Pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptor (PAC1-R) are positioned to modulate afferent signaling in the cochlea.

PubMed

Drescher, M J; Drescher, D G; Khan, K M; Hatfield, J S; Ramakrishnan, N A; Abu-Hamdan, M D; Lemonnier, L A

2006-09-29

Pituitary adenylyl cyclase-activating polypeptide (PACAP), via its specific receptor pituitary adenylyl cyclase-activating polypeptide receptor 1 (PAC1-R), is known to have roles in neuromodulation and neuroprotection associated with glutamatergic and cholinergic neurotransmission, which, respectively, are believed to form the primary basis for afferent and efferent signaling in the organ of Corti. Previously, we identified transcripts for PACAP preprotein and multiple splice variants of its receptor, PAC1-R, in microdissected cochlear subfractions. In the present work, neural localizations of PACAP and PAC1-R within the organ of Corti and spiral ganglion were examined, defining sites of PACAP action. Immunolocalization of PACAP and PAC1-R in the organ of Corti and spiral ganglion was compared with immunolocalization of choline acetyltransferase (ChAT) and synaptophysin as efferent neuronal markers, and glutamate receptor 2/3 (GluR2/3) and neurofilament 200 as afferent neuronal markers, for each of the three cochlear turns. Brightfield microscopy giving morphological detail for individual immunolocalizations was followed by immunofluorescence detection of co-localizations. PACAP was found to be co-localized with ChAT in nerve fibers of the intraganglionic spiral bundle and beneath the inner and outer hair cells within the organ of Corti. Further, evidence was obtained that PACAP is expressed in type I afferent axons leaving the spiral ganglion en route to the auditory nerve, potentially serving as a neuromodulator in axonal terminals. In contrast to the efferent localization of PACAP within the organ of Corti, PAC1-R immunoreactivity was co-localized with afferent dendritic neuronal marker GluR2/3 in nerve fibers passing beneath and lateral to the inner hair cell and in fibers at supranuclear and basal sites on outer hair cells. Given the known association of PACAP with catecholaminergic neurotransmission in sympathoadrenal function, we also re-examined the issue of whether the organ of Corti receives adrenergic innervation. We now demonstrate the existence of nerve fibers within the organ of Corti which are immunoreactive for the adrenergic marker dopamine beta-hydroxylase (DBH). DBH immunoreactivity was particularly prominent in nerve fibers both at the base and near the cuticular plate of outer hair cells of the apical turn, extending to the non-sensory Hensen's cell region. Evidence was obtained for limited co-localization of DBH with PAC1-R and PACAP. In the process of this investigation, we obtained evidence that efferent and afferent nerve fibers, in addition to adrenergic nerve fibers, are present at supranuclear sites on outer hair cells and distributed within the non-sensory epithelium of the apical cochlear turn for rat, based upon immunoreactivity for the corresponding neuronal markers. Overall, PACAP is hypothesized to act within the organ of Corti as an efferent neuromodulator of afferent signaling via PAC1-R that is present on type I afferent dendrites, in position to afford protection from excitotoxicity. Additionally, PACAP/PAC1-R may modulate secretion of catecholamines from adrenergic terminals within the organ of Corti.

[The relationship between the sympathetic nerves and immunocytes in the spleen].

PubMed

Saito, H

1991-02-01

Ever since Galen, the ancient Greek physician, said "Melancholic women develop disease more than sanguine women," it has been said that the mental condition affects the physical condition. However, there is hardly any scientific verification. About half a century ago, Selye (1936) proposed a relationship between stress and immune function, and it is becoming increasingly clear that the nervous system and immune system interact with each other. Also researchers have strongly hoped to demonstrate the existence of specific pathways by which immunocytes can be directly regulated by the nervous elements instead of by the humoral influence of immunomodulators. In this study, the author showed by electron microscopic observation how the immunocytes in the guinea pig spleen are directly innervated. The sustentacular supporting element of the guinea pig spleen is the connective tissue system which includes the capsulo-trabecular, peri-vascular and reticular systems. The latter system is composed of the outer sheath of the reticular cell or its cellular processes which have abundant microfilaments and the inner minute connective tissue space in which lamina densa-like material, collagenous fibrils, elastic fibers and nervous elements are present. The sympathetic adrenergic nerves for the spleen enter the organ, and scatter around the arterial walls. All components of the connective tissue system are continuous with each other, and the nervous elements appearing in the reticular system are the elongated ones from other connective tissue systems, especially peri-vascular connective tissue. Thus, the adrenergic nerves are more abundant in the white pulp, into which the central artery penetrates, than in the red pulp which arterioles or capillaries pass through. The minute connective tissue space of the reticular system may be called the noradrenalin (NA) canal because catecholamine released from the naked adrenergic nerve terminals in this tissue diffuses and is stored in this enclosed space. The reticular system in the spleen divides the parenchyma into small non-endothelial vascular spaces owing to its meshwork, and free mobile immunocytes, such as T-cells, B-cells and macrophages, stagnate in these spaces. This stagnation of the mobile immunocytes and the presence of the adrenergic nerves in the NA canals provide the chance for the immunocytes and nerves to meet each other in the following fashion; the reticular cell sheaths show the exposed phenomena owing to the contraction of the microfilament-rich reticular cell processes, caused by noradrenalin in the NA canal, and the nervous elements in the NA canals can face the nonendothelial vascular spaces where mobile immunocytes pass freely.(ABSTRACT TRUNCATED AT 400 WORDS)

Sympathetic nerves: How do they affect angiogenesis, particularly during wound healing of soft tissues?

PubMed

Pan, Liangli; Tang, Jianbing; Liu, Hongwei; Cheng, Biao

2016-01-01

Angiogenesis is essential for wound healing, and angiogenesis impairment can result in chronic ulcers. Studies have shown that the sympathetic nervous system has an important role in angiogenesis. In recent years, researchers have focused on the roles of sympathetic nerves in tumor angiogenesis. In fact, sympathetic nerves can affect angiogenesis in the wound healing of soft tissues, and may have a similar mechanism of action as that seen in tumorigenesis. Sympathetic nerves act primarily through interactions between the neurotransmitters released from nerve endings and receptors present in target organs. Among this, activation or inhibition of adrenergic receptors (mainly β-adrenergic receptors) influence formation of new blood vessels considerably. As sympathetic nerves locate near pericytes in microvessel, go along the capillaries and there are adrenergic receptors present in endothelial cells and pericytes, sympathetic nerves may participate in angiogenesis by influencing the endothelial cells and pericytes of new capillaries. Studying the roles of sympathetic nerves on the angiogenesis of wound healing can contribute to understanding the mechanisms of tissue repair, tissue regeneration, and tumorigenesis, thereby providing new therapeutic perspectives.

Influence of the autonomic nervous system on calcium homeostasis in the rat.

PubMed

Stern, J E; Cardinali, D P

1994-01-01

The local surgical manipulation of sympathetic and parasympathetic nerves innervating the thyroid-parathyroid territory was employed to search for the existence of a peripheral neuroendocrine link controlling parathyroid hormone (PTH) and calcitonin (CT) release. From 8 to 24 h after superior cervical ganglionectomy (SCGx), at the time of wallerian degeneration of thyroid-parathyroid sympathetic nerve terminals, an alpha-adrenergic inhibition, together with a minor beta-adrenergic stimulation, of hypercalcemia-induced CT release, and an alpha-adrenoceptor inhibition of hypocalcemia-induced PTH release were found. In chronically SCGx rats PTH response to EDTA was slower, and after CaCl2 injection, serum calcium attained higher levels in face of normal CT levels. SCGx blocked the PTH increase found in sham-operated rats stressed by a subcutaneous injection of turpentine oil, but did not affect the greater response to EDTA. The higher hypocalcemia seen after turpentine oil was no longer observed in SCGx rats. The effects of turpentine oil stress on calcium and CT responses to a bolus injection of CaCl2 persisted in rats subjected to SCGx 14 days earlier. Interruption of thyroid-parathyroid parasympathetic input conveyed by the thyroid nerves (TN) and the inferior laryngeal nerves (ILN) caused a fall in total serum calcium, an increase of PTH levels and a decrease of CT levels, when measured 10 days after surgery. Greater responses of serum CT and PTH were detected in TN-sectioned, and in TN- or ILN-sectioned rats, respectively. Physiological concentrations of CT decreased, and those of PTH increased, in vitro cholinergic activity in rat SCG, measured as specific choline uptake, and acetylcholine synthesis and release. The results indicate that cervical autonomic nerves constitute a pathway through which the brain modulates calcium homeostasis.

Endogenous calcitonin gene-related peptide (CGRP) mediates adrenergic-dependent vasodilation induced by nicotine in mesenteric resistance arteries of the rat

PubMed Central

Shiraki, Hinako; Kawasaki, Hiromu; Tezuka, Satoko; Nakatsuma, Akira; Kurosaki, Yuji

2000-01-01

The mechanisms underlying vasodilator effect of nicotine on mesenteric resistance blood vessels and the role of calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves were studied in the rat. Mesenteric vascular beds isolated from Wistar rats were perfused with Krebs solution, and perfusion pressure was measured with a pressure transducer. In preparations with intact endothelium and contracted by perfusion with Krebs solution containing methoxamine, perfusion of nicotine (1–100 μM) for 1 min caused a concentration-dependent vasodilator response without vasoconstriction. The nicotine-induced vasodilation was markedly inhibited by hexamethonium (nicotinic cholinoceptor antagonist, 10 μM) and blocked by guanethidine (adrenergic neuron blocker, 5 μM). Either denervation by cold storage (4°C for 72 h) or adrenergic denervation by 6-hydroxydopamine (toxin for adrenergic neurons, 2 mM for 20 min incubation, twice) blocked the nicotine-induced vasodilation. Neither endothelium removal with perfusion of sodium deoxycholate (1.80 mg ml−1, for 30 s) nor treatment with Nω-nitro-L-arginine (nitric oxide synthase inhibitor, 100 μM), atropine (muscarinic cholinoceptor antagonist, 10 nM) or propranolol (β-adrenoceptor antagonist, 100 nM) affected the nicotine-induced vasodilation. In preparations without endothelium, treatment with capsaicin (depleting CGRP-containing sensory nerves, 1 μM) or human CGRP[8–37] (CGRP receptor antagonist, 0.5 μM) markedly inhibited the nicotine-induced vasodilation. These results suggest that, in the mesenteric resistance artery of the rat, nicotine induces vasodilation, which is independent of the function of the endothelium and is involved in activation of CGRPergic nerves. It is also suggested that nicotine stimulates presynaptic nicotinic cholinoceptors on adrenergic nerves to release adrenergic neurotransmitters, which then act on CGRPergic nerves to release endogenous CGRP from the nerve. PMID:10882393

Identification of the origin of adrenergic and cholinergic nerve fibers within the superior hypogastric plexus of the human fetus

PubMed Central

Zaitouna, Mazen; Alsaid, Bayan; Diallo, Djibril; Benoit, Gérard; Bessede, Thomas

2013-01-01

Nerve fibers contributing to the superior hypogastric plexus (SHP) and the hypogastric nerves (HN) are currently considered to comprise an adrenergic part of the autonomic nervous system located between vertebrae (T1 and L2), with cholinergic aspects originating from the second to fourth sacral spinal segments (S2, S3 and S4). The aim of this study was to identify the origin and the nature of the nerve fibers within the SHP and the HN, especially the cholinergic fibers, using computer-assisted anatomic dissection (CAAD). Serial histological sections were performed at the level of the lumbar spine and pelvis in five human fetuses between 14 and 30 weeks of gestation. Sections were treated with histological staining [hematoxylin-eosin (HE) and Masson's trichrome (TriM)] and with immunohistochemical methods to detect nerve fibers (anti-S100), adrenergic fibers (anti-TH), cholinergic fibers (anti-VAChT) and nitrergic fibers (anti-nNOS). The sections were then digitalized using a high-resolution scanner and the 3D images were reconstructed using winsurf software. These experiments revealed the coexistence of adrenergic and cholinergic fibers within the SHP and the HNs. One-third of these cholinergic fibers were nitrergic fibers [anti-VACHT (+)/anti-NOS (+)] and potentially pro-erectile, while the others were non-nitrergic [anti-VACHT (+)/anti-NOS (−)]. We found these cholinergic fibers arose from the lumbar nerve roots. This study described the nature of the SHP nerve fibers which gives a better understanding of the urinary and sexual dysfunctions after surgical injuries. PMID:23668336

The role of β-adrenergic blockers in Parkinson's disease: possible genetic and cell-signaling mechanisms.

PubMed

Luong, Khanh vinh quoc; Nguyen, Lan Thi Hoàng

2013-06-01

Genetic studies have identified numerous factors linking β-adrenergic blockade to Parkinson's disease (PD), including human leukocyte antigen genes, the renin-angiotensin system, poly(adenosine diphosphate-ribose) polymerase 1, nerve growth factor, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate. β-Adrenergic blockade has also been implicated in PD via its effects on matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase 2, and nitric oxide synthase. β-Adrenergic blockade may have a significant role in PD; therefore, the characterization of β-adrenergic blockade in patients with PD is needed.

Neurogenic regulation of renal tubular sodium reabsorption.

PubMed

DiBona, G F

1977-08-01

The evidence supporting a role for direct neurogenic control of renal tubular sodium reabsorption is reviewed. Electron microscopic and fluorescence histochemical studies have demonstrated adrenergic nerve terminals in direct contact with basement membranes of mammalian (rat, dog, and monkey) renal tubular epithelial cells. Low-level direct or baroreceptor reflex stimulation of renal sympathetic nerves produces an increase in renal tubular sodium reabsorption without alterations in glomerular filtration rate, renal blood flow, or intrarenal distribution of blood flow. Antinatriuresis was prevented by prior treatment of the kidney with guanethidine or phenoxybenzamine. Rat kidney micropuncture studies have localized a site of enhanced tubular sodium reabsorption to the proximal tubule. Possible indirect mediation of the antinatriuresis by other humoral agents known to be released from the kidney on renal nerve stimulation (angiotensin II, prostaglandin) was excluded by experiments with appropriate blocking agents. The possible effects of anesthesia and uncertainties about the completeness of surgical renal denervation and other tubular segmental sites of action are critically analyzed. The clinical implications of this mechanism in pathologic conditions of sodium and water retention are discussed and and a prospectus for future work is presented.

[Changes in the electrical activity of the rabbit proximal colon in vivo by stimulation of the vagus and splanchnic nerves].

PubMed

Julé, Y

1975-05-01

1. Using extracellular electrodes placed on the serosa, we recorded the modifications of the electrical activity of the colonic muslce fibers caused by the stimulation of vagal and splanchnic nerve fibers. 2. Vagal stimulation produces two types of junction potentials: excitatory junction potentials (EJPs) and inhibitory junction potentials (IJPs). The IJPs are elicited by stimulation of vagal fibers which innervate intramural non-adrenergic inhibitory neurons. 3. The conduction velocity of the nerve impulse along the vagal pre-ganglionic fibers is 1.01 m/sec for excitatory fibers and 0.5. m/sec for inhibitory fibers. 4. Splanchnic fiber stimulation causes EJP disappearance, blocking transmission between preganglionic fibers and intramural excitatory neurons, and a decrease in IJP amplitude that most likely indicates a previous hyperpolarization of the smooth muscle. 5. IJP persistence during splanchnic stimulation proves that sympathetic inhibition does not modify the transmission of the vagal influx onto the non-adrenergic inhibitory neurons of the intramural plexuses. 6. Through a comparative study of proximal and distal colonic innervation, we are able to show that there is a similar organization of both regions, that is a double inhibitory innervation: an adrenergic one of a sympathetic origin, and a non adrenergic one of a parasympathetic origin.

Sympathetic nerve stimulation induces local endothelial Ca2+ signals to oppose vasoconstriction of mouse mesenteric arteries

PubMed Central

Nausch, Lydia W. M.; Bonev, Adrian D.; Heppner, Thomas J.; Tallini, Yvonne; Kotlikoff, Michael I.

2012-01-01

It is generally accepted that the endothelium regulates vascular tone independent of the activity of the sympathetic nervous system. Here, we tested the hypothesis that the activation of sympathetic nerves engages the endothelium to oppose vasoconstriction. Local inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ signals (“pulsars”) in or near endothelial projections to vascular smooth muscle (VSM) were measured in an en face mouse mesenteric artery preparation. Electrical field stimulation of sympathetic nerves induced an increase in endothelial cell (EC) Ca2+ pulsars, recruiting new pulsar sites without affecting activity at existing sites. This increase in Ca2+ pulsars was blocked by bath application of the α-adrenergic receptor antagonist prazosin or by TTX but was unaffected by directly picospritzing the α-adrenergic receptor agonist phenylephrine onto the vascular endothelium, indicating that nerve-derived norepinephrine acted through α-adrenergic receptors on smooth muscle cells. Moreover, EC Ca2+ signaling was not blocked by inhibitors of purinergic receptors, ryanodine receptors, or voltage-dependent Ca2+ channels, suggesting a role for IP3, rather than Ca2+, in VSM-to-endothelium communication. Block of intermediate-conductance Ca2+-sensitive K+ channels, which have been shown to colocalize with IP3 receptors in endothelial projections to VSM, enhanced nerve-evoked constriction. Collectively, our results support the concept of a transcellular negative feedback module whereby sympathetic nerve stimulation elevates EC Ca2+ signals to oppose vasoconstriction. PMID:22140050

Effects of a beta-adrenergic blocking agent timolol on intra ocular pressure responses induced by stimulation of cervical sympathetic nerve in the cat.

PubMed

Naito, A; Izumi, H; Karita, K; Tamai, M

2001-12-01

We clarified whether the intraocular pressure (IOP) response elicited by stimulation of the cervical sympathetic nerve (CSN) is influenced by changes in the baseline of IOP level and by beta-adrenergic blockade. The CSN was stimulated electrically for 30 seconds (10 V, 0.1-100 Hz, 2 milliseconds pulse duration) in urethane (100 mg/kg i.v.)-chloralose (50 mg/kg i.v.)-anesthetized, paralyzed cats. The IOP was monitored manometrically, and a controlled saline infusion was delivered into the anterior chamber to gradually increase IOP. CSN stimulation was delivered at the various baseline IOP levels so obtained. When required, a beta-adrenergic blocker timolol (2%) was delivered into the conjunctival cul-de-sac. The normal IOP in our cats was 25+/-3 mmHg. This value decreased transiently on CSN stimulation. The amplitude of this IOP response depended on stimulus frequency and the pre-stimulus baseline IOP level. Topical administration of timolol increased the IOP response to CSN stimulation at a given baseline level. These results suggest that beta-adrenergic blockade increases the alpha-adrenergic mediated-IOP reduction elicited by CSN stimulation at given baseline IOP level.

Peptidergic innervation of the human male genital tract.

PubMed

Gu, J; Polak, J M; Probert, L; Islam, K N; Marangos, P J; Mina, S; Adrian, T E; McGregor, G P; O'Shaughnessy, D J; Bloom, S R

1983-08-01

Four peptides--vasoactive intestinal polypeptide, substance P, somatostatin and a peptide-like avian pancreatic polypeptide--have been found in nerves of the human male genitalia using highly sensitive and specific methods of immunocytochemistry and radioimmunoassay. Five other peptides (met-enkephalin, leu-enkephalin, neurotensin, bombesin and cholecystokinin-8) were absent. Vasoactive intestinal polypeptide was the most abundant peptide, its highest concentration being in the proximal corpus cavernosum. Immunoelectron microscopy localized this peptide to large (97 +/- 20 nm), round, electron-dense granules of p-type nerve terminals. Vasoactive intestinal polypeptide-immunoreactive neuronal cell bodies were found in the prostate gland and the root of the corpus cavernosum. Substance P immunoreactive material was present in smaller concentration and was mainly localized in nerves around the corpuscular receptors of the glans penis. Somatostatin immunoreactive nerves were associated mainly with the smooth muscle of the seminal vesicle and the vas deferens. When antiserum to avian pancreatic polypeptide was applied, certain nerves were stained, particularly in the vas deferens, the prostate gland and the seminal vesicle. However, chromatography detected no pure avian pancreatic polypeptide suggesting the presence of a structurally related substance, possibly neuropeptide Y, which cross-reacts with the avian pancreatic polypeptide antiserum. Similar distributions between vasoactive intestinal polypeptide-immunoreactive and acetylcholinesterase-positive nerves and between avian pancreatic polypeptide-immunoreactive and adrenergic nerves were observed. A general neuronal marker, neuron-specific enolase, was used to investigate the general pattern of the organ's innervation. The abundance and distribution patterns of these peptide-immunoreactive nerves indicate that they may play important roles in the male sexual physiology.

Are there any functional differences of the enteric nervous system between the right-sided diverticular colon and the left-sided diverticular colon? An in vitro study.

PubMed

Tomita, Ryouichi

2014-05-01

To evaluate functional differences of the enteric nervous system (ENS) in patients between right-side colonic diverticula (RCD) and left-sided colonic diverticula (LCD), the author compared the ENS responses between RCD and LCD. Ten specimens were obtained from 10 patients with RCD, and 16 specimens were taken from 16 LCD. As a control, twenty-two specimens of right-sided normal colon (RNC) were obtained from 22 colonic cancers. Twenty-four specimens of left sided normal colon (LNC) were obtained from 24 colonic cancers. A mechanography was used to evaluate in vitro muscle responses to electrical field stimulation (EFS) before and after treatment with various autonomic nerve blockers. Before blockade of the adrenergic and cholinergic nerves, the incidences of contraction via cholinergic nerve in the colons with diverticula were significantly greater than those in the normal colons (right-sided colon; p = 0.0022, left-sided colon; p < 0.0001). There were no significant differences between RNC and LNC (p = 0.3606), and between RCD and LCD (p = 0.7684). After the blockade of adrenergic and cholinergic nerves, the incidence of relaxation via non-adrenergic non-cholinergic inhibitory (NANC) nerve in the normal colons was significantly greater than that in the diverticular colons (right-sided colon; p = 0.0435, left-sided colon; p = 0.0034). There were no significant differences between RNC and LNC (p = 0.2909) and between RCD and LCD (p = 0.9464). Cholinergic nerves were dominant in bilateral diverticular colon compared with bilateral normal colon. NANC inhibitory nerves were dominant in bilateral normal colon compared with bilateral diverticular colon. There were also no functional differences of the ENS between RCD and LCD.

Protons modulate perivascular axo-axonal neurotransmission in the rat mesenteric artery.

PubMed

Takatori, Shingo; Hirai, Kazuhiro; Ozaki, Shuichiro; Tangsucharit, Panot; Fukushima-Miyashita, Satoko; Goda, Mitsuhiro; Hashikawa-Hobara, Narumi; Ono, Nobufumi; Kawasaki, Hiromu

2014-12-01

Previous studies have demonstrated that nicotine releases protons from adrenergic nerves via stimulation of nicotinic ACh receptors and activates transient receptor potential vanilloid-1 (TRPV1) receptors located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves, resulting in vasodilatation. The present study investigated whether perivascular nerves release protons, which modulate axon-axonal neurotransmission. Perfusion pressure and pH levels of perfusate in rat-perfused mesenteric vascular beds without endothelium were measured with a pressure transducer and a pH meter respectively. Periarterial nerve stimulation (PNS) initially induced vasoconstriction, which was followed by long-lasting vasodilatation and decreased pH levels in the perfusate. Cold-storage denervation of the preparation abolished the decreased pH and vascular responses to PNS. The adrenergic neuron blocker guanethidine inhibited PNS-induced vasoconstriction and effects on pH, but not PNS-induced vasodilatation. Capsaicin (CGRP depletor), capsazepine and ruthenium red (TRPV1 inhibitors) attenuated the PNS-induced decrease in pH and vasodilatation. In denuded preparations, ACh caused long-lasting vasodilatation and lowered pH; these effects were inhibited by capsaicin pretreatment and atropine, but not by guanethidine or mecamylamine. Capsaicin injection induced vasodilatation and a reduction in pH, which were abolished by ruthenium red. The use of a fluorescent pH indicator demonstrated that application of nicotine, ACh and capsaicin outside small mesenteric arteries reduced perivascular pH levels and these effects were abolished in a Ca(2+) -free medium. These results suggest that protons are released from perivascular adrenergic and CGRPergic nerves upon PNS and these protons modulate transmission in CGRPergic nerves. © 2014 The British Pharmacological Society.

Nervous control of fish swimbladders.

PubMed

Nilsson, Stefan

2009-01-01

The swimbladder of teleost fish receives a rich and complex innervation by nerve fibres of the autonomic nervous system. While an understanding of the form and function of a non-adrenergic, non-cholinergic innervation is slowly emerging, the pattern of control by the "classical" cholinergic and adrenergic innervation is becoming relatively well understood. This short review describes the autonomic innervation patterns, and attempts to summarise the role of cholinergic and adrenergic pathways in the control of gas secretion and resorption in the teleost swimbladder.

α-Adrenoceptor blockade modifies neurally induced atrial arrhythmias

PubMed Central

Richer, Louis-Philippe; Vinet, Alain; Kus, Teresa; Cardinal, René; Ardell, Jeffrey L.; Armour, John Andrew

2008-01-01

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by α-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (α1-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (α2-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined α-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by α1,2-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal α-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that α-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system. PMID:18716036

Alpha-adrenoceptor blockade modifies neurally induced atrial arrhythmias.

PubMed

Richer, Louis-Philippe; Vinet, Alain; Kus, Teresa; Cardinal, René; Ardell, Jeffrey L; Armour, John Andrew

2008-10-01

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by alpha-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (alpha(1)-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (alpha(2)-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined alpha-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by alpha(1,2)-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal alpha-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that alpha-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

Cholinergic innervation of human mesenteric lymphatic vessels.

PubMed

D'Andrea, V; Bianchi, E; Taurone, S; Mignini, F; Cavallotti, C; Artico, M

2013-11-01

The cholinergic neurotransmission within the human mesenteric lymphatic vessels has been poorly studied. Therefore, our aim is to analyse the cholinergic nerve fibres of lymphatic vessels using the traditional enzymatic techniques of staining, plus the biochemical modifications of acetylcholinesterase (AChE) activity. Specimens obtained from human mesenteric lymphatic vessels were subjected to the following experimental procedures: 1) drawing, cutting and staining of tissues; 2) staining of total nerve fibres; 3) enzymatic staining of cholinergic nerve fibres; 4) homogenisation of tissues; 5) biochemical amount of proteins; 6) biochemical amount of AChE activity; 6) quantitative analysis of images; 7) statistical analysis of data. The mesenteric lymphatic vessels show many AChE positive nerve fibres around their wall with an almost plexiform distribution. The incubation time was performed at 1 h (partial activity) and 6 h (total activity). Moreover, biochemical dosage of the same enzymatic activity confirms the results obtained with morphological methods. The homogenates of the studied tissues contain strong AChE activity. In our study, the lymphatic vessels appeared to contain few cholinergic nerve fibres. Therefore, it is expected that perivascular nerve stimulation stimulates cholinergic nerves innervating the mesenteric arteries to release the neurotransmitter AChE, which activates muscarinic or nicotinic receptors to modulate adrenergic neurotransmission. These results strongly suggest, that perivascular cholinergic nerves have little or no effect on the adrenergic nerve function in mesenteric arteries. The cholinergic nerves innervating mesenteric arteries do not mediate direct vascular responses.

Modification by choline of adrenergic transmission in rat mesenteric arteries

PubMed Central

Malik, K. U.; McGiff, J. C.

1971-01-01

1. The action of choline on the vasoconstrictor responses of the perfused mesenteric arteries of the rat to sympathetic nerve stimulation and to injected noradrenaline has been investigated. 2. The infusion of choline (500 μg/ml), for periods of 15 s, increased the response to sympathetic nerve stimulation, whereas the infusion of the same concentration for 20 min greatly reduced the response to nerve stimulation. Choline (up to 500 μg/ml), infused either for short or long periods, did not alter the response to injected noradrenaline. 3. The inhibitory action of choline on the response to nerve stimulation was abolished either by an increase in the calcium concentration from 1·8 to 5·4 mM or by simultaneous infusion of (+)-amphetamine or atropine. 4. The results suggest that choline in concentrations of 500 μg/ml has the same effect on adrenergic transmission in mesenteric arteries as acetylcholine at concentrations of 5 ng/ml. PMID:4339884

DISTRIBUTION OF BIOLOGICALLY ACTIVE COMPOUNDS IN THE BODY.

DTIC Science & Technology

and organ granules; Adrenomedullary response to 2-deoxyglucose in the hypothyroid, euthyroid, and hyperthyroid rat; Effect of respiratory acidosis on...vasoconstrictor effects of directly and indirectly acting sympathomimetic amines in cats; The adrenergic innervation of the vas deferens and the...accessory male genital gland; Distribution and function of adrenergic nerves in the rabbit fallopian tube; Effects of acute heart failure and

Distribution of adrenergic and cholinergic nerve fibres within intrinsic nerves at the level of the human heart hilum.

PubMed

Petraitiene, Viktorija; Pauza, Dainius H; Benetis, Rimantas

2014-06-01

The disbalance between adrenergic (sympathetic) and cholinergic (parasympathetic) cardiac inputs facilitates cardiac arrhythmias, including the lethal ones. In spite of the fact that the morphological pattern of the epicardiac ganglionated subplexuses (ENsubP) has been previously described in detail, the distribution of functionally distinct axons in human intrinsic nerves was not investigated thus far. Therefore, the aim of the present study was to quantitatively evaluate the distribution of tyrosine hydroxylase (TH)- and choline acetyltransferase (ChAT)-positive axons within intrinsic nerves at the level of the human heart hilum (HH), since they are of pivotal importance for determining proper treatment options for different arrhythmias. Tissue samples containing the intrinsic nerves from seven epicardiac subplexuses were obtained from nine human hearts without cardiac pathology and processed for immunofluorescent detection of TH and ChAT. The nerve area was measured and the numbers of axons were counted using microphotographs of nerve profiles. The densities of fibres were extrapolated and compared between subplexuses. ChAT-immunoreactive (IR) fibres were evidently predominant (>56%) in nerves of dorsal (DRA) and ventral right atrial (VRA) ENsubP. Within both left (LC) and right coronary ENsubP, the most abundant (70.9 and 83.0%, respectively) were TH-IR axons. Despite subplexal dependence, ChAT-IR fibres prevailed in comparatively thinner nerves, whereas TH-IR fibres in thicker ones. Morphometry showed that at the level of HH: (i) LC subplexal nerves were found to be the thickest (25 737 ± 4131 μm(2)) ones, whereas the thinnest (2604 ± 213 μm(2)) nerves concentrated in DRA ENsubP; (ii) the density of ChAT-IR axons was highest (6.8 ± 0.6/100 μm(2)) in the ventral left atrial nerves and lowest (3.2 ± 0.1/100 μm(2)) in left dorsal ENsubP and (iii) the density of TH-IR fibres was highest (15.9 ± 2.1/100 μm(2)) in LC subplexal nerves and lowest (4.4 ± 0.3/100 μm(2)) in VRA nerves. (i) The principal intrinsic adrenergic neural pathways in the human heart proceed via both coronary ENsubP that supply cardiac ventricles and (ii) the majority of cholinergic nerve fibres access the human heart through DRA and VRA ENsubP and extend towards the right atrium, including the region of the sinuatrial node. © The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Enhanced 5-hydroxytryptamine (5-HT) release from vascular adrenergic nerves in spontaneously hypertensive rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawasaki, H.; Urabe, M.; Takasaki, K.

1986-03-01

The release of 5-HT from vascular adrenergic nerves was compared between normotensive Wistar Kyoto rats (WKY) and SHR. The mesenteric vascular bed isolated from WKY and SHR was perfused with Krebs solution at a constant flow rate of 5 ml/min. Periarterial nerve stimulation (PNS) was delivered at 4 to 16 Hz for 30 sec. In the SHR preparation, the pressor response to PNS, previously decreased by prazonsin (50 nM), was greatly potentiated after treatment with 5-HT(1 ..mu..M) for 15 min and a frequency-dependent pressor response to PNS reappeared, whereas the 5-HT treatment did not alter the pressor response to exogenousmore » norepinephrine (1 nmol) previously reduced by prazonsin. The potentiation of pressor response to PNS after 5-HT treatment was small in the WKY preparation. This potentiation in both WKY and SHR did not occur in the presence of ketanserin (10 nM). In the preparation labeled with (/sup 3/H)-5-HT, PNS (4-16 Hz) evoked a frequency-dependent increase of (/sup 3/H)-efflux, which was abolished by treatment with tetrodotoxin (100 nM) or 6-hydroxydopamine (50 mg/kg i.p. x 2) and in calcium-free Krebs solution. The PNS evoked-(/sup 3/H)-efflux was much greater in SHR than WKY. These results suggest that the release of 5-HT from vascular adrenergic nerves by PNS is enhanced in the SHR preparation.« less

Substance P is a functional neurotransmitter in the rat parotid gland.

PubMed

Gallacher, D V

1983-09-01

The technique of electrical field stimulation was employed to stimulate the intrinsic nerves of isolated rat parotid gland fragments. Responses to field stimulation were recorded as changes in enzyme secretion (amylase release), radiolabelled ion fluxes (86Rb efflux) and electrophysiological effects (changes in acinar cell membrane potential and input resistance). All effects of field stimulation were abolished by the neurotoxin, tetrodotoxin (TTX). Selective use of pharmacological antagonists revealed that both the sympathetic and parasympathetic nerves to this tissue were being excited by field stimulation. Importantly a significant component of the response to field stimulation persisted in the presence of combined autonomic receptor blockade by atropine, phentolamine and propranolol, i.e. due to release of a non-cholinergic, non-adrenergic neurotransmitter. The non-cholinergic, non-adrenergic neurotransmitter evoked amylase release, 86Rb efflux and electrophysiological effects seen as changes in acinar cell membrane potential and conductance, i.e. stimulus-permeability coupled. Two biologically active peptides, substance P (SP) and vasoactive intestinal polypeptide (VIP) were shown to evoke amylase release in the presence of combined autonomic blockade. VIP however did not evoke any increase in 86Rb efflux, i.e. not stimulus-permeability coupled. All the effects of the non-cholinergic, non-adrenergic transmitter were mimicked by substance P which evokes 86Rb efflux and electrophysiological effects in addition to amylase release. The non-cholinergic, non-adrenergic field stimulus effects on amylase release and 86Rb efflux were abolished or markedly attenuated in tissues which had been desensitized by prior exposure to exogenous substance P. In the presence of VIP, however, the non-cholinergic, non-adrenergic effects persisted and were apparently potentiated. Acute application of the neurotoxin capsaicin first stimulated a transient release of amylase and subsequently abolished the non-cholinergic, non-adrenergic field stimulus-evoked enzyme release. The putative substance P antagonist, D-Pro2, D-Trp7,9 substance P, reversibly blocked the response to both non-cholinergic, non-adrenergic nerve stimulation and exogenous substance P. It was demonstrated however that prolonged exposure to this antagonist is associated with non-reversible and, importantly, non-specific neurotoxic effects. It is concluded that substance P or a closely related peptide is a functional neurotransmitter in the rat parotid gland.

Volume Transmission in Central Dopamine and Noradrenaline Neurons and Its Astroglial Targets.

PubMed

Fuxe, Kjell; Agnati, Luigi F; Marcoli, Manuela; Borroto-Escuela, Dasiel O

2015-12-01

Already in the 1960s the architecture and pharmacology of the brainstem dopamine (DA) and noradrenaline (NA) neurons with formation of vast numbers of DA and NA terminal plexa of the central nervous system (CNS) indicated that they may not only communicate via synaptic transmission. In the 1980s the theory of volume transmission (VT) was introduced as a major communication together with synaptic transmission in the CNS. VT is an extracellular and cerebrospinal fluid transmission of chemical signals like transmitters, modulators etc. moving along energy gradients making diffusion and flow of VT signals possible. VT interacts with synaptic transmission mainly through direct receptor-receptor interactions in synaptic and extrasynaptic heteroreceptor complexes and their signaling cascades. The DA and NA neurons are specialized for extrasynaptic VT at the soma-dendrtitic and terminal level. The catecholamines released target multiple DA and adrenergic subtypes on nerve cells, astroglia and microglia which are the major cell components of the trophic units building up the neural-glial networks of the CNS. DA and NA VT can modulate not only the strength of synaptic transmission but also the VT signaling of the astroglia and microglia of high relevance for neuron-glia interactions. The catecholamine VT targeting astroglia can modulate the fundamental functions of astroglia observed in neuroenergetics, in the Glymphatic system, in the central renin-angiotensin system and in the production of long-distance calcium waves. Also the astrocytic and microglial DA and adrenergic receptor subtypes mediating DA and NA VT can be significant drug targets in neurological and psychiatric disease.

The foetal pig pineal gland is richly innervated by nerve fibres containing catecholamine-synthesizing enzymes, neuropeptide Y (NPY) and C-terminal flanking peptide of NPY, but it does not secrete melatonin.

PubMed

Bulc, Michał; Lewczuk, Bogdan; Prusik, Magdalena; Całka, Jarosław

2013-05-01

Innervation of the mammalian pineal gland during prenatal development is poorly recognized. Therefore, immunofluorescence studies of the pineals of 70- and 90-day-old foetuses of the domestic pig were performed using antibodies against tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DβH), neuropeptide Y (NPY) and C-terminal flanking peptide of NPY (CPON). The investigated glands were supplied by numerous nerve fibres containing TH and DβH. The density of these fibres was higher in the distal and middle parts of the gland than in the proximal one. NPY and CPON were identified in the majority of DβH-positive fibres as well as in a small population of DβH-negative fibres localized mainly in the proximal part of the pineal. The immunoreactive fibres were more numerous in 90-day-old foetuses than in 70-day-old ones. The effect of norepinephrine on melatonin secretion by the foetal pineals in the short-term organ culture was studied to determine the role of DβH-positive fibres during prenatal life. For the same purpose melatonin was measured in the blood in the umbilical cords and in the jugular vein of the mother. The pineals of both groups of foetuses did not secrete melatonin in the organ culture, independently of the presence or absence of norepinephrine in the medium. Melatonin concentrations in the blood in the umbilical cords of foetuses from the same litter and in the jugular vein of their mother were similar. The presence of adrenergic nerve fibres in the pig pineal during gestation does not seem to be associated with the control of melatonin secretion.

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

NASA Technical Reports Server (NTRS)

Meck, Janice V.; Waters, Wendy W.; Ziegler, Michael G.; deBlock, Heidi F.; Mills, Paul J.; Robertson, David; Huang, Paul L.

2004-01-01

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.

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

PubMed

Meck, Janice V; Waters, Wendy W; Ziegler, Michael G; deBlock, Heidi F; Mills, Paul J; Robertson, David; Huang, Paul L

2004-04-01

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.

Trifurcation of the tibial nerve within the tarsal tunnel.

PubMed

Develi, Sedat

2018-05-01

The tibial nerve is the larger terminal branch of the sciatic nerve and it terminates in the tarsal tunnel by giving lateral and medial plantar nerves. We present a rare case of trifurcation of the tibial nerve within the tarsal tunnel. The variant nerve curves laterally after branching from the tibial nerve and courses deep to quadratus plantae muscle. Interestingly, posterior tibial artery was also terminating by giving three branches. These branches were accompanying the terminal branches of the tibial nerve.

