oblongata, adrenergic neurons were found between gigantocellular reticular nucleus and paragigantocellular reticular nucleus. In the area postrema portion of medulla oblongata, noradrenergic neurons were found in the nucleus tractus solitarius, and area postrema. And dopaminergic or adrenergic neurons were also found in dorsal motor nucleus of vagus. In the caudal medulla oblongata, noradrenergic neurons were found in the medial part of nucleus tractus solitarius and superior part of the lateral reticular nucleus.

Study on Catecholaminergic Neurons in Central Pathways Supplying the Vagus Nerve / 대한해부학회지

This study aimed to carry out the reconstruction of whole tract of the vagus nerve using new powerful neurotracer which can migrate easily to the neighboring neurons through synapse and identify whether catecholaminergic neurons exist or not in the central vagal pathways. Pesudorabies virus (PRV-Ba) was used as a neurotracer and antibody to the PRV-Ba was used to localize the tracer in neurons immunohistochemically. The PRV-Ba was injected into the cervical portion of the vagus nerve of Sprague-Dawley rats. After 3 to 4 days of survival periods, brain tissues were fixed, sectioned and stained using anti-PRV-Ba and ABC method subsequently. Motor neurons of the vagus nerve were originated exclsively from dorsal motor nucleus of the vagus nerve and nucleus ambiguus in the medulla oblongata which project fiber by way of nucleus tractus solitarius up to the cerebrum including the paraventricular nucleus. Double labelled neurons were found mostly throughout the brainstem. The adrenergic inputs arose from the C1, C2, and C3 cell groups. Noradrenergic inputs originated predominately from A5 cell group, with lesser contributions from A1 and A7 cell groups as well as locus ceruleus. Some weakly stained TH-immunoreac-tive neurons, presumably dopaminergic, were labelled in the paraventicular nucleus. In conclusion, motor neurons projecting to the vagus nerve includes noradrenergic neurons of the brainstem and from a dopaminergic neurons in the paraventicular nucleus.

The Effect of Intrastriatal 6-Hydroxydopamine injection on the Expression of Neurotrophic factors in the Rat Brain

BACKGROUND AND PURPOSE: Neurotrophic factors has been a subject of interest in the research of Parkinson's disease. In this experiment, intrastriatal 6-Hydroxydopamine(6-OHDA) injection was used to observe the effect of dopaminergic deafferentiation on the neurotrophic factor mRNA expression in the rat brain. METHODS: Male Sprague Dawley rats (250~300 gm) were treated to produce specific unilateral dopaminergic deafferentiation via injection of 6-OHDA at the right striatum without effect on the noradrenergic system. Treatment group (N=20) received same volume of vitamin C at the same site. The rats were sacrificed 3 hours, 12 hours, 24 hours, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, after injection. The expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), tyrosine hydroxylase (TH), and enkephalin (ENK) mRNA were observed by in situ hybridization histochemistry in the hippocampus, striatum and substantia nigra. RESULTS: The expression of BDNF mRNA was increased in the cerebral cortex, dentate gyrus, and hippocampus. In the cerebral cortex, the increase of expression was peaked at 12 hours after 6-OHDA injection and confined to injection side. In the dentate gyrus, the expression was significantly increased in the injection side at 12 hours after injection, after that increased expression was observed in both side. The expression of NGF mRNA was increased in the dentate gyrus and cerebral cortex of lesion side at 3 hours and 12 hours after 6-OHDA injection. However, the expression of NT-3 mRNA was not changed. The expression of TH mRNA was gradually decreased in the substantia nigra compacta of injection side from 1 week to 4 weeks after 6-OHDA injection. The expression of enkephalin mRNA was increased from 24 hours, peaked at 1week, and returned to basal level at 4 weeks after injection in the injection side. CONCLUSION: From this results, it may suggest that the expression of neurotrophic factors in the cerebral cortex, dentate gyrus and hippocampus are closely related with the degeneration of dopaminergic neurons, not with the degeneration of noradrenergic neurons.