Reflex regulation of airway sympathetic nerves in guinea-pigs

PubMed Central

Oh, Eun Joo; Mazzone, Stuart B; Canning, Brendan J; Weinreich, Daniel

2006-01-01

Sympathetic nerves innervate the airways of most species but their reflex regulation has been essentially unstudied. Here we demonstrate sympathetic nerve-mediated reflex relaxation of airway smooth muscle measured in situ in the guinea-pig trachea. Retrograde tracing, immunohistochemistry and electrophysiological analysis identified a population of substance P-containing capsaicin-sensitive spinal afferent neurones in the upper thoracic (T1–T4) dorsal root ganglia (DRG) that innervate the airways and lung. After bilateral vagotomy, atropine pretreatment and precontraction of the trachealis with histamine, nebulized capsaicin (10–60 μm) evoked a 63 ± 7% reversal of the histamine-induced contraction of the trachealis. Either the β-adrenoceptor antagonist propranolol (2 μm, administered directly to the trachea) or bilateral sympathetic nerve denervation of the trachea essentially abolished these reflexes (10 ± 9% and 6 ± 4% relaxations, respectively), suggesting that they were mediated primarily, if not exclusively, by sympathetic adrenergic nerve activation. Cutting the upper thoracic dorsal roots carrying the central processes of airway spinal afferents also markedly blocked the relaxations (9 ± 5% relaxation). Comparable inhibitory effects were observed following intravenous pretreatment with neurokinin receptor antagonists (3 ± 7% relaxations). These reflexes were not accompanied by consistent changes in heart rate or blood pressure. By contrast, stimulating the rostral cut ends of the cervical vagus nerves also evoked a sympathetic adrenergic nerve-mediated relaxation that were accompanied by marked alterations in blood pressure. The results indicate that the capsaicin-induced reflex-mediated relaxation of airway smooth muscle following vagotomy is mediated by sequential activation of tachykinin-containing spinal afferent and sympathetic efferent nerves innervating airways. This sympathetic nerve-mediated response may serve to oppose airway contraction induced by parasympathetic nerve activation in the airways. PMID:16581869

Calcium Signaling in Mitral Cell Dendrites of Olfactory Bulbs of Neonatal Rats and Mice during Olfactory Nerve Stimulation and Beta-Adrenoceptor Activation

ERIC Educational Resources Information Center

Yuan, Qi; Mutoh, Hiroki; Debarbieux, Franck; Knopfel, Thomas

2004-01-01

Synapses formed by the olfactory nerve (ON) provide the source of excitatory synaptic input onto mitral cells (MC) in the olfactory bulb. These synapses, which relay odor-specific inputs, are confined to the distally tufted single primary dendrites of MCs, the first stage of central olfactory processing. Beta-adrenergic modulation of electrical…

Organisation of autonomic nervous structures in the small intestine of chinchilla (Chinchilla laniger, Molina).

PubMed

Nowak, E

2014-08-01

Using histochemical, histological and immunocytochemical methods, organisation of the autonomic nerve structures in small intestine of chinchilla was investigated. Myenteric plexus was localised between circular and longitudinal layers of the smooth muscles. Forming network nodes, the small autonomic, cholinergic ganglia were linked with the bundles of nerve fibres. Adrenergic structures were visible as specific varicose, rosary-like fibres forming bundles of parallel fibres connecting network nodes. Structures of the submucosal plexus formed a finer network than those of the myenteric plexus. Moreover, in 'whole-mount' specimens, fibres forming thick perivascular plexuses were also observed. Immunocytochemical studies confirmed the cholinergic and adrenergic character of the investigated structures. VAChT-positive neurones were found only in myenteric plexus, and numerous VAChT-positive and DBH-positive fibres were found in both plexuses. © 2013 Blackwell Verlag GmbH.

Neuroanatomy and neurophysiology related to sexual dysfunction in male neurogenic patients with lesions to the spinal cord or peripheral nerves.

PubMed

Everaert, K; de Waard, W I Q; Van Hoof, T; Kiekens, C; Mulliez, T; D'herde, C

2010-03-01

Review article. The neuroanatomy and physiology of psychogenic erection, cholinergic versus adrenergic innervation of emission and the predictability of outcome of vibration and electroejaculation require a review and synthesis. University Hospital Belgium. We reviewed the literature with PubMed 1973-2008. Erection, emission and ejaculation are separate phenomena and have different innervations. It is important to realize, which are the afferents and efferents and where the motor neuron of the end organ is located. When interpreting a specific lesion it is important to understand if postsynaptic fibres are intact or not. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. For vibratory-evoked ejaculation, the reflex arch must be complete; for electroejaculation, the postsynaptic neurons (paravertebral ganglia) must be intact. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. In neurogenic disease, a good knowledge of neuroanatomy and physiology makes understanding of sexual dysfunction possible and predictable. The minimal requirement for the success of penile vibration is a preserved reflex arch and the minimal requirement for the success of electroejaculation is the existence of intact post-ganglionic fibres.

Neuroanatomy of the Pig Cardiac Ventricles. A Stereomicroscopic, Confocal and Electron Microscope Study.

PubMed

Pauziene, Neringa; Rysevaite-Kyguoliene, Kristina; Alaburda, Paulius; Pauza, Audrys G; Skukauskaite, Monika; Masaityte, Aiste; Laucaityte, Goda; Saburkina, Inga; Inokaitis, Hermanas; Plisiene, Jurgita; Pauza, Dainius H

2017-10-01

Although the pig is a model for heart disease, the neuroanatomy of cardiac ventricles (CV) in this species remains undetailed. We aimed to define the innervation pattern of pig CV, combining histochemistry for acetylcholinesterase, immunofluorescent labeling and electron microscopy. Forty nine examined pig hearts show that the major nerves supplying the ventral side of CV descend from the venous part of the heart hilum. Fewer in number and smaller in size, epicardial nerves supply the dorsal half of the CV. Epicardial nerves on the left ventricle are thicker than those on the right. Ventricular ganglia of various sizes distribute at the basal level of both CV. Averagely, we found 3,848 ventricular neuronal somata per heart. The majority of somata were cholinergic, although ganglionic cells of different neurochemical phenotypes (positive for nNOS, ChAT/nNOS, or ChAT/TH) were also observed. Large and most numerous nerves proceeded within the epicardium. Most of endocardium and myocardium contained a network of nerve bundles and nerve fibers (NFs). But, a large number of thin nerves extended along the bundle of His and its branches. The majority of NFs were adrenergic, while cholinergic NFs were scarce yet more abundant than nitrergic ones. Sensory NFs positive for CGRP were the second most abundant phenotype after adrenergic NFs in all layers of the ventricular wall. Electron microscopy elucidated that ultrastructure of nerves varied between different areas of CV. The described structural organization of CV provides an anatomical basis for further functional and pathophysiological studies in the pig heart. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:1756-1780, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Proteolytic cleavage and PKA phosphorylation of α1C subunit are not required for adrenergic regulation of CaV1.2 in the heart.

PubMed

Katchman, Alexander; Yang, Lin; Zakharov, Sergey I; Kushner, Jared; Abrams, Jeffrey; Chen, Bi-Xing; Liu, Guoxia; Pitt, Geoffrey S; Colecraft, Henry M; Marx, Steven O

2017-08-22

Calcium influx through the voltage-dependent L-type calcium channel (Ca V 1.2) rapidly increases in the heart during "fight or flight" through activation of the β-adrenergic and protein kinase A (PKA) signaling pathway. The precise molecular mechanisms of β-adrenergic activation of cardiac Ca V 1.2, however, are incompletely known, but are presumed to require phosphorylation of residues in α 1C and C-terminal proteolytic cleavage of the α 1C subunit. We generated transgenic mice expressing an α 1C with alanine substitutions of all conserved serine or threonine, which is predicted to be a potential PKA phosphorylation site by at least one prediction tool, while sparing the residues previously shown to be phosphorylated but shown individually not to be required for β-adrenergic regulation of Ca V 1.2 current (17-mutant). A second line included these 17 putative sites plus the five previously identified phosphoregulatory sites (22-mutant), thus allowing us to query whether regulation requires their contribution in combination. We determined that acute β-adrenergic regulation does not require any combination of potential PKA phosphorylation sites conserved in human, guinea pig, rabbit, rat, and mouse α 1C subunits. We separately generated transgenic mice with inducible expression of proteolytic-resistant α 1C Prevention of C-terminal cleavage did not alter β-adrenergic stimulation of Ca V 1.2 in the heart. These studies definitively rule out a role for all conserved consensus PKA phosphorylation sites in α 1C in β-adrenergic stimulation of Ca V 1.2, and show that phosphoregulatory sites on α 1C are not redundant and do not each fractionally contribute to the net stimulatory effect of β-adrenergic stimulation. Further, proteolytic cleavage of α 1C is not required for β-adrenergic stimulation of Ca V 1.2.

Autonomic innervation of the muscles in the wall of the bladder and proximal urethra of male rats.

PubMed Central

Watanabe, H; Yamamoto, T Y

1979-01-01

The muscular coat of the body of the rat bladder is innervated almost exclusively by cholinergic endings:adrenergic endings are rare. In the inner longitudinal muscle layer of the proximal urethra, 53% of 310 autonomic nerve endings observed in close relation to the smooth muscle cells were adrenergic and the remaining 47% cholinergic. The middle circular muscle layer of the proximal urethra was innervated predominantly by adrenergic endings: in this layer 86% of the total of 335 endings examined wre regarded as adrenergic. A similar predominantly adrenergic innervation was noted in the outer longitudinal layer of the proximal urethra. A number of striated muscle fibres arose from the outermost striated muscle layer of the proximal urethra and intruded deeply into the outer and middle smooth muscle layers. These intruding striated muscle fibres also received direct autonomic (mostly adrenergic) innervation. The significance of these findings in relation to the physiology of the lower urinary tracts is discussed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 Fig. 16 PMID:489473

[Adrenergic innervation of the kidneys in man and various laboratory animals].

PubMed

Shvalev, V N; Chzhao, L Kh

1988-07-01

By means of the neurohistochemical method for slice incubation in 2% solution of glyoxylic acid, innervation of the kidneys of a 57-year-old man after a sudden cardiac death has been investigated, as well as innervation of the kidneys in white rat, rabbit, guinea pig and cat. A rich adrenergic innervation in the organ's blood vessels has been revealed. In particular, adrenergic nervous fibers have been found along the course of afferent glomerular arterioles. Together with innervation of the proximal and distal convoluted tubules, a high density of the terminal adrenergic nervous plexus is revealed along the course of the nephron loops. Adrenergic nervous plexuses of high density are found in the area of the initial part of the urinary excretory pathways and their connection with nervous plexuses of the kidney itself.

Comparison of Glutamate Turnover in Nerve Terminals and Brain Tissue During [1,6-13C2]Glucose Metabolism in Anesthetized Rats.

PubMed

Patel, Anant B; Lai, James C K; Chowdhury, Golam I M; Rothman, Douglas L; Behar, Kevin L

2017-01-01

The 13 C turnover of neurotransmitter amino acids (glutamate, GABA and aspartate) were determined from extracts of forebrain nerve terminals and brain homogenate, and fronto-parietal cortex from anesthetized rats undergoing timed infusions of [1,6- 13 C 2 ]glucose or [2- 13 C]acetate. Nerve terminal 13 C fractional labeling of glutamate and aspartate was lower than those in whole cortical tissue at all times measured (up to 120 min), suggesting either the presence of a constant dilution flux from an unlabeled substrate or an unlabeled (effectively non-communicating on the measurement timescale) glutamate pool in the nerve terminals. Half times of 13 C labeling from [1,6- 13 C 2 ]glucose, as estimated by least squares exponential fitting to the time course data, were longer for nerve terminals (Glu C4 , 21.8 min; GABA C2 21.0 min) compared to cortical tissue (Glu C4 , 12.4 min; GABA C2 , 14.5 min), except for Asp C3 , which was similar (26.5 vs. 27.0 min). The slower turnover of glutamate in the nerve terminals (but not GABA) compared to the cortex may reflect selective effects of anesthesia on activity-dependent glucose use, which might be more pronounced in the terminals. The 13 C labeling ratio for glutamate-C4 from [2- 13 C]acetate over that of 13 C-glucose was twice as large in nerve terminals compared to cortex, suggesting that astroglial glutamine under the 13 C glucose infusion was the likely source of much of the nerve terminal dilution. The net replenishment of most of the nerve terminal amino acid pools occurs directly via trafficking of astroglial glutamine.

Alpha1-adrenergic blockers: current usage considerations.

PubMed

Sica, Domenic A

2005-12-01

Alpha1-adrenergic-blocking drugs are effective in reducing blood pressure and do so in a fashion comparable to most other antihypertensive drug classes. These compounds are most effective in patients in the upright position, reducing systolic and diastolic pressures by 8%-10%. Alpha1-adrenergic-blocking drugs incrementally reduce blood pressure when combined with most drug classes and are the only antihypertensive drug class to improve plasma lipid profiles. Alpha1-adrenergic-blocking drugs are also accepted as important elements of the treatment plan for symptomatic benign prostatic hypertrophy. Dose escalation of an alpha1-adrenergic-blocking drug can trigger renal Na+ retention, and the ensuing volume expansion can attenuate its blood pressure-lowering effect. Orthostatic hypotension can occur with these compounds, particularly when a patient is volume-contracted. Dizziness, headache, and drowsiness are common side effects with alpha1-adrenergic blockers. A modest decline in the use of doxazosin and other alpha1-adrenergic-blocking drugs has occurred coincident to the early termination of the doxazosin treatment arm in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

Desipramine increases cardiac parasympathetic activity via α2-adrenergic mechanism in rats.

PubMed

Kawada, Toru; Akiyama, Tsuyoshi; Shimizu, Shuji; Fukumitsu, Masafumi; Kamiya, Atsunori; Sugimachi, Masaru

2017-07-01

Desipramine (DMI) is a blocker of neuronal norepinephrine (NE) uptake transporter. Although intravenous DMI has been shown to cause centrally-mediated sympathoinhibition and peripheral NE accumulation, its parasympathetic effect remains to be elucidated. We hypothesized that intravenous DMI activates the cardiac vagal nerve via an α 2 -adrenergic mechanism. Using a cardiac microdialysis technique, changes in myocardial interstitial acetylcholine (ACh) levels in the left ventricular free wall in response to intravenous DMI (1mg·kg -1 ) were examined in anesthetized rats. In rats with intact vagi (n=7), intravenous DMI increased ACh from 1.67±0.43 to 2.48±0.66nM (P<0.01). In rats with vagotomy (n=5), DMI did not significantly change ACh (from 0.92±0.16 to 0.85±0.23nM). In rats with intact vagi pretreated with intravenous yohimbine (2mg·kg -1 ), DMI did not significantly change ACh (from 1.25±0.23 to 1.13±0.15nM). In conclusion, while DMI is generally considered to be an agent that predominantly affects sympathetic neurotransmission, it can activate the cardiac vagal nerve via α 2 -adrenergic stimulation in experimental settings in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

Sympathetic restraint of respiratory sinus arrhythmia: implications for vagal-cardiac tone assessment in humans

NASA Technical Reports Server (NTRS)

Taylor, J. A.; Myers, C. W.; Halliwill, J. R.; Seidel, H.; Eckberg, D. L.

2001-01-01

Clinicians and experimentalists routinely estimate vagal-cardiac nerve traffic from respiratory sinus arrhythmia. However, evidence suggests that sympathetic mechanisms may also modulate respiratory sinus arrhythmia. Our study examined modulation of respiratory sinus arrhythmia by sympathetic outflow. We measured R-R interval spectral power in 10 volunteers that breathed sequentially at 13 frequencies, from 15 to 3 breaths/min, before and after beta-adrenergic blockade. We fitted changes of respiratory frequency R-R interval spectral power with a damped oscillator model: frequency-dependent oscillations with a resonant frequency, generated by driving forces and modified by damping influences. beta-Adrenergic blockade enhanced respiratory sinus arrhythmia at all frequencies (at some, fourfold). The damped oscillator model fit experimental data well (39 of 40 ramps; r = 0.86 +/- 0.02). beta-Adrenergic blockade increased respiratory sinus arrhythmia by amplifying respiration-related driving forces (P < 0.05), without altering resonant frequency or damping influences. Both spectral power data and the damped oscillator model indicate that cardiac sympathetic outflow markedly reduces heart period oscillations at all frequencies. This challenges the notion that respiratory sinus arrhythmia is mediated simply by vagal-cardiac nerve activity. These results have important implications for clinical and experimental estimation of human vagal cardiac tone.

Neuropeptide Y as a presynaptic modulator of norepinephrine release from the sympathetic nerve fibers in the pig pineal gland.

PubMed

Ziółkowska, N; Lewczuk, B; Przybylska-Gornowicz, B

2015-01-01

Norepinephrine (NE) released from the sympathetic nerve endings is the main neurotransmitter controlling melatonin synthesis in the mammalian pineal gland. Although neuropeptide Y (NPY) co-exists with NE in the pineal sympathetic nerve fibers it also occurs in a population of non-adrenergic nerve fibers located in this gland. The role of NPY in pineal physiology is still enigmatic. The present study characterizes the effect of NPY on the depolarization-evoked 3H-NE release from the pig pineal explants. The explants of the pig pineal gland were loaded with 3H-NE in the presence of pargyline and superfused with Tyrode medium. They were exposed twice to the modified Tyrode medium containing 60 mM of K+ to evoke the 3H-NE release via depolarization. NPY, specific agonists of Y1- and Y2- receptors and pharmacologically active ligands of α2-adrenoceptors were added to the medium before and during the second depolarization. The radioactivity was measured in medium fractions collected every 2 minutes during the superfusion. NPY (0.1-10 μM) significantly decreased the depolarization-induced 3H-NE release. Similar effect was observed after the treatment with Y2-agonist: NPY13-36, but not with Y1-agonist: [Leu31,Pro34]-NPY. The tritium overflow was lower in the explants exposed to the 5 μM NPY and 1 μM rauwolscine than to rauwolscine only. The effects of 5 μM NPY and 0.05 μM UK 14,304 on the depolarization-evoked 3H-NE release were additive. The results show that NPY is involved in the regulation of NE release from the sympathetic terminals in the pig pineal gland, inhibiting this process via Y2-receptors.

Sex, ageing and resting blood pressure: gaining insights from the integrated balance of neural and haemodynamic factors.

PubMed

Hart, Emma C; Joyner, Michael J; Wallin, B Gunnar; Charkoudian, Nisha

2012-05-01

Young women tend to have lower blood pressure, and less risk of hypertension, compared to young men. As people age, both blood pressure and the risk of hypertension increase in both sexes; this occurs most strikingly in women after menopause. However, the mechanisms for these influences of sex and age remain incompletely understood. In this review we are specifically interested in the interaction between neural (sympathetic nerve activity; SNA) and haemodynamic factors (cardiac output, blood pressure and vascular resistance) and how these change with sex and age. While peripheral vascular SNA can vary 7- to 10-fold among normotensive young men and women, it is reproducible in a given individual. Surprisingly, higher levels of SNA are not associated with higher blood pressures in these groups. In young men, high SNA is associated with higher total peripheral vascular resistance (TPR), and appears to be balanced by lower cardiac output and less peripheral vascular responsiveness to adrenergic stimulation. Young women do not exhibit the SNA-TPR relationship. Recent evidence suggests that β-adrenergic vasodilatation offsets the vasoconstrictor effects of α-adrenergic vasoconstriction in young women, which may contribute to the generally lower blood pressures in this group. Sympathetic nerve activity increases with age, and in groups over 40, levels of SNA are more tightly linked to levels of blood pressure. The potentially protective β-adrenergic effect seen in young women appears to be lost after menopause and probably contributes to the increased blood pressure and increased risk of hypertension seen in older women.

Functional and structural microanatomy of the fetal sciatic nerve.

PubMed

Creze, Maud; Zaitouna, Mazen; Krystel, Nyangoh Timoh; Diallo, Djibril; Lebacle, Cédric; Bellin, Marie-France; Ducreux, Denis; Benoit, Gérard; Bessede, Thomas

2017-10-01

The ultrastructure of a nerve has implications for surgical nerve repair. The aim of our study was to characterize the fascicular versus fibrillar anatomy and the autonomic versus somatic nature of the fetal sciatic nerve (SN). Immunohistochemistry for vesicular acetylcholine transporter, tyrosine hydroxylase, and peripheral myelin protein 22 was performed to identify cholinergic, adrenergic, and somatic axons, respectively, in the human fetal SN. Two-dimensional (2D) analysis and 3D reconstructions were performed. The fetal SN is composed of one-third stromal tissue and two-thirds neural tissue. Autonomic fibers are predominant over somatic fibers within the neural tissue. The distribution of somatic fibers is initially random, but then become topographically organized after intra- and interfascicular rearrangements have occurred within the nerve. The fetal model presents limitations but enables illustration of the nature of the nerve fibers and the 3D fascicular anatomy of the SN. Muscle Nerve 56: 787-796, 2017. © 2017 Wiley Periodicals, Inc.

Ubiquitin–Synaptobrevin Fusion Protein Causes Degeneration of Presynaptic Motor Terminals in Mice

PubMed Central

Liu, Yun; Li, Hongqiao; Sugiura, Yoshie; Han, Weiping; Gallardo, Gilbert; Khvotchev, Mikhail; Zhang, Yinan; Kavalali, Ege T.; Südhof, Thomas C.

2015-01-01

Protein aggregates containing ubiquitin (Ub) are commonly observed in neurodegenerative disorders, implicating the involvement of the ubiquitin proteasome system (UPS) in their pathogenesis. Here, we aimed to generate a mouse model for monitoring UPS function using a green fluorescent protein (GFP)-based substrate that carries a “noncleavable” N-terminal ubiquitin moiety (UbG76V). We engineered transgenic mice expressing a fusion protein, consisting of the following: (1) UbG76V, GFP, and a synaptic vesicle protein synaptobrevin-2 (UbG76V-GFP-Syb2); (2) GFP-Syb2; or (3) UbG76V-GFP-Syntaxin1, all under the control of a neuron-specific Thy-1 promoter. As expected, UbG76V-GFP-Syb2, GFP-Syb2, and UbG76V-GFP-Sytaxin1 were highly expressed in neurons, such as motoneurons and motor nerve terminals of the neuromuscular junction (NMJ). Surprisingly, UbG76V-GFP-Syb2 mice developed progressive adult-onset degeneration of motor nerve terminals, whereas GFP-Syb2 and UbG76V-GFP-Syntaxin1 mice were normal. The degeneration of nerve terminals in UbG76V-GFP-Syb2 mice was preceded by a progressive impairment of synaptic transmission at the NMJs. Biochemical analyses demonstrated that UbG76V-GFP-Syb2 interacted with SNAP-25 and Syntaxin1, the SNARE partners of synaptobrevin. Ultrastructural analyses revealed a marked reduction in synaptic vesicle density, accompanying an accumulation of tubulovesicular structures at presynaptic nerve terminals. These morphological defects were largely restricted to motor nerve terminals, as the ultrastructure of motoneuron somata appeared to be normal at the stages when synaptic nerve terminals degenerated. Furthermore, synaptic vesicle endocytosis and membrane trafficking were impaired in UbG76V-GFP-Syb2 mice. These findings indicate that UbG76V-GFP-Syb2 may compete with endogenous synaptobrevin, acting as a gain-of-function mutation that impedes SNARE function, resulting in the depletion of synaptic vesicles and degeneration of the nerve terminals. SIGNIFICANCE STATEMENT Degeneration of motor nerve terminals occurs in amyotrophic lateral sclerosis (ALS) patients as well as in mouse models of ALS, leading to progressive paralysis. What causes a motor nerve terminal to degenerate remains unknown. Here we report on transgenic mice expressing a ubiquitinated synaptic vesicle protein (UbG76V-GFP-Syb2) that develop progressive degeneration of motor nerve terminals. These mice may serve as a model for further elucidating the underlying cellular and molecular mechanisms of presynaptic nerve terminal degeneration. PMID:26290230

Identification of the functional domain in the transcription factor RTEF-1 that mediates alpha 1-adrenergic signaling in hypertrophied cardiac myocytes.

PubMed

Ueyama, T; Zhu, C; Valenzuela, Y M; Suzow, J G; Stewart, A F

2000-06-09

Cardiac myocytes respond to alpha(1)-adrenergic receptor stimulation by a progressive hypertrophy accompanied by the activation of many fetal genes, including skeletal muscle alpha-actin. The skeletal muscle alpha-actin gene is activated by signaling through an MCAT element, the binding site of the transcription enhancer factor-1 (TEF-1) family of transcription factors. Previously, we showed that overexpression of the TEF-1-related factor (RTEF-1) increased the alpha(1)-adrenergic response of the skeletal muscle alpha-actin promoter, whereas TEF-1 overexpression did not. Here, we identified the functional domains and specific sequences in RTEF-1 that mediate the alpha(1)-adrenergic response. Chimeric TEF-1 and RTEF-1 expression constructs localized the region responsible for the alpha(1)-adrenergic response to the carboxyl-terminal domain of RTEF-1. Site-directed mutagenesis was used to inactivate eight serine residues of RTEF-1, not present in TEF-1, that are putative targets of alpha(1)-adrenergic-dependent kinases. Mutation of a single serine residue, Ser-322, reduced the alpha(1)-adrenergic activation of RTEF-1 by 70% without affecting protein stability, suggesting that phosphorylation at this serine residue accounts for most of the alpha(1)-adrenergic response. Thus, these results demonstrate that RTEF-1 is a direct target of alpha(1)-adrenergic signaling in hypertrophied cardiac myocytes.

Central projections of the lateral line and eighth nerves in the bowfin, Amia calva.

PubMed

McCormick, C A

1981-03-20

The first-order connections of the anterior and posterior lateral line nerves and of the eighth nerve were determined in the bowfin, Amia calva, using experimental degeneration and anterograde HRP transport techniques. The termination sites of these nerves define a dorsal lateralis cell column and a ventral octavus cell column. The anterior and posterior lateralis nerves distribute ipsilaterally to two medullary nuclei-nucleus medialis and nucleus caudalis. Nucleus medialis comprises the rostral two-thirds of the lateralis column and contains large, Purkinje-like cells dorsally and polygonal, granule, and fusiform cells ventrally. Nucleus caudalis is located posterior to nucleus medialis and consists of small, granule cells. Anterior lateralis fibers terminate ventrally to ventromedially in both nucleus medialis and nucleus caudalis. Posterior lateralis fibers terminate dorsally to dorsolaterally within these two nuclei. A sparse anterior lateralis input may also be present on the dendrites of one of the nuclei within the octavus cell column, nucleus magnocellularis. In contrast, the anterior and posterior rami of the eighth nerve each terminate within four medullary nuclei which comprise the octavus cell column: the anterior, magnocellular, descending, and posterior octavus nuclei. An eighth nerve projection to the medial reticular formation is also present. Some fibers of the lateralis and eighth nerves terminate within the ipsilateral eminentia granularis of the cerebellum. Lateralis fibers distribute to approximately the lateral half of this structure with posterior lateral line fibers terminating laterally and anterior lateral line fibers terminating medially. Eighth nerve fibers distribute to the medial half of the eminentia granularis.

Cardiac effects produced by long-term stimulation of thoracic autonomic ganglia or nerves: implications for interneuronal interactions within the thoracic autonomic nervous system.

PubMed

Butler, C; Watson-Wright, W M; Wilkinson, M; Johnstone, D E; Armour, J A

1988-03-01

Electrical stimulation of an acutely decentralized stellate or middle cervical ganglion or cardiopulmonary nerve augments cardiac chronotropism or inotropism; as the stimulation continues there is a gradual reduction of this augmentation following the peak response, i.e., an inhibition of augmentation. The amount of this inhibition was found to be dependent upon the region of the heart investigated and the neural structure stimulated. The cardiac parameters which were augmented the most displayed the greatest inhibition. Maximum augmentation or inhibition occurred, in most instances, when 5-20 Hz stimuli were used. Inhibition of augmentation was overcome when the stimulation frequency was subsequently increased or following the administration of nicotine or tyramine, indicating that the inhibition was not primarily due to the lack of availability of noradrenaline in the nerve terminals of the efferent postganglionic sympathetic neurons. Furthermore, as infusions of isoproterenol or noradrenaline during the period of inhibition could still augment cardiac responses, whereas during the early peak responses they did not, the inhibition of augmentation does not appear to be due primarily to down regulation of cardiac myocyte beta-adrenergic receptors. The inhibition was modified by hexamethonium but not by phentolamine or atropine. Inhibition occurred when all ipsilateral cardiopulmonary nerves connected with acutely decentralized middle cervical and stellate ganglia were stimulated, whereas significant inhibition did not occur when these nerves were stimulated after they had been disconnected from the ipsilateral decentralized ganglia. Taken together these data indicate that the inhibition of cardiac augmentation which occurs during relatively long-term stimulation of intrathoracic sympathetic neural elements is due in large part to nicotinic cholinergic synaptic mechanisms that lie primarily in the major thoracic autonomic ganglia. They also indicate that long-term stimulation in intrathoracic sympathetic neural elements with frequencies as low as 2 Hz may augment the heart as much as higher stimulation frequencies, depending upon the structure stimulated and the cardiovascular parameter monitored.

Biphasic non-adrenergic, non-cholinergic relaxations of the mouse anococcygeus muscle.

PubMed Central

Gibson, A.; Yu, O.

1983-01-01

Trains of field stimulation of 60 s duration caused a biphasic relaxation of carbachol (50 microM)-induced tone in the mouse anococcygeus. The optimal pulse frequency and width were 10 Hz and 1 ms respectively. Tetrodotoxin (31, 124, and 310 nM) caused a dose-dependent reduction in the magnitude of both phases. Neither phase was affected by (+/-)-propranolol (1 microM), neostigmine (1 microM), (+)-tubocurarine (100 microM), or apamin (500 nM). Biphasic relaxations were observed in muscles from 6-hydroxydopamine pretreated mice. Haemolysed blood (10, 40, and 100 microliter/ml) reduced the magnitude of the first phase of nerve-induced relaxation to a greater extent than the second. This effect was reversible. Following a prolonged train of inhibitory nerve stimulation (10 Hz; 10 min) the magnitude of the first phase was reduced only slightly, but the second markedly. The possible relationships between the biphasic relaxation to field stimulation and putative non-adrenergic, non-cholinergic transmitters in the mouse anococcygeus are discussed. PMID:6652345

Effects of hemicholinium and bretylium on the release of autonomic transmitters in the isolated sino-atrial node

PubMed Central

Appel, W. C.; Vincenzi, F. F.

1970-01-01

1. In the isolated, spontaneously beating, sino-atrial node of the rabbit selective electrical excitation of intranodal autonomic nerve fibres results in a biphasic chronotropic response. This chronotropic response (negative followed by positive chronotropism) is due to the release of the autonomic transmitters (acetylcholine and noradrenaline, respectively) from intranodal nerve fibres. 2. In the presence of 2 × 10-4 g/ml hemicholinium, the negative chronotropic (cholinergic) response is abolished while the positive chronotropic (adrenergic) response is unaltered. 3. In the presence of 5 × 10-6 g/ml bretylium, the positive chronotropic response is abolished while the negative chronotropic response is little affected. 4. After blockade of the negative chronotropic response by hemicholinium, bretylium abolishes the remaining positive chronotropic response. The effect of bretylium is not altered in the presence of hemicholinium. 5. Considering currently accepted mechanisms of action for hemicholinium and bretylium, the results of these experiments do not lend support to the cholinergic link hypothesis of adrenergic neuro-effector transmission. PMID:5492897

Effects of hemicholinium and bretylium on the release of autonomic transmitters in the isolated sino-atrial node.

PubMed

Appel, W C; Vincenzi, F F

1970-10-01

1. In the isolated, spontaneously beating, sino-atrial node of the rabbit selective electrical excitation of intranodal autonomic nerve fibres results in a biphasic chronotropic response. This chronotropic response (negative followed by positive chronotropism) is due to the release of the autonomic transmitters (acetylcholine and noradrenaline, respectively) from intranodal nerve fibres.2. In the presence of 2 x 10(-4) g/ml hemicholinium, the negative chronotropic (cholinergic) response is abolished while the positive chronotropic (adrenergic) response is unaltered.3. In the presence of 5 x 10(-6) g/ml bretylium, the positive chronotropic response is abolished while the negative chronotropic response is little affected.4. After blockade of the negative chronotropic response by hemicholinium, bretylium abolishes the remaining positive chronotropic response. The effect of bretylium is not altered in the presence of hemicholinium.5. Considering currently accepted mechanisms of action for hemicholinium and bretylium, the results of these experiments do not lend support to the cholinergic link hypothesis of adrenergic neuro-effector transmission.

Acute corneal epithelial debridement unmasks the corneal stromal nerve responses to ocular stimulation in rats: implications for abnormal sensations of the eye.

PubMed

Hirata, Harumitsu; Mizerska, Kamila; Dallacasagrande, Valentina; Guaiquil, Victor H; Rosenblatt, Mark I

2017-05-01

It is widely accepted that the mechanisms for transducing sensory information reside in the nerve terminals. Occasionally, however, studies have appeared demonstrating that similar mechanisms may exist in the axon to which these terminals are connected. We examined this issue in the cornea, where nerve terminals in the epithelial cell layers are easily accessible for debridement, leaving the underlying stromal (axonal) nerves undisturbed. In isoflurane-anesthetized rats, we recorded extracellularly from single trigeminal ganglion neurons innervating the cornea that are excited by ocular dryness and cooling: low-threshold (<2°C cooling) and high-threshold (>2°C) cold-sensitive plus dry-sensitive neurons playing possible roles in tearing and ocular pain. We found that the responses in both types of neurons to dryness, wetness, and menthol stimuli were effectively abolished by the debridement, indicating that their transduction mechanisms lie in the nerve terminals. However, some responses to the cold, heat, and hyperosmolar stimuli in low-threshold cold-sensitive plus dry-sensitive neurons still remained. Surprisingly, the responses to heat in approximately half of the neurons were augmented after the debridement. We were also able to evoke these residual responses and follow the trajectory of the stromal nerves, which we subsequently confirmed histologically. The residual responses always disappeared when the stromal nerves were cut at the limbus, suggesting that the additional transduction mechanisms for these sensory modalities originated most likely in stromal nerves. The functional significance of these residual and enhanced responses from stromal nerves may be related to the abnormal sensations observed in ocular disease. NEW & NOTEWORTHY In addition to the traditional view that the sensory transduction mechanisms exist in the nerve terminals, we report here that the proximal axons (stromal nerves in the cornea from which these nerve terminals originate) may also be capable of transducing sensory information. We arrived at this conclusion by removing the epithelial cell layers of the cornea in which the nerve terminals reside but leaving the underlying stromal nerves undisturbed. Copyright © 2017 the American Physiological Society.

Acute corneal epithelial debridement unmasks the corneal stromal nerve responses to ocular stimulation in rats: implications for abnormal sensations of the eye

PubMed Central

Mizerska, Kamila; Dallacasagrande, Valentina; Guaiquil, Victor H.; Rosenblatt, Mark I.

2017-01-01

It is widely accepted that the mechanisms for transducing sensory information reside in the nerve terminals. Occasionally, however, studies have appeared demonstrating that similar mechanisms may exist in the axon to which these terminals are connected. We examined this issue in the cornea, where nerve terminals in the epithelial cell layers are easily accessible for debridement, leaving the underlying stromal (axonal) nerves undisturbed. In isoflurane-anesthetized rats, we recorded extracellularly from single trigeminal ganglion neurons innervating the cornea that are excited by ocular dryness and cooling: low-threshold (<2°C cooling) and high-threshold (>2°C) cold-sensitive plus dry-sensitive neurons playing possible roles in tearing and ocular pain. We found that the responses in both types of neurons to dryness, wetness, and menthol stimuli were effectively abolished by the debridement, indicating that their transduction mechanisms lie in the nerve terminals. However, some responses to the cold, heat, and hyperosmolar stimuli in low-threshold cold-sensitive plus dry-sensitive neurons still remained. Surprisingly, the responses to heat in approximately half of the neurons were augmented after the debridement. We were also able to evoke these residual responses and follow the trajectory of the stromal nerves, which we subsequently confirmed histologically. The residual responses always disappeared when the stromal nerves were cut at the limbus, suggesting that the additional transduction mechanisms for these sensory modalities originated most likely in stromal nerves. The functional significance of these residual and enhanced responses from stromal nerves may be related to the abnormal sensations observed in ocular disease. NEW & NOTEWORTHY In addition to the traditional view that the sensory transduction mechanisms exist in the nerve terminals, we report here that the proximal axons (stromal nerves in the cornea from which these nerve terminals originate) may also be capable of transducing sensory information. We arrived at this conclusion by removing the epithelial cell layers of the cornea in which the nerve terminals reside but leaving the underlying stromal nerves undisturbed. PMID:28250152

Endogenous PKI gamma limits the duration of the anti-apoptotic effects of PTH and beta-adrenergic agonists in osteoblasts.

PubMed

Chen, Xin; Song, In-Hwan; Dennis, James E; Greenfield, Edward M

2007-05-01

PKI gamma knockdown substantially extended the anti-apoptotic effects of PTH and beta-adrenergic agonists, whereas PKI gamma overexpression decreased these effects. Therefore, inhibition of PKI gamma activity may provide a useful co-therapy in combination with intermittent PTH or beta-adrenergic agonists for bone loss in conditions such as osteoporosis. PTH has both catabolic and anabolic effects on bone, which are primarily caused by cAMP/protein kinase A (PKA) signaling and regulation of gene expression. We previously showed that protein kinase inhibitor-gamma (PKI gamma) is required for efficient termination of cAMP/PKA signaling and gene expression after stimulation with PTH or beta-adrenergic agonists. Inhibition of osteoblast apoptosis is thought to be an important, but transient, mechanism partly responsible for the anabolic effects of intermittent PTH. Therefore, we hypothesized that endogenous PKI gamma also terminates the anti-apoptotic effect of PTH. PKI gamma knockdown by antisense transfection or siRNA was used to examine the ability of endogenous PKI gamma to modulate the anti-apoptotic effects of PTH and beta-adrenergic agonists in ROS 17/2.8 cells. Knockdown of PKI gamma substantially extended the anti-apoptotic effects of PTH, whether apoptosis was induced by etoposide or dexamethasone. In contrast, overexpression of PKI gamma decreased the anti-apoptotic effect of PTH pretreatment. This study is also the first demonstration that beta-adrenergic agonists mimic the anti-apoptotic effects of PTH in osteoblasts. Moreover, PKI gamma knockdown also substantially extended this anti-apoptotic effect of beta-adrenergic agonists. Taken together, these results show that endogenous PKI gamma limits the duration of the anti-apoptotic effects of cAMP/PKA signaling in osteoblasts. Because significant individual variability exists in the anabolic responses to PTH therapy in current clinical treatment of osteoporosis, inhibition of PKI gamma activity may provide a useful co-therapy in combination with intermittent PTH or beta-adrenergic agonists for bone loss in conditions such as osteoporosis. However, the potential use of such a co-therapy would depend on it not adversely affecting bone formation or other organ systems.

Release of [3H-noradrenaline from the motor adrenergic nerves of the anococcygeus muscle by lysergic acid diethylamide, tyramine or nerve stimulation.

PubMed Central

McGrath, J C; Olverman, H J

1978-01-01

1 A method is described for labelling the neuronal noradrenaline (NA) stores of rat anococcygeus with [3H]-NA and detecting subsequent release of 3H from the superfused tissue by nerve stimulation or drugs. 2 Lysergic acid diethylamide (LSD) or tyramine but not barium chloride or carbachol increased the efflux of 3H although each drug produced an equivalent contractile response. This confirms that LDS has an indirect sympathomimetic action. 3 LSD was found to produce a proportionately smaller reduction of the nerve-induced efflux of 3H than of the accompanying contractile response. 4 The inhibition of nerve-induced contractile responses by LSD was shown to be independent of the neuronal uptake of noradrenaline and any post-junctional inhibition demonstrated to be non-specific. PMID:728688

Structural basis for modulation and agonist specificity of HCN pacemaker channels.

PubMed

Zagotta, William N; Olivier, Nelson B; Black, Kevin D; Young, Edgar C; Olson, Rich; Gouaux, Eric

2003-09-11

The family of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels are crucial for a range of electrical signalling, including cardiac and neuronal pacemaker activity, setting resting membrane electrical properties and dendritic integration. These nonselective cation channels, underlying the I(f), I(h) and I(q) currents of heart and nerve cells, are activated by membrane hyperpolarization and modulated by the binding of cyclic nucleotides such as cAMP and cGMP. The cAMP-mediated enhancement of channel activity is largely responsible for the increase in heart rate caused by beta-adrenergic agonists. Here we have investigated the mechanism underlying this modulation by studying a carboxy-terminal fragment of HCN2 containing the cyclic nucleotide-binding domain (CNBD) and the C-linker region that connects the CNBD to the pore. X-ray crystallographic structures of this C-terminal fragment bound to cAMP or cGMP, together with equilibrium sedimentation analysis, identify a tetramerization domain and the mechanism for cyclic nucleotide specificity, and suggest a model for ligand-dependent channel modulation. On the basis of amino acid sequence similarity to HCN channels, the cyclic nucleotide-gated, and eag- and KAT1-related families of channels are probably related to HCN channels in structure and mechanism.

Vagus nerve stimulation enhances perforant path-CA3 synaptic transmission via the activation of β-adrenergic receptors and the locus coeruleus.

PubMed

Shen, Huilian; Fuchino, Yuta; Miyamoto, Daisuke; Nomura, Hiroshi; Matsuki, Norio

2012-05-01

Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression and has cognition-enhancing effects in patients with Alzheimer's disease. The hippocampus is widely recognized to be related to epilepsy, depression, and Alzheimer's disease. One possible mechanism of VNS involves its effect on the hippocampus; i.e. it increases the release of noradrenaline in the hippocampus. However, the effect of VNS on synaptic transmission in the hippocampus is unknown. To determine whether VNS modulates neurotransmission in the hippocampus, we examined the effects of VNS on perforant path (PP)-CA3 synaptic transmission electrophysiologically in anaesthetized rats. VNS induces a persistent enhancement of PP-CA3 field excitatory post-synaptic potentials (fEPSPs). Arc, an immediate early gene, was used to identify active brain regions after VNS. The locus coeruleus (LC), which contains the perikarya of noradrenergic projections, harboured more Arc-positive cells, as measured by in-situ hybridization, after 10-min VNS. In addition, electrical lesions of LC neurons or intraventricular administration of the β-adrenergic receptor antagonist timolol prevented the enhancement of PP-CA3 responses by VNS. In conclusion, the protracted increase in PP-CA3 synaptic transmission that is induced by VNS entails activation of the LC and β-adrenergic receptors. Our novel findings suggest that information from the periphery modulates synaptic transmission in the CA3 region of the hippocampus.

Development of the terminal nerve system in the shark Scyliorhinus canicula.

PubMed

Quintana-Urzainqui, Idoia; Anadón, Ramón; Candal, Eva; Rodríguez-Moldes, Isabel

2014-01-01

The nervus terminalis (or terminal nerve) system was discovered in an elasmobranch species more than a century ago. Over the past century, it has also been recognized in other vertebrate groups, from agnathans to mammals. However, its origin, functions or relationship with the olfactory system are still under debate. Despite the abundant literature about the nervus terminalis system in adult elasmobranchs, its development has been overlooked. Studies in other vertebrates have reported newly differentiated neurons of the terminal nerve system migrating from the olfactory epithelium to the telencephalon as part of a 'migratory mass' of cells associated with the olfactory nerve. Whether the same occurs in developing elasmobranchs (adults showing anatomically separated nervus terminalis and olfactory systems) has not yet been determined. In this work we characterized for the first time the development of the terminal nerve and ganglia in an elasmobranch, the lesser spotted dogfish (Scyliorhinus canicula), by means of tract-tracing techniques combined with immunohistochemical markers for the terminal nerve (such as FMRF-amide peptide), for the developing components of the olfactory system (Gα0 protein, GFAP, Pax6), and markers for early postmitotic neurons (HuC/D) and migrating immature neurons (DCX). We discriminated between embryonic olfactory and terminal nerve systems and determined that both components may share a common origin in the migratory mass. We also localized the exact point where they split off near the olfactory nerve-olfactory bulb junction. The study of the development of the terminal nerve system in a basal gnathostome contributes to the knowledge of the ancestral features of this system in vertebrates, shedding light on its evolution and highlighting the importance of elasmobranchs for developmental and evolutionary studies. © 2014 S. Karger AG, Basel.

Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor.

PubMed

Pügge, Carolin; Mediratta, Jai; Marcus, Noah J; Schultz, Harold D; Schiller, Alicia M; Zucker, Irving H

2016-02-01

Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in α1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without α1-adrenergic blockade. α1-adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P < 0.05). ExT diminished the decline in baseline RBF and RVC and restored changes during hypoxia to those of the prepaced state. α1-adrenergic blockade partially prevented the decline in RBF and RVC in CHF-SED rabbits and eliminated the differences in hypoxia responses between SED and ExT animals. Unilateral renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. α1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by α1-adrenergic receptors. Nonetheless, α1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney. Copyright © 2016 the American Physiological Society.

Autonomic control of body temperature and blood pressure: influences of female sex hormones.

PubMed

Charkoudian, Nisha; Hart, Emma C J; Barnes, Jill N; Joyner, Michael J

2017-06-01

Female reproductive hormones exert important non-reproductive influences on autonomic regulation of body temperature and blood pressure. Estradiol and progesterone influence thermoregulation both centrally and peripherally, where estradiol tends to promote heat dissipation, and progesterone tends to promote heat conservation and higher body temperatures. Changes in thermoregulation over the course of the menstrual cycle and with hot flashes at menopause are mediated by hormonal influences on neural control of skin blood flow and sweating. The influence of estradiol is to promote vasodilation, which, in the skin, results in greater heat dissipation. In the context of blood pressure regulation, both central and peripheral hormonal influences are important as well. Peripherally, the vasodilator influence of estradiol contributes to the lower blood pressures and smaller risk of hypertension seen in young women compared to young men. This is in part due to a mechanism by which estradiol augments beta-adrenergic receptor mediated vasodilation, offsetting alpha-adrenergic vasoconstriction, and resulting in a weak relationship between muscle sympathetic nerve activity and total peripheral resistance, and between muscle sympathetic nerve activity and blood pressure. After menopause, with the loss of reproductive hormones, sympathetic nerve activity, peripheral resistance and blood pressure become more strongly related, and sympathetic nerve activity (which increases with age) becomes a more important contributor to the prevailing level of blood pressure. Continuing to increase our understanding of sex hormone influences on body temperature and blood pressure regulation will provide important insight for optimization of individualized health care for future generations of women.

Zebrafish heart as a model to study the integrative autonomic control of pacemaker function

PubMed Central

Stoyek, Matthew R.; Quinn, T. Alexander; Croll, Roger P.

2016-01-01

The cardiac pacemaker sets the heart's primary rate, with pacemaker discharge controlled by the autonomic nervous system through intracardiac ganglia. A fundamental issue in understanding the relationship between neural activity and cardiac chronotropy is the identification of neuronal populations that control pacemaker cells. To date, most studies of neurocardiac control have been done in mammalian species, where neurons are embedded in and distributed throughout the heart, so they are largely inaccessible for whole-organ, integrative studies. Here, we establish the isolated, innervated zebrafish heart as a novel alternative model for studies of autonomic control of heart rate. Stimulation of individual cardiac vagosympathetic nerve trunks evoked bradycardia (parasympathetic activation) and tachycardia (sympathetic activation). Simultaneous stimulation of both vagosympathetic nerve trunks evoked a summative effect. Effects of nerve stimulation were mimicked by direct application of cholinergic and adrenergic agents. Optical mapping of electrical activity confirmed the sinoatrial region as the site of origin of normal pacemaker activity and identified a secondary pacemaker in the atrioventricular region. Strong vagosympathetic nerve stimulation resulted in a shift in the origin of initial excitation from the sinoatrial pacemaker to the atrioventricular pacemaker. Putative pacemaker cells in the sinoatrial and atrioventricular regions expressed adrenergic β2 and cholinergic muscarinic type 2 receptors. Collectively, we have demonstrated that the zebrafish heart contains the accepted hallmarks of vertebrate cardiac control, establishing this preparation as a viable model for studies of integrative physiological control of cardiac function by intracardiac neurons. PMID:27342878

Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system.

PubMed

Shiuchi, Tetsuya; Haque, Mohammad Shahidul; Okamoto, Shiki; Inoue, Tsuyoshi; Kageyama, Haruaki; Lee, Suni; Toda, Chitoku; Suzuki, Atsushi; Bachman, Eric S; Kim, Young-Bum; Sakurai, Takashi; Yanagisawa, Masashi; Shioda, Seiji; Imoto, Keiji; Minokoshi, Yasuhiko

2009-12-01

Hypothalamic neurons containing orexin (hypocretin) are activated during motivated behaviors and active waking. We show that injection of orexin-A into the ventromedial hypothalamus (VMH) of mice or rats increased glucose uptake and promoted insulin-induced glucose uptake and glycogen synthesis in skeletal muscle, but not in white adipose tissue, by activating the sympathetic nervous system. These effects of orexin were blunted in mice lacking beta-adrenergic receptors but were restored by forced expression of the beta(2)-adrenergic receptor in both myocytes and nonmyocyte cells of skeletal muscle. Orexin neurons are activated by conditioned sweet tasting and directly excite VMH neurons, thereby increasing muscle glucose metabolism and its insulin sensitivity. Orexin and its receptor in VMH thus play a key role in the regulation of muscle glucose metabolism associated with highly motivated behavior by activating muscle sympathetic nerves and beta(2)-adrenergic signaling.

Evidence that the human cutaneous venoarteriolar response is not mediated by adrenergic mechanisms

NASA Technical Reports Server (NTRS)

Crandall, C. G.; Shibasaki, M.; Yen, T. C.

2002-01-01

The venoarteriolar response causes vasoconstriction to skin and muscle via local mechanisms secondary to venous congestion. The purpose of this project was to investigate whether this response occurs through alpha-adrenergic mechanisms. In supine individuals, forearm skin blood flow was monitored via laser-Doppler flowmetry over sites following local administration of terazosin (alpha(1)-antagonist), yohimbine (alpha(2)-antagonist), phentolamine (non-selective alpha-antagonist) and bretylium tosylate (inhibits neurotransmission of adrenergic nerves) via intradermal microdialysis or intradermal injection. In addition, skin blood flow was monitored over an area of forearm skin that was locally anaesthetized via application of EMLA (2.5 % lidocaine (lignocaine) and 2.5 % prilocaine) cream. Skin blood flow was also monitored over adjacent sites that received the vehicle for the specified drug. Each trial was performed on a minimum of seven subjects and on separate days. The venoarteriolar response was engaged by lowering the subject's arm from heart level such that the sites of skin blood flow measurement were 34 +/- 1 cm below the heart. The arm remained in this position for 2 min. Selective and non-selective alpha-adrenoceptor antagonism and presynaptic inhibition of adrenergic neurotransmission did not abolish the venoarteriolar response. However, local anaesthesia blocked the venoarteriolar response without altering alpha-adrenergic mediated vasoconstriction. These data suggest that the venoarteriolar response does not occur through adrenergic mechanisms as previously reported. Rather, the venoarteriolar response may due to myogenic mechanisms associated with changes in vascular pressure or is mediated by a non-adrenergic, but neurally mediated, local mechanism.

Developmental changes in the role of a pertussis toxin sensitive guanine nucleotide binding protein in the rat cardiac alpha sub 1 -adrenergic system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, H.M.

1989-01-01

During development, the cardiac alpha{sub 1}-adrenergic chronotropic response changes from positive in the neonate to negative in the adult. This thesis examined the possibility of a developmental change in coupling of a PT-sensitive G-protein to the alpha{sub 1}-adrenergic receptor. Radioligand binding experiments performed with the iodinated alpha{sub 1}-selective radioligand ({sup 125}I)-I-2-({beta}-(4-hydroxphenyl)ethylaminomethyl)tetralone (({sup 125}I)-IBE 2254) demonstrated that the alpha{sub 1}-adrenergic receptor is coupled to a G-protein in both neonatal and adult rat hearts. However, in the neonate the alpha{sub 1}-adrenergic receptor is coupled to a PT-insensitive G-protein, whereas in the adult the alpha{sub 1}-adrenergic receptor is coupled to both a PT-insensitivemore » and a PT-sensitive G-protein. Consistent with the results from binding experiments, PT did not have any effect on the alpha{sub 1}-mediated positive chronotropic response in the neonate, whereas in the adult the alpha{sub 1}-mediated negative chronotropic response was completely converted to a positive one after PT-treatment. This thesis also examined the possibility of an alteration in coupling of the alpha{sub 1}-adrenergic receptor to its effector under certain circumstances such as high potassium (K{sup +}) depolarization in nerve-muscle (NM) co-cultures, a system which has been previously shown to be a convenient in vitro model to study the mature inhibitory alpha{sub 1}-response.« less

Neuropeptide tyrosine (NPY)--a major cardiac neuropeptide.

PubMed

Gu, J; Polak, J M; Adrian, T E; Allen, J M; Tatemoto, K; Bloom, S R

1983-05-07

A newly discovered bioactive peptide, neuropeptide tyrosine (NPY), has been found in the human cardiac nervous system. Dense concentrations of NPY-immunoreactive nerve fibres were found in association with nodal tissue (atrioventricular node 22.1 +/- 3.7 pmol/g). NPY nerve fibres were seen in close contact with cardiac muscle fibres and were also found around the coronary vessels (19.6 +/- 6.2 pmol/g). Analysis of the peptide by high-performance liquid chromatography demonstrated that it was present in a single molecular form, closely similar or identical to that of the isolated bioactive peptide. Cardiac function in man has long been known to be influenced by cholinergic and adrenergic nerves. There now appears to be a further component of the nervous system in the human heart, involving peptidergic nerves containing NPY.

Modulation of experimental arthritis by vagal sensory and central brain stimulation.

PubMed

Bassi, Gabriel Shimizu; Dias, Daniel Penteado Martins; Franchin, Marcelo; Talbot, Jhimmy; Reis, Daniel Gustavo; Menezes, Gustavo Batista; Castania, Jaci Airton; Garcia-Cairasco, Norberto; Resstel, Leonardo Barbosa Moraes; Salgado, Helio Cesar; Cunha, Fernando Queiróz; Cunha, Thiago Mattar; Ulloa, Luis; Kanashiro, Alexandre

2017-08-01

Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations. Copyright © 2017 Elsevier Inc. All rights reserved.

Ganglionic adrenergic action modulates ovarian steroids and nitric oxide in prepubertal rat.

PubMed

Delgado, Silvia Marcela; Casais, Marilina; Sosa, Zulema; Rastrilla, Ana María

2006-08-01

Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. The purpose of this work was to analyse the ganglionic adrenergic influence on the ovarian release of steroids and NO and the possible steroids/NO relationship. The experiments were carried out in the ex vivo coeliac ganglion-superior ovarian nerve (SON)-ovary system of prepubertal rats. The coeliac ganglion-SON-ovary system was incubated in Krebs Ringer-bicarbonate buffer in presence of adrenergic agents in the ganglionic compartment. The accumulation of progesterone, androstenedione, oestradiol and NO in the ovarian incubation liquid was measured. Norepinephrine in coeliac ganglion inhibited the liberation of progesterone and increased androstenedione, oestradiol and NO in ovary. The addition of alpha and beta adrenergic antagonists also showed different responses in the liberation of the substances mentioned before, which, from a physiological point of view, reveals the presence of adrenergic receptors in coeliac ganglion. In relation to propranolol, it does not revert the effect of noradrenaline on the liberation of progesterone, which leads us to think that it might also have a "per se" effect on the ganglion, responsible for the ovarian response observed for progesterone. Finally, we can conclude that the ganglionic adrenergic action via SON participates on the regulation of the prepubertal ovary in one of two ways: either increasing the NO, a gaseous neurotransmitter with cytostatic characteristics, to favour the immature follicles to remain dormant or increasing the liberation of androstenedione and oestradiol, the steroids necessary for the beginning of the near first estral cycle.

α-Adrenergic effects on low-frequency oscillations in blood pressure and R-R intervals during sympathetic activation.

PubMed

Kiviniemi, Antti M; Frances, Maria F; Tiinanen, Suvi; Craen, Rosemary; Rachinsky, Maxim; Petrella, Robert J; Seppänen, Tapio; Huikuri, Heikki V; Tulppo, Mikko P; Shoemaker, J Kevin

2011-08-01

The present study was designed to address the contribution of α-adrenergic modulation to the genesis of low-frequency (LF; 0.04-0.15 Hz) oscillations in R-R interval (RRi), blood pressure (BP) and muscle sympathetic nerve activity (MSNA) during different sympathetic stimuli. Blood pressure and RRi were measured continuously in 12 healthy subjects during 5 min periods each of lower body negative pressure (LBNP; -40 mmHg), static handgrip exercise (HG; 20% of maximal force) and postexercise forearm circulatory occlusion (PECO) with and without α-adrenergic blockade by phentolamine. Muscle sympathetic nerve activity was recorded in five subjects during LBNP and in six subjects during HG and PECO. Low-frequency powers and median frequencies of BP, RRi and MSNA were calculated from power spectra. Low-frequency power during LBNP was lower with phentolamine versus without for both BP and RRi oscillations (1.6 ± 0.6 versus 1.2 ± 0.7 ln mmHg(2), P = 0.049; and 6.9 ± 0.8 versus 5.4 ± 0.9 ln ms(2), P = 0.001, respectively). In contrast, the LBNP with phentolamine increased the power of high-frequency oscillations (0.15-0.4 Hz) in BP and MSNA (P < 0.01 for both), which was not observed during saline infusion. Phentolamine also blunted the increases in the LBNP-induced increase in frequency of LF oscillations in BP and RRi. Phentolamine decreased the LF power of RRi during HG (P = 0.015) but induced no other changes in LF powers or frequencies during HG. Phentolamine resulted in decreased frequency of LF oscillations in RRi (P = 0.004) during PECO, and a similar tendency was observed in BP and MSNA. The power of LF oscillation in MSNA did not change during any intervention. We conclude that α-adrenergic modulation contributes to LF oscillations in BP and RRi during baroreceptor unloading (LBNP) but not during static exercise. Also, α-adrenergic modulation partly explains the shift to a higher frequency of LF oscillations during baroreceptor unloading and muscle metaboreflex activation.

Presynaptic excitability.

PubMed

Jackson, M B

1995-01-01

Based on functional characterizations with electrophysiological techniques, the channels in nerve terminals appear to be as diverse as channels in nerve cell bodies (Table I). While most presynaptic Ca2+ channels superficially resemble either N-type or L-type channels, variations in detail have necessitated the use of subscripts and other notations to indicate a nerve terminal-specific subtype (e.g., Wang et al., 1993). Variations such as these pose a serious obstacle to the identification of presynaptic channels based solely on the effects of channel blockers on synaptic transmission. Pharmacological sensitivity alone is not likely to help in determining functional properties. Crucial details, such as voltage sensitivity and inactivation, require direct examination. It goes without saying that every nerve terminal membrane contains Ca2+ channels as an entry pathway so that Ca2+ can trigger secretion. However, there appears to be no general specification of channel type, other than the exclusion of T-type Ca2+ channels. T-type Ca2+ channels are defined functionally by strong inactivation and low threshold. Some presynaptic Ca2+ channels inactivate (posterior pituitary and Xenopus nerve terminals), and others have a somewhat reduced voltage threshold (retinal bipolar neurons and squid giant synapse). Perhaps it is just a matter of time before a nerve terminal Ca2+ channel is found with both of these properties. The high threshold and strong inactivation of T-type Ca2+ channels are thought to be adaptations for oscillations and the regulation of bursting activity in nerve cell bodies. The nerve terminals thus far examined have no endogenous electrical activity, but rather are driven by the cell body. On functional grounds, it is then reasonable to anticipate finding T-type Ca2+ channels in nerve terminals that can generate electrical activity on their own. The rarity of such behavior in nerve terminals may be associated with the rarity of presynaptic T-type Ca2+ channels. In four of the five preparations reviewed in this chapter--motor nerve, squid giant synapse, ciliary ganglion, and retina bipolar neurons--evidence was presented that supports a location for Ca2+ channels that is very close to active zones of secretion. All of these synapses secrete from clear vesicles, and the speed and specificity of transduction provided by proximity may be a common feature of these rapid synapses. In contrast, the posterior pituitary secretion apparatus may be triggered by higher-affinity Ca2+ receptors and lower concentrations of Ca2+ (Lindau et al., 1992). This would correspond with the slower performance of peptidergic secretion, but because of the large stimuli needed to evoke release from neurosecretosomes, the possibility remains that the threshold for secretion is higher than that reported. While the role of Ca2+ as a trigger of secretion dictates a requirement for voltage-activated Ca2+ channels as universal components of the presynaptic membrane, the presence of other channels is more difficult to predict. Depolarizations caused by voltage-activated Na+ channels activate the presynaptic Ca2+ channels, but whether this depolarization requires Na+ channels in the presynaptic membrane itself may depend on the electrotonic length of the nerve terminal. Variations in density between motor nerve terminals may reflect species differences in geometry. The high Na+ channel density in the posterior pituitary reflects the great electrotonic length of this terminal arbor. Whether Na+ channels are abundant or not in a presynaptic membrane, K+ channels provide the most robust mechanism for limiting depolarization-induced Ca2+ entry. K+ channel blockers enhance transmission at most synapses. In general, K+ channels are abundant in nerve terminals, although their apparent lower priority compared to Ca2+ channels in the eyes of many investigators leaves us with fewer detailed investigations in some preparations. Most nerve terminals have more than

Modifications of Gustatory Nerve Synapses onto Nucleus of the Solitary Tract Neurons Induced by Dietary Sodium-Restriction During Development

PubMed Central

MAY, OLIVIA L.; ERISIR, ALEV; HILL, DAVID L.

2008-01-01

The terminal fields of nerves carrying gustatory information to the rat brainstem show a remarkable amount of expansion in the nucleus of the solitary tract (NTS) as a result of early dietary sodium restriction. However, the extent to which these axonal changes represent corresponding changes in synapses is not known. To identify the synaptic characteristics that accompany the terminal field expansion, the greater superficial petrosal (GSP), chorda tympani (CT), and glossopharyngeal (IX) nerves were labeled in rats fed a sodium-restricted diet during pre- and postnatal development. The morphology of these nerve terminals within the NTS region where the terminal fields of all three nerves overlap was evaluated by transmission electron microscopy. Compared to data from control rats, CT axons were the most profoundly affected. The density of CT arbors and synapses quadrupled as a result of the near life-long dietary manipulation. In contrast, axon and synapse densities of GSP and IX nerves were not modified in sodium-restricted rats. Furthermore, compared to controls, CT terminals displayed more instances of contacts with postsynaptic dendritic protrusions and IX terminals synapsed more frequently with dendritic shafts. Thus, dietary sodium restriction throughout pre- and postnatal development had differential effects on the synaptic organization of the three nerves in the NTS. These anatomical changes may underlie the impact of sensory restriction during development on the functional processing of taste information and taste-related behaviors. PMID:18366062

Modifications of gustatory nerve synapses onto nucleus of the solitary tract neurons induced by dietary sodium-restriction during development.

PubMed

May, Olivia L; Erisir, Alev; Hill, David L

2008-06-01

The terminal fields of nerves carrying gustatory information to the rat brainstem show a remarkable amount of expansion in the nucleus of the solitary tract (NTS) as a result of early dietary sodium restriction. However, the extent to which these axonal changes represent corresponding changes in synapses is not known. To identify the synaptic characteristics that accompany the terminal field expansion, the greater superficial petrosal (GSP), chorda tympani (CT), and glossopharyngeal (IX) nerves were labeled in rats fed a sodium-restricted diet during pre- and postnatal development. The morphology of these nerve terminals within the NTS region where the terminal fields of all three nerves overlap was evaluated by transmission electron microscopy. Compared to data from control rats, CT axons were the most profoundly affected. The density of CT arbors and synapses quadrupled as a result of the near life-long dietary manipulation. In contrast, axon and synapse densities of GSP and IX nerves were not modified in sodium-restricted rats. Furthermore, compared to controls, CT terminals displayed more instances of contacts with postsynaptic dendritic protrusions and IX terminals synapsed more frequently with dendritic shafts. Thus, dietary sodium restriction throughout pre- and postnatal development had differential effects on the synaptic organization of the three nerves in the NTS. These anatomical changes may underlie the impact of sensory restriction during development on the functional processing of taste information and taste-related behaviors.

[Changes in the innervation of the taste buds in diabetic rats].

PubMed

Hevér, Helén; Altdorfer, Károly; Zelles, Tivadar; Batbayar, Bayarchimeg; Fehér, Erzsébet

2013-03-24

Abnormal sensations such as pain and impairment of taste are symptoms of approximately 10% of patients having diabetes mellitus. The aim of the study was to investigate and quantify the different neuropeptide containing nerve fibres in the vallate papilla of the diabetic rat. Immunohistochemical methods were used to study the changes of the number of different neuropeptide containing nerve terminals located in the vallate papillae in diabetic rats. Diabetes was induced in the rats with streptozotocin. Two weeks after streptozotocin treatment the number of the substance P, galanin, vasoactive intestinal polypeptide and neuropeptide Y immunoreactive nerve terminals was significantly increased (p<0.05) in the tunica mucosa of the tongue. The number of the lymphocytes and mast cells was also increased significantly. Some of the immunoreactive nerve terminals were located in the lingual epithelium both intragemmally and extragemmally and were seen to comprise dense bundles in the lamina propria just beneath the epithelium. No taste cells were immunoreactive for any of the investigated peptides. Vasoactive intestinal polypeptide and neuropeptide Y immunoreactive nerve fibres were not detected in the taste buds. For weeks after streptozotocin administration the number of the substance P, calcitonin gene related peptide and galanin immunoreactive nerve terminals was decreased both intragemmally and intergemmally. In case of immediate insulin treatment, the number of the immunoreactive nerve terminals was similar to that of the controls, however, insulin treatment given 1 week later to diabetic rats produced a decreased number of nerve fibers. Morphometry revealed no significant difference in papilla size between the control and diabetic groups, but there were fewer taste buds (per papilla). Increased number of immunoreactive nerve terminals and mast cells 2 weeks after the development of diabetes was the consequence of neurogenic inflammation which might cause vasoconstriction and lesions of the oral mucosa. Taste impairment, which developed 4 weeks after streptozotocin treatment could be caused by neuropathic defects and degeneration or morphological changes in the taste buds and nerve fibres.

Neural control of Substance P-induced upregulation and release of macrophage migration inhibitory factor in the rat bladder

PubMed Central

Vera, Pedro L.; Wang, Xihai; Meyer-Siegler, Katherine L.

2009-01-01

OBJECTIVE Macrophage migration inhibitory factor (MIF) is increased in the intraluminal fluid after experimental inflammation and mediates pro-inflammatory effects on the bladder. We examined the contribution of nerve activity and of specific neurotransmitter systems on the mechanism of MIF release from the bladder during inflammation. MATERIALS & METHODS Male Sprague-Dawley rats were anesthetized, bladders were emptied and filled with saline. Rats received saline (s.c.; control; 0.1 ml/100 g bodyweight) or substance P (40 μg/kg in saline; s.c.; 0.1 ml/100 g bodyweight) and also received hexamethonium (50 mg/kg;i.p.; in saline; 0.1 ml/100 g body weight); intravesical lidocaine (2%; 0.3 ml), atropine (3 mg/kg in saline; i.v.; 0.1 ml/100 g body weight), propranolol (3 mg/kg in saline; i.v.; 0.1 ml/100 g body weight) or phentolamine (10 mg/kg in saline; i.v.; 0.1 ml/100 g body weight). After of 1 hour, the intravesical fluid was removed and the bladder was excised. MIF levels in the intraluminal fluid were measured by ELISA and Western-blotting. MIF expression in bladder homogenates was examined using RT-PCR. RESULTS Either intravesical lidocaine or ganglionic blockage with hexamethonium prevented Substance P-induced MIF release. In addition, pretreatment with atropine and phentolamine, but not propranolol, also prevented MIF release. MIF upregulation in the bladder, while increased with Substance P treatment, was only prevented by intravesical lidocaine. CONCLUSION Substance P-induced MIF release in the bladder is mediated through nerve activation. Post-ganglionic parasympathetic (via muscarinic receptors) and sympathetic (via alpha-adrenergic receptors) fibers mediate MIF release while activation of bladder afferent nerve terminals upregulate MIF. PMID:18499160

MYONEURAL JUNCTIONS OF TWO ULTRASTRUCTURALLY DISTINCT TYPES IN EARTHWORM BODY WALL MUSCLE

PubMed Central

Rosenbluth, Jack

1972-01-01

The longitudinal muscle of the earthworm body wall is innervated by nerve bundles containing axons of two types which form two corresponding types of myoneural junction with the muscle fibers Type I junctions resemble cholinergic neuromuscular junctions of vertebrate skeletal muscle and are characterized by three features: (a) The nerve terminals contain large numbers of spherical, clear, ∼500 A vesicles plus a small number of larger dense-cored vesicles (b) The junctional gap is relatively wide (∼900 A), and it contains a basement membrane-like material, (c) The postjunctional membrane, although not folded, displays prominent specializations on both its external and internal surfaces The cytoplasmic surface is covered by a dense matrix ∼200 A thick which appears to be the site of insertion of fine obliquely oriented cytoplasmic filaments The external surface exhibits rows of projections ∼200 A long whose bases consist of hexagonally arrayed granules seated in the outer dense layer of the plasma membrane The concentration of these hexagonally disposed elements corresponds to the estimated concentration of both receptor sites and acetylcholinesterase sites at cholinergic junctions elsewhere. Type II junctions resemble the adrenergic junctions in vertebrate smooth muscle and exhibit the following structural characteristics: (a) The nerve fibers contain predominantly dense-cored vesicles ∼1000 A in diameter (b) The junctional gap is relatively narrow (∼150 A) and contains no basement membrane-like material, (c) Postjunctional membrane specialization is minimal. It is proposed that the structural differences between the two types of myoneural junction reflect differences in the respective transmitters and corresponding differences in the mechanisms of transmitter action and/or inactivation. PMID:5044759

Nervus terminalis ganglion of the bonnethead shark (Sphyrna tiburo): evidence for cholinergic and catecholaminergic influence on two cell types distinguished by peptide immunocytochemistry.

PubMed

White, J; Meredith, M

1995-01-16

The nervus terminalis is a ganglionated vertebrate cranial nerve of unknown function that connects the brain and the peripheral nasal structures. To investigate its function, we have studied nervus terminalis ganglion morphology and physiology in the bonnethead shark (Sphyrna tiburo), where the nerve is particularly prominent. Immunocytochemistry for gonadotropin-releasing hormone (GnRH) and Leu-Pro-Leu-Arg-Phe-NH2 (LPLRFamide) revealed two distinct populations of cells. Both were acetylcholinesterase positive, but LPLR-Famide-immunoreactive cells consistently stained more darkly for acetylcholinesterase activity. Tyrosine hydroxylase immunocytochemistry revealed fibers and terminal-like puncta in the ganglion, primarily in areas containing GnRH-immunoreactive cells. Consistent with the anatomy, in vitro electrophysiological recordings provided evidence for cholinergic and catecholaminergic actions. In extracellular recordings, acetylcholine had a variable effect on baseline ganglion cell activity, whereas norepinephrine consistently reduced activity. Electrical stimulation of the nerve trunks suppressed ganglion activity, as did impulses from the brain in vivo. During electrical suppression, acetylcholine consistently increased activity, and norepinephrine decreased activity. Muscarinic and, to a lesser extent, alpha-adrenergic antagonists both increased activity during the electrical suppression, suggesting involvement of both systems. Intracellular recordings revealed two types of ganglion cells that were distinguishable pharmacologically and physiologically. Some cells were hyperpolarized by cholinergic agonists and unaffected by norepinephrine; these cells did not depolarize with peripheral nerve trunk stimulation. Another group of cells did depolarize with peripheral trunk stimulation; a representative of this group was depolarized by carbachol and hyperpolarized by norepinephrine. These and other data suggest that the bonnethead nervus terminalis ganglion contains at least two cell populations that respond differently to acetylcholine and norepinephrine. The bonnethead nervus terminalis ganglion appears to differ fundamentally from sensory and autonomic ganglia but does share some features with the neural circuits of forebrain GnRH systems.

The autonomic laboratory

NASA Technical Reports Server (NTRS)

Low, P. A.; Opfer-Gehrking, T. L.

1999-01-01

The autonomic nervous system can now be studied quantitatively, noninvasively, and reproducibly in a clinical autonomic laboratory. The approach at the Mayo Clinic is to study the postganglionic sympathetic nerve fibers of peripheral nerve (using the quantitative sudomotor axon reflex test [QSART]), the parasympathetic nerves to the heart (cardiovagal tests), and the regulation of blood pressure by the baroreflexes (adrenergic tests). Patient preparation is extremely important, since the state of the patient influences the results of autonomic function tests. The autonomic technologist in this evolving field needs to have a solid core of knowledge of autonomic physiology and autonomic function tests, followed by training in the performance of these tests in a standardized fashion. The range and utilization of tests of autonomic function will likely continue to evolve.

The terminal latency of the phrenic nerve correlates with respiratory symptoms in amyotrophic lateral sclerosis.

PubMed

Park, Jin-Sung; Park, Donghwi

2017-09-01

The aim of the study was to investigate the electrophysiological parameters in phrenic nerve conduction studies (NCS) that sensitively reflect latent respiratory insufficiency present in amyotrophic lateral sclerosis (ALS). Forty-nine patients with ALS were examined, and after exclusion, 21 patients with ALS and their phrenic NCS results were reviewed. The patients were divided into two groups according to their respiratory sub-score in the ALS functional rating scale - revised (Group A, sub-score 12vs. Group B, sub-score 11). We compared the parameters of phrenic NCS between the two groups. There were no significant differences in the clinical characteristics between the two groups. Using a multivariate model, we found that the terminal latency of the phrenic nerve was the only parameter that was associated with early symptoms of respiratory insufficiency (p<0.05). The optimal cutoff value for the terminal latency of the phrenic nerve was 7.65ms (sensitivity 80%, specificity 68.2%). The significantly prolonged terminal latency of the phrenic nerve in our study may reflect a profound distal motor axonal dysfunction of the phrenic nerve in patients with ALS in the early stage of respiratory insufficiency that can be used as a sensitive electrophysiological marker reflecting respiratory symptoms in ALS. The terminal latency of the phrenic nerve is useful for early detection of respiratory insufficiency in patients with ALS. Copyright © 2017. Published by Elsevier B.V.

Presynaptic control of transmission along the pathway mediating disynaptic reciprocal inhibition in the cat

PubMed Central

Enríquez-Denton, M; Nielsen, J; Perreault, M-C; Morita, H; Petersen, N; Hultborn, H

2000-01-01

In cat lumbar motoneurones, disynaptic inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of antagonist motor nerves were depressed for at least 150 ms following conditioning stimulation of flexor (1.7-2 times threshold (T)) and ankle extensor (5T) nerves. The aim of the present study was to investigate the possibility that this depression is caused by presynaptic inhibitory mechanisms acting at the terminals of group I afferent fibres projecting to the Ia inhibitory interneurones and/or the terminals of these interneurones to the target motoneurones. Conditioning stimulation of flexor, but not ankle extensor, nerves evoked a depression of the monosynaptic Ia excitatory postsynaptic potentials (EPSPs) recorded intracellularly in Ia inhibitory interneurones. This depression lasted between 200 and 700 ms and was not accompanied by a depression of the monosynaptic EPSPs evoked by stimulation of descending pathways. These results suggest that flexor, but not ankle extensor, group I afferent fibres can modulate sensory transmission at the synapse between Ia afferent fibres and Ia inhibitory interneurones. Conditioning stimulation of flexor muscle nerves, extensor muscle nerves and cutaneous nerves produced a long-lasting increase in excitability of the terminals of the Ia inhibitory interneurones. The increase in the excitability of the terminals was not secondary to an electrotonic spread of synaptic excitation at the soma. Indeed, concomitant with the excitability increase of the terminals there were signs of synaptic inhibition in the soma. The unitary IPSPs induced in target motoneurones following the spike activity of single Ia inhibitory interneurones were depressed by conditioning stimulation of muscle and cutaneous nerves. Since the conditioning stimulation also evoked compound IPSPs in those motoneurones, a firm conclusion as to whether unitary IPSP depression involved presynaptic inhibitory mechanism of the terminals of the interneurones could not be reached. The possibility that the changes in excitability of the Ia interneuronal terminals reflect the presence of a presynaptic inhibitory mechanism similar to that operating at the terminals of the afferent fibres (presynaptic inhibition) is discussed.1. In cat lumbar motoneurones, disynaptic inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of antagonist motor nerves were depressed for at least 150 ms following conditioning stimulation of flexor (1.7-2 times threshold (T)) and ankle extensor (5T) nerves. The aim of the present study was to investigate the possibility that this depression is caused by presynaptic inhibitory mechanisms acting at the terminals of group I afferent fibres projecting to the Ia inhibitory interneurones and/or the terminals of these interneurones to the target motoneurones. PMID:10922013

Differential expression and role of hyperglycemia induced oxidative stress in epigenetic regulation of β1, β2 and β3-adrenergic receptors in retinal endothelial cells

PubMed Central

2014-01-01

Background Aberrant epigenetic profiles are concomitant with a spectrum of developmental defects and diseases. Role of methylation is an increasingly accepted factor in the pathophysiology of diabetes and its associated complications. This study aims to examine the correlation between oxidative stress and methylation of β1, β2 and β3-adrenergic receptors and to analyze the differential variability in the expression of these genes under hyperglycemic conditions. Methods Human retinal endothelial cells were cultured in CSC complete medium in normal (5 mM) or high (25 mM) glucose to mimic a diabetic condition. Reverse transcription PCR and Western Blotting were performed to examine the expression of β1, β2 and β3-adrenergic receptors. For detections, immunocytochemistry was used. Bisulfite sequencing method was used for promoter methylation analysis. Apoptosis was determined by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Dichlorodihydrofluorescein diacetate (DCFH-DA) assay was used to measure reactive oxygen species (ROS) production in the cells. Results β1 and β3-adrenergic receptors were expressed in retinal endothelial cells while β2-adrenergic receptor was not detectable both at protein and mRNA levels. Hyperglycemia had no significant effect on β1 and β2-adrenergic receptors methylation and expression however β3-adrenergic receptors showed a significantly higher expression (p < 0.05) and methylation (p < 0.01) in high and low glucose concentration respectively. Apoptosis and oxidative stress were inversely correlated with β3-adrenergic receptors methylation with no significant effect on β1 and β2-adrenergic receptors. β2-adrenergic receptor was hypermethylated with halted expression. Conclusion Our study demonstrates that β1 and β3-adrenergic receptors expressed in human retinal endothelial cells. Oxidative stress and apoptosis are inversely proportional to the extent of promoter methylation, suggesting that methylation loss might be due to oxidative stress-induced DNA damage. PMID:24885710

Ultrastructural and molecular biologic comparison of classic proprioceptors and palisade endings in sheep extraocular muscles.

PubMed

Rungaldier, Stefanie; Heiligenbrunner, Stefan; Mayer, Regina; Hanefl-Krivanek, Christiane; Lipowec, Marietta; Streicher, Johannes; Blumer, Roland

2009-12-01

To analyze and compare the structural and molecular features of classic proprioceptors like muscle spindles and Golgi tendon organs (GTOs) and putative proprioceptors (palisade endings) in sheep extraocular muscle (EOMs). The EOMs of four sheep were analyzed. Frozen sections or wholemount preparations of the samples were immunohistochemically labeled and analyzed by confocal laser scanning microscopy. Triple labeling with different combinations of antibodies against neurofilament, synaptophysin, and choline acetyltransferase (ChAT), as well as alpha-bungarotoxin and phalloidin, was performed. Microscopic anatomy of the nerve end organs was analyzed by transmission electron microscopy. The microscopic anatomy demonstrated that muscle spindles and GTOs had a perineural capsule and palisade endings a connective tissue capsule. Sensory nerve terminals in muscle spindles and GTOs contained only a few vesicles, whereas palisade nerve terminals were full of clear vesicles. Likewise, motor terminals in the muscle spindles' polar regions were full of clear vesicles. Immunohistochemistry showed that sensory nerve fibers as well as their sensory nerve terminals in muscle spindles and GTOs were ChAT-negative. Palisade endings were supplied by ChAT-positive nerve fibers, and the palisade complexes including palisade nerve terminals were also ChAT-immunoreactive. Motor terminals in muscle spindles were ChAT and alpha-bungarotoxin positive. The present study demonstrated in sheep EOMs that palisade endings are innervated by cholinergic axons exhibiting characteristics typical of motoneurons, whereas muscle spindles (except the polar regions) and GTOs are supplied by noncholinergic axons. These results raise the question of whether palisade endings are candidates for proprioceptors in EOMs.

Ultrastructural and molecular biologic comparison of classical proprioceptors and palisade endings in sheep extraocular muscles

PubMed Central

RUNGALDIER, Stefanie; HEILIGENBRUNNER, Stefan; MAYER, Regina; HANEFL-KRIVANEK, Christiane; LIPOWEC, Marietta; STREICHER, Johannes; BLUMER, Roland

2016-01-01

Purpose To analyze and compare the structural and molecular features of classical proprioceptors like muscle spindles and Golgi tendon organs (GTOs) and putative proprioceptors (palisade endings) in sheep extraocular muscle (EOMs). Methods The EOMs of four sheep were analyzed. Frozen sections or whole mount preparations of the samples were immunohistochemically labeled and analyzed by confocal laser scanning microscopy. Triple labeling with different combinations of antibodies against neurofilament, synaptophysin and choline acetyltransferase (ChAT) as well as α-bungarotoxin and phalloidin was performed. Microscopic anatomy of the nerve end organs was analyzed by transmission electron microscopy. Results The microscopic anatomy demonstrated that muscle spindles and GTOs had a perineural capsule and palisade endings a connective tissue capsule. Sensory nerve terminals in muscle spindles and GTOs contained only few vesicles whereas palisade nerve terminals were full of clear vesicles. Likewise, motor terminals in the muscle spindles’ polar regions were full of clear vesicles. Immunohistochemistry showed that sensory nerve fibers as well as their sensory nerve terminals in muscle spindles and GTOs were ChAT-negative. Palisade endings were supplied by ChAT-positive nerve fibers and the palisade complexes including palisade nerve terminals were also ChAT-immunoreactive. Motor terminals in muscle spindles were ChAT and α-bungarotoxin -positive. Conclusions The present study demonstrated in sheep EOMs that palisade endings are innervated by cholinergic axons exhibiting characteristics typical for motoneurons whereas muscle spindles (except the polar regions) and GTOs are supplied by non-cholinergic axons. These results question whether palisade endings are candidates for proprioceptors in EOMs. PMID:19553627

The structure and innervation of the saccopleural membrane of the domestic fowl, Gallus gallus: an ultrastructural and immunohistochemical study.

PubMed Central

Cook, R D; Vaillant, C; King, A S

1987-01-01

Microscopic studies have shown the saccopleural membrane in the respiratory system of the domestic fowl to consist of a sheet of three dense layers of collagen fibres covered dorsally and ventrally by mainly simple squamous epithelium. On the ventral surface, which faces into the caudal thoracic air sac, there are occasional ridges of pseudostratified ciliated epithelium. Many nerve bundles are present throughout the membrane, the larger bundles of myelinated and unmyelinated axons being confined to the lamina propria under the dorsal epithelium (parietal pleura). In addition to axonal profiles with the ultrastructural appearance of cholinergic or adrenergic axons, peptidergic-type axons were identified. Immunofluorescence studies demonstrated VIP-, substance P-, somatostatin- and enkephalin-immunoreactive fibres in the membrane. Although it has been suggested that receptors may be present in this region of the respiratory system, none of the axons have features suggestive of sensory terminals, although many axonal profiles are closely associated with the epithelia where no obvious effector cells are present. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:3654325

Autonomic nerve development contributes to prostate cancer progression.

PubMed

Magnon, Claire; Hall, Simon J; Lin, Juan; Xue, Xiaonan; Gerber, Leah; Freedland, Stephen J; Frenette, Paul S

2013-07-12

Nerves are a common feature of the microenvironment, but their role in tumor growth and progression remains unclear. We found that the formation of autonomic nerve fibers in the prostate gland regulates prostate cancer development and dissemination in mouse models. The early phases of tumor development were prevented by chemical or surgical sympathectomy and by genetic deletion of stromal β2- and β3-adrenergic receptors. Tumors were also infiltrated by parasympathetic cholinergic fibers that promoted cancer dissemination. Cholinergic-induced tumor invasion and metastasis were inhibited by pharmacological blockade or genetic disruption of the stromal type 1 muscarinic receptor, leading to improved survival of the mice. A retrospective blinded analysis of prostate adenocarcinoma specimens from 43 patients revealed that the densities of sympathetic and parasympathetic nerve fibers in tumor and surrounding normal tissue, respectively, were associated with poor clinical outcomes. These findings may lead to novel therapeutic approaches for prostate cancer.

Expanded Terminal Fields of Gustatory Nerves Accompany Embryonic BDNF Overexpression in Mouse Oral Epithelia

PubMed Central

Sun, Chengsan; Dayal, Arjun

2015-01-01

Brain-derived neurotrophic factor (BDNF) is expressed in gustatory epithelia and is required for gustatory neurons to locate and innervate their correct target during development. When BDNF is overexpressed throughout the lingual epithelium, beginning embryonically, chorda tympani fibers are misdirected and innervate inappropriate targets, leading to a loss of taste buds. The remaining taste buds are hyperinnervated, demonstrating a disruption of nerve/target matching in the tongue. We tested the hypothesis here that overexpression of BDNF peripherally leads to a disrupted terminal field organization of nerves that carry taste information to the brainstem. The chorda tympani, greater superficial petrosal, and glossopharyngeal nerves were labeled in adult wild-type (WT) mice and in adult mice in which BDNF was overexpressed (OE) to examine the volume and density of their central projections in the nucleus of the solitary tract. We found that the terminal fields of the chorda tympani and greater superficial petrosal nerves and overlapping fields that included these nerves in OE mice were at least 80% greater than the respective field volumes in WT mice. The shapes of terminal fields were similar between the two groups; however, the density and spread of labels were greater in OE mice. Unexpectedly, there were also group-related differences in chorda tympani nerve function, with OE mice showing a greater relative taste response to a concentration series of sucrose. Overall, our results show that disruption in peripheral innervation patterns of sensory neurons have significant effects on peripheral nerve function and central organization of their terminal fields. PMID:25568132

Modeling neuropeptide transport in various types of nerve terminals containing en passant boutons.

PubMed

Kuznetsov, I A; Kuznetsov, A V

2015-03-01

We developed a mathematical model for simulating neuropeptide transport inside dense core vesicles (DCVs) in axon terminals containing en passant boutons. The motivation for this research is a recent experimental study by Levitan and colleagues (Bulgari et al., 2014) which described DCV transport in nerve terminals of type Ib and type III as well as in nerve terminals of type Ib with the transcription factor DIMM. The goal of our modeling is validating the proposition put forward by Levitan and colleagues that the dramatic difference in DCV number in type Ib and type III terminals can be explained by the difference in DCV capture in type Ib and type III boutons rather than by differences in DCV anterograde transport and half-life of resident DCVs. The developed model provides a tool for studying the dynamics of DCV transport in various types of nerve terminals. The model is also an important step in gaining a better mechanistic understanding of transport processes in axons and identifying directions for the development of new models in this area. Copyright © 2014 Elsevier Inc. All rights reserved.

Desmin and nerve terminal expression during embryonic development of the lateral pterygoid muscle in mice.

PubMed

Yamamoto, Masahito; Shinomiya, Takashi; Kishi, Asuka; Yamane, Shigeki; Umezawa, Takashi; Ide, Yoshinobu; Abe, Shinichi

2014-09-01

In adults, the lateral pterygoid muscle (LPM) is usually divided into the upper and lower head, between which the buccal nerve passes. Recent investigations have demonstrated foetal developmental changes in the topographical relationship between the human LPM and buccal nerve. However, as few studies have investigated this issue, we clarified the expression of desmin and nerve terminal distribution during embryonic development of the LPM in mice. We utilized immunohistochemical staining and reverse transcription chain reaction (RT-PCR) to clarify the expression of desmin and nerve terminal distribution. We observed weak expression of desmin in the LPM at embryonic day (ED) 11, followed by an increase in expression from embryonic days 12-15. In addition, starting at ED 12, we observed preferential accumulation of desmin in the vicinity of the myotendinous junction, a trend that did not change up to ED 15. Nerve terminal first appeared at ED 13 and formed regularly spaced linear arrays at the centre of the muscle fibre by ED 15. The results of immunohistochemical staining agreed with those of RT-PCR analysis. We found that desmin accumulated in the vicinity of the myotendinous junction starting at ED 12, prior to the onset of jaw movement. We speculate that the accumulation of desmin is due to factors other than mechanical stress experienced during early muscle contraction. Meanwhile, the time point at which nerve terminals first appeared roughly coincided with the onset of jaw movement. Copyright © 2014 Elsevier Ltd. All rights reserved.

Intestinal nerves and ion transport: stimuli, reflexes, and responses.

PubMed

Hubel, K A

1985-03-01

The effects of extrinsic and intrinsic nerves on ion and water transport by the intestine are considered and discussed in terms of their possible physiological function. Adrenergic nerves enter the small intestine via mesenteric nerves. Adrenergic tone is usually absent in tissues in vitro but is present in vivo. The nerves increase absorption in response to homeostatic changes associated with acute depletion of extracellular fluid. Cholinergic tone that reduces fluid absorption or causes secretion has been detected in the small intestine of humans, dogs, and cats and in the colon of humans. Extrinsic cholinergic fibers generally do not affect ion transport in small intestine but probably do so in colon. Whether peptides liberated in the mucosa affect enterocytes directly is not clear. Studies on humans and rabbits suggest that the role of substance P is minor. The physiological roles of vasoactive intestinal polypeptide (VIP) and somatostatin remain to be defined. Intraluminal factors also affect ion and water transport. Mucosal rubbing, distension, and cholera toxin cause fluid secretion; acid solutions in the duodenum cause alkaline secretion; these stimuli and hypertonic glucose liberate serotonin into the lumen, the mesenteric venous blood, or both. It has been proposed that the enterochromaffin cell is an epithelial sensory cell that responds to noxious stimuli within the lumen by liberating serotonin. The serotonin initiates a neural reflex through a nicotinic ganglion to liberate a secretagogue that acts on the enterocyte. The function of VIP in this proposed reflex is unclear. The variety of intraluminal stimuli that influence epithelial function implies that there is more than one type of epithelial sensory cell (or sensory mechanism). Prostaglandins may mediate the alkaline secretion caused by acid in the duodenum. There may be other effective substances. Although it has been known for years that intraluminal stimuli affect the coordination of smooth muscle functions, it is not known whether similar stimuli also influence salt and water transport as a meal traverses the alimentary canal.

Selectivity of the uptake of glutamate and GABA in two morphologically distinct insect neuromuscular synapses.

PubMed

van Marle, J; Piek, T; Lammertse, T; Lind, A; Van Weeren-Kramer, J

1985-11-25

The common inhibitor (CI) and slow excitor tibiae (SETi) innervated slow muscles 135cd of the locust Schistocerca gregaria were incubated under high-affinity uptake conditions either in [3H]GABA or in [3H]glutamate. [3H]GABA is accumulated in the glia of the nerve endings of the CI as well as the SETi; however, it is accumulated only in the terminal axons of the CI, not in the terminal axons of the SETi. The grain densities above the glia and above the CI terminal axons are approximately 2 grains/micron2. After incubation in [3H]glutamate the grain densities above the CI terminal axons and the SETi terminal axons are approximately 4 grains/micron2; the grain densities above the glia of both types of nerve endings are approximately 17 grains/micron2. The relatively high labeling (3 grains/micron2) of the muscles after incubation in the presence of glutamate is ascribed to the high metabolic requirements of slow muscles. The conclusion is drawn that a high-affinity uptake system for GABA is present in the CI terminal axons and in the glia of both the CI and SETi nerve endings. However, while the glutamate uptake in the CI and SETi nerve endings of the slow 135cd is comparable to the high-affinity uptake of glutamate in the fast excitor tibiae (FETi) nerve endings of the fast retractor unguis muscle, a high-affinity uptake of glutamate was only demonstrated in the glia of both types of nerve endings. A high-affinity uptake in the terminal axons of the CI and SETi may be masked by an extensively low-affinity uptake of glutamate by the muscles.

Caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury is mediated via RhoA and ROCK activation in major pelvic ganglion.

PubMed

Hannan, Johanna L; Matsui, Hotaka; Sopko, Nikolai A; Liu, Xiaopu; Weyne, Emmanuel; Albersen, Maarten; Watson, Joseph W; Hoke, Ahmet; Burnett, Arthur L; Bivalacqua, Trinity J

2016-07-08

Axonal injury due to prostatectomy leads to Wallerian degeneration of the cavernous nerve (CN) and erectile dysfunction (ED). Return of potency is dependent on axonal regeneration and reinnervation of the penis. Following CN injury (CNI), RhoA and Rho-associated protein kinase (ROCK) increase in penile endothelial and smooth muscle cells. Previous studies indicate that nerve regeneration is hampered by activation of RhoA/ROCK pathway. We evaluated the role of RhoA/ROCK pathway in CN regulation following CNI using a validated rat model. CNI upregulated gene and protein expression of RhoA/ROCK and caspase-3 mediated apoptosis in the major pelvic ganglion (MPG). ROCK inhibitor (ROCK-I) prevented upregulation of RhoA/ROCK pathway as well as activation of caspase-3 in the MPG. Following CNI, there was decrease in the dimer to monomer ratio of neuronal nitric oxide synthase (nNOS) protein and lowered NOS activity in the MPG, which were prevented by ROCK-I. CNI lowered intracavernous pressure and impaired non-adrenergic non-cholinergic-mediated relaxation in the penis, consistent with ED. ROCK-I maintained the intracavernous pressure and non-adrenergic non-cholinergic-mediated relaxation in the penis following CNI. These results suggest that activation of RhoA/ROCK pathway mediates caspase-3 dependent apoptosis of nitrergic neurons in the MPG following CNI and that ROCK-I can prevent post-prostatectomy ED.

α1A-Adrenergic Receptor Antagonism Improves Erectile and Cavernosal Responses in Rats With Cavernous Nerve Injury and Enhances Neurogenic Responses in Human Corpus Cavernosum From Patients With Erectile Dysfunction Secondary to Radical Prostatectomy.

PubMed

Martínez-Salamanca, Juan I; La Fuente, José M; Martínez-Salamanca, Eduardo; Fernández, Argentina; Pepe-Cardoso, Augusto J; Louro, Nuno; Carballido, Joaquín; Angulo, Javier

2016-12-01

Cavernous nerve injury (CNI) in rats and radical prostatectomy (RP) in men result in loss of nitrergic function and increased adrenergic-neurogenic contractions of cavernosal tissue. To evaluate the modulation of the α-adrenergic system as a strategy to relieve erectile dysfunction (ED) and functional cavernosal alterations induced by CNI. A non-selective α-blocker (phentolamine 1 mg/kg daily), a selective α 1A -blocker (silodosin [SILOD] 0.1 mg/kg daily), or vehicle was orally administered for 4 weeks after bilateral crush CNI (BCNI). Erectile and neurogenic responses of the corpus cavernosum (CC) were evaluated. The acute effects of SILOD also were evaluated in vivo (0.03 mg/kg intravenously) and ex vivo (10 nmol/L). The effects of SILOD and tadalafil (TAD) on nitrergic relaxations were determined in human CC from patients with ED with a vascular etiology or ED secondary to RP. Erectile responses in vivo in rats and neurogenic contractions and relaxations of rat and human CC. Long-term treatment with SILOD significantly improved erectile responses and allowed for the potentiation of erectile responses by acute treatment with TAD (0.3 mg/kg intravenously) in rats with BCNI. SILOD partly recovered nitrergic relaxations and normalized neurogenic contractions in CC from rats with BCNI. Long-term treatment with SILOD partly prevented BCNI-induced decreases in neuronal nitric oxide synthase expression. Acute administration of SILOD (0.03 mg/kg intravenously) improved erectile responses in vivo and potentiated nitrergic relaxation and decreased neurogenic contractions ex vivo in CC from rats with BCNI. In human CC from patients with ED with a vascular etiology, TAD (30 nmol/L), SILOD (10 nmol/L), or their combination increased nitrergic relaxations. Potentiation by TAD was lost in human CC from patients with ED after RP but was recovered after co-treatment with SILOD. α-Adrenergic modulation, especially selective α 1A -blockade, improves erectile and cavernosal functions after BCNI. Modulation of the adrenergic system, mainly in combination strategies, could have a role in the management of ED after RP. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Selective inhibition by dactinomycin of NANC sensory bronchoconstriction and [125I]NKA binding due to NK-2 receptor antagonism.

PubMed

Lou, Y P; Delay-Goyet, P; Lundberg, J M

1992-03-01

In the present study, dactinomycin (10(-5) M) inhibited the non-adrenergic, non-cholinergic bronchoconstriction upon antidromic vagal nerve stimulation (1 Hz for 1 min) in the isolated perfused guinea-pig lung by 84%. The release of calcitonin gene-related peptide was unchanged, however, suggesting a postjunctional action. Dactinomycin (10(-5), 5 x 10(-5) M) also reduced non-adrenergic non-cholinergic bronchial contractions (maximally by 75%) induced by electrical field stimulation or capsaicin, while the cholinergic component and non-adrenergic non-cholinergic relaxation remained intact. The neurokinin-2 receptor antagonist L-659,877 (10(-6) M) had a similar effect as dactinomycin, inhibiting the non-adrenergic non-cholinergic bronchial contractions by 69%, while the neurokinin-1 receptor antagonist CP-96,345 (10(-6) M) had no effect. The bronchoconstriction evoked by neurokinin A, the selective neurokinin-2 receptor agonist Nle10neurokinin A (4-10) and capsaicin was markedly inhibited by dactinomycin while the contraction induced by substance P (SP), the selective neurokinin-1 receptor agonist Sar9Met(O2)11SP, endothelin-1 and acetylcholine was not affected. In autoradiographic experiments on guinea-pig lung, [125I]neurokinin A-labelled sections showed dense binding in the bronchial smooth muscle layer. Dactinomycin inhibited the specific binding of [125I]neurokinin A in a concentration-dependent manner (IC50 = 6.3 x 10(-6) M) and 66% of [125I]neurokinin A total binding was inhibited by 10(-4) M dactinomycin. In the rat colon, [125I]neurokinin A binding to neurokinin-2 sites on circular smooth muscle was inhibited by dactinomycin with an IC50 value of 7.9 x 10(-6) M. Dactinomycin failed to reduce increased nerve-evoked contractions or those caused by Nle10neurokinin A (4-10) per se in the rat vas deferens, which are considered to be mediated by neurokinin-2 receptor activation. In the rat portal vein, dactinomycin did not influence the contractions caused by the neurokinin-3 selective agonist Pro7neurokinin B. In conclusion, dactinomycin selectively inhibited neurokinin-2 receptor activation in guinea-pig lung and rat colon, but not in rat vas deferens, which may depend on the existence of different neurokinin-2 receptor subtypes. Neurokinin A is most likely the main endogenous excitatory non-adrenergic non-cholinergic transmitter in guinea-pig bronchi.

[Morphologic studies of the protective role of catechin on kanamycin otoneurotoxicity in SD rats].

PubMed

Liu, Guo-hui; Xie, Ding-hua; Wu, Wei-jing

2002-12-28

To determine the protection of catechin on aminoglycoside antibiotics otoneurotoxicity in SD rats, and observe the morphologic changes of cochlear efferent nerve terminals and outer hair cells after the injection of kanamycin and the feeding of catechin by the stomach tube. Thirty-eight SD rats were randomly assigned into three experimental groups (KM-treated, catechin-treated, KM and catechin in combination) and one control group. The KM-treated group was given kanamycin in a dose of 500 mg.(kg.d)-1 for 14 days. The catechin-treated group was given catechin once by the stomach tube in a dose of 400 mg.(kg.d)-1. Two kinds of medicine were simultaneously given in the KM+ catechin group. Transmission electron microscopy was utilized to observe the subcellular structure of efferent nerve fibers and outer hair cells. The densities of efferent nerve fibers and terminals were examined and the numbers of efferent nerve fibers and terminals were numerated by the surface preparation using modified histochemical staining for acetylcholinesterase (AchE). The damage in the group protected by catechin was relieved compared with the unprotected group. No damage was found in the catechin-treated alone group and controls. The densities and numbers of efferent nerve fibers and terminals were obviously fewer in the unprotected group than in the protected group and controls(P < 0.05). There was no significant difference in the numbers of efferent nerve fibers and terminals of the group protected by catechin compared with the controls and the catechin-treated group (P > 0.05). Catechin significantly protects MOC efferent nerves in kanamycin otoneurotoxicity.

The dimensions and characteristics of the subepidermal nerve plexus in human skin--terminal Schwann cells constitute a substantial cell population within the superficial dermis.

PubMed

Reinisch, Christina M; Tschachler, Erwin

2012-03-01

The skin constitutes the largest sensorial organ. Its nervous system consists of different types of afferent nerve fibers which spread out immediately beneath the skin surface to sense temperature, touch and pain. Our aim was to investigate the dimension and topographic relationship of the different nerve fibers of the subepidermal nerve plexus in human hairy skin and to analyze numbers and marker expression of terminal Schwann cells. Nerve fibers and Schwann cells were investigated on dermal sheet preparations and thick sections of skin from various body regions of 10 individuals. The dimension of subepidermal nerve fibers varied between different body sites with highest values in chest skin (100 ± 18 mm/mm(2)) and lowest in posterior forearm skin (53 ± 10 mm/mm(2)). The majority of fibers (85.79%) were unmyelinated, thus representing C-fibers, of which 7.84% were peptidergic. Neurofilament-positive fibers (A-fibers) accounted for 14.21% and fibers positive for both neurofilament and myelin (Aβ-fibers) for only 0.18%. The number of Schwann cells varied in accordance with nerve fiber length from 453 ± 108 on chest skin to 184 ± 58/mm(2) in skin of the posterior forearm. Terminal Schwann cells showed a marker profile comparable to Schwann cells in peripheral nerves with the notable exception of expression of NGFr, NCAM, L1CAM and CD146 on myelinating Schwann cells in the dermis but not in peripheral nerves. Our data show that terminal Schwann cells constitute a substantial cell population within the papillary dermis and that both nerve fiber length and Schwann cell numbers vary considerably between different body sites. Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Oral sapropterin augments reflex vasoconstriction in aged human skin through noradrenergic mechanisms.

PubMed

Stanhewicz, Anna E; Alexander, Lacy M; Kenney, W Larry

2013-10-01

Reflex vasoconstriction is attenuated in aged skin due to a functional loss of adrenergic vasoconstriction. Bioavailability of tetrahydrobiopterin (BH4), an essential cofactor for catecholamine synthesis, is reduced with aging. Locally administered BH4 increases vasoconstriction through adrenergic mechanisms in aged human skin. We hypothesized that oral sapropterin (Kuvan, a pharmaceutical BH4) would augment vasoconstriction elicited by whole-body cooling and tyramine perfusion in aged skin. Ten healthy subjects (age 75 ± 2 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized, double-blind crossover design. Venous blood samples were collected prior to, and 3 h following ingestion. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer, 2) 5 mM BH4, and 3) 5 mM yohimbine + 1 mM propranolol (Y+P; to inhibit adrenergic vasoconstriction). Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasoconstriction was induced by lowering and then clamping whole-body skin temperature (Tsk) using a water-perfused suit. Following whole-body cooling, subjects were rewarmed and 1 mM tyramine was perfused at each site to elicit endogenous norepinephrine release from the perivascular nerve terminal. Cutaneous vascular conductance was calculated as CVC = LDF/mean arterial pressure and expressed as change from baseline (ΔCVC). Plasma BH4 was elevated 3 h after ingestion of sapropterin (43.8 ± 3 vs. 19.1 ± 2 pmol/ml; P < 0.001). Sapropterin increased reflex vasoconstriction at the Ringer site at Tsk ≤ 32.5°C (P < 0.05). Local BH4 perfusion augmented reflex vasoconstriction at Tsk ≤ 31.5°C with placebo treatment only (P < 0.05). There was no treatment effect on reflex vasoconstriction at the BH4-perfused or Y+P-perfused sites. Sapropterin increased pharmacologically induced vasoconstriction at the Ringer site (-0.19 ± 0.03 vs. -0.08 ± 0.02 ΔCVC; P = 0.01). There was no difference in pharmacologically induced vasoconstriction between treatments at the BH4-perfused site (-0.16 ± 0.04 vs. -0.14 ± 0.03 ΔCVC; P = 0.60) or the Y+P-perfused site (-0.05 ± 0.02 vs.-0.06 ± 0.02 ΔCVC; P = 0.79). Sapropterin increases both reflex (cold-induced) and pharmacologically induced vasoconstriction through adrenergic mechanisms and may be a viable intervention to improve reflex vasoconstriction in aged humans.

Oral sapropterin augments reflex vasoconstriction in aged human skin through noradrenergic mechanisms

PubMed Central

Stanhewicz, Anna E.; Kenney, W. Larry

2013-01-01

Reflex vasoconstriction is attenuated in aged skin due to a functional loss of adrenergic vasoconstriction. Bioavailability of tetrahydrobiopterin (BH4), an essential cofactor for catecholamine synthesis, is reduced with aging. Locally administered BH4 increases vasoconstriction through adrenergic mechanisms in aged human skin. We hypothesized that oral sapropterin (Kuvan, a pharmaceutical BH4) would augment vasoconstriction elicited by whole-body cooling and tyramine perfusion in aged skin. Ten healthy subjects (age 75 ± 2 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized, double-blind crossover design. Venous blood samples were collected prior to, and 3 h following ingestion. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer, 2) 5 mM BH4, and 3) 5 mM yohimbine + 1 mM propranolol (Y+P; to inhibit adrenergic vasoconstriction). Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasoconstriction was induced by lowering and then clamping whole-body skin temperature (T̄sk) using a water-perfused suit. Following whole-body cooling, subjects were rewarmed and 1 mM tyramine was perfused at each site to elicit endogenous norepinephrine release from the perivascular nerve terminal. Cutaneous vascular conductance was calculated as CVC = LDF/mean arterial pressure and expressed as change from baseline (ΔCVC). Plasma BH4 was elevated 3 h after ingestion of sapropterin (43.8 ± 3 vs. 19.1 ± 2 pmol/ml; P < 0.001). Sapropterin increased reflex vasoconstriction at the Ringer site at T̄sk ≤ 32.5°C (P < 0.05). Local BH4 perfusion augmented reflex vasoconstriction at T̄sk ≤ 31.5°C with placebo treatment only (P < 0.05). There was no treatment effect on reflex vasoconstriction at the BH4-perfused or Y+P-perfused sites. Sapropterin increased pharmacologically induced vasoconstriction at the Ringer site (−0.19 ± 0.03 vs. −0.08 ± 0.02 ΔCVC; P = 0.01). There was no difference in pharmacologically induced vasoconstriction between treatments at the BH4-perfused site (−0.16 ± 0.04 vs. −0.14 ± 0.03 ΔCVC; P = 0.60) or the Y+P-perfused site (−0.05 ± 0.02 vs.−0.06 ± 0.02 ΔCVC; P = 0.79). Sapropterin increases both reflex (cold-induced) and pharmacologically induced vasoconstriction through adrenergic mechanisms and may be a viable intervention to improve reflex vasoconstriction in aged humans. PMID:23869061

Cholinergic inhibition of adrenergic neurosecretion in the rabbit iris-ciliary body

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jumblatt, J.E.; North, G.T.

The prejunctional effects of cholinergic agents on release of norepinephrine from sympathetic nerve endings were investigated in the isolated, superfused rabbit iris-ciliary body. Stimulation-evoked release of /sup 3/H-norepinephrine was inhibited by the cholinergic agonists methacholine, oxotremorine, muscarine, carbamylcholine and acetylcholine (plus eserine), but was unmodified by pilocarpine or nicotine. Agonist-induced inhibition was antagonized selectively by atropine, indicating a muscarinic response. Atropine alone markedly enhanced norepinephrine release, revealing considerable tonic activation of prejunctional cholinergic receptors in this system. Prejunctional inhibition by carbamylcholine was found to completely override the facilitative action of forskolin or 8-bromo-cyclic AMP on neurotransmitter release. Cholinergic and alphamore » 2-adrenergic effects on neurosecretion were non-additive, suggesting that the underlying receptors coexist at neurotransmitter release sites.« less

High-Bandwidth Atomic Force Microscopy Reveals A Mechanical spike Accompanying the Action Potential in mammalian Nerve Terminals

NASA Astrophysics Data System (ADS)

Salzberg, Brian M.

2008-03-01

Information transfer from neuron to neuron within nervous systems occurs when the action potential arrives at a nerve terminal and initiates the release of a chemical messenger (neurotransmitter). In the mammalian neurohypophysis (posterior pituitary), large and rapid changes in light scattering accompany secretion of transmitter-like neuropeptides. In the mouse, these intrinsic optical signals are intimately related to the arrival of the action potential (E-wave) and the release of arginine vasopressin and oxytocin (S-wave). We have used a high bandwidth (20 kHz) atomic force microscope (AFM) to demonstrate that these light scattering signals are associated with changes in nerve terminal volume, detected as nanometer-scale movements of a cantilever positioned on top of the neurohypophysis. The most rapid mechanical response, the ``spike'', has duration comparable to that of the action potential (˜2 ms) and probably reflects an increase in terminal volume due to H2O movement associated with Na^+-influx. Elementary calculations suggest that two H2O molecules accompanying each Na^+-ion could account for the ˜0.5-1.0 å increase in the diameter of each terminal during the action potential. Distinguishable from the mechanical ``spike'', a slower mechanical event, the ``dip'', represents a decrease in nerve terminal volume, depends upon Ca^2+-entry, as well as on intra-terminal Ca^2+-transients, and appears to monitor events associated with secretion. A simple hypothesis is that this ``dip'' reflects the extrusion of the dense core granule that comprises the secretory products. These dynamic high bandwidth AFM recordings are the first to monitor mechanical events in nervous systems and may provide novel insights into the mechanism(s) by which excitation is coupled to secretion at nerve terminals.

Dopamine D1 and D2 Receptor Immunoreactivities in the Arcuate-Median Eminence Complex and their Link to the Tubero-Infundibular Dopamine Neurons

PubMed Central

Romero-Fernandez, W.; Borroto-Escuela, D.O.; Vargas-Barroso, V.; Narváez, M.; Di Palma, M.; Agnati, L.F.; Sahd, J. Larriva

2014-01-01

Dopamine D1 and D2 receptor immunohistochemistry and Golgi techniques were used to study the structure of the adult rat arcuate-median eminence complex, and determine the distribution of the dopamine D1 and D2 receptor immunoreactivities therein, particularly in relation to the tubero-infundibular dopamine neurons. Punctate dopamine D1 and D2 receptor immunoreactivities, likely located on nerve terminals, were enriched in the lateral palisade zone built up of nerve terminals, while the densities were low to modest in the medial palisade zone. A codistribution of dopamine D1 receptor or dopamine D2 receptor immunoreactive puncta with tyrosine hydroxylase immunoreactive nerve terminals was demonstrated in the external layer. Dopamine D1 receptor but not dopamine D2 receptor immnunoreactivites nerve cell bodies were found in the ventromedial part of the arcuate nucleus and in the lateral part of the internal layer of the median eminence forming a continuous cell mass presumably representing neuropeptide Y immunoreactive nerve cell bodies. The major arcuate dopamine/ tyrosine hydroxylase nerve cell group was found in the dorsomedial part. A large number of tyrosine hydroxylase immunoreactive nerve cell bodies in this region demonstrated punctate dopamine D1 receptor immunoreactivity but only a few presented dopamine D2 receptor immunoreactivity which were mainly found in a substantial number of tyrosine hydroxylase cell bodies of the ventral periventricular hypothalamic nucleus, also belonging to the tuberoinfundibular dopamine neurons. Structural evidence for projections of the arcuate nerve cells into the median eminence was also obtained. Distal axons formed horizontal axons in the internal layer issuing a variable number of collaterals classified into single or multiple strands located in the external layer increasing our understanding of the dopamine nerve terminal networks in this region. Dopamine D1 and D2 receptors may therefore directly and differentially modulate the activity and/or Dopamine synthesis of substantial numbers of tubero-infundibular dopamine neurons at the somatic and terminal level. The immunohistochemical work also gives support to the view that dopamine D1 receptors and/or dopamine D2 receptors in the lateral palisade zone by mediating dopamine volume transmission may contribute to the inhibition of luteinizing hormone releasing hormone release from nerve terminals in this region. PMID:25308843

Dopamine D1 and D2 receptor immunoreactivities in the arcuate-median eminence complex and their link to the tubero-infundibular dopamine neurons.

PubMed

Romero-Fernandez, W; Borroto-Escuela, D O; Vargas-Barroso, V; Narváez, M; Di Palma, M; Agnati, L F; Larriva Sahd, J; Fuxe, K

2014-07-18

Dopamine D1 and D2 receptor immunohistochemistry and Golgi techniques were used to study the structure of the adult rat arcuate-median eminence complex, and determine the distribution of the dopamine D1 and D2 receptor immunoreactivities therein, particularly in relation to the tubero-infundibular dopamine neurons. Punctate dopamine D1 and D2 receptor immunoreactivities, likely located on nerve terminals, were enriched in the lateral palisade zone built up of nerve terminals, while the densities were low to modest in the medial palisade zone. A codistribution of dopamine D1 receptor or dopamine D2 receptor immunoreactive puncta with tyrosine hydroxylase immunoreactive nerve terminals was demonstrated in the external layer. Dopamine D1 receptor but not dopamine D2 receptor immnunoreactivites nerve cell bodies were found in the ventromedial part of the arcuate nucleus and in the lateral part of the internal layer of the median eminence forming a continuous cell mass presumably representing neuropeptide Y immunoreactive nerve cell bodies. The major arcuate dopamine/ tyrosine hydroxylase nerve cell group was found in the dorsomedial part. A large number of tyrosine hydroxylase immunoreactive nerve cell bodies in this region demonstrated punctate dopamine D1 receptor immunoreactivity but only a few presented dopamine D2 receptor immunoreactivity which were mainly found in a substantial number of tyrosine hydroxylase cell bodies of the ventral periventricular hypothalamic nucleus, also belonging to the tubero-infundibular dopamine neurons. Structural evidence for projections of the arcuate nerve cells into the median eminence was also obtained. Distal axons formed horizontal axons in the internal layer issuing a variable number of collaterals classified into single or multiple strands located in the external layer increasing our understanding of the dopamine nerve terminal networks in this region.  Dopamine D1 and D2 receptors may therefore directly and differentially modulate the activity and /or Dopamine synthesis of substantial numbers of tubero-infundibular dopamine neurons at the somatic and terminal level. The immunohistochemical work also gives support to the view that dopamine D1 receptors and/or dopamine D2 receptors in the lateral palisade zone by mediating dopamine volume transmission may contribute to the inhibition of luteinizing hormone releasing hormone release from nerve terminals in this region.

Palisade endings in extraocular muscles of the monkey are immunoreactive for choline acetyltransferase and vesicular acetylcholine transporter.

PubMed

Konakci, Kadriye Zeynep; Streicher, Johannes; Hoetzenecker, Wolfram; Haberl, Ines; Blumer, Michael Josef Franz; Wieczorek, Grazyna; Meingassner, Josef Gottfried; Paal, Szabolcs Levente; Holzinger, Daniel; Lukas, Julius-Robert; Blumer, Roland

2005-12-01

To analyze palisade endings in extraocular muscles (EOMs) of a primate species and to examine our previous findings in cat that palisade endings are putative effector organs. Eleven monkeys (Macaca fascicularis) of both sexes, between 4 and 6 years of age were analyzed. Whole EOM myotendons were immunostained with four combinations of triple-fluorescent labeling and examined by confocal laser scanning microscopy. Labeling included antibodies against choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), neurofilament, and synaptophysin. Muscle fibers were counterstained with phalloidin. Palisade endings were observed in all monkey EOMs. Nerve fibers extended from the muscle into the tendon and looped back to divide into a terminal arborization (palisade ending) around a single muscle fiber tip. In approximately 30% of the cases, nerve fibers supplying palisade endings often established motor terminals outside the palisade complex. Nerve fibers forming palisade endings were ChAT-neurofilament positive. Axonal branches of palisade endings were ChAT-neurofilament positive as well. All palisade nerve terminals exhibited ChAT-synaptophysin immunoreactivity. Within the palisade complex, palisade nerve terminals exhibited VAChT immunoreactivity. All palisade nerve terminals were VAChT-synaptophysin immunoreactive. The results confirm that in the monkey, palisade endings contain acetylcholine and are therefore most likely effector organs. Palisade endings are also present in human EOMs and because of their location at the myotendinous junction, these organs are of crucial interest for strabismus surgery.

Molecular Machines Determining the Fate of Endocytosed Synaptic Vesicles in Nerve Terminals

PubMed Central

Fassio, Anna; Fadda, Manuela; Benfenati, Fabio

2016-01-01

The cycle of a synaptic vesicle (SV) within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions. The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on: (i) the cyclin-dependent kinase-5 (cdk5) and calcineurin (CN) control of the recycling pool of SVs; (ii) the role of small GTPases of the Rab and ADP-ribosylation factor (Arf) families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission. PMID:27242505

Molecular Machines Determining the Fate of Endocytosed Synaptic Vesicles in Nerve Terminals.

PubMed

Fassio, Anna; Fadda, Manuela; Benfenati, Fabio

2016-01-01

The cycle of a synaptic vesicle (SV) within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions. The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on: (i) the cyclin-dependent kinase-5 (cdk5) and calcineurin (CN) control of the recycling pool of SVs; (ii) the role of small GTPases of the Rab and ADP-ribosylation factor (Arf) families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission.

Selective binding, uptake, and retrograde transport of tetanus toxin by nerve terminals in the rat iris. An electron microscope study using colloidal gold as a tracer

PubMed Central

1978-01-01

A series of specific macromolecules (tetanus toxin, cholera toxin, nerve growth factor [NGF], and several lectins) have been shown to be transported retrogradely with high selectivity from terminals to cell bodies in various types of neurons. Under identical experimental conditions (low protein concentrations injected), most other macromolecules, e.g. horseradish peroxidase (HRP), albumin, ferritin, are not transported in detectable amounts. In the present EM study, we demonstrate selective binding of tetanus toxin to the surface membrane of nerve terminals, followed by uptake and subsequent retorgrade axonal transport. Tetanus toxin or albumin was adsorbed to colloidal gold particles (diam 200 A). The complex was shown to be stable and well suited as an EM tracer. 1-4 h after injection into the anterior eye chamber of adult rats, tetanus toxin-gold particles were found to be selectively associated with membranes of nerve terminals and preterminal axons. Inside terminals and axons, the tracer was localized mainly in smooth endoplasmic reticulum (SER)-like membrane compartments. In contrast, association of albumin-gold complexes with nervous structures was never observed, in spite of extensive uptake into fibroblasts. Electron microscope and biochemical experiments showed selective retrograde transport of tetanus toxin-gold complexes to the superior cervical ganglion. Specific binding to membrane components at nerve terminals and subsequent internalization and retrograde transport may represent an important pathway for macromolecules carrying information from target organs to the perikarya of their innervating neurons. PMID:659508

Neural control of blood flow during exercise in human metabolic syndrome.

PubMed

Limberg, Jacqueline K; Morgan, Barbara J; Sebranek, Joshua J; Proctor, Lester T; Eldridge, Marlowe W; Schrage, William G

2014-09-01

α-Adrenergic-mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome (MetSyn) when compared with control animals. In an attempt to translate such findings to humans, we hypothesized that adults with MetSyn (n = 14, 35 ± 3 years old) would exhibit greater α-adrenergic responsiveness during exercise when compared with age-matched healthy control subjects (n = 16, 31 ± 3 years old). We measured muscle sympathetic nerve activity (MSNA; microneurography) and forearm blood flow (Doppler ultrasound) during dynamic forearm exercise (15% of maximal voluntary contraction). α-Adrenergic agonists (phenylephrine and clonidine) and an antagonist (phentolamine) were infused intra-arterially to assess α-adrenergic receptor responsiveness and restraint, respectively. Resting MSNA was ∼35% higher in adults with MetSyn (P < 0.05), but did not change in either group with dynamic exercise. Clonidine-mediated vasoconstriction was greater in adults with MetSyn (P < 0.01). Group differences in vascular responses to phenylephrine and phentolamine were not detected (P > 0.05). Interestingly, exercise-mediated vasodilatation was greater in MetSyn (P < 0.05). Adults with MetSyn exhibit greater resting MSNA and clonidine-mediated vasoconstriction, yet preserved functional sympatholysis and higher exercise blood flow during low-intensity hand-grip exercise when compared with age-matched healthy control subjects. These results suggest that adults with MetSyn exhibit compensatory vascular control mechanisms capable of preserving blood flow responses to exercise in the face of augmented sympathetic adrenergic activity. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

Relaxations of the isolated portal vein of the rabbit induced by nicotine and electrical stimulation

PubMed Central

Hughes, J.; Vane, J. R.

1970-01-01

1. A pharmacological analysis of the inhibitory innervation of the isolated portal vein of the rabbit has been made. 2. In untreated preparations, transmural stimulation elicited a long-lasting relaxation at low frequencies (0·2-1 Hz); at higher frequencies a contraction followed by a prolonged after-relaxation occurred. Tetrodotoxin abolished the contractions but a higher dose was required to abolish the relaxations. Veratrine lowered the threshold of stimulation for producing relaxations in the untreated vein. The relaxations were unaffected by hyoscine or hexamethonium. They were reduced or altered by antagonists of α-adrenoceptors for catecholamines and by adrenergic neurone blockade. They were sometimes slightly reduced by antagonists of β-adrenoceptors. 3. In the presence of antagonists of α-adrenoceptors, electrical stimulation elicited relaxations which increased with frequency of stimulation and became maximal at 20-30 Hz. These relaxations were partially reduced by antagonists of β-adrenoceptors, or by adrenergic neurone block; the antagonisms were more pronounced at the higher frequencies of stimulation. Noradrenaline also caused relaxations which were abolished by β-adrenoceptor blocking drugs. Cocaine increased the sensitivity to noradrenaline by 7-8 fold after α-adrenoceptor blockade but had little or no effect on the relaxations induced by electrical stimulation at high frequencies. 4. In the presence of antagonists of α- and β-adrenoceptors, or adrenergic neurone blocking agents, or in veins taken from rabbits pretreated with reserpine, electrical stimulation elicited rapid relaxations which were greatest at 20-30 Hz. These relaxations were increased by veratrine and abolished by tetrodotoxin or by storing the vein for 9 days at 4° C. They were unaffected by antagonists of acetylcholine, or by dipyridamole. 5. Prostaglandins E1, E2 and F2α inhibited contractions elicited by electrical stimulation and noradrenaline, but in higher doses caused contractions themselves. 6. Nicotine (10-6-10-5 g/ml) relaxed the portal vein; higher concentrations elicited mixed inhibitory and excitatory effects. All these effects were abolished by tetrodotoxin, cocaine, hexamethonium or storage. The contractor effects were abolished by drugs or procedures that blocked adrenergic mechanisms. 7. The relaxations produced by nicotine in untreated preparations and in veins from rabbits pretreated with reserpine were mediated mainly by a non-adrenergic non-cholinergic nervous mechanism. Relaxations induced by nicotine in the presence of antagonists of a-adrenoceptors were only partially antagonized by antagonists of f3-adrenoceptors. 8. It was concluded that all the effects of nicotine and transmural stimulation were mediated by nerves. Part of the inhibitory effects was mediated by non-adrenergic, non-cholinergic nerves. PMID:4394338

Redistribution of Cav2.1 channels and calcium ions in nerve terminals following end-to-side neurorrhaphy: ionic imaging analysis by TOF-SIMS.

PubMed

Liu, Chiung-Hui; Chang, Hung-Ming; Tseng, To-Jung; Lan, Chyn-Tair; Chen, Li-You; Youn, Su-Chung; Lee, Jian-Jr; Mai, Fu-Der; Chou, Jui-Feng; Liao, Wen-Chieh

2016-11-01

The P/Q-type voltage-dependent calcium channel (Cav2.1) in the presynaptic membranes of motor nerve terminals plays an important role in regulating Ca 2+ transport, resulting in transmitter release within the nervous system. The recovery of Ca 2+ -dependent signal transduction on motor end plates (MEPs) and innervated muscle may directly reflect nerve regeneration following peripheral nerve injury. Although the functional significance of calcium channels and the levels of Ca 2+ signalling in nerve regeneration are well documented, little is known about calcium channel expression and its relation with the dynamic Ca 2+ ion distribution at regenerating MEPs. In the present study, end-to-side neurorrhaphy (ESN) was performed as an in vivo model of peripheral nerve injury. The distribution of Ca 2+ at regenerating MEPs following ESN was first detected by time-of-flight secondary ion mass spectrometry, and the specific localization and expression of Cav2.1 channels were examined by confocal microscopy and western blotting. Compared with other fundamental ions, such as Na + and K + , dramatic changes in the Ca 2+ distribution were detected along with the progression of MEP regeneration. The re-establishment of Ca 2+ distribution and intensity were correlated with the functional recovery of muscle in ESN rats. Furthermore, the re-clustering of Cav2.1 channels after ESN at the nerve terminals corresponded with changes in the Ca 2+ distribution. These results indicated that renewal of the Cav2.1 distribution within the presynaptic nerve terminals may be necessary for initiating a proper Ca 2+ influx and shortening the latency of muscle contraction during nerve regeneration.

Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage*

PubMed Central

Goth, Christoffer K.; Tuhkanen, Hanna E.; Khan, Hamayun; Lackman, Jarkko J.; Wang, Shengjun; Narimatsu, Yoshiki; Hansen, Lasse H.; Overall, Christopher M.; Clausen, Henrik; Schjoldager, Katrine T.; Petäjä-Repo, Ulla E.

2017-01-01

The β1-adrenergic receptor (β1AR) is a G protein-coupled receptor (GPCR) and the predominant adrenergic receptor subtype in the heart, where it mediates cardiac contractility and the force of contraction. Although it is the most important target for β-adrenergic antagonists, such as β-blockers, relatively little is yet known about its regulation. We have shown previously that β1AR undergoes constitutive and regulated N-terminal cleavage participating in receptor down-regulation and, moreover, that the receptor is modified by O-glycosylation. Here we demonstrate that the polypeptide GalNAc-transferase 2 (GalNAc-T2) specifically O-glycosylates β1AR at five residues in the extracellular N terminus, including the Ser-49 residue at the location of the common S49G single-nucleotide polymorphism. Using in vitro O-glycosylation and proteolytic cleavage assays, a cell line deficient in O-glycosylation, GalNAc-T-edited cell line model systems, and a GalNAc-T2 knock-out rat model, we show that GalNAc-T2 co-regulates the metalloproteinase-mediated limited proteolysis of β1AR. Furthermore, we demonstrate that impaired O-glycosylation and enhanced proteolysis lead to attenuated receptor signaling, because the maximal response elicited by the βAR agonist isoproterenol and its potency in a cAMP accumulation assay were decreased in HEK293 cells lacking GalNAc-T2. Our findings reveal, for the first time, a GPCR as a target for co-regulatory functions of site-specific O-glycosylation mediated by a unique GalNAc-T isoform. The results provide a new level of β1AR regulation that may open up possibilities for new therapeutic strategies for cardiovascular diseases. PMID:28167537

Morphology of presumptive rapidly adapting receptors in the rat bronchus.

PubMed Central

Kappagoda, C T; Skepper, J N; McNaughton, L; Siew, E E; Navaratnam, V

1990-01-01

The present investigation was undertaken in rats to determine whether sensory nerves exist in apposition to the bronchial microvessels which may function as rapidly adapting receptors (RAR). The primary and secondary bronchi on both sides were removed and processed for light and electron microscopy. Nerves were frequently found in relation to venules external to the muscle coat of bronchi. They comprised myelinated axons which ended individually as non-myelinated convoluted terminals enclosed within a loose capsule of attenuated cells. Serial sections showed that these terminals were not related to ganglion cells. Cervical vagal section and injection of HRP-WGA into the nodose ganglion provided corroborative evidence of the sensory nature of these terminals. Vagal section caused degenerative changes in the encapsulated nerve terminals in the bronchial walls and horseradish peroxidase labelling was demonstrable in such terminals. Moreover, immunocytochemical studies demonstrated the presence of calcitonin gene regulated peptide and substance P in these structures. It is suggested that they comprise the RAR. Encapsulated nerve terminals were not found in the epithelial layer, in the submucous coat or in the muscularis of bronchi. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 PMID:1691164

Effects of Oxaliplatin Treatment on the Myenteric Plexus Innervation and Glia in the Murine Distal Colon.

PubMed

Stojanovska, Vanesa; McQuade, Rachel M; Miller, Sarah; Nurgali, Kulmira

2018-05-01

Oxaliplatin (platinum-based chemotherapeutic agent) is a first-line treatment of colorectal malignancies; its use associates with peripheral neuropathies and gastrointestinal side effects. These gastrointestinal dysfunctions might be due to toxic effects of oxaliplatin on the intestinal innervation and glia. Male Balb/c mice received intraperitoneal injections of sterile water or oxaliplatin (3 mg/kg/d) triweekly for 2 weeks. Colon tissues were collected for immunohistochemical assessment at day 14. The density of sensory, adrenergic, and cholinergic nerve fibers labeled with calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), and vesicular acetylcholine transporter (VAChT), respectively, was assessed within the myenteric plexus of the distal colon. The number and proportion of excitatory neurons immunoreactive (IR) against choline acetyltransferase (ChAT) were counted, and the density of glial subpopulations was determined by using antibodies specific for glial fibrillary acidic protein (GFAP) and s100β protein. Oxaliplatin treatment induced significant reduction of sensory and adrenergic innervations, as well as the total number and proportion of ChAT-IR neurons, and GFAP-IR glia, but increased s100β expression within the myenteric plexus of the distal colon. Treatment with oxaliplatin significantly alters nerve fibers and glial cells in the colonic myenteric plexus, which could contribute to long-term gastrointestinal side effects following chemotherapeutic treatment.

Palisade endings are present in canine extraocular muscles and have a cholinergic phenotype

PubMed Central

RUNGALDIER, Stefanie; POMIKAL, Christine; STREICHER, Johannes; BLUMER, Roland

2016-01-01

Classical proprioceptors, like Golgi tendon organs and muscle spindles are absent in the extraocular muscles (EOMs) of most mammals. Instead, a nerve end organ was detected in the EOMs of each species including sheep, cats, rabbits, rats, monkeys, and man examined so far: the palisade ending. Until now no evidence appeared that palisade endings are present in canine EOMs. We analyzed dog EOMs by confocal laser scanning microscopy, 3D reconstruction, and transmission electron microscopy. In EOM wholemount preparations stained with antibodies against neurofilament and synaptophysin we found typical palisade endings. Nerve fibers coming from the muscle extended into the tendon. There, the nerve fibers turned 180° and returned to branch into preterminal axons which established nerve terminals around a single muscle fiber tip. Fine structural analyses revealed that each palisade ending in dog EOMs established nerve terminals on the tendon. In some palisade endings we found nerve terminals contacting the muscle fiber as well. Such neuromuscular contacts had a basal lamina in the synaptic cleft thereby resembling motor terminals. By using antibodies against choline acetyltransferase (ChAT) we proved that canine palisade endings are ChAT-immunoreactive. This study shows that palisade endings are present in canine EOMs. In line with prior findings in cat and monkey, palisade endings in dog have a cholinergic phenotype. PMID:19766165

Compartmentalized beta subunit distribution determines characteristics and ethanol sensitivity of somatic, dendritic, and terminal large-conductance calcium-activated potassium channels in the rat central nervous system.

PubMed

Wynne, P M; Puig, S I; Martin, G E; Treistman, S N

2009-06-01

Neurons are highly differentiated and polarized cells, whose various functions depend upon the compartmentalization of ion channels. The rat hypothalamic-neurohypophysial system (HNS), in which cell bodies and dendrites reside in the hypothalamus, physically separated from their nerve terminals in the neurohypophysis, provides a particularly powerful preparation in which to study the distribution and regional properties of ion channel proteins. Using electrophysiological and immunohistochemical techniques, we characterized the large-conductance calcium-activated potassium (BK) channel in each of the three primary compartments (soma, dendrite, and terminal) of HNS neurons. We found that dendritic BK channels, in common with somatic channels but in contrast to nerve terminal channels, are insensitive to iberiotoxin. Furthermore, analysis of dendritic BK channel gating kinetics indicates that they, like somatic channels, have fast activation kinetics, in contrast to the slow gating of terminal channels. Dendritic and somatic channels are also more sensitive to calcium and have a greater conductance than terminal channels. Finally, although terminal BK channels are highly potentiated by ethanol, somatic and dendritic channels are insensitive to the drug. The biophysical and pharmacological properties of somatic and dendritic versus nerve terminal channels are consistent with the characteristics of exogenously expressed alphabeta1 versus alphabeta4 channels, respectively. Therefore, one possible explanation for our findings is a selective distribution of auxiliary beta1 subunits to the somatic and dendritic compartments and beta4 to the terminal compartment. This hypothesis is supported immunohistochemically by the appearance of distinct punctate beta1 or beta4 channel clusters in the membrane of somatic and dendritic or nerve terminal compartments, respectively.

Increase of transcription factor EB (TFEB) and lysosomes in rat DRG neurons and their transportation to the central nerve terminal in dorsal horn after nerve injury.

PubMed

Jung, J; Uesugi, N; Jeong, N Y; Park, B S; Konishi, H; Kiyama, H

2016-01-28

In the spinal dorsal horn (DH), nerve injury activates microglia and induces neuropathic pain. Several studies clarified an involvement of adenosine triphosphate (ATP) in the microglial activation. However, the origin of ATP together with the release mechanism is unclear. Recent in vitro study revealed that an ATP marker, quinacrine, in lysosomes was released from neurite terminal of dorsal root ganglion (DRG) neurons to extracellular space via lysosomal exocytosis. Here, we demonstrate a possibility that the lysosomal ingredient including ATP released from DRG neurons by lysosomal-exocytosis is an additional source of the glial activation in DH after nerve injury. After rat L5 spinal nerve ligation (SNL), mRNA for transcription factor EB (TFEB), a transcription factor controlling lysosomal activation and exocytosis, was induced in the DRG. Simultaneously both lysosomal protein, LAMP1- and vesicular nuclear transporter (VNUT)-positive vesicles were increased in L5 DRG neurons and ipsilateral DH. The quinacrine staining in DH was increased and co-localized with LAMP1 immunoreactivity after nerve injury. In DH, LAMP1-positive vesicles were also co-localized with a peripheral nerve marker, Isolectin B4 (IB4) lectin. Injection of the adenovirus encoding mCherry-LAMP1 into DRG showed that mCherry-positive lysosomes are transported to the central nerve terminal in DH. These findings suggest that activation of lysosome synthesis including ATP packaging in DRG, the central transportation of the lysosome, and subsequent its exocytosis from the central nerve terminal of DRG neurons in response to nerve injury could be a partial mechanism for activation of microglia in DH. This lysosome-mediated microglia activation mechanism may provide another clue to control nociception and pain. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Noradrenergic System in Down Syndrome and Alzheimer's Disease A Target for Therapy.

PubMed

Phillips, Cristy; Fahimi, Atoossa; Das, Devsmita; Mojabi, Fatemeh S; Ponnusamy, Ravikumar; Salehi, Ahmad

2016-01-01

Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic terminals to the majority of brain regions, particularly those involved in cognitive function. Both Alzheimer's disease (AD) and Down syndrome (DS) are characterized by similar pathology including significant LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals has been linked to alterations in brain regions vital for cognition, mood, and executive function. While the mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are not fully understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology and cognitive decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission have undergone limited testing. Among those deployed to date are NE reuptake inhibitors, presynaptic α-adrenergic receptor antagonists, NE prodrugs, and β-adrenergic agonists. Here we examine alterations in the NE-ergic system in AD and DS and suggest that NE-ergic system rescue is a plausible treatment strategy for targeting cognitive decline in both disorders.

Prejunctional and postjunctional actions of heptanol and 18 beta-glycyrretinic acid in the rodent vas deferens.

PubMed

Rahman, Faisal; Manchanda, Rohit; Brain, Keith L

2009-06-15

Heptanol and 18 beta-glycyrrhetinic acid (18 beta GA) block gap junctions, but have other actions on transmitter release that have not been characterised. This study investigates the prejunctional and postjunctional effects of these compounds in guinea pig and mouse vas deferens using intracellular electrophysiological recording and confocal Ca(2+) imaging of sympathetic nerve terminals. In mice, heptanol (2 mM) reversibly decreased the amplitude of purinergic excitatory junction potentials (EJPs; 52+/-5%, P<0.05) while having little effect on spontaneous excitatory junction potentials (sEJPs). Heptanol (2 mM) reversibly abolished the nerve terminal Ca(2+) transient in 52% of terminals. 18 beta GA (10 microM) decreased the mean EJP amplitude, and increased input resistance in both mouse (137+/-17%, P<0.05) and guinea pig (354+/-50%, P<0.001) vas deferens indicating gap junction blockade. Further, 18 beta GA increased the sEJP frequency significantly in guinea pigs (by 71+/-25%, P<0.05) and in 5 out of 6 tissues in mice (19+/-3%, P<0.05). Moreover, 18 beta GA depolarised cells from both mice (11+/-1%, P<0.01) and guinea pigs (8+/-1%, P<0.005). Therefore, we conclude that heptanol (2 mM) decreases neurotransmitter release (given the decrease in EJP amplitude) by abolishing the nerve terminal action potential in a proportion of nerve terminals. 18 betaGA (10 microM) effectively blocks the gap junctions, but the increase in sEJP frequency suggests an additional prejunctional effect, which might involve the induction of spontaneous nerve terminal action potentials.

[Experimental studies for the improvement of facial nerve regeneration].

PubMed

Guntinas-Lichius, O; Angelov, D N

2008-02-01

Using a combination of the following, it is possible to investigate procedures to improve the morphological and functional regeneration of the facial nerve in animal models: 1) retrograde fluorescence tracing to analyse collateral axonal sprouting and the selectivity of reinnervation of the mimic musculature, 2) immunohistochemistry to analyse both the terminal axonal sprouting in the muscles and the axon reaction within the nucleus of the facial nerve, the peripheral nerve, and its environment, and 3) digital motion analysis of the muscles. To obtain good functional facial nerve regeneration, a reduction of terminal sprouting in the mimic musculature seems to be more important than a reduction of collateral sprouting at the lesion site. Promising strategies include acceleration of nerve regeneration, forced induced use of the paralysed face, mechanical stimulation of the face, and transplantation of nerve-growth-promoting olfactory epithelium at the lesion site.

Mechanisms of reflex bladder activation by pudendal afferents

PubMed Central

Woock, John P.; Yoo, Paul B.

2011-01-01

Activation of pudendal afferents can evoke bladder contraction or relaxation dependent on the frequency of stimulation, but the mechanisms of reflex bladder excitation evoked by pudendal afferent stimulation are unknown. The objective of this study was to determine the contributions of sympathetic and parasympathetic mechanisms to bladder contractions evoked by stimulation of the dorsal nerve of the penis (DNP) in α-chloralose anesthetized adult male cats. Bladder contractions were evoked by DNP stimulation only above a bladder volume threshold equal to 73 ± 12% of the distension-evoked reflex contraction volume threshold. Bilateral hypogastric nerve transection (to eliminate sympathetic innervation of the bladder) or administration of propranolol (a β-adrenergic antagonist) decreased the stimulation-evoked and distension-evoked volume thresholds by −25% to −39%. Neither hypogastric nerve transection nor propranolol affected contraction magnitude, and robust bladder contractions were still evoked by stimulation at volume thresholds below the distension-evoked volume threshold. As well, inhibition of distention-evoked reflex bladder contractions by 10 Hz stimulation of the DNP was preserved following bilateral hypogastric nerve transection. Administration of phentolamine (an α-adrenergic antagonist) increased stimulation-evoked and distension-evoked volume thresholds by 18%, but again, robust contractions were still evoked by stimulation at volumes below the distension-evoked threshold. These results indicate that sympathetic mechanisms contribute to establishing the volume dependence of reflex contractions but are not critical to the excitatory pudendal to bladder reflex. A strong correlation between the magnitude of stimulation-evoked bladder contractions and bladder volume supports that convergence of pelvic afferents and pudendal afferents is responsible for bladder excitation evoked by pudendal afferents. Further, abolition of stimulation-evoked bladder contractions following administration of hexamethonium bromide confirmed that contractions were generated by pelvic efferent activation via the pelvic ganglion. These findings indicate that pudendal afferent stimulation evokes bladder contractions through convergence with pelvic afferents to increase pelvic efferent activity. PMID:21068196

The nervus terminalis in the chick: a FMRFamide-immunoreactive and AChE-positive nerve.

PubMed

Wirsig-Wiechmann, C R

1990-07-16

The chick terminal nerve (TN) was examined by immunocytochemical and histochemical methods. Molluscan cardioexcitatory peptide-immunoreactive (FMRFamide-ir) and acetylcholinesterase (AChE)-positive TN perikarya and fibers were distributed along olfactory and trigeminal nerves. FMRFamide-ir TN fibers terminated in the olfactory lamina propria and epithelium and in ganglia along the rostroventral nasal septum. This initial description of several populations of avian TN neurons should provide the foundation for future developmental studies of this system.

Peripheral nerve hyperexcitability with preterminal nerve and neuromuscular junction remodeling is a hallmark of Schwartz-Jampel syndrome.

PubMed

Bauché, Stéphanie; Boerio, Delphine; Davoine, Claire-Sophie; Bernard, Véronique; Stum, Morgane; Bureau, Cécile; Fardeau, Michel; Romero, Norma Beatriz; Fontaine, Bertrand; Koenig, Jeanine; Hantaï, Daniel; Gueguen, Antoine; Fournier, Emmanuel; Eymard, Bruno; Nicole, Sophie

2013-12-01

Schwartz-Jampel syndrome (SJS) is a recessive disorder with muscle hyperactivity that results from hypomorphic mutations in the perlecan gene, a basement membrane proteoglycan. Analyses done on a mouse model have suggested that SJS is a congenital form of distal peripheral nerve hyperexcitability resulting from synaptic acetylcholinesterase deficiency, nerve terminal instability with preterminal amyelination, and subtle peripheral nerve changes. We investigated one adult patient with SJS to study this statement in humans. Perlecan deficiency due to hypomorphic mutations was observed in the patient biological samples. Electroneuromyography showed normal nerve conduction, neuromuscular transmission, and compound nerve action potentials while multiple measures of peripheral nerve excitability along the nerve trunk did not detect changes. Needle electromyography detected complex repetitive discharges without any evidence for neuromuscular transmission failure. The study of muscle biopsies containing neuromuscular junctions showed well-formed post-synaptic element, synaptic acetylcholinesterase deficiency, denervation of synaptic gutters with reinnervation by terminal sprouting, and long nonmyelinated preterminal nerve segments. These data support the notion of peripheral nerve hyperexcitability in SJS, which would originate distally from synergistic actions of peripheral nerve and neuromuscular junction changes as a result of perlecan deficiency. Copyright © 2013 Elsevier B.V. All rights reserved.

[A preliminary study on the role of substance P in histamine-nasal-spray-induced allergic conjunctivitis in guinea pigs].

PubMed

Li, Tong; Zhao, Changqing

2015-10-01

To investigate the effect of the non adrenergic non cholinergic nerve (NANC) and substance P (SP) in allergic rhinoconjunctivitis by observing histamine nasal provocation induced conjunctivitis in guinea pigs. Forty male guinea pigs were randomly divided into five groups with each group consisting of eight guinea pigs. All anesthetized guinea pigs were exposed either to histamine (0.2%, 5 µl) (group B~E) or saline (5 µl, group A) via unilateral nostril. No pretreatment was done in group A and B while pretreatment was done in groups C~E through injection into the unilateral common carotid artery with cholinergic nerve inhibitor (atropine, 1 mg/kg, group C), cholinergic nerve inhibitor plus adrenergic nerve inhibitors (atropine, 1 mg/kg, phentolamine, 1 mg/kg plus Esmolol, 1 mg/kg, group D) and cholinergic nerve inhibitor, adrenergic nerve inhibitors plus SP receptor antagonist (the same treatment with group D plus D-SP 10(-6) mol/L, 1 µl/g, group E), respectively. To assess the ipsilateral conjunctival inflammatory reaction, conjunctiva leakage with Evans blue dye assessments and HE staining of conjunctival tissues were performed. The SP expression in ipsilateral conjunctival tissue in different groups of guinea pigs were assessed by immunofluorescence and RT-PCR. The activity of eosinophils was assessed by eosinophil major basic protein 1 (MBP1) with RT-PCR, meanwhile, the activity of mast cells was assessed by tryptase with RT-PCR. SPSS 17.0 software was used to analyze the data. At 30 min after nasal application of histamine, ipsilateral conjunctivitis was successfully induced as shown by the change of conjunctiva leakage and histology. The content of Evans blue in ipsilateral conjunctival tissue of group A~E was (13.78 ± 2.48), (29.62 ± 3.31), (19.03 ± 1.47), (18.42 ± 2.52), (14.83 ± 2.14) µg/ml, respectively. There was statistically significant difference between group A and B (t = -10.66, P < 0.05), group B and C (t = 7.97, P < 0.05), group C and E (t = 4.51, P < 0.05). PT-PCR assays showed the relative expression of SP mRNA in ipsilateral conjunctival tissues of group A~E was (1.00 ± 0.04), (1.61 ± 0.09), (1.26 ± 0.03), (1.27 ± 0.06), (1.08 ± 0.05), respectively. There was statistically significant difference between group A and B (t = -22.04, P < 0.05), group B and C (t = 12.93, P < 0.05), group C and E (t = 11.85, P < 0.05). The expression of tryptase of ipsilateral conjunctiva was (1.00 ± 0.01), (1.01 ± 0.05), (1.02 ± 0.17), (1.00 ± 0.14), (1.01 ± 0.20), and the expression of MBP1 was (1.00 ± 0.03), (1.02 ± 0.15), (0.94 ± 0.08), (1.01 ± 0.07), (0.98 ± 0.13) in A~E groups. There was not statistically significant difference among five groups (F value was 1.93, 0.57, both P > 0.05). Histamine nasal provocation induced allergic inflammatory response of ipsilateral conjunctiva in guinea pigs. Neural factors including NANC nerves and its medium SP participated this nose-ocular reflex process. These data help to develop a more scientific clinical treatment strategy.

Neuropeptides and nitric oxide synthase in the gill and the air-breathing organs of fishes.

PubMed

Zaccone, Giacomo; Mauceri, Angela; Fasulo, Salvatore

2006-05-01

Anatomical and histochemical studies have demonstrated that the bulk of autonomic neurotransmission in fish gill is attributed to cholinergic and adrenergic mechanisms (Nilsson. 1984. In: Hoar WS, Randall DJ, editors. Fish physiology, Vol. XA. Orlando: Academic Press. p 185-227; Donald. 1998. In: Evans DH, editor. The physiology of fishes, 2nd edition. Boca Raton: CRC Press. p 407-439). In many tissues, blockade of adrenergic and cholinergic transmission results in residual responses to nerve stimulation, which are termed NonAdrenergic, NonCholinergic (NANC). The discovery of nitric oxide (NO) has provided a basis for explaining many examples of NANC transmissions with accumulated physiological and pharmacological data indicating its function as a primary NANC transmitter. Little is known about the NANC neurotransmission, and studies on neuropeptides and NOS (Nitric Oxide Synthase) are very fragmentary in the gill and the air-breathing organs of fishes. Knowledge of the distribution of nerves and effects of perfusing agonists may help to understand the mechanisms of perfusion regulation in the gill (Olson. 2002. J Exp Zool 293:214-231). Air breathing as a mechanism for acquiring oxygen has evolved independently in several groups of fishes, necessitating modifications of the organs responsible for the exchange of gases. Aquatic hypoxia in freshwaters has been probably the more important selective force in the evolution of air breathing in vertebrates. Fishes respire with gills that are complex structures with many different effectors and potential control systems. Autonomic innervation of the gill has received considerable attention. An excellent review on branchial innervation includes Sundin and Nilsson's (2002. J Exp Zool 293:232-248) with an emphasis on the anatomy and basic functioning of afferent and efferent fibers of the branchial nerves. The chapters by Evans (2002. J Exp Zool 293:336-347) and Olson (2002) provide new challenges about a variety of neurocrine, endocrine, paracrine and autocrine signals that modulate gill perfusion and ionic transport. The development of the immunohistochemical techniques has led to a new phase of experimentation and to information mainly related to gills rather than air-breathing organs of fishes. During the last few years, identification of new molecules as autonomic neurotransmitters, monoamines and NO, and of their multiple roles as cotransmitters, has reshaped our knowledge of the mechanisms of autonomic regulation of various functions in the organs of teleosts (Donald, '98).NO acts as neurotransmitter and is widely distributed in the nerves and the neuroepithelial cells of the gill, the nerves of visceral muscles of the lung of polypterids, the vascular endothelial cells in the air sac of Heteropneustes fossilis and the respiratory epithelium in the swimbladder of the catfish Pangasius hypophthalmus. In addition, 5-HT, enkephalins and some neuropeptides, such as VIP and PACAP, seem to be NANC transmitter candidates in the fish gill and polypterid lung. The origin and function of NANC nerves in the lung of air-breathing fishes await investigation. Several mechanisms have developed in the Vertebrates to control the flow of blood to respiratory organs. These mechanisms include a local production of vasoactive substances, a release of endocrine hormones into the circulation and neuronal mechanisms. Air breathers may be expected to have different control mechanisms compared with fully aquatic fishes. Therefore, we need to know the distribution and function of autonomic nerves in the air-breathing organs of the fishes.

Integration of Synaptic Vesicle Cargo Retrieval with Endocytosis at Central Nerve Terminals

PubMed Central

Cousin, Michael A.

2017-01-01

Central nerve terminals contain a limited number of synaptic vesicles (SVs) which mediate the essential process of neurotransmitter release during their activity-dependent fusion. The rapid and accurate formation of new SVs with the appropriate cargo is essential to maintain neurotransmission in mammalian brain. Generating SVs containing the correct SV cargo with the appropriate stoichiometry is a significant challenge, especially when multiple modes of endocytosis exist in central nerve terminals, which occur at different locations within the nerve terminals. These endocytosis modes include ultrafast endocytosis, clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) which are triggered by specific patterns of neuronal activity. This review article will assess the evidence for the role of classical adaptor protein complexes in SV retrieval, discuss the role of monomeric adaptors and how interactions between specific SV cargoes can facilitate retrieval. In addition it will consider the evidence for preassembled plasma membrane cargo complexes and their role in facilitating these endocytosis modes. Finally it will present a unifying model for cargo retrieval at the presynapse, which integrates endocytosis modes in time and space. PMID:28824381

Effect of O-methyl-β-cyclodextrin-modified magnetic nanoparticles on the uptake and extracellular level of l-glutamate in brain nerve terminals.

PubMed

Horák, Daniel; Beneš, Milan; Procházková, Zuzana; Trchová, Miroslava; Borysov, Arsenii; Pastukhov, Artem; Paliienko, Konstantin; Borisova, Tatiana

2017-01-01

Changes in cholesterol concentration in the plasma membrane of presynaptic nerve terminals nonspecifically modulate glutamate transport and homeostasis in the central nervous system. Reduction of the cholesterol content in isolated rat brain nerve terminals (synaptosomes) using cholesterol-depleting agents decreases the glutamate uptake and increases the extracellular level of glutamate in nerve terminals. Extraction of cholesterol from the plasma membrane and its further removal from the synaptosomes by external magnetic field can be achieved by means of magnetic nanoparticles with immobilized cholesterol-depleting agent such as O-methyl-β-cyclodextrin (MCD). A simple approach is developed for preparation of maghemite (γ-Fe 2 O 3 ) nanoparticles containing chemically bonded MCD. The method is based on preparation of a silanization agent containing MCD. It is synthesized by the reaction of triethoxy(3-isocyanatopropyl)silane with MCD. Base-catalyzed silanization of superparamagnetic γ-Fe 2 O 3 provides a relatively stable colloid product containing 48μmol of MCDg -1 . MCD-modified γ-Fe 2 O 3 nanoparticles decrease the initial rate of the uptake and accumulation of l-[ 14 C]glutamate and increase the extracellular l-[ 14 C]glutamate level in the preparation of nerve terminals. The effect of MCD-immobilized nanoparticles is the same as that of MCD solution; moreover, magnetic manipulation of the nanoparticles enables removal of bonded cholesterol. Copyright © 2016 Elsevier B.V. All rights reserved.

Lacosamide diminishes dryness-induced hyperexcitability of corneal cold sensitive nerve terminals.

PubMed

Kovács, Illés; Dienes, Lóránt; Perényi, Kristóf; Quirce, Susana; Luna, Carolina; Mizerska, Kamila; Acosta, M Carmen; Belmonte, Carlos; Gallar, Juana

2016-09-15

Lacosamide is an anti-epileptic drug that is also used for the treatment of painful diabetic neuropathy acting through voltage-gated sodium channels. The aim of this work was to evaluate the effects of acute application of lacosamide on the electrical activity of corneal cold nerve terminals in lacrimo-deficient guinea pigs. Four weeks after unilateral surgical removal of the main lachrimal gland in guinea pigs, corneas were excised and superfused in vitro at 34°C for extracellular electrophysiological recording of nerve terminal impulse activity of cold thermosensitive nerve terminals. The characteristics of the spontaneous and the stimulus-evoked (cooling ramps from 34°C to 15°C) activity before and in presence of lacosamide 100µM and lidocaine 100µM were compared. Cold nerve terminals (n=34) recorded from dry eye corneas showed significantly enhanced spontaneous activity (8.0±1.1 vs. 5.2±0.7imp/s; P<0.05) and cold response (21.2±1.7 vs. 16.8±1.3imp/s; P<0.05) as well as reduced cold threshold (1.5±0.1 vs. 2.8±0.2 Δ°C; P<0.05) to cooling ramps compared to terminals (n=58) from control animals. Both lacosamide and lidocaine decreased spontaneous activity and peak response to cooling ramps significantly (P<0.05). Temperature threshold was increased by the addition of lidocaine (P<0.05) but not lacosamide (P>0.05) to the irrigation fluid. In summary, the application of lacosamide results in a significant decrease of the augmented spontaneous activity and responsiveness to cold of corneal sensory nerves from tear-deficient animals. Based on these promising results we speculate that lacosamide might be used to reduce the hyperexcitability of corneal cold receptors caused by prolonged ocular surface dryness due to hyposecretory or evaporative dry eye disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Quantitative monitoring of activity-dependent bulk endocytosis of synaptic vesicle membrane by fluorescent dextran imaging

PubMed Central

Clayton, Emma Louise; Cousin, Michael Alan

2012-01-01

Activity-dependent bulk endocytosis (ADBE) is the dominant synaptic vesicle (SV) retrieval mode in central nerve terminals during periods of intense neuronal activity. Despite this fact there are very few real time assays that report the activity of this critical SV retrieval mode. In this paper we report a simple and quantitative assay of ADBE using uptake of large flourescent dextrans as fluid phase markers. We show that almost all dextran uptake occurs in nerve terminals, using co-localisation with the fluorescent probe FM1-43. We also demonstrate that accumulated dextran cannot be unloaded by neuronal stimulation, indicating its specific loading into bulk endosomes and not SVs. Quantification of dextran uptake was achieved by using thresholding analysis to count the number of loaded nerve terminals, since monitoring the average fluorescence intensity of these nerve terminals did not accurately report the extent of ADBE. Using this analysis we showed that dextran uptake occurs very soon after stimulation and that it does not persist when stimulation terminates. Thus we have devised a simple and quantitative method to monitor ADBE in living neurones, which will be ideal for real time screening of small molecule inhibitors of this key SV retrieval mode. PMID:19766140

Independent inputs by VGLUT2- and VGLUT3-positive glutamatergic terminals onto rat sympathetic preganglionic neurons.

PubMed

Nakamura, Kazuhiro; Wu, Sheng-Xi; Fujiyama, Fumino; Okamoto, Keiko; Hioki, Hiroyuki; Kaneko, Takeshi

2004-03-01

To characterize glutamatergic axon terminals onto sympathetic preganglionic neurons (SPNs), we visualized immunohistochemically three vesicular glutamate transporters (VGLUTs) in the intermediolateral cell column (IML) of rat thoracic spinal cord. VGLUT2 and VGLUT3 immunoreactivities but not VGLUT1 immunoreactivity were distributed in the IML and found in terminals making asymmetric synapses and apposed to dendrites immunopositive for choline acetyltransferase, an SPN marker. VGLUT2 and VGLUT3 immunoreactivities were not co-localized with each other. A population of VGLUT2-immunoreactive but not VGLUT3-immunoreactive terminals were adrenergic or noradrenergic. Some of VGLUT3-immunoreactive but not VGLUT2-immunoreactive terminals contained serotonin. These results indicate at least two independent glutamatergic terminal populations, which include a distinct monoaminergic subpopulation, making excitatory inputs onto SPNs. Copyright 2004 Lippincott Williams & Wilkins

Spinal α2-adrenergic and muscarinic receptors and the NO release cascade mediate supraspinally produced effectiveness of gabapentin at decreasing mechanical hypersensitivity in mice after partial nerve injury

PubMed Central

Takasu, Keiko; Honda, Motoko; Ono, Hideki; Tanabe, Mitsuo

2006-01-01

After partial nerve injury, the central analgesic effect of systemically administered gabapentin is mediated by both supraspinal and spinal actions. We further evaluate the mechanisms related to the supraspinally mediated analgesic actions of gabapentin involving the descending noradrenergic system. Intracerebroventricularly (i.c.v.) administered gabapentin (100 μg) decreased thermal and mechanical hypersensitivity in a murine chronic pain model that was prepared by partial ligation of the sciatic nerve. These effects were abolished by intrathecal (i.t.) injection of either yohimbine (3 μg) or idazoxan (3 μg), α2-adrenergic receptor antagonists. Pretreatment with atropine (0.3 mg kg−1, i.p. or 0.1 μg, i.t.), a muscarinic receptor antagonist, completely suppressed the effect of i.c.v.-injected gabapentin on mechanical hypersensitivity, whereas its effect on thermal hypersensitivity remained unchanged. Similar effects were obtained with pirenzepine (0.1 μg, i.t.), a selective M1-muscarinic receptor antagonist, but not with methoctramine (0.1 and 0.3 μg, i.t.), a selective M2-muscarinic receptor antagonist. The cholinesterase inhibitor neostigmine (0.3 ng, i.t.) potentiated only the analgesic effect of i.c.v. gabapentin on mechanical hypersensitivity, confirming spinal acetylcholine release downstream of the supraspinal action of gabapentin. Moreover, the effect of i.c.v. gabapentin on mechanical but not thermal hypersensitivity was reduced by i.t. injection of L-NAME (3 μg) or L-NMMA (10 μg), both of which are nitric oxide (NO) synthase inhibitors. Systemically administered naloxone (10 mg kg−1, i.p.), an opioid receptor antagonist, failed to suppress the analgesic actions of i.c.v. gabapentin, indicating that opioid receptors are not involved in activation of the descending noradrenergic system by gabapentin. Thus, the supraspinally mediated effect of gabapentin on mechanical hypersensitivity involves activation of spinal α2-adrenergic receptors followed by muscarinic receptors (most likely M1) and the NO cascade. In contrast, the effect of supraspinal gabapentin on thermal hypersensitivity is independent of the spinal cholinergic–NO system. PMID:16582934

The 'glial' glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings.

PubMed

Suchak, Sachin K; Baloyianni, Nicoletta V; Perkinton, Michael S; Williams, Robert J; Meldrum, Brian S; Rattray, Marcus

2003-02-01

The excitatory amino acid transporters (EAAT) removes neurotransmitters glutamate and aspartate from the synaptic cleft. Most CNS glutamate uptake is mediated by EAAT2 into glia, though nerve terminals show evidence for uptake, through an unknown transporter. Reverse-transcriptase PCR identified the expression of EAAT1, EAAT2, EAAT3 and EAAT4 mRNAs in primary cultures of mouse cortical or striatal neurones. We have used synaptosomes and glial plasmalemmal vesicles (GPV) from adult mouse and rat CNS to identify the nerve terminal transporter. Western blotting showed detectable levels of the transporters EAAT1 (GLAST) and EAAT2 (Glt-1) in both synaptosomes and GPVs. Uptake of [3H]D-aspartate or [3H]L-glutamate into these preparations revealed sodium-dependent uptake in GPV and synaptosomes which was inhibited by a range of EAAT blockers: dihydrokainate, serine-o-sulfate, l-trans-2,4-pyrrolidine dicarboxylate (PDC) (+/-)-threo-3-methylglutamate and (2S,4R )-4-methylglutamate. The IC50 values found for these compounds suggested functional expression of the 'glial, transporter, EAAT2 in nerve terminals. Additionally blockade of the majority EAAT2 uptake sites with 100 micro m dihydrokainate, failed to unmask any functional non-EAAT2 uptake sites. The data presented in this study indicate that EAAT2 is the predominant nerve terminal glutamate transporter in the adult rodent CNS.

Palisade endings are present in canine extraocular muscles and have a cholinergic phenotype.

PubMed

Rungaldier, Stefanie; Pomikal, Christine; Streicher, Johannes; Blumer, Roland

2009-11-20

Classical proprioceptors, like Golgi tendon organs and muscle spindles are absent in the extraocular muscles (EOMs) of most mammals. Instead, a nerve end organ was detected in the EOMs of each species including sheep, cat, rabbit, rat, monkey, and human examined so far: the palisade ending. Until now no clear evidence appeared that palisade endings are also present in canine EOMs. Here, we analyzed dog EOMs by confocal laser scanning microscopy, 3D reconstruction, and transmission electron microscopy. In EOM wholemount preparations stained with antibodies against neurofilament and synaptophysin we could demonstrate typical palisade endings. Nerve fibers coming from the muscle extend into the tendon. There, the nerve fibers turn 180 degrees and return to branch into preterminal axons which establish nerve terminals around a single muscle fiber tip. Fine structural analysis revealed that each palisade ending in dog EOMs establish nerve terminals on the tendon. In some palisade endings we found nerve terminals contacting the muscle fiber as well. Such neuromuscular contacts have a basal lamina in the synaptic cleft. By using an antibody against choline acetyltransferase (ChAT) we proved that canine palisade endings are ChAT-immunoreactive. This study shows that palisade endings are present in canine EOMs. In line with prior findings in cat and monkey, palisade endings in dog have a cholinergic phenotype.

Renal dopamine containing nerves. What is their functional significance?

PubMed

DiBona, G F

1990-06-01

Biochemical and morphological studies indicate that there are nerves within the kidney that contain dopamine and that various structures within the kidney contain dopamine receptors. However, the functional significance of these renal dopamine containing nerves in relation to renal dopamine receptors is unknown. The functional significance could be defined by demonstrating that an alteration in one or more renal functions occurring in response to reflex or electrical activation of efferent renal nerves is dependent on release of dopamine as the neurotransmitter from the renal nerve terminals acting on renal dopamine receptors. Thus, the hypothesis becomes: reflex or electrical activation of efferent renal nerves causes alterations in renal function (eg, renal blood flow, water and solute handling) that are inhibited by specific and selective dopamine receptor antagonists. As reviewed herein, the published experimental data do not support the hypothesis. Therefore, the view that alterations in one or more renal functions occurring in response to reflex or electrical activation of efferent renal nerves are dependent on release of dopamine as the neurotransmitter from the renal nerve terminals acting on renal dopamine receptors remains unproven.

Type-7 metabotropic glutamate receptors negatively regulate α1-adrenergic receptor signalling.

PubMed

Iacovelli, Luisa; Di Menna, Luisa; Peterlik, Daniel; Stangl, Christina; Orlando, Rosamaria; Molinaro, Gemma; De Blasi, Antonio; Bruno, Valeria; Battaglia, Giuseppe; Flor, Peter J; Uschold-Schmidt, Nicole; Nicoletti, Ferdinando

2017-02-01

We studied the interaction between mGlu7 and α 1 -adrenergic receptors in heterologous expression systems, brain slices, and living animals. L-2-Amino-4-phosphonobutanoate (L-AP4), and l-serine-O-phosphate (L-SOP), which activate group III mGlu receptors, restrained the stimulation of polyphosphoinositide (PI) hydrolysis induced by the α 1 -adrenergic receptor agonist, phenylephrine, in HEK 293 cells co-expressing α 1 -adrenergic and mGlu7 receptors. The inibitory action of L-AP4 was abrogated by (i) the mGlu7 receptor antagonist, XAP044; (ii) the C-terminal portion of type-2 G protein coupled receptor kinase; and (iii) the MAP kinase inhibitors, UO126 and PD98059. This suggests that the functional interaction between mGlu7 and α 1 -adrenergic receptors was mediated by the βγ-subunits of the G i protein and required the activation of the MAP kinase pathway. Remarkably, activation of neither mGlu2 nor mGlu4 receptors reduced α 1 -adrenergic receptor-mediated PI hydrolysis. In mouse cortical slices, both L-AP4 and L-SOP were able to attenuate norepinephrine- and phenylephrine-stimulated PI hydrolysis at concentrations consistent with the activation of mGlu7 receptors. L-AP4 failed to affect norepinephrine-stimulated PI hydrolysis in cortical slices from mGlu7 -/- mice, but retained its inhibitory activity in slices from mGlu4 -/- mice. At behavioural level, i.c.v. injection of phenylephrine produced antidepressant-like effects in the forced swim test. The action of phenylephrine was attenuated by L-SOP, which was inactive per se. Finally, both phenylephrine and L-SOP increased corticosterone levels in mice, but the increase was halved when the two drugs were administered in combination. Our data demonstrate that α 1 -adrenergic and mGlu7 receptors functionally interact and suggest that this interaction might be targeted in the treatment of stress-related disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Non-adrenergic, non-cholinergic, non-purinergic contractions of the urothelium/lamina propria of the pig bladder.

PubMed

Moro, C; Chess-Williams, R

2012-10-01

Acetylcholine, and to a lesser extent ATP, mediates neurogenic contractions of bladder smooth muscle. Recently, the urothelium and lamina propria have also been shown to have contractile properties, but the neurotransmitters involved in mediating responses to nerve stimulation have not been investigated. Isolated strips of porcine urothelium with lamina propria were electrically field stimulated and contractions recorded. Drugs interfering with neurotransmission were then employed to identify which neurotransmitters mediated responses. Strips of urothelium/lamina propria developed spontaneous contractions with a frequency of 3.5±0.1 cycles min⁻¹ and amplitude of 0.84±0.06 g. Electrical field stimulation at 5, 10, and 20 Hz resulted in frequency-related contractions (1.13±0.36 g, 1.59±0.46 g and 2.20±0.53 g, respectively, n=13), and these were reduced in the presence of tetrodotoxin (1 μm) by 77±20% at 5 Hz, 79±7% at 10 Hz and 74±12% at 20 Hz (all P<0.01), indicating they were predominantly neurogenic in nature. Neither the muscarinic antagonist atropine (10 μm), the adrenergic neurone blocker guanethidine (10 μm) nor desensitization of the purinergic receptors with α,β-methylene ATP (10 μm) affected the contractile amplitude. Similarly, responses were not affected by the nitric oxide synthase inhibitor L-NNA (100 μm) or drugs that interfere with peptide neurotransmission (capsaicin, NK2 antagonist GR159897, protease inhibitors). In conclusion, electrical depolarization of the nerves present in the porcine urothelium/lamina propria results in frequency-dependent contractions, which are predominantly neurogenic in nature. These contractions are resistant to drugs that inhibit the adrenergic, cholinergic and purinergic systems. The neurotransmitter involved in the responses of this tissue is therefore unknown but does not appear to be a peptide. © 2012 Blackwell Publishing Ltd.

Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage.

PubMed

Goth, Christoffer K; Tuhkanen, Hanna E; Khan, Hamayun; Lackman, Jarkko J; Wang, Shengjun; Narimatsu, Yoshiki; Hansen, Lasse H; Overall, Christopher M; Clausen, Henrik; Schjoldager, Katrine T; Petäjä-Repo, Ulla E

2017-03-17

The β 1 -adrenergic receptor (β 1 AR) is a G protein-coupled receptor (GPCR) and the predominant adrenergic receptor subtype in the heart, where it mediates cardiac contractility and the force of contraction. Although it is the most important target for β-adrenergic antagonists, such as β-blockers, relatively little is yet known about its regulation. We have shown previously that β 1 AR undergoes constitutive and regulated N-terminal cleavage participating in receptor down-regulation and, moreover, that the receptor is modified by O -glycosylation. Here we demonstrate that the polypeptide GalNAc-transferase 2 (GalNAc-T2) specifically O -glycosylates β 1 AR at five residues in the extracellular N terminus, including the Ser-49 residue at the location of the common S49G single-nucleotide polymorphism. Using in vitro O -glycosylation and proteolytic cleavage assays, a cell line deficient in O -glycosylation, GalNAc-T-edited cell line model systems, and a GalNAc-T2 knock-out rat model, we show that GalNAc-T2 co-regulates the metalloproteinase-mediated limited proteolysis of β 1 AR. Furthermore, we demonstrate that impaired O -glycosylation and enhanced proteolysis lead to attenuated receptor signaling, because the maximal response elicited by the βAR agonist isoproterenol and its potency in a cAMP accumulation assay were decreased in HEK293 cells lacking GalNAc-T2. Our findings reveal, for the first time, a GPCR as a target for co-regulatory functions of site-specific O -glycosylation mediated by a unique GalNAc-T isoform. The results provide a new level of β 1 AR regulation that may open up possibilities for new therapeutic strategies for cardiovascular diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Human Lymphatic Mesenteric Vessels: Morphology and Possible Function of Aminergic and NPY-ergic Nerve Fibers.

PubMed

D'Andrea, Vito; Panarese, Alessandra; Taurone, Samanta; Coppola, Luigi; Cavallotti, Carlo; Artico, Marco

2015-09-01

The lymphatic vessels have been studied in different organs from a morphological to a clinical point of view. Nevertheless, the knowledge of the catecholaminergic control of the lymphatic circulation is still incomplete. The aim of this work is to study the presence and distribution of the catecholaminergic and NPY-ergic nerve fibers in the whole wall of the human mesenteric lymphatic vessels in order to obtain knowledge about their morphology and functional significance. The following experimental procedures were performed: 1) drawing of tissue containing lymphatic vessels; 2) cutting of tissue; 3) staining of tissue; 4) staining of nerve fibers; 5) histofluorescence microscopy for the staining of catecholaminergic nerve fibers; 6) staining of neuropeptide Y like-immune reactivity; 7) biochemical assay of proteins; 8) measurement of noradrenaline; 9) quantitative analysis of images; 10) statistical analysis of data. Numerous nerve fibers run in the wall of lymphatic vessels. Many of them are catecholaminergic in nature. Some nerve fibers are NPY-positive. The biochemical results on noradrenaline amounts are in agreement with morphological results on catecholaminergic nerve fibers. Moreover, the morphometric results, obtained by the quantitative analysis of images and the subsequent statistical analysis of data, confirm all our morphological and biochemical data. The knowledge of the physiological or pathological mechanism regulating the functions of the lymphatic system is incomplete. Nevertheless the catecholaminergic nerve fibers of the human mesenteric lymphatic vessels come from the adrenergic periarterial plexuses of the mesenterial arterial bed. NPY-ergic nerve fibers may modulate the microcirculatory mesenterial bed in different pathological conditions.

Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields

PubMed Central

Lucas, Daniel; Bruns, Ingmar; Battista, Michela; Mendez-Ferrer, Simon; Magnon, Claire; Kunisaki, Yuya

2012-01-01

The mechanisms mediating hematopoietic stem and progenitor cell (HSPC) mobilization by G-CSF are complex. We have found previously that G-CSF–enforced mobilization is controlled by peripheral sympathetic nerves via norepinephrine (NE) signaling. In the present study, we show that G-CSF likely alters sympathetic tone directly and that methods to increase adrenergic activity in the BM microenvironment enhance progenitor mobilization. Peripheral sympathetic nerve neurons express the G-CSF receptor and ex vivo stimulation of peripheral sympathetic nerve neurons with G-CSF reduced NE reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability. Based on these data, we investigated the NE reuptake inhibitor desipramine in HSPC mobilization. Whereas desipramine did not by itself elicit circulating HSPCs, it increased G-CSF–triggered mobilization efficiency significantly and rescued mobilization in a model mimicking “poor mobilizers.” Therefore, these data suggest that blockade of NE reuptake may be a novel therapeutic target to increase stem cell yield in patients. PMID:22422821

Extralaryngeal division of the recurrent laryngeal nerve: a new description for the inferior laryngeal nerve.

PubMed

Yalcin, Bulent; Tunali, Selcuk; Ozan, Hasan

2008-05-01

Extralaryngeal division of the recurrent laryngeal nerve was contradictory in the literature. We aimed to investigate extralaryngeal division of the nerve, and also propose a new description for the inferior laryngeal nerve. Sixty specimens (120 sides) were examined for this project, including 41 men and 19 women cadavers between the ages of 40 and 89 years at death. In one right side, terminal segment of the nerve gave off many small branches surrounding the inferior thyroid artery then reaching the larynx, trachea, thyroid gland and esophagus. In eight sides, terminal segment of the nerve had no extralaryngeal division and entered the larynx as a single trunk. In 110 sides, the nerve had extralaryngeal division. One hundred and three nerves had two laryngeal and one to three extralaryngeal branches. Two types were described in this group. In type I (66 nerves), both branches arose from the same level of nerve. Type I had two subtypes: type Ia, the origin of the branches was just below the inferior constrictor muscle; type Ib, the origin of the branches was 15-35 mm below the muscle. In type II (37 nerves), the laryngeal branches arose just 3-5 mm above the extralaryngeal branches. We observed that the laryngeal and extralaryngeal branches arose generally from the same point of the recurrent laryngeal nerve. The inferior laryngeal nerve is thus very short, or even nonexistent. Therefore, we suggest that if the term "superior laryngeal nerve" is a given, standard, and accepted term, then the term "inferior laryngeal nerve" should also be accepted instead of the term "recurrent laryngeal nerve."

Surgical Approaches to Facial Nerve Deficits

PubMed Central

Birgfeld, Craig; Neligan, Peter

2011-01-01

The facial nerve is one of the most commonly injured cranial nerves. Once injured, the effects on form, function, and psyche are profound. We review the anatomy of the facial nerve from the brain stem to its terminal branches. We also discuss the physical exam findings of facial nerve injury at various levels. Finally, we describe various reconstructive options for reanimating the face and restoring both form and function. PMID:22451822

Occlusion of carotid artery and hypergravity loading of animals caused similar effects on L-[14C]glutamate uptake in rat brain nerve terminals

NASA Astrophysics Data System (ADS)

Borisova, Tatiana; Sivko, Roman; Krisanova, Natalia

Changes in sodium-dependent L-[14C]glutamate uptake in rat brain nerve terminals was com-paratively analysed after hypergravity loading of animals (centrifugation of rats in special con-tainers at 10 G for 1 hour) and unilateral occlusion of carotid artery (20 min). The initial velocity of L-[14C]glutamate uptake was decreased from 2.5 ± 0.2 nmol x min-1 x mg-1 of proteins to 2.05 ± 0.1 nmol x min-1 x mg-1 of proteins after hypergravity and after occlusion -up to 2.25 ± 0.1 nmol x min-1 x mg-1 of proteins. Recently, we have shown that a decrease in L-[14C]glutamate uptake was at least partially caused by the redaction in the membrane potential of nerve terminals and the proton gradient of synaptic vesicles. These parameters were analysed after unilateral occlusion of carotid artery, where one brain hemisphere was used as a control, whereas the second one as subjected to ischemic/hypoxic conditions. Similarly with hypergravity, we revealed a decrease in the membrane potential of nerve terminals by ˜ 10 % and a reduction of the proton gradient of synaptic vesicles by ˜ 5 % after occlusion of carotid artery. Thus, a decrease in the activity of glutamate transporters after hypergrav-ity and unilateral occlusion of carotid artery was at least partially caused by changes in the membrane potential of nerve terminals and the proton gradient of synaptic vesicles. This fact may be considered in support of the suggestion that ischemia/hypoxia was a main unspecific stressor, which caused the alterations in glutamatergic neurotransmission under conditions of hypergravity.

Maintenance of Mouse Gustatory Terminal Field Organization Is Disrupted following Selective Removal of Peripheral Sodium Salt Taste Activity at Adulthood

PubMed Central

Sun, Chengsan

2017-01-01

Neural activity plays a critical role in the development of central circuits in sensory systems. However, the maintenance of these circuits at adulthood is usually not dependent on sensory-elicited neural activity. Recent work in the mouse gustatory system showed that selectively deleting the primary transduction channel for sodium taste, the epithelial sodium channel (ENaC), throughout development dramatically impacted the organization of the central terminal fields of three nerves that carry taste information to the nucleus of the solitary tract. More specifically, deleting ENaCs during development prevented the normal maturation of the fields. The present study was designed to extend these findings by testing the hypothesis that the loss of sodium taste activity impacts the maintenance of the normal adult terminal field organization in male and female mice. To do this, we used an inducible Cre-dependent genetic recombination strategy to delete ENaC function after terminal field maturation occurred. We found that removal of sodium taste neural activity at adulthood resulted in significant reorganization of mature gustatory afferent terminal fields in the nucleus of the solitary tract. Specifically, the chorda tympani and greater superficial petrosal nerve terminal fields were 1.4× and 1.6× larger than age-matched controls, respectively. By contrast, the glossopharyngeal nerve, which is not highly sensitive to sodium taste stimulation, did not undergo terminal field reorganization. These surprising results suggest that gustatory nerve terminal fields remain plastic well into adulthood, which likely impacts central coding of taste information and taste-related behaviors with altered taste experience. SIGNIFICANCE STATEMENT Neural activity plays a major role in the development of sensory circuits in the mammalian brain. However, the importance of sensory-driven activity in maintaining these circuits at adulthood, especially in subcortical structures, appears to be much less. Here, we tested whether the loss of sodium taste activity in adult mice impacts the maintenance of how taste nerves project to the first central relay. We found that specific loss of sodium-elicited taste activity at adulthood produced dramatic and selective reorganization of terminal fields in the brainstem. This demonstrates, for the first time, that taste-elicited activity is necessary for the normal maintenance of central gustatory circuits at adulthood and highlights a level of plasticity not seen in other sensory system subcortical circuits. PMID:28676575

An Experimental Brain Missile Wound: Ascertaining Pathophysiology and Evaluating Treatments to Lower Mortality and Morbidity

DTIC Science & Technology

1990-10-26

cerebral arteries may be from an enhanced sympathetic tonus modulated by endothelial prostacyclin synthesis (47) Prostacyclin, a potent vasodilator...right rear leg after treatment of the incision area with topical anesthetic (2% lidocaine ). An 78 endotracheal tube, smeared with topical anesthetic (2...influence the firing rate of 5-HT neurons and inhibit 5-HT synthesis (7,100,114). Adrenergic nerve endings have been localized in the Bl-B3, B7 and B9 cell

Over-the-counter drugs block heart accumulation of MIBG

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sherman, P.S.; Fisher, S.J.; Wieland, D.M.

1985-05-01

Previous work in the authors' laboratory using chemically sympathectomized animals showed that > 50% of meta-iodobenzyl-guanidine (MIBG) in the heart is localized in adrenergic nerves. In the present study, commonly used drugs known to alter the uptake and/or release of norepinephrine by adrenergic neurons have been evaluated for their effect on the biodistribution of MIBG. Pseudoephedrine (Sudafed), phenylpropanolamine (Dexatrim) and phenylephrine (Neosynephrine) were administered (5 mg/kg, i.p.) to rats; amphetamine was also evaluated (0.8mg/kg, i.p.). Thirty minutes later I-125-MIBG (0.2-0.4 Ci/mm) was injected i.v.; animals (N=3) were sacrificed 2 h following radiotracer. Compared to controls (N = 3), drug pretreatmentsmore » resulted in large decreases in radiotracer concentration in adrenergic-rich tissues such as left atrium, left ventricle, spleen and parotid glands. Pseudoephedrine caused decreases (%) of 78, 57, 48 and 35 in the four tissues, respectively. Each of the four drugs caused a greater decrease in I-125-MIBG concentration in the left atrium than in the left ventricle. Comparative studies using H-3-norepinephrine are in progress. Entex, a nasal decongestant containing both phenylephrine and phenylpropanolamine, markedly diminished the heart and salivary gland accumulation of I-123-MIBG in a normal male volunteer. These preliminary studies suggest that commonly used sympathomimetic agents, including some over-the-counter preparations, decrease the accumulation of MIBG in adrenergic neurons. These results also suggest that patients should be carefully screened for drug usage prior to MIBG scintigraphy of the heart.« less

Isolation of Synaptosomes, Synaptic Plasma Membranes, and Synaptic Junctional Complexes.

PubMed

Michaelis, Mary L; Jiang, Lei; Michaelis, Elias K

2017-01-01

Isolation of synaptic nerve terminals or synaptosomes provides an opportunity to study the process of neurotransmission at many levels and with a variety of approaches. For example, structural features of the synaptic terminals and the organelles within them, such as synaptic vesicles and mitochondria, have been elucidated with electron microscopy. The postsynaptic membranes are joined to the presynaptic "active zone" of transmitter release through cell adhesion molecules and remain attached throughout the isolation of synaptosomes. These "post synaptic densities" or "PSDs" contain the receptors for the transmitters released from the nerve terminals and can easily be seen with electron microscopy. Biochemical and cell biological studies with synaptosomes have revealed which proteins and lipids are most actively involved in synaptic release of neurotransmitters. The functional properties of the nerve terminals, such as responses to depolarization and the uptake or release of signaling molecules, have also been characterized through the use of fluorescent dyes, tagged transmitters, and transporter substrates. In addition, isolated synaptosomes can serve as the starting material for the isolation of relatively pure synaptic plasma membranes (SPMs) that are devoid of organelles from the internal environment of the nerve terminal, such as mitochondria and synaptic vesicles. The isolated SPMs can reseal and form vesicular structures in which transport of ions such as sodium and calcium, as well as solutes such as neurotransmitters can be studied. The PSDs also remain associated with the presynaptic membranes during isolation of SPM fractions, making it possible to isolate the synaptic junctional complexes (SJCs) devoid of the rest of the plasma membranes of the nerve terminals and postsynaptic membrane components. Isolated SJCs can be used to identify the proteins that constitute this highly specialized region of neurons. In this chapter, we describe the steps involved in isolating synaptosomes, SPMs, and SJCs from brain so that these preparations can be used with new technological advances to address many as yet unanswered questions about the synapse and its remarkable activities in neuronal cell communication.

Oral vitamin C enhances the adrenergic vasoconstrictor response to local cooling in human skin.

PubMed

Yamazaki, Fumio

2012-05-01

Local administration of ascorbic acid (Asc) at a supraphysiological concentration inhibits the cutaneous vasoconstrictor response to local cooling (LC). However, whether orally ingesting Asc inhibits the LC-induced vasoconstrictor response remains unknown. The purpose of the present study was to examine the acute influence of oral Asc on the adrenergic vasoconstrictor response to LC in human skin. In experiment 1, skin blood flow (SkBF) was measured by laser-Doppler flowmetry at three sites (forearm, calf, palm). The three skin sites were locally cooled from 34 to 24°C at -1°C/min and maintained at 24°C for 20 min before (Pre) and 1.5 h after (Post) oral Asc (2-g single dose) or placebo supplementation. Cutaneous vascular conductance (CVC) was calculated as the ratio of SkBF to blood pressure and expressed relative to the baseline value before LC. Oral Asc enhanced (P < 0.05) the reductions in CVC in the forearm (Pre, -50.3 ± 3.3%; Post, -57.8 ± 2.2%), calf (Pre, -52.6 ± 3.7%; Post, -66.1 ± 4.3%), and palm (Pre, -46.2 ± 6.2%; Post, -60.4 ± 5.6%) during LC. The placebo did not change the responses at any site. In experiment 2, to examine whether the increased vasoconstrictor response caused by oral Asc is due to the adrenergic system, the release of neurotransmitters from adrenergic nerves in forearm skin was blocked locally by iontophoresis of bretylium tosylate (BT). Oral Asc enhanced (P < 0.05) the reductions in CVC at untreated control sites but did not change the responses at BT-treated sites during LC. In experiment 3, to further examine whether adrenergically mediated vasoconstriction is enhanced by oral Asc, 0.1 mM tyramine was administered using intradermal microdialysis in the forearm skin at 34°C in the Pre and Post periods. Oral Asc increased (P < 0.05) the tyramine-induced reduction in CVC. These findings suggest that oral Asc acutely enhances the cutaneous vasoconstrictor responses to LC through the modification of adrenergic sympathetic mechanisms.

Muscarinic acetylcholine receptor subtype expression in avian vestibular hair cells, nerve terminals and ganglion cells.

PubMed

Li, G Q; Kevetter, G A; Leonard, R B; Prusak, D J; Wood, T G; Correia, M J

2007-04-25

Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the CNS and peripheral nervous system and play an important role in modulating the cell activity and function. We have shown that the cholinergic agonist carbachol reduces the pigeon's inwardly rectifying potassium channel (pKir2.1) ionic currents in native vestibular hair cells. We have cloned and sequenced pigeon mAChR subtypes M2-M5 and we have studied the expression of all five mAChR subtypes (M1-M5) in the pigeon vestibular end organs (semicircular canal ampullary cristae and utricular maculae), vestibular nerve fibers and the vestibular (Scarpa's) ganglion using tissue immunohistochemistry (IH), dissociated single cell immunocytochemistry (IC) and Western blotting (WB). We found that vestibular hair cells, nerve fibers and ganglion cells each expressed all five (M1-M5) mAChR subtypes. Two of the three odd-numbered mAChRs (M1, M5) were present on the hair cell cilia, supporting cells and nerve terminals. And all three odd numbered mAChRs (M1, M3 and M5) were expressed on cuticular plates, myelin sheaths and Schwann cells. Even-numbered mAChRs were seen on the nerve terminals. M2 was also shown on the cuticular plates and supporting cells. Vestibular efferent fibers and terminals were not identified in our studies. Results from WB of the dissociated vestibular epithelia, nerve fibers and vestibular ganglia were consistent with the results from IH and IC. Our findings suggest that there is considerable co-expression of the subtypes on the neural elements of the labyrinth. Further electrophysiological and pharmacological studies should delineate the mechanisms of action of muscarinic acetylcholine receptors on structures in the labyrinth.

Peripheral axotomy of the rat mandibular trigeminal nerve leads to an increase in VIP and decrease of other primary afferent neuropeptides in the spinal trigeminal nucleus.

PubMed

Atkinson, M E; Shehab, S A

1986-12-01

In the vasoactive intestinal polypeptide (VIP)-rich lumbosacral spinal cord, VIP increases at the expense of other neuropeptides after primary sensory nerve axotomy. This study was undertaken to ascertain whether similar changes occur in peripherally axotomised cranial sensory nerves. VIP immunoreactivity increased in the terminal region of the mandibular nerve in the trigeminal nucleus caudalis following unilateral section of the sensory root of the mandibular trigeminal nerve at the foramen orale. Other primary afferent neuropeptides (substance P, cholecystokinin and somatostatin) were depleted and fluoride-resistant acid phosphatase activity was abolished in the same circumscribed areas of the nucleus caudalis. The rise in VIP and depletion of other markers began 4 days postoperatively and was maximal by 10 days, these levels remaining unchanged up to 1 year postoperatively. VIP-immunoreactive cell bodies were absent from trigeminal ganglia from the unoperated side but small and medium cells stained intensely in the ganglia of the operated side after axotomy. These observations indicate that increase of VIP in sensory nerve terminals is a general phenomenon occurring in both cranial and spinal sensory terminal areas. The intense VIP immunoreactivity in axotomised trigeminal ganglia suggests that the increased levels of VIP in the nucleus caudalis are of peripheral origin, indicating a change in expression of neuropeptides within primary afferent neurons following peripheral axotomy.

Prevention and Treatment of Noise-Induced Tinnitus. Revision

DTIC Science & Technology

2013-07-01

CTBP2 immunolabeling) for their loss following noise. Sub-Task 1c: Assessment of Auditory Nerve ( VGLUT1 immunolabel) terminals on neurons in Ventral...and Dorsal Cochlear Nucleus (VCN, DCN) for their loss following noise. Sub-Task 1d: Assessment of VGLUT2 , VAT & VGAT immunolabeled terminals in VCN...significant reduction in connections compared to animals without noise exposure. Sub-Task 1c: Assessment of Auditory Nerve ( VGLUT1 immunolabel

Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle

PubMed Central

Patel, Anant B.; Lai, James C. K.; Chowdhury, Golam M. I.; Hyder, Fahmeed; Rothman, Douglas L.; Shulman, Robert G.; Behar, Kevin L.

2014-01-01

Previous 13C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy-d-glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG6P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG6P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo, indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions. PMID:24706914

Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle.

PubMed

Patel, Anant B; Lai, James C K; Chowdhury, Golam M I; Hyder, Fahmeed; Rothman, Douglas L; Shulman, Robert G; Behar, Kevin L

2014-04-08

Previous (13)C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy-D-glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG6P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG6P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo, indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions.

Adenosine A2B and A3 receptor location at the mouse neuromuscular junction.

PubMed

Garcia, Neus; Priego, Mercedes; Hurtado, Erica; Obis, Teresa; Santafe, Manel M; Tomàs, Marta; Lanuza, Maria Angel; Tomàs, Josep

2014-07-01

To date, four subtypes of adenosine receptors have been cloned (A(1)R, A(2A)R, A(2B)R, and A(3)R). In a previous study we used confocal immunocytochemistry to identify A(1)R and A(2A)R receptors at mouse neuromuscular junctions (NMJs). The data shows that these receptors are localized differently in the three cells (muscle, nerve and glia) that configure the NMJs. A(1)R localizes in the terminal teloglial Schwann cell and nerve terminal, whereas A(2A)R localizes in the postsynaptic muscle and in the axon and nerve terminal. Here, we use Western blotting to investigate the presence of A(2B)R and A(3)R receptors in striated muscle and immunohistochemistry to localize them in the three cells of the adult neuromuscular synapse. The data show that A(2B)R and A(3)R receptors are present in the nerve terminal and muscle cells at the NMJs. Neither A(2B)R nor A(3)R receptors are localized in the Schwann cells. Thus, the four subtypes of adenosine receptors are present in the motor endings. The presence of these receptors in the neuromuscular synapse allows the receptors to be involved in the modulation of transmitter release. © 2014 Anatomical Society.

Ulcerative colitis: ultrastructure of interstitial cells in myenteric plexus.

PubMed

Rumessen, J J; Vanderwinden, J-M; Horn, T

2010-10-01

Interstitial cells of Cajal (ICC) are key regulatory cells in the gut. In the colon of patients with severe ulcerative colitis (UC), myenteric ICC had myoid ultrastructural features and were in close contact with nerve terminals. In all patients as opposed to controls, some ICC profiles showed degenerative changes, such as lipid droplets and irregular vacuoles. Nerve terminals often appeared swollen and empty. Glial cells, muscle cells, and fibroblast-like cells (FLC) showed no alterations. FLC enclosed macrophages (MLC), which were in close contact with naked axon terminals. The organization and cytological changes may be of pathophysiological significance in patients with UC.

Observations on the elimination of polyneuronal innervation in developing mammalian skeletal muscle.

PubMed Central

O'Brien, R A; Ostberg, A J; Vrbová, G

1978-01-01

1. The mechanism responsible for the elimination of polyneuronal innervation in developing rat soleus muscles was studied electrophysiologically and histologically. 2. Initially all the axons contacting a single end-plate have simple bulbous terminals. As elimination proceeds one axon develops terminal branches while the other terminals remain bulbous and may be seen in contact with, or a short distance away from, the end-plate. It is suggested that the branched terminal remains in contact with the muscle fibre while the other terminals withdraw. 3. At a time when polyneuronal innervation can no longer be detected electrophysiologically, the histological technique still shows the presence of end-plates contacted by more than one nerve terminal. 4. The effect of activity on the disappearance of polyneuronal innervation was examined. Activity was increased by electrical stimulation of the right sciatic nerve. This procedure also produced reflex activity in the contralateral limb. In both cases polyneuronal innervation was eliminated more rapidly in the active muscles. 5. The finding that proteolytic enzymes are released from muscles treated with acetylcholine (ACh), and the observation of the more rapid elimination of supernumerary terminals at the end-plates of active muscles, lead to the suggestion that superfluous nerve-muscle contacts are removed by the proteolytic enzymes in response to neuromuscular activity. The selective stabilization of only one of the terminals is discussed in the light of these results. Images Plate 1 Plate 2 PMID:722562

Diadenosine Polyphosphates Suppress the Effects of Sympathetic Nerve Stimulation in Rabbit Heart Pacemaker.

PubMed

Abramochkin, D V; Pustovit, K B; Kuz'min, V S

2017-09-01

The modulatory influence of diadenosine tetraphosphate (Ap4A) and diadenosine pentaphosphate (Ap5A) on the effect of intramural autonomic nerve stimulation in isolated rabbit sinoatrial node were examined. Electrical activity of the sinoatrial node was recorded intracellularly. Against the background of blockade of adrenergic effects with propranolol (3×10 -6 M) or in preparations isolated 2 h after injection of reserpine (2 mg/kg), nerve stimulation induced short-term membrane hyperpolarization and diminished the sinus node firing rate. These phenomena were not affected by Ap4A or Ap5A (10 -5 M). Under the action of atropine (3×10 -6 M) that completely eliminated the cholinergic influences, nerve stimulation enhanced the sinus node firing rate by 17.30±3.45% from the initial rate. Both Ap4A and Ap5A moderated the stimulation-induced elevation of firing rate to 9.9±2.8 and 10.5±2.9%, respectively. The data suggest that diadenosine polyphosphates significantly modulate the sympathetic influences on the heart rhythm, but have no effect on the parasympathetic control over activity of sinoatrial node.

Novel Immunohistochemical Techniques Using Discrete Signal Amplification Systems for Human Cutaneous Peripheral Nerve Fiber Imaging

PubMed Central

Wang, Ningshan; Gibbons, Christopher H.; Freeman, Roy

2011-01-01

Confocal imaging uses immunohistochemical binding of specific antibodies to visualize tissues, but technical obstacles limit more widespread use of this technique in the imaging of peripheral nerve tissue. These obstacles include same-species antibody cross-reactivity and weak fluorescent signals of individual and co-localized antigens. The aims of this study were to develop new immunohistochemical techniques for imaging of peripheral nerve fibers. Three-millimeter punch skin biopsies of healthy individuals were fixed, frozen, and cut into 50-µm sections. Tissues were stained with a variety of antibody combinations with two signal amplification systems, streptavidin-biotin-fluorochrome (sABC) and tyramide-horseradish peroxidase-fluorochrome (TSA), used simultaneously to augment immunohistochemical signals. The combination of the TSA and sABC amplification systems provided the first successful co-localization of sympathetic adrenergic and sympathetic cholinergic nerve fibers in cutaneous human sweat glands and vasomotor and pilomotor systems. Primary antibodies from the same species were amplified individually without cross-reactivity or elevated background interference. The confocal fluorescent signal-to-noise ratio increased, and image clarity improved. These modifications to signal amplification systems have the potential for widespread use in the study of human neural tissues. PMID:21411809

The ovine fetal endocrine reflex responses to haemorrhage are not mediated by cardiac nerves

PubMed Central

Wood, Charles E

2002-01-01

This study was designed to test the hypothesis that cardiac receptors tonically inhibit the secretion of renin, arginine vasopressin (AVP) and adrenocorticotropic hormone (ACTH) in late-gestation fetal sheep. Eight chronically catheterised fetal sheep between 122 and 134 days gestation were subjected to injection or infusion of saline or 4 % procaine into the pericardial space. Fetal blood pressure and heart rate were monitored and fetal blood samples were drawn to measure the response to these injections. Injection of procaine into the pericardial space effectively blocked cardiac nerves, as evidenced by a reduction in the variability of fetal heart rate and by the blockade of reflex reductions in fetal heart rate after intravenous injection of phenylephrine (an α-adrenergic agonist which raises blood pressure). Injection of saline had no discernable effects on any of the measured variables. A single injection of procaine, followed by a slow infusion, produced a transient blockade of cardiac nerves. Multiple injections of procaine produced a sustained blockade of cardiac nerves and a sustained rise in fetal plasma renin activity and ACTH. In none of the experiments did procaine significantly alter fetal plasma AVP concentrations. In 11 fetuses between 121 and 134 days gestation, we combined the cardiac nerve blockade with slow haemorrhage to test the cardiac nerves as mediators of the endocrine response to haemorrhage in utero. Cardiac nerve blockade exaggerated the fetal blood gas response to haemorrhage somewhat but did not significantly alter the magnitude of the ACTH, AVP, or plasma renin activity response to haemorrhage. We conclude that cardiac nerves in the late-gestation fetal sheep have minor influences on plasma renin activity and ACTH in normovolaemic fetuses, but that changes in cardiac nerve activity do not mediate the endocrine responsiveness to haemorrhage. PMID:12042365

Lack of functional and morphological susceptibility of the greater superficial petrosal nerve to developmental dietary sodium restriction.

PubMed

Sollars, S I; Hill, D L

2000-12-01

Restriction of dietary sodium during gestation has major effects on taste function and anatomy in the offspring. The chorda tympani nerve of offspring that are maintained on sodium-reduced chow throughout life (NaDep) has reduced neurophysiological responses to sodium and altered morphology of its terminal field in the nucleus of the solitary tract. There are many anatomical and physiological similarities between the chorda tympani nerve that innervates taste buds on the anterior tongue and the greater superficial petrosal nerve (GSP) that innervates taste buds on the palate. To determine if the GSP is similarly susceptible to the effects of dietary sodium restriction, the present study examined neurophysiological responses and the terminal field of the GSP in NaDep and control rats. Neurophysiological responses of the GSP to a variety of sodium and non-sodium stimuli did not differ between NaDep and control rats. Furthermore, the volume and shape of the GSP terminal field in the nucleus of the solitary tract did not differ between the groups. Therefore, despite the high degree of functional and anatomical correspondence between the chorda tympani nerve and the GSP, the GSP does not appear to be susceptible to the effects of lifelong dietary sodium restriction.

The phylogeny and ontogeny of autonomic control of the heart and cardiorespiratory interactions in vertebrates.

PubMed

Taylor, Edwin W; Leite, Cleo A C; Sartori, Marina R; Wang, Tobias; Abe, Augusto S; Crossley, Dane A

2014-03-01

Heart rate in vertebrates is controlled by activity in the autonomic nervous system. In spontaneously active or experimentally prepared animals, inhibitory parasympathetic control is predominant and is responsible for instantaneous changes in heart rate, such as occur at the first air breath following a period of apnoea in discontinuous breathers like inactive reptiles or species that surface to air breathe after a period of submersion. Parasympathetic control, exerted via fast-conducting, myelinated efferent fibres in the vagus nerve, is also responsible for beat-to-beat changes in heart rate such as the high frequency components observed in spectral analysis of heart rate variability. These include respiratory modulation of the heartbeat that can generate cardiorespiratory synchrony in fish and respiratory sinus arrhythmia in mammals. Both may increase the effectiveness of respiratory gas exchange. Although the central interactions generating respiratory modulation of the heartbeat seem to be highly conserved through vertebrate phylogeny, they are different in kind and location, and in most species are as yet little understood. The heart in vertebrate embryos possesses both muscarinic cholinergic and β-adrenergic receptors very early in development. Adrenergic control by circulating catecholamines seems important throughout development. However, innervation of the cardiac receptors is delayed and first evidence of a functional cholinergic tonus on the heart, exerted via the vagus nerve, is often seen shortly before or immediately after hatching or birth, suggesting that it may be coordinated with the onset of central respiratory rhythmicity and subsequent breathing.

Biochemical factors modulating female genital sexual arousal physiology.

PubMed

Traish, Abdulmaged M; Botchevar, Ella; Kim, Noel N

2010-09-01

Female genital sexual arousal responses are complex neurophysiological processes consisting of central and peripheral components that occur following sexual stimulation. The peripheral responses in sexual arousal include genital vasocongestion, engorgement and lubrication resulting from a surge of vaginal and clitoral blood flow. These hemodynamic events are mediated by a host of neurotransmitters and vasoactive agents. To discuss the role of various biochemical factors modulating female genital sexual arousal responses. A comprehensive literature review was conducted using the PubMed database and citations were selected, based on topical relevance, and examined for study methodology and major findings. Data from peer-reviewed publications. Adrenergic as well as non-adrenergic non-cholinergic neurotransmitters play an important role in regulating genital physiological responses by mediating vascular and non-vascular smooth muscle contractility. Vasoactive peptides and neuropeptides also modulate genital sexual responses by regulating vascular and non-vascular smooth muscle cells and epithelial function. The endocrine milieu, particularly sex steroid hormones, is critical in the maintenance of tissue structure and function. Reduced levels of estrogens and androgen are associated with dramatic alterations in genital tissue structure, including the nerve network, as well as the response to physiological modulators. Furthermore, estrogen and androgen deficiency is associated with reduced expression of sex steroid receptors and most importantly with attenuated genital blood flow and lubrication in response to pelvic nerve stimulation. This article provides an integrated framework describing the physiological and molecular basis of various pathophysiological conditions associated with female genital sexual arousal dysfunction. © 2010 International Society for Sexual Medicine.

Substance P immunoreactive nerve terminals in the dorsolateral nucleus of the tractus solitarius: roles in the baroreceptor reflex.

PubMed

Massari, V J; Shirahata, M; Johnson, T A; Lauenstein, J M; Gatti, P J

1998-03-02

Physiological and light microscopic evidence suggest that substance P (SP) may be a neurotransmitter contained in first-order sensory baroreceptor afferents; however, ultrastructural support for this hypothesis is lacking. We have traced the central projections of the carotid sinus nerve (CSN) in the cat by utilizing the transganglionic transport of horseradish peroxidase (HRP). The dorsolateral subnucleus of the nucleus tractus solitarius (dlNTS) was processed for the histochemical visualization of transganglionically labeled CSN afferents and for the immunocytochemical visualization of SP by dual labeling light and electron microscopic methods. Either HRP or SP was readily identified in single-labeled unmyelinated axons, myelinated axons, and nerve terminals in the dlNTS. SP immunoreactivity was also identified in unmyelinated axons, myelinated axons, and nerve terminals in the dlNTS, which were simultaneously identified as CSN primary afferents. However, only 15% of CSN terminals in the dlNTS were immunoreactive for SP. Therefore, while the ultrastructural data support the hypothesis that SP immunoreactive first-order neurons are involved in the origination of the baroreceptor reflex, they suggest that only a modest part of the total sensory input conveyed from the carotid sinus baroreceptors to the dlNTS is mediated by SP immunoreactive CSN terminals. Five types of axo-axonic synapses were observed in the dlNTS. SP immunoreactive CSN afferents were very rarely involved in these synapses. Furthermore, SP terminals were never observed to form the presynaptic element in an axo-axonic synapse with a CSN afferent. Therefore, SP does not appear to be involved in the modulation of the baroreceptor reflex in the dlNTS. Copyright 1998 Elsevier Science B.V.

Nanoparticle inhalation alters systemic arteriolar vasoreactivity through sympathetic and cyclooxygenase-mediated pathways

PubMed Central

Knuckles, Travis L.; Yi, Jinghai; Frazer, David G.; Leonard, Howard D.; Chen, Bean T.; Castranova, Vince; Nurkiewicz, Timothy R.

2016-01-01

The widespread increase in the production and use of nanomaterials has increased the potential for nanoparticle exposure; however, the biological effects of nanoparticle inhalation are poorly understood. Rats were exposed to nanosized titanium dioxide aerosols (10 µg lung burden); at 24 h post-exposure, the spinotrapezius muscle was prepared for intravital microscopy. Nanoparticle exposure did not alter perivascular nerve stimulation (PVNS)-induced arteriolar constriction under normal conditions; however, adrenergic receptor inhibition revealed a more robust effect. Nanoparticle inhalation reduced arteriolar dilation in response to active hyperaemia (AH). In both PVNS and AH experiments, nitric oxide synthase (NOS) inhibition affected only controls. Whereas cyclooxygenase (COX) inhibition only attenuated AH-induced arteriolar dilation in nanoparticle-exposed animals. This group displayed an enhanced U46619 constriction and attenuated iloprost-induced dilation. Collectively, these studies indicate that nanoparticle exposure reduces microvascular NO bioavailability and alters COX-mediated vasoreactivity. Furthermore, the enhanced adrenergic receptor sensitivity suggests an augmented sympathetic responsiveness. PMID:21830860

Terminal-Nerve-Derived Neuropeptide Y Modulates Physiological Responses in the Olfactory Epithelium of Hungry Axolotls (Ambystoma mexicanum)

PubMed Central

Mousley, Angela; Polese, Gianluca; Marks, Nikki J.; Eisthen, Heather L.

2007-01-01

The vertebrate brain actively regulates incoming sensory information, effectively filtering input and focusing attention toward environmental stimuli that are most relevant to the animal's behavioral context or physiological state. Such centrifugal modulation has been shown to play an important role in processing in the retina and cochlea, but has received relatively little attention in olfaction. The terminal nerve, a cranial nerve that extends underneath the lamina propria surrounding the olfactory epithelium, displays anatomical and neurochemical characteristics that suggest that it modulates activity in the olfactory epithelium. Using immunocytochemical techniques, we demonstrate that neuropeptide Y (NPY) is abundantly present in the terminal nerve in the axolotl (Ambystoma mexicanum), an aquatic salamander. Because NPY plays an important role in regulating appetite and hunger in many vertebrates, we investigated the possibility that NPY modulates activity in the olfactory epithelium in relation to the animal's hunger level. We therefore characterized the full length NPY gene from axolotls to enable synthesis of authentic axolotl NPY for use in electrophysiological experiments. We find that axolotl NPY modulates olfactory epithelial responses evoked by L-glutamic acid, a food-related odorant, but only in hungry animals. Similarly, whole-cell patch-clamp recordings demonstrate that bath application of axolotl NPY enhances the magnitude of a tetrodotoxin-sensitive inward current, but only in hungry animals. These results suggest that expression or activity of NPY receptors in the olfactory epithelium may change with hunger level, and that terminal nerve-derived peptides modulate activity in the olfactory epithelium in response to an animal's changing behavioral and physiological circumstances. PMID:16855098

Terminal nerve-derived neuropeptide y modulates physiological responses in the olfactory epithelium of hungry axolotls (Ambystoma mexicanum).

PubMed

Mousley, Angela; Polese, Gianluca; Marks, Nikki J; Eisthen, Heather L

2006-07-19

The vertebrate brain actively regulates incoming sensory information, effectively filtering input and focusing attention toward environmental stimuli that are most relevant to the animal's behavioral context or physiological state. Such centrifugal modulation has been shown to play an important role in processing in the retina and cochlea, but has received relatively little attention in olfaction. The terminal nerve, a cranial nerve that extends underneath the lamina propria surrounding the olfactory epithelium, displays anatomical and neurochemical characteristics that suggest that it modulates activity in the olfactory epithelium. Using immunocytochemical techniques, we demonstrate that neuropeptide Y (NPY) is abundantly present in the terminal nerve in the axolotl (Ambystoma mexicanum), an aquatic salamander. Because NPY plays an important role in regulating appetite and hunger in many vertebrates, we investigated the possibility that NPY modulates activity in the olfactory epithelium in relation to the animal's hunger level. We therefore characterized the full-length NPY gene from axolotls to enable synthesis of authentic axolotl NPY for use in electrophysiological experiments. We find that axolotl NPY modulates olfactory epithelial responses evoked by l-glutamic acid, a food-related odorant, but only in hungry animals. Similarly, whole-cell patch-clamp recordings demonstrate that bath application of axolotl NPY enhances the magnitude of a tetrodotoxin-sensitive inward current, but only in hungry animals. These results suggest that expression or activity of NPY receptors in the olfactory epithelium may change with hunger level, and that terminal nerve-derived peptides modulate activity in the olfactory epithelium in response to an animal's changing behavioral and physiological circumstances.

Intramuscular Distribution of the Abducens Nerve in the Lateral Rectus Muscle for the Management of Strabismus.

PubMed

Shin, Hyun Jin; Lee, Shin-Hyo; Shin, Kang-Jae; Koh, Ki-Seok; Song, Wu-Chul

2018-06-01

To elucidate the intramuscular distribution and branching patterns of the abducens nerve in the lateral rectus (LR) muscle so as to provide anatomical confirmation of the presence of compartmentalization, including for use in clinical applications such as botulinum toxin injections. Thirty whole-mount human cadaver specimens were dissected and then Sihler's stain was applied. The basic dimensions of the LR and its intramuscular nerve distribution were investigated. The distances from the muscle insertion to the point at which the abducens nerve enters the LR and to the terminal nerve plexus were also measured. The LR was 46.0 mm long. The abducens nerve enters the muscle on the posterior one-third of the LR and then typically divides into a few branches (average of 1.8). This supports a segregated abducens nerve selectively innervating compartments of the LR. The intramuscular nerve distribution showed a Y-shaped ramification with root-like arborization. The intramuscular nerve course finished around the middle of the LR (24.8 mm posterior to the insertion point) to form the terminal nerve plexus. This region should be considered the optimal target site for botulinum toxin injections. We have also identified the presence of an overlapping zone and communicating nerve branches between the neighboring LR compartments. Sihler's staining is a useful technique for visualizing the entire nerve network of the LR. Improving the knowledge of the nerve distribution patterns is important not only for researchers but also clinicians to understand the functions of the LR and the diverse pathophysiology of strabismus.

Afferent fibers and sensory ganglion cells within the oculomotor nerve in some mammals and man. II. Electrophysiological investigations.

PubMed

Manni, E; Bortolami, R; Pettorossi, V E; Lucchi, M L; Callegari, E

1978-01-01

The main aim of the present study was to localize with electrophysiological techniques the central projections and terminations of the aberrant trigeminal fibres contained in the oculomotor nerve of the lamb. After severing a trigeminal root, single-shock electrical stimulation of the trigeminal axons present in the central stump of the ipsilateral oculomotor nerve evoked field potentials in the area of, i) the subnucleus gelatinosus of the nucleus caudalis trigemini at the level of C1-C2; ii) the main sensory trigeminal nucleus; iii) the descending trigeminal nucleus and tract; iv) the adjacent reticular formation. Units whose discharge rate was influenced by such a stimulation were also found in the same territories. These regions actually exhibited degenerations after cutting an oculomotor nerve. We conclude, therefore, that the trigeminal fibres which leave the Vth nerve at the level of the cavernous sinus and enter the brain stem through the IIIrd nerve, end in the same structures which receive the terminations of the afferent fibres entering the brain stem through the sensory trigeminal root.

Crayfish neuromuscular facilitation activated by constant presynaptic action potentials and depolarizing pulses

PubMed Central

Zucker, Robert S.

1974-01-01

1. Experiments were conducted to test the hypothesis that facilitation of transmitter release in response to repetitive stimulation of the exciter motor axon to the crayfish claw opener muscle is due to an increase in the amplitude or duration of the action potential in presynaptic terminals. No consistent changes were found in the nerve terminal potential (n.t.p.) recorded extracellularly at synaptic sites on the surface of muscle fibres. 2. Apparent changes in n.t.p. are attributed to three causes. (i) Some recordings are shown to be contaminated by non-specific muscle responses which grow during facilitation. (ii) Some averaged n.t.p.s exhibit opposite changes in amplitude and duration which suggest a change in the synchrony of presynaptic nerve impulses at different frequencies. (iii) Some changes in n.t.p. are blocked by γ-methyl glutamate, an antagonist of the post-synaptic receptor, which suggests that these changes are caused by small muscle movements. 3. The only change in n.t.p. believed to represent an actual change in the intracellular signal is a reduction in n.t.p. amplitude to the second of two stimuli separated by a brief interval. 4. Tetra-ethyl ammonium ions increase synaptic transmission about 20% and prolong the n.t.p. about 15%. This result suggests that an increase in n.t.p. large enough to increase transmission by the several hundred per cent occurring during facilitation would be detected. 5. The nerve terminals are electrically excitable, and most synaptic sites have a diphasic or triphasic n.t.p., which suggests that the motor neurone terminals are actively invaded by nerve impulses. 6. When nerve impulses are blocked in tetrodotoxin, depolarization of nerve terminals increases the frequency of miniature excitatory junctional potentials (e.j.p.s), and a phasic e.j.p. can be evoked by large, brief depolarizing pulses. Responses to repetitive or paired depolarizations of constant amplitude and duration exhibit a facilitation similar to that of e.j.p.s evoked by nerve impulses. 7. It is concluded that facilitation in the crayfish claw opener is not due to a change in the presynaptic action potential, but is due to some change at a later step in the depolarization—secretion process. PMID:4153766

Crayfish neuromuscular facilitation activated by constant presynaptic action potentials and depolarizing pulses.

PubMed

Zucker, R S

1974-08-01

1. Experiments were conducted to test the hypothesis that facilitation of transmitter release in response to repetitive stimulation of the exciter motor axon to the crayfish claw opener muscle is due to an increase in the amplitude or duration of the action potential in presynaptic terminals. No consistent changes were found in the nerve terminal potential (n.t.p.) recorded extracellularly at synaptic sites on the surface of muscle fibres.2. Apparent changes in n.t.p. are attributed to three causes.(i) Some recordings are shown to be contaminated by non-specific muscle responses which grow during facilitation.(ii) Some averaged n.t.p.s exhibit opposite changes in amplitude and duration which suggest a change in the synchrony of presynaptic nerve impulses at different frequencies.(iii) Some changes in n.t.p. are blocked by gamma-methyl glutamate, an antagonist of the post-synaptic receptor, which suggests that these changes are caused by small muscle movements.3. The only change in n.t.p. believed to represent an actual change in the intracellular signal is a reduction in n.t.p. amplitude to the second of two stimuli separated by a brief interval.4. Tetra-ethyl ammonium ions increase synaptic transmission about 20% and prolong the n.t.p. about 15%. This result suggests that an increase in n.t.p. large enough to increase transmission by the several hundred per cent occurring during facilitation would be detected.5. The nerve terminals are electrically excitable, and most synaptic sites have a diphasic or triphasic n.t.p., which suggests that the motor neurone terminals are actively invaded by nerve impulses.6. When nerve impulses are blocked in tetrodotoxin, depolarization of nerve terminals increases the frequency of miniature excitatory junctional potentials (e.j.p.s), and a phasic e.j.p. can be evoked by large, brief depolarizing pulses. Responses to repetitive or paired depolarizations of constant amplitude and duration exhibit a facilitation similar to that of e.j.p.s evoked by nerve impulses.7. It is concluded that facilitation in the crayfish claw opener is not due to a change in the presynaptic action potential, but is due to some change at a later step in the depolarization-secretion process.

Maintenance of Mouse Gustatory Terminal Field Organization Is Disrupted following Selective Removal of Peripheral Sodium Salt Taste Activity at Adulthood.

PubMed

Skyberg, Rolf; Sun, Chengsan; Hill, David L

2017-08-09

Neural activity plays a critical role in the development of central circuits in sensory systems. However, the maintenance of these circuits at adulthood is usually not dependent on sensory-elicited neural activity. Recent work in the mouse gustatory system showed that selectively deleting the primary transduction channel for sodium taste, the epithelial sodium channel (ENaC), throughout development dramatically impacted the organization of the central terminal fields of three nerves that carry taste information to the nucleus of the solitary tract. More specifically, deleting ENaCs during development prevented the normal maturation of the fields. The present study was designed to extend these findings by testing the hypothesis that the loss of sodium taste activity impacts the maintenance of the normal adult terminal field organization in male and female mice. To do this, we used an inducible Cre-dependent genetic recombination strategy to delete ENaC function after terminal field maturation occurred. We found that removal of sodium taste neural activity at adulthood resulted in significant reorganization of mature gustatory afferent terminal fields in the nucleus of the solitary tract. Specifically, the chorda tympani and greater superficial petrosal nerve terminal fields were 1.4× and 1.6× larger than age-matched controls, respectively. By contrast, the glossopharyngeal nerve, which is not highly sensitive to sodium taste stimulation, did not undergo terminal field reorganization. These surprising results suggest that gustatory nerve terminal fields remain plastic well into adulthood, which likely impacts central coding of taste information and taste-related behaviors with altered taste experience. SIGNIFICANCE STATEMENT Neural activity plays a major role in the development of sensory circuits in the mammalian brain. However, the importance of sensory-driven activity in maintaining these circuits at adulthood, especially in subcortical structures, appears to be much less. Here, we tested whether the loss of sodium taste activity in adult mice impacts the maintenance of how taste nerves project to the first central relay. We found that specific loss of sodium-elicited taste activity at adulthood produced dramatic and selective reorganization of terminal fields in the brainstem. This demonstrates, for the first time, that taste-elicited activity is necessary for the normal maintenance of central gustatory circuits at adulthood and highlights a level of plasticity not seen in other sensory system subcortical circuits. Copyright © 2017 the authors 0270-6474/17/377619-12$15.00/0.

Neuromodulatory properties of fluorescent carbon dots: effect on exocytotic release, uptake and ambient level of glutamate and GABA in brain nerve terminals.

PubMed

Borisova, Tatiana; Nazarova, Anastasia; Dekaliuk, Mariia; Krisanova, Natalia; Pozdnyakova, Natalia; Borysov, Arsenii; Sivko, Roman; Demchenko, Alexander P

2015-02-01

Carbon dots (C-dots), a recently discovered class of fluorescent nano-sized particles with pure carbon core, have great bioanalytical potential. Neuroactive properties of fluorescent C-dots obtained from β-alanine by microwave heating were assessed based on the analysis of their effects on the key characteristics of GABA- and glutamatergic neurotransmission in isolated rat brain nerve terminals. It was found that C-dots (40-800 μg/ml) in dose-dependent manner: (1) decreased exocytotic release of [(3)H]GABA and L-[(14)C]glutamate; (2) reduced acidification of synaptic vesicles; (3) attenuated the initial velocity of Na(+)-dependent transporter-mediated uptake of [(3)H]GABA and L-[(14)C]glutamate; (4) increased the ambient level of the neurotransmitters, nevertheless (5) did not change significantly the potential of the plasma membrane of nerve terminals. Almost complete suppression of exocytotic release of the neurotransmitters was caused by C-dots at a concentration of 800 μg/ml. Fluorescent and neuromodulatory features combined in C-dots create base for their potential usage for labeling and visualization of key processes in nerve terminals, and also in theranostics. In addition, natural presence of carbon-containing nanoparticles in the human food chain and in the air may provoke the development of neurologic consequences. Copyright © 2014 Elsevier Ltd. All rights reserved.

High probability neurotransmitter release sites represent an energy efficient design

PubMed Central

Lu, Zhongmin; Chouhan, Amit K.; Borycz, Jolanta A.; Lu, Zhiyuan; Rossano, Adam J; Brain, Keith L.; Zhou, You; Meinertzhagen, Ian A.; Macleod, Gregory T.

2016-01-01

Nerve terminals contain multiple sites specialized for the release of neurotransmitters. Release usually occurs with low probability, a design thought to confer many advantages. High probability release sites are not uncommon but their advantages are not well understood. Here we test the hypothesis that high probability release sites represent an energy efficient design. We examined release site probabilities and energy efficiency at the terminals of two glutamatergic motor neurons synapsing on the same muscle fiber in Drosophila larvae. Through electrophysiological and ultrastructural measurements we calculated release site probabilities to differ considerably between terminals (0.33 vs. 0.11). We estimated the energy required to release and recycle glutamate from the same measurements. The energy required to remove calcium and sodium ions subsequent to nerve excitation was estimated through microfluorimetric and morphological measurements. We calculated energy efficiency as the number of glutamate molecules released per ATP molecule hydrolyzed, and high probability release site terminals were found to be more efficient (0.13 vs. 0.06). Our analytical model indicates that energy efficiency is optimal (~0.15) at high release site probabilities (~0.76). As limitations in energy supply constrain neural function, high probability release sites might ameliorate such constraints by demanding less energy. Energy efficiency can be viewed as one aspect of nerve terminal function, in balance with others, because high efficiency terminals depress significantly during episodic bursts of activity. PMID:27593375

The role of α-adrenergic receptors in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man

PubMed Central

Fairfax, Seth T; Holwerda, Seth W; Credeur, Daniel P; Zuidema, Mozow Y; Medley, John H; Dyke II, Peter C; Wray, D Walter; Davis, Michael J; Fadel, Paul J

2013-01-01

Sympathetic vascular transduction is commonly understood to act as a basic relay mechanism, but under basal conditions, competing dilatory signals may interact with and alter the ability of sympathetic activity to decrease vascular conductance. Thus, we determined the extent to which spontaneous bursts of muscle sympathetic nerve activity (MSNA) mediate decreases in forearm vascular conductance (FVC) and the contribution of local α-adrenergic receptor-mediated pathways to the observed FVC responses. In 19 young men, MSNA (microneurography), arterial blood pressure and brachial artery blood flow (duplex Doppler ultrasound) were continuously measured during supine rest. These measures were also recorded in seven men during intra-arterial infusions of normal saline, phentolamine (PHEN) and PHEN with angiotensin II (PHEN+ANG). The latter was used to control for increases in resting blood flow with α-adrenergic blockade. Spike-triggered averaging was used to characterize beat-by-beat changes in FVC for 15 cardiac cycles following each MSNA burst and a peak response was calculated. Following MSNA bursts, FVC initially increased by +3.3 ± 0.3% (P= 0.016) and then robustly decreased to a nadir of −5.8 ± 1.6% (P < 0.001). The magnitude of vasoconstriction appeared graded with the number of consecutive MSNA bursts; while individual burst size only had a mild influence. Neither PHEN nor PHEN+ANG infusions affected the initial rise in FVC, but both infusions significantly attenuated the subsequent decrease in FVC (–2.1 ± 0.7% and –0.7 ± 0.8%, respectively; P < 0.001 vs. normal saline). These findings indicate that spontaneous MSNA bursts evoke robust beat-by-beat decreases in FVC that are exclusively mediated via α-adrenergic receptors. PMID:23652594

Inhibition of Adrenergic and Non-Adrenergic Smooth Muscle Contraction in the Human Prostate by the Phosphodiesterase 10-Selective Inhibitor TC-E 5005.

PubMed

Hennenberg, Martin; Schott, Melanie; Kan, Aysenur; Keller, Patrick; Tamalunas, Alexander; Ciotkowska, Anna; Rutz, Beata; Wang, Yiming; Strittmatter, Frank; Herlemann, Annika; Yu, Qingfeng; Stief, Christian G; Gratzke, Christian

2016-11-01

The phosphodiesterase (PDE) 5 inhibitor tadalafil is available for treatment of male lower urinary tract symptoms (LUTS), while the role of other PDE isoforms for prostate smooth muscle tone is still unknown. Here, we examined effects of the PDE10-selective inhibitor TC-E 5005 on smooth muscle contraction in human prostate tissue. Prostate samples were obtained from patients undergoing radical prostatectomy. Expression of PDE10 was addressed by RT-PCR, Western blot, and fluorescence staining with different markers. Effects of TC-E 5005 and tadalafil on contraction, and relaxation of prostate strips were studied via organ bath. PDE10A was detectable by RT-PCR, Western blot, and fluorescence staining in prostate tissues. Colocalization with markers suggested expression of PDE10A in smooth muscle cells and catecholaminergic nerves. Norepinephrine, the α1 -adrenergic agonist phenylephrine, the thromboxane A2 analogue U46619, and endothelins 1-3 induced concentration-dependent contractions of prostate strips, while electric field stimulation (EFS) induced frequence-dependent contractions. Application of TC-E 5005 (500 nM) caused significant inhibition of norepinephrine-, phenylephrine-, and endothelin-3-induced contractions. Inhibition of EFS-induced contractions by TC-E 5005 ranged around 50%, resembling inhibition of EFS-induced contractions by tadalafil (10 μM). The prostacyclin analog treprostinil and the nitric oxide donor DEA NONOate induced relaxations of precontracted prostate strips, which were significantly amplified by TCE 5005. The PDE10-selective inhibitor TC-E 5005 inhibits adrenergic and neurogenic smooth muscle contractions in the human prostate. TC-E 5005 inhibits neurogenic contractions with similar efficacy than tadalafil, so that urodynamic effects in vivo appear possible. Prostate 76:1364-1374, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Cannabinoid Type 1 Receptors Transiently Silence Glutamatergic Nerve Terminals of Cultured Cerebellar Granule Cells

PubMed Central

Ramírez-Franco, Jorge; Bartolomé-Martín, David; Alonso, Beatris; Torres, Magdalena; Sánchez-Prieto, José

2014-01-01

Cannabinoid receptors are the most abundant G protein-coupled receptors in the brain and they mediate retrograde short-term inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at many excitatory synapses. The induction of presynaptically silent synapses is a means of modulating synaptic strength, which is important for synaptic plasticity. Persistent activation of cannabinoid type 1 receptors (CB1Rs) mutes GABAergic terminals, although it is unclear if CB1Rs can also induce silencing at glutamatergic synapses. Cerebellar granule cells were transfected with VGLUT1-pHluorin to visualise the exo-endocytotic cycle. We found that prolonged stimulation (10 min) of cannabinoid receptors with the agonist HU-210 induces the silencing of previously active synapses. However, the presynaptic silencing induced by HU-210 is transient as it reverses after 20 min. cAMP with forskolin prevented CB1R-induced synaptic silencing, via activation of the Exchange Protein directly Activated by cAMP (Epac). Furthermore, Epac activation accelerated awakening of already silent boutons. Electron microscopy revealed that silencing was associated with synaptic vesicle (SV) redistribution within the nerve terminal, which diminished the number of vesicles close to the active zone of the plasma membrane. Finally, by combining functional and immunocytochemical approaches, we observed a strong correlation between the release capacity of the nerve terminals and RIM1α protein content, but not that of Munc13-1 protein. These results suggest that prolonged stimulation of cannabinoid receptors can transiently silence glutamatergic nerve terminals. PMID:24533119

A study of the role of renal nerves in the renal responses to 60° head-up tilt in the anaesthetized dog

PubMed Central

DiBona, G. F.; Johns, E. J.

1980-01-01

1. Renal responses to 10 min of 60° head-up tilt were measured in anaesthetized dogs in which renal perfusion pressure was maintained at a relatively constant value. 2. Tilting was associated with a fall in systemic blood pressure and an increase in heart rate. Renal blood flow and glomerular filtration rate remained constant while there was a significant decrease in both absolute and fractional excretion of sodium. 3. Animals which had undergone acute renal denervation were tilted. The cardiovascular responses were similar to intact animals. A fall in renal blood flow was observed but the glomerular filtration rate was maintained at a steady value during tilting. The decreased renal tubular excretion of sodium measured in intact animals was abolished. 4. Alpha-adrenergic blockade of the kidney was achieved by infusion of phentolamine into the renal artery. Tilting of these animals caused cardiovascular changes similar to those observed in control animals but renal blood flow, glomerular filtration rate and sodium handling remained unchanged. 5. Animals in which both carotid sinuses had been acutely denervated were tilted. Systemic blood pressure fell as in intact animals, but the rise in heart rate was significantly less. Renal blood flow, glomerular filtration rate and the rate of sodium excretion were unchanged. 6. A 10 min period of 60° head-up tilt in anaesthetized dogs resulted in an unchanged renal blood flow and glomerular filtration rate which was associated with a decrease in both fractional excretion of sodium and sodium excretion. The renal sympathetic nerves were shown to be responsible for these changes in tubular sodium handling which appeared to exert their action via renal tubular α-adrenergic receptors. This activation of the renal nerves appeared to be mediated by the carotid sinus baroreceptor reflex. PMID:7381761

Development of the peptidergic innervation of human heart.

PubMed Central

Gordon, L; Polak, J M; Moscoso, G J; Smith, A; Kuhn, D M; Wharton, J

1993-01-01

The aim of the present investigation was to study the developing peptidergic innervation of the human fetal heart of 7-24 wk gestational age. An immunohistochemical approach was adopted and the total innervation visualised with antisera to general neuronal and Schwann cell markers, while the onset and development of specific neuropeptide-containing subpopulations were investigated using antisera to neuropeptide Y (NPY), somatostatin, vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and substance P (SP). Cardiac ganglia and nerves were demonstrated from 7 wk of gestation whereas peptide-immunoreactive nerves were not observed until the 10th week of gestation. NPY-immunoreactive nerve fibres constituted the major subpopulation of peptide-containing nerves identified in the fetal heart, exhibiting a descending atrial to ventricular density gradient, and were first identified during the 10th wk of gestation. Somatostatin- and VIP-immunoreactive nerves appeared at 10-12 wk of gestation and were mainly distributed in the atria. Somatostatin immunoreactivity was localised to cell bodies in cardiac ganglia, as well as to nerve fibres, indicating an intrinsic origin for this nerve subpopulation. Conversely, the other peptide-containing nerves appear to be of extrinsic origin, including those immunoreactive for VIP. Intracardiac neurons exhibit a transient expression of tyrosine hydroxylase immunoreactivity. Putative sympathetic nerve fibres, displaying tyrosine hydroxylase and NPY immunoreactivity, were demonstrated before the adrenergic innervation has previously been shown to be present by formaldehyde-induced fluorescence staining of catecholamines. The onset of the CGRP- and SP-immunoreactive innervation, at 18-24 wk of gestation, followed the appearance of other peptide-containing nerves, suggesting that the sensory, afferent innervation occurs later than the autonomic. The differential appearance and distribution of peptide-containing nerve subpopulations indicate that there is a chronological order to the development of the autonomic and sensory components of human cardiac innervation. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:7505778

Recovery of the sub-basal nerve plexus and superficial nerve terminals after corneal epithelial injury in mice.

PubMed

Downie, Laura E; Naranjo Golborne, Cecilia; Chen, Merry; Ho, Ngoc; Hoac, Cam; Liyanapathirana, Dasun; Luo, Carol; Wu, Ruo Bing; Chinnery, Holly R

2018-06-01

Our aim was to compare regeneration of the sub-basal nerve plexus (SBNP) and superficial nerve terminals (SNT) following corneal epithelial injury. We also sought to compare agreement when quantifying nerve parameters using different image analysis techniques. Anesthetized, female C57BL/6 mice received central 1-mm corneal epithelial abrasions. Four-weeks post-injury, eyes were enucleated and processed for PGP9.5 to visualize the corneal nerves using wholemount immunofluorescence staining and confocal microscopy. The percentage area of the SBNP and SNT were quantified using: ImageJ automated thresholds, ImageJ manual thresholds and manual tracings in NeuronJ. Nerve sum length was quantified using NeuronJ and Imaris. Agreement between methods was considered with Bland-Altman analyses. Four-weeks post-injury, the sum length of nerve fibers in the SBNP, but not the SNT, was reduced compared with naïve eyes. In the periphery, but not central cornea, of both naïve and injured eyes, nerve fiber lengths in the SBNP and SNT were strongly correlated. For quantifying SBNP nerve axon area, all image analysis methods were highly correlated. In the SNT, there was poor correlation between manual methods and auto-thresholding, with a trend towards underestimating nerve fiber area using auto-thresholding when higher proportions of nerve fibers were present. In conclusion, four weeks after superficial corneal injury, there is differential recovery of epithelial nerve axons; SBNP sum length is reduced, however the sum length of SNTs is similar to naïve eyes. Care should be taken when selecting image analysis methods to compare nerve parameters in different depths of the corneal epithelium due to differences in background autofluorescence. Copyright © 2018 Elsevier Ltd. All rights reserved.

Cigarette smoking impairs nitric oxide-mediated cerebral blood flow increase: Implications for Alzheimer's disease.

PubMed

Toda, Noboru; Okamura, Tomio

2016-08-01

Cerebral blood flow is mainly regulated by nitrergic (parasympathetic, postganglionic) nerves and nitric oxide (NO) liberated from endothelial cells in response to shear stress and stretch of vasculature, whereas sympathetic vasoconstrictor control is quite weak. On the other hand, peripheral vascular resistance and blood flow are mainly controlled by adrenergic vasoconstrictor nerves; endothelium-derived NO and nitrergic nerves play some roles as vasodilator factors. Cigarette smoking impairs NO synthesis in cerebral vascular endothelial cells and nitrergic nerves leading to interference with cerebral blood flow and glucose metabolism in the brain. Smoking-induced cerebral hypoperfusion is induced by impairment of synthesis and actions of NO via endothelial nitric oxide synthase (eNOS)/neuronal NOS (nNOS) inhibition and by increased production of oxygen radicals, resulting in decreased actions of NO on vascular smooth muscle. Nicotine acutely and chronically impairs the action of endothelial NO and also inhibits nitrergic nerve function in chronic use. Impaired cerebral blood supply promotes the synthesis of amyloid β that accelerates blood flow decrease. This vicious cycle is thought to be one of the important factors involving in Alzheimer's disease (AD). Quitting smoking is undoubtedly one of the important ways to prevent and delay the genesis or slow the progress of impaired cognitive function and AD. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Immunocytochemical localization of glutamic acid decarboxylase (GAD) and substance P in neural areas mediating motion-induced emesis: Effects of vagal stimulation on GAD immunoreactivity

NASA Technical Reports Server (NTRS)

Damelio, F.; Gibbs, M. A.; Mehler, W. R.; Daunton, Nancy G.; Fox, Robert A.

1991-01-01

Immunocytochemical methods were employed to localize the neurotransmitter amino acid gamma-aminobutyric acid (GABA) by means of its biosynthetic enzyme glutamic acid decarboxylase (GAD) and the neuropeptide substance P in the area postrema (AP), area subpostrema (ASP), nucleus of the tractus solitarius (NTS), and gelatinous nucleus (GEL). In addition, electrical stimulation was applied to the night vagus nerve at the cervical level to assess the effects on GAD-immunoreactivity (GAR-IR). GAD-IR terminals and fibers were observed in the AP, ASP, NTS, and GEL. They showed pronounced density at the level of the ASP and gradual decrease towards the solitary complex. Nerve cells were not labelled in our preparations. Ultrastructural studies showed symmetric or asymmetric synaptic contracts between labelled terminals and non-immunoreactive dendrites, axons, or neurons. Some of the labelled terminals contained both clear- and dense-core vesicles. Our preliminary findings, after electrical stimulation of the vagus nerve, revealed a bilateral decrease of GAD-IR that was particularly evident at the level of the ASP. SP-immunoreactive (SP-IR) terminals and fibers showed varying densities in the AP, ASP, NTS, and GEL. In our preparations, the lateral sub-division of the NTS showed the greatest accumulation. The ASP showed medium density of immunoreactive varicosities and terminals and the AP and GEL displayed scattered varicose axon terminals. The electron microscopy revealed that all immunoreactive terminals contained clear-core vesicles which make symmetric or asymmetric synaptic contact with unlabelled dendrites. It is suggested that the GABAergic terminals might correspond to vagal afferent projections and that GAD/GABA and substance P might be co-localized in the same terminal allowing the possibility of a regulated release of the transmitters in relation to demands.

Laboratory practical to study the differential innervation pathways of urinary tract smooth muscle.

PubMed

Rembetski, Benjamin E; Cobine, Caroline A; Drumm, Bernard T

2018-06-01

In the mammalian lower urinary tract, there is a reciprocal relationship between the contractile state of the bladder and urethra. As the bladder fills with urine, it remains relaxed to accommodate increases in volume, while the urethra remains contracted to prevent leakage of urine from the bladder to the exterior. Disruptions to the normal contractile state of the bladder and urethra can lead to abnormal micturition patterns and urinary incontinence. While both the bladder and urethra are smooth-muscle organs, they are differentially contracted by input from cholinergic and sympathetic nerves, respectively. The laboratory practical described here provides an experiential approach to understanding the anatomy of the lower urinary tract. Several key factors in urinary tract physiology are outlined, e.g., the bladder is contracted by activation of the parasympathetic pathway via cholinergic stimulation on muscarinic receptors, whereas the urethra is contracted by activation of the sympathetic pathway via adrenergic stimulation on α 1 -adrenoceptors. This is achieved by measuring the force generated by bladder and urethra smooth muscle to demonstrate that acetylcholine contracts the smooth muscle of the bladder, whereas adrenergic agonists contract the urethral smooth muscle. An inhibition of these effects is also demonstrated by application of the muscarinic receptor antagonist atropine and the α 1 -adrenergic receptor blocker phentolamine. A list of suggested techniques and exam questions to evaluate student understanding on this topic is also provided.

Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro.

PubMed

Hassel, Bjørnar; Elsais, Ahmed; Frøland, Anne-Sofie; Taubøll, Erik; Gjerstad, Leif; Quan, Yi; Dingledine, Raymond; Rise, Frode

2015-05-01

Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer's disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [(14) C]fructose or its AGE-prone metabolite [(14) C]glyceraldehyde into rat neocortex in vivo led to formation of (14) C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [(14) C]fructose-labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. This was supported by high expression of hexokinase 1, which channels fructose into glycolysis, and whose activity was similar with fructose or glucose as substrates. By contrast, the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only 4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. The genes encoding aldose reductase and sorbitol dehydrogenase, enzymes of the polyol pathway that forms glucose from fructose, were expressed in rat neocortex. These results point to fructose being transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity. We asked how the brain handles fructose, which may react spontaneously with proteins to form 'advanced glycation end products' and trigger inflammation. Neocortical cells took up and metabolized extracellular fructose oxidatively in vivo, and isolated nerve terminals did so in vitro. The low expression of fructose transporter Glut5 limited uptake of extracellular fructose. Hexokinase was a main pathway for fructose metabolism, but ketohexokinase (which leads to glyceraldehyde formation) was expressed too. Neocortical cells also took up and metabolized glyceraldehyde oxidatively. © 2015 International Society for Neurochemistry.

Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity.

PubMed

Pardanaud, Luc; Pibouin-Fragner, Laurence; Dubrac, Alexandre; Mathivet, Thomas; English, Isabel; Brunet, Isabelle; Simons, Michael; Eichmann, Anne

2016-08-19

Arterial endothelial cells are morphologically, functionally, and molecularly distinct from those found in veins and lymphatic vessels. How arterial fate is acquired during development and maintained in adult vessels is incompletely understood. We set out to identify factors that promote arterial endothelial cell fate in vivo. We developed a functional assay, allowing us to monitor and manipulate arterial fate in vivo, using arteries isolated from quails that are grafted into the coelom of chick embryos. Endothelial cells migrate out from the grafted artery, and their colonization of host arteries and veins is quantified. Here we show that sympathetic innervation promotes arterial endothelial cell fate in vivo. Removal of sympathetic nerves decreases arterial fate and leads to colonization of veins, whereas exposure to sympathetic nerves or norepinephrine imposes arterial fate. Mechanistically, sympathetic nerves increase endothelial ERK (extracellular signal-regulated kinase) activity via adrenergic α1 and α2 receptors. These findings show that sympathetic innervation promotes arterial endothelial fate and may lead to novel approaches to improve arterialization in human disease. © 2016 American Heart Association, Inc.

Morphology of P2X3-immunoreactive nerve endings in the rat laryngeal mucosa.

PubMed

Takahashi, Natsumi; Nakamuta, Nobuaki; Yamamoto, Yoshio

2016-02-01

The morphological characteristics of P2X3-immunoreactive nerve endings in the laryngeal mucosa were herein examined using immunohistochemistry with confocal laser microscopy. Ramified intraepithelial nerve endings immunoreactive to P2X3 were distributed in the epiglottis and arytenoid region. The axon terminals of P2X3-immunoreactive ramified endings were beaded or flat in shape. These endings were also immunoreactive to P2X2 and not identical to the nerve endings immunoreactive to Na(+)-K(+)-ATPase α3-subunit, substance P (SP), and calcitonin gene-related peptide (CGRP). P2X3-immunoreactive axon terminals were also immunoreactive to vGLUT1, vGLUT2, and vGLUT3. In addition to ramified endings, P2X3-immunoreactive nerve endings were associated with α-gustducin-immunoreactive solitary chemosensory cells and/or SNAP25-immunoreactive neuroendocrine cells. Furthermore, P2X3-immunoreactive nerve endings were also observed in the taste bud-like chemosensory cell clusters of the stratified squamous epithelium covering epiglottic and arytenoid cartilage. The P2X3-immunoreactive nerve endings that associated with sensory and/or endocrine cells and chemosensory cell clusters were also immunoreactive to P2X2, vGLUT1, vGLUT2, and vGLUT3, but not to SP or CGRP. In conclusion, P2X3-immunoreactive nerve endings may be classified into two types, i.e., intraepithelial ramified nerve endings and nerve endings associated with chemosensory cells and neuroendocrine cells.

Facilitatory effects of piracetam on excitability of motor nerve terminals and neuromuscular transmission.

PubMed

Hall, E D; Von Voigtlander, P F

1987-11-01

The possible in vivo facilitatory effects of the pyrrolidine acetamide no-otropic agent piracetam on neuromuscular transmission, were studied based upon reports of enhancement of central cholinergic function. Piracetam was shown to antagonize the lethal effects of the neuromuscular blocking agent hemicholinium-3 (HC-3), in female CF-1 mice when administered in a dose of 100 mg/kg (i.p.) simultaneously with HC-3. A 30 mg/kg (i.p.) dose of piracetam was ineffective by itself, although it potentiated the protective effects of choline (25 mg/kg i.p.). The analogs of piracetam, aniracetam, oxiracetam, pramiracetam and dupracetam also significantly antagonized the lethality of HC-3 at doses over a 30-300 mg/kg range. The acute facilitatory properties of piracetam on neuromuscular transmission were examined in more detail in vivo in the soleus nerve muscle preparation of the cat. A 100 mg/kg (i.v.) dose of piracetam, while having no effect on its own, significantly enhanced the ability of a 200 micrograms/kg (i.v.) dose of edrophonium to produce a potentiation of muscle contraction dependent on repetitive discharges in the soleus motor nerve terminals. In preparations in which the motor nerve terminals of the soleus were in a partially degenerated state as a result of section of the motor axons 48 hr earlier, piracetam acted to restore their sensitivity to edrophonium. Furthermore, in both normal and partially degenerated preparations, piracetam significantly decreased the neuromuscular blocking effects of a 150 micrograms/kg (i.v.) dose of d-tubocurarine. The mechanism of the neuromuscular facilitatory effects of piracetam on neuromuscular transmission is discussed in terms of an enhanced excitability of motor nerve terminals together with an action to increase the synthesis and/or release of acetylcholine.

The origin of the post-tetanic hyperpolarization of mammalian motor nerve terminals

PubMed Central

Gage, P. W.; Hubbard, J. I.

1966-01-01

1. Motor nerve terminals in magnesium-poisoned rat hemidiaphragm-phrenic nerve preparations in vitro were stimulated with short depolarizing pulses of approximately threshold strength and the evoked antidromic responses recorded from the phrenic nerve. The percentage of these 1/sec or 0·5/sec stimuli to which there was no antidromic response was used as a quantitative measure of the terminal excitability. After standard tetanic stimulation (1000 impulses at 100/sec) the excitability of the terminals was depressed for an average duration of 60-70 sec, during most of which time no antidromic responses to stimuli of pretetanic intensity were recorded. There was no significant interaction between stimuli to the terminals at rates of 1 or 0·5/sec. 2. Potassium-free solutions at first increased, then decreased, the post-tetanic depression of excitability. Raising [K]o threefold (15 mM) abolished the post-tetanic depression and often converted it to an exaltation of excitability. 3. Polarizing currents were applied to the terminals with a second electrode. Depolarizing currents increased, while hyperpolarizing currents decreased, the post-tetanic depression of excitability. 4. In solutions with 70% of the normal NaCl content replaced by sucrose, the post-tetanic depression of excitability was reversibly prolonged. 5. In the presence of 7·7 × 10-6 M digoxin or 0·42 mM ouabain there was a small reversible reduction of post-tetanic excitability. 6. After exposure to solutions containing no glucose or to solutions containing 3-5 mM sodium azide the excitability of the terminals was not altered by the tetanus. After washing with the control solution, post-tetanic depression of excitability returned. Antimycin-A (1·8 × 10-6 M) had little or no effect upon post-tetanic excitability. 7. It was concluded that the post-tetanic depression of excitability reflected hyperpolarization of the terminals and that this hyperpolarization was caused by a shift of the membrane potential towards the potassium equilibrium potential because of an increase in potassium permeability. ImagesFig. 1 PMID:5921834

Variation in Lingual Nerve Course: A Human Cadaveric Study

PubMed Central

Al-Amery, Samah M.; Nambiar, Phrabhakaran; Naidu, Murali

2016-01-01

The lingual nerve is a terminal branch of the mandibular nerve. It is varied in its course and in its relationship to the mandibular alveolar crest, submandibular duct and also the related muscles in the floor of the mouth. This study aims to understand the course of the lingual nerve from the molar area until its insertion into the tongue muscle. This cadaveric research involved the study of 14 hemi-mandibles and consisted of two parts: (i) obtaining morphometrical measurements of the lingual nerve to three landmarks on the alveolar ridge, and (b) understanding non-metrical or morphological appearance of its terminal branches inserting in the ventral surface of the tongue. The mean distance between the fourteen lingual nerves and the alveolar ridge was 12.36 mm, and they were located 12.03 mm from the lower border of the mandible. These distances were varied when near the first molar (M1), second molar (M2) and third molar (M3). The lingual nerve coursed on the floor of the mouth for approximately 25.43 mm before it deviated toward the tongue anywhere between the mesial of M1 and distal of M2. Thirteen lingual nerves were found to loop around the submandibular duct for an average distance of 6.92 mm (95% CI: 5.24 to 8.60 mm). Their looping occurred anywhere between the M2 and M3. In 76.9% of the cases the loop started around the M3 region and the majority (69.2%) of these looping ended at between the first and second molars and at the lingual developmental groove of the second molar. It gave out as many as 4 branches at its terminal end at the ventral surface of the tongue, with the presence of 2 branches being the most common pattern. An awareness of the variations of the lingual nerve is important to prevent any untoward complications or nerve injury and it is hoped that these findings will be useful for planning of surgical procedures related to the alveolar crest, submandibular gland/ duct and surrounding areas. PMID:27662622

Gross anatomy and development of the peripheral nervous system.

PubMed

Catala, Martin; Kubis, Nathalie

2013-01-01

The nervous system is divided into the central nervous system (CNS) composed of the brain, the brainstem, the cerebellum, and the spinal cord and the peripheral nervous system (PNS) made up of the different nerves arising from the CNS. The PNS is divided into the cranial nerves III to XII supplying the head and the spinal nerves that supply the upper and lower limbs. The general anatomy of the PNS is organized according to the arrangement of the fibers along the rostro-caudal axis. The control of the development of the PNS has been unravelled during the last 30 years. Motor nerves arise from the ventral neural tube. This ventralization is induced by morphogenetic molecules such as sonic hedgehog. In contrast, the sensory elements of the PNS arise from a specific population of cells originating from the roof of the neural tube, namely the neural crest. These cells give rise to the neurons of the dorsal root ganglia, the autonomic ganglia and the paraganglia including the adrenergic neurons of the adrenals. Furthermore, the supportive glial Schwann cells of the PNS originate from the neural crest cells. Growth factors as well as myelinating proteins are involved in the development of the PNS. Copyright © 2013 Elsevier B.V. All rights reserved.

Evidence for crustacean cardioactive peptide-like innervation of the gut in Locusta migratoria.

PubMed

Donini, Andrew; Ngo, Caroline; Lange, Angela B

2002-11-01

Hindguts from female Vth instar larvae, young adults (1-2 days) and old adults (>10 days) are equally sensitive to the crustacean cardioactive peptide (CCAP), with changes in contraction occurring at a threshold concentration of 10(-9)M and maximal responses observed at concentrations ranging between 10(-7) and 5x10(-6)M. An immunohistochemical examination of the gut of Locusta migratoria with an antiserum raised against CCAP revealed an extensive network of CCAP-like immunoreactive processes on the hindgut and posterior midgut via the 11th sternal nerve arising from the terminal abdominal ganglion. Anterograde filling of the 11th sternal nerve with neurobiotin revealed extensive processes and terminals on the hindgut. Retrograde filling of the branch of the 11th sternal nerve which innervates the hindgut with neurobiotin revealed two bilaterally paired cells in the terminal abdominal ganglion which co-localized with CCAP-like immunoreactivity. Results suggest that a CCAP-like substance acts as a neurotransmitter/neuromodulator at the locust hindgut.

Stevia Nonsweetener Fraction Displays an Insulinotropic Effect Involving Neurotransmission in Pancreatic Islets.

PubMed

Piovan, Silvano; Pavanello, Audrei; Peixoto, Giuliana Maria Ledesma; Matiusso, Camila Cristina Ianoni; de Moraes, Ana Maria Praxedes; Martins, Isabela Peixoto; Malta, Ananda; Palma-Rigo, Kesia; da Silva Franco, Claudinéia Conationi; Milani, Paula Gimenez; Dacome, Antonio Sérgio; da Costa, Silvio Claudio; de Freitas Mathias, Paulo Cezar; Mareze-Costa, Cecília Edna

2018-01-01

Stevia rebaudiana (Bert.) Bertoni besides being a source of noncaloric sweeteners is also an important source of bioactive molecules. Many plant extracts, mostly obtained with ethyl acetate solvent, are rich in polyphenol compounds that present insulinotropic effects. To investigate whether the nonsweetener fraction, which is rich in phenolic compounds isolated from Stevia rebaudiana with the solvent ethyl acetate (EAF), has an insulinotropic effect, including interference at the terminals of the autonomic nervous system of the pancreatic islets of rats. Pancreatic islets were isolated from Wistar rats and incubated with EAF and inhibitory or stimulatory substances of insulin secretion, including cholinergic and adrenergic agonists and antagonists. EAF potentiates glucose-stimulated insulin secretion (GSIS) only in the presence of high glucose and calcium-dependent concentrations. EAF increased muscarinic insulinotropic effects in pancreatic islets, interfering with the muscarinic receptor subfamily M 3 . Adrenergic inhibitory effects on GSIS were attenuated in the presence of EAF, which interfered with the adrenergic α 2 receptor. Results suggest that EAF isolated from stevia leaves is a potential therapy for treating type 2 diabetes mellitus by stimulating insulin secretion only in high glucose concentrations, enhancing parasympathetic signal transduction and inhibiting sympathetic signal transduction in beta cells.

Stevia Nonsweetener Fraction Displays an Insulinotropic Effect Involving Neurotransmission in Pancreatic Islets

PubMed Central

Pavanello, Audrei; Peixoto, Giuliana Maria Ledesma; Matiusso, Camila Cristina Ianoni; de Moraes, Ana Maria Praxedes; Martins, Isabela Peixoto; Palma-Rigo, Kesia; da Silva Franco, Claudinéia Conationi; Milani, Paula Gimenez; Dacome, Antonio Sérgio; da Costa, Silvio Claudio; de Freitas Mathias, Paulo Cezar; Mareze-Costa, Cecília Edna

2018-01-01

Stevia rebaudiana (Bert.) Bertoni besides being a source of noncaloric sweeteners is also an important source of bioactive molecules. Many plant extracts, mostly obtained with ethyl acetate solvent, are rich in polyphenol compounds that present insulinotropic effects. To investigate whether the nonsweetener fraction, which is rich in phenolic compounds isolated from Stevia rebaudiana with the solvent ethyl acetate (EAF), has an insulinotropic effect, including interference at the terminals of the autonomic nervous system of the pancreatic islets of rats. Pancreatic islets were isolated from Wistar rats and incubated with EAF and inhibitory or stimulatory substances of insulin secretion, including cholinergic and adrenergic agonists and antagonists. EAF potentiates glucose-stimulated insulin secretion (GSIS) only in the presence of high glucose and calcium-dependent concentrations. EAF increased muscarinic insulinotropic effects in pancreatic islets, interfering with the muscarinic receptor subfamily M3. Adrenergic inhibitory effects on GSIS were attenuated in the presence of EAF, which interfered with the adrenergic α 2 receptor. Results suggest that EAF isolated from stevia leaves is a potential therapy for treating type 2 diabetes mellitus by stimulating insulin secretion only in high glucose concentrations, enhancing parasympathetic signal transduction and inhibiting sympathetic signal transduction in beta cells. PMID:29853880

Immunohistochemical demonstration of enkephalin-containing nerve fibers in guinea pig and rat lungs.

PubMed

Shimosegawa, T; Foda, H D; Said, S I

1989-08-01

Met-enkephalin (Met-Enk) and Leu-enkephalin (Leu-Enk), the opioid peptides originally isolated from the brain, are believed to act as inhibitory neuromodulators at various synaptic sites. In this immunohistochemical study, we have investigated the localization and distribution of Met- and Leu-Enk immunoreactivities in airways and pulmonary vessels of guinea pigs and rats. Immunoreactivities to both peptides were found in nerve fibers and nerve terminals distributed mainly to the trachea and major bronchi, and were especially prevalent in the smooth muscle layer, in the lamina propria, and around tracheal and bronchial glands, but not in the epithelium. Few immunoreactive nerve fibers were detected in smaller bronchi, bronchioles, and alveoli. Enkephalin-immunoreactive nerve fibers were also localized in the walls of pulmonary and bronchial vessels. Within airway microganglia, immunoreactivity was observed in a few nerve terminals, but not in ganglion cell bodies. Met- and Leu-Enk immunoreactive nerve fibers showed similar distribution patterns, though minor differences were noted between the two species: Enk-immunoreactive nerve fibers in the smooth muscle layer were more abundant in guinea pigs than in rats, whereas those in mucous glands were richer in rats than in guinea pigs. These results document the presence of Met- and Leu-Enk immunoreactivity in nerve fibers supplying guinea pig and rat airways and pulmonary vessels, and provide a morphologic basis for the view that enkephalins are likely neurotransmitters or neuromodulators in the lung.

Kisspeptin level in the aging ovary is regulated by the sympathetic nervous system.

PubMed

Fernandois, Daniela; Cruz, Gonzalo; Na, Eun Kyung; Lara, Hernán E; Paredes, Alfonso H

2017-01-01

Previous work has demonstrated that the increase in the activity of sympathetic nerves, which occurs during the subfertility period in female rats, causes an increase in follicular cyst development and impairs follicular development. In addition, the increase in ovarian sympathetic activity of aged rats correlates with an increased expression of kisspeptin (KISS1) in the ovary. This increase in KISS1 could participate in the decrease in follicular development that occurs during the subfertility period. We aimed to determine whether the blockade of ovarian sympathetic tone prevents the increase in KISS1 expression during reproductive aging and improves follicular development. We performed 2 experiments in rats: (1) an in vivo blockade of beta-adrenergic receptor with propranolol (5.0 mg/kg) and (2) an ovarian surgical denervation to modulate the sympathetic system at these ages. We measured Kisspeptin and follicle-stimulating hormone receptor (FSHR) mRNA and protein levels by qRT-PCR and western blot and counted primordial, primary and secondary follicles at 8, 10 and 12 months of age. The results showed that ovarian KISS1 decreased but FSHR increased after both propranolol administration and the surgical denervation in rats of 8, 10 and 12 months of age. An increase in FSHR was related to an increase in the number of smaller secondary follicles and a decreased number of primordial follicles at 8, 10 and 12 months of age. These results suggest that intraovarian KISS1 is regulated by sympathetic nerves via a beta-adrenergic receptor and participates locally in ovarian follicular development in reproductive aging. © 2017 Society for Endocrinology.

Longterm effects of cardiac mediastinal nerve cryoablation on neural inducibility of atrial fibrillation in canines.

PubMed

Leiria, Tiago Luiz Luz; Glavinovic, Tamara; Armour, J Andrew; Cardinal, René; de Lima, Gustavo Glotz; Kus, Teresa

2011-04-26

In canines, excessive activation of select mediastinal nerve inputs to the intrinsic cardiac nervous system induces atrial fibrillation (AF). Since ablation of neural elements is proposed as an adjunct to circumferential pulmonary vein ablation for AF, we investigated the short and long-term effects of mediastinal nerve ablation on AF inducibility. Under general anesthesia, in 11 dogs several mediastinal nerve sites were identified on the superior vena cava that, when stimulated electrically during the atrial refractory period, reproducibly initiated AF. Cryoablation of one nerve site was then performed and inducibility retested early (1-2 months post Cryo; n=7) or late (4 months post Cryo; n=4). Four additional dogs that underwent a sham procedure were retested 1 to 2 months post-surgery. Stimulation induced AF at 91% of nerve sites tested in control versus 21% nerve sites early and 54% late post-ablation (both P<0.05). Fewer stimuli were required to induce AF in controls versus the Early Cryo group; this capacity returned to normal values in the Late Cryo group. AF episodes were longer in control versus the Early or Late Cryo groups. Heart rate responses to vagal or stellate ganglion stimulation, as well as to local nicotine infusion into the right coronary artery, were similar in all groups. In conclusion, focal damage to intrinsic cardiac neuronal inputs causes short-term stunning of neuronal inducibility of AF without major loss of overall adrenergic or cholinergic efferent neuronal control. That recovery of AF inducibility occurs rapidly post-surgery indicates the plasticity of intrathoracic neuronal elements to focal injury. Copyright © 2011 Elsevier B.V. All rights reserved.

N-cadherin expression in palisade nerve endings of rat vellus hairs.

PubMed

Kaidoh, Toshiyuki; Inoué, Takao

2008-02-01

Palisade nerve endings (PNs) are mechanoreceptors around vellus hairs of mammals. Each lanceolate nerve ending (LN) of the PN is characterized by a sensory nerve ending symmetrically sandwiched by two processes of type II terminal Schwann cells (tSCIIs). However, the molecular mechanisms underlying the structural organization of the PN are poorly understood. Electron microscopy showed that adherens junctions appeared to adhere to the sensory nerve ending and tSCII processes, so we examined the location of the N-cadherin adhesion system in PNs of rat vellus hairs by using immunoelectron microscopy. N-cadherin localized near both ends of the cell boundary between sensory nerve ending and tSCII processes, which corresponded to the sites of adherens junctions. We further found cadherin-associated proteins, alpha- and beta-catenins, at the linings of adherens junctions. Three-dimensional reconstruction of immunoelectron microscopic serial thin sections showed four linear arrays of N-cadherin arranged longitudinally along the LN beneath the four longitudinal borders of two tSCII processes. In contrast, sensory nerve fibers just proximal to the LNs formed common unmyelinated nerve fibers, in which N-cadherin was located mainly at the mesaxon of type I terminal Schwann cells (tSCIs). These results suggest that the four linear arrays of N-cadherin-mediated junctions adhere the sensory nerve ending and tSCII processes side by side to form the characteristic structure of the LN, and the structural differences between the LNs and the proximal unmyelinated nerve fibers possibly are due to the difference in the pattern of N-cadherin expression between sensory nerve endings and tSCII or tSCI processes. (c) 2007 Wiley-Liss, Inc.

The clinical toxicology of metamfetamine.

PubMed

Schep, Leo J; Slaughter, Robin J; Beasley, D Michael G

2010-08-01

Metamfetamine is a highly addictive amfetamine analog that acts primarily as a central nervous system (CNS) stimulant. The escalating abuse of this drug in recent years has lead to an increasing burden upon health care providers. An understanding of the drug's toxic effects and their medical treatment is therefore essential for the successful management of patients suffering this form of intoxication. The aim of this review is to summarize all main aspects of metamfetamine poisoning including epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management. A summary of the literature on metamfetamine was compiled by systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news reports, and web material. Epidemiology. Following its use in the Second World War, metamfetamine gained popularity as an illicit drug in Japan and later the United States. Its manufacture and use has now spread to include East and South-East Asia, North America, Mexico, and Australasia, and its world-wide usage, when combined with amfetamine, exceeds that of all other drugs of abuse except cannabis. Mechanisms of toxicity. Metamfetamine acts principally by stimulating the enhanced release of catecholamines from sympathetic nerve terminals, particularly of dopamine in the mesolimbic, mesocortical, and nigrostriatal pathways. The consequent elevation of intra-synaptic monoamines results in an increased activation of central and peripheral α±- and β-adrenergic postsynaptic receptors. This can cause detrimental neuropsychological, cardiovascular, and other systemic effects, and, following long-term abuse, neuronal apoptosis and nerve terminal degeneration. Toxicokinetics. Metamfetamine is rapidly absorbed and well distributed throughout the body, with extensive distribution across high lipid content tissues such as the blood-brain barrier. In humans the major metabolic pathways are aromatic hydroxylation producing 4-hydroxymetamfetamine and N-demethylation to form amfetamine. Metamfetamine is excreted predominantly in the urine and to a lesser extent by sweating and fecal excretion, with reported terminal half-lives ranging from ∼5 to 30 h. Clinical features. The clinical effects of metamfetamine poisoning can vary widely, depending on dose, route, duration, and frequency of use. They are predominantly characteristic of an acute sympathomimetic toxidrome. Common features reported include tachycardia, hypertension, chest pain, various cardiac dysrhythmias, vasculitis, headache, cerebral hemorrhage, hyperthermia, tachypnea, and violent and aggressive behaviour. Management. Emergency stabilization of vital functions and supportive care is essential. Benzodiazepines alone may adequately relieve agitation, hypertension, tachycardia, psychosis, and seizure, though other specific therapies can also be required for sympathomimetic effects and their associated complications. Metamfetamine may cause severe sympathomimetic effects in the intoxicated patient. However, with appropriate, symptom-directed supportive care, patients can be expected to make a full recovery.

Modulation of the Cholinergic Mechanisms in the Bronchial Smooth Muscle.

DTIC Science & Technology

1984-06-01

after addition of the muscarinic agonist oxotremorine . Presynaptic Ach receptors were first reported to occur on nor- adrenergic terminals...muscarinic agonist, oxotremorine , reduced the output of [3H,-Ach by only 20% (Paper IV, Figure 4). This is a strong indication for the existence of...presynaptic muscarinic receptors, which modulate the release of Ach. The oxotremorine reduced release of [3H]-Ach upon stimulation was not mediated by a

Active uptake of substance P carboxy-terminal heptapeptide (5-11) into rat brain and rabbit spinal cord slices.

PubMed

Nakata, Y; Kusaka, Y; Yajima, H; Segawa, T

1981-12-01

We previously reported that nerve terminals and glial cells lack an active uptake system capable of terminating transmitter action of substance P (SP). In the present study, we demonstrated the existence of an active uptake system for SP carboxy-terminal heptapeptide, (5-11)SP. When the slices from either rat brain or rabbit spinal cord were incubated with [3H](5-11)SP, the uptake of (5-11)SP into slices was observed. The uptake system has the properties of an active transport mechanism: it is dependent on temperature and sensitive to hypoosmotic treatment and is inhibited by ouabain and dinitrophenol (DNP). In the brain, (5-11)SP was accumulated by means of a high-affinity and a low-affinity uptake system. The Km and the Vmax values for the high-affinity system were 4.20 x 10(-8) M and 7.59 fmol/10 mg wet weight/min, respectively, whereas these values for the low-affinity system were 1.00 x 10(-6) M and 100 fmol/10 mg wet weight/min, respectively. In the spinal cord, there was only one uptake system, with a Km value of 2.16 x 10(-7) M and Vmax value of 26.2 fmol/10 mg wet weight/min. These results suggest that when SP is released from nerve terminals, it is hydrolysed into (5-11)SP before or after acting as a neurotransmitter, which is in turn accumulated into nerve terminals. Therefore, the uptake system may represent a possible mechanism for the inactivation of SP.

Iatrogenic nerve injuries during shoulder surgery.

PubMed

Carofino, Bradley C; Brogan, David M; Kircher, Michelle F; Elhassan, Bassem T; Spinner, Robert J; Bishop, Allen T; Shin, Alexander Y

2013-09-18

The current literature indicates that neurologic injuries during shoulder surgery occur infrequently and result in little if any morbidity. The purpose of this study was to review one institution's experience treating patients with iatrogenic nerve injuries after shoulder surgery. A retrospective review of the records of patients evaluated in a brachial plexus specialty clinic from 2000 to 2010 identified twenty-six patients with iatrogenic nerve injury secondary to shoulder surgery. The records were reviewed to determine the operative procedure, time to presentation, findings on physical examination, treatment, and outcome. The average age was forty-three years (range, seventeen to seventy-two years), and the average delay prior to referral was 5.4 months (range, one to fifteen months). Seven nerve injuries resulted from open procedures done to treat instability; nine, from arthroscopic surgery; four, from total shoulder arthroplasty; and six, from a combined open and arthroscopic operation. The injury occurred at the level of the brachial plexus in thirteen patients and at a terminal nerve branch in thirteen. Fifteen patients (58%) did not recover nerve function after observation and required surgical management. A structural nerve injury (laceration or suture entrapment) occurred in nine patients (35%), including eight of the thirteen who presented with a terminal nerve branch injury and one of the thirteen who presented with an injury at the level of the brachial plexus. Nerve injuries occurring during shoulder surgery can produce severe morbidity and may require surgical management. Injuries at the level of a peripheral nerve are more likely to be surgically treatable than injuries of the brachial plexus. A high index of suspicion and early referral and evaluation should be considered when evaluating patients with iatrogenic neurologic deficits after shoulder surgery.

Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines.

PubMed

Thomas, David M; Dowgiert, Jennifer; Geddes, Timothy J; Francescutti-Verbeem, Dina; Liu, Xiuli; Kuhn, Donald M

2004-09-09

Neurotoxic amphetamines cause damage to monoamine nerve terminals of the striatum by unknown mechanisms. Microglial activation contributes to the neuronal damage that accompanies injury, disease, and inflammation, but a role for these cells in amphetamine-induced neurotoxicity has received little attention. We show presently that D-methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), D-amphetamine, and p-chloroamphetamine, each of which has been linked to dopamine (DA) or serotonin nerve terminal damage, result in microglial activation in the striatum. The non-neurotoxic amphetamines l-methamphetamine, fenfluramine, and DOI do not have this effect. All drugs that cause microglial activation also increase expression of glial fibrillary acidic protein (GFAP). At a minimum, microglial activation serves as a pharmacologically specific marker for striatal nerve terminal damage resulting only from those amphetamines that exert neurotoxicity. Because microglia are known to produce many of the reactive species (e.g., nitric oxide, superoxide, cytokines) that mediate the neurotoxicity of the amphetamine-class of drugs, their activation could represent an early and essential event in the neurotoxic cascade associated with high-dose amphetamine intoxication.

Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep

PubMed Central

Chen, Xiaochuan; Green, Alice S.; Macko, Antoni R.; Yates, Dustin T.; Kelly, Amy C.

2013-01-01

Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and β-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances β-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater (P < 0.05) plasma NE concentrations and exhibited hyperglycemia (P < 0.01) and hypoinsulinemia (P < 0.01) compared with controls. GSIS during the NE infusion was also reduced (P < 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater (P < 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (α1D, α2A, α2C, and β1), G protein subunit-αi-2, and uncoupling protein 2 were lower (P < 0.05) compared with controls, but β-cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets. PMID:24253046

The blood flow in the periodontal ligament regulated by the sympathetic and sensory nerves in the cat.

PubMed

Karita, K; Izumi, H; Tabata, T; Kuriwada, S; Sasano, T; Sanjo, D

1989-01-01

This study was carried out to investigate the nervous control of the blood flow in the periodontal ligament measured by laser Doppler flowmeter. Ten adult cats were anesthetized with pentobarbital sodium (initial dose of 30 mg/kg, i.v. and maintenance dose of 5 mg/kg, i.v.). After enucleating the left eye ball, the superior alveolar nerve was exposed. The bone overlying the labial aspect of the left maxillary canine tooth root was pared away until a transparent layer of bone was left covering the periodontal ligament. A laser light from a probe of the flowmeter fixed at the tooth was beamed through the thinned bone. Three different patterns of responses were observed following the electrical stimulation of the distal end of the cut superior alveolar nerve: an increasing, a decreasing and a biphasic change of blood flow. The application of capsaicin onto the superior alveolar nerve reduced the response of blood flow increase but had no effect on the response of blood flow decrease. On the other hand, the response of blood flow decrease was completely inhibited by the pretreatment with phentolamine while the response of blood flow increase was not affected. The present results suggest that blood flow in the periodontal ligament of cats is controlled by sympathetic alpha-adrenergic fibers for vasoconstriction and by sensory fibers for vasodilation.

Molecular characteristics suggest an effector function of palisade endings in extraocular muscles.

PubMed

Konakci, Kadriye Zeynep; Streicher, Johannes; Hoetzenecker, Wolfram; Blumer, Michael Josef Franz; Lukas, Julius-Robert; Blumer, Roland

2005-01-01

To analyze palisade endings in cat extraocular muscles (EOMs) and to clarify whether these EOM-specific organs are sensory or motor. Twelve cats aged between 1 and 16 years were analyzed. Whole EOM tendons were immunostained using four different combinations of triple fluorescence labeling. Triple labeling included antibodies against choline acetyltransferase (ChAT), neurofilament, synaptophysin, and alpha-bungarotoxin. Preparations were examined by confocal laser scanning microscopy. ChAT-labeled EOMs were also analyzed by immunoelectron microscopy. Three-dimensional reconstructions were made of palisade endings. Palisade endings were found in the distal and proximal myotendinous regions of cat EOMs. These endings arose from thin nerve fibers coming from the muscle and extending into the tendon. There, the nerve fibers turned back 180 degrees to divide into terminal branches around the muscle fiber tips. Terminal branches established numerous contacts with the tendon attached to the muscle fiber tip and only a few contacts with the muscle fiber. Often, nerve fibers forming palisade endings on muscle fiber tips were observed to establish multiple motor contacts on muscle fibers outside palisade endings. Three-dimensional reconstructions depicted the complex morphology of the palisade endings. All nerve fibers supplying palisade endings stained positively for ChAT and neurofilament. All nerve terminals in palisade endings were ChAT and synaptophysin positive. Only neuromuscular contacts in palisade endings were positive for alpha-bungarotoxin, as well. This study provides evidence that palisade endings in cat EOMs have effector function. The findings may be of significance for strabismus surgery because palisade endings are also found in human EOMs.

Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response.

PubMed

Qiao, Guanxi; Chen, Minhui; Bucsek, Mark J; Repasky, Elizabeth A; Hylander, Bonnie L

2018-01-01

An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking β-blockers have better outcomes. Clinical trials testing whether β-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon.

Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response

PubMed Central

Qiao, Guanxi; Chen, Minhui; Bucsek, Mark J.; Repasky, Elizabeth A.; Hylander, Bonnie L.

2018-01-01

An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking β-blockers have better outcomes. Clinical trials testing whether β-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon. PMID:29479349

Inhaled ammonium persulphate inhibits non-adrenergic, non-cholinergic relaxations in the guinea pig isolated trachea.

PubMed

Dellabianca, A; Faniglione, M; De Angelis, S; Colucci, M; Cervio, M; Balestra, B; Tonini, S; Candura, S M

2010-01-01

Persulphates can act both as irritants and sensitizers in inducing occupational asthma. A dysfunction of nervous control regulating the airway tone has been hypothesized as a mechanism underlying bronchoconstriction in asthma. It was the aim of this study to investigate whether inhaled ammonium persulphate affects the non-adrenergic, non-cholinergic (NANC) inhibitory innervation, the cholinergic nerve-mediated contraction or the muscular response to the spasmogens, carbachol or histamine, in the guinea pig epithelium-free, isolated trachea. Male guinea pigs inhaled aerosols containing ammonium persulphate (10 mg/m(3) for 30 min for 5 days during 3 weeks). Control animals inhaled saline aerosol. NANC relaxations to electrical field stimulation at 3 Hz were evaluated in whole tracheal segments as intraluminal pressure changes. Drugs inactivating peptide transmission, nitric oxide synthase, carbon monoxide production by haem oxygenase-2 and soluble guanylyl cyclase were used to assess the involvement of various inhibitory neurotransmitters. Carbachol and histamine cumulative concentration-response curves were obtained. In both groups, nitric oxide and carbon monoxide participated to the same extent as inhibitory neurotransmitters. In exposed animals, the tracheal NANC relaxations were reduced to 45.9 +/- 12.1% (p < 0.01). The cholinergic nerve-mediated contractions to electrical field stimulation and the muscular response to histamine were not modified by ammonium persulphate exposure. The muscular response to carbachol was unaffected up to 1 microM. Conversely, the response to the maximal concentration of carbachol (3 microM) was increased (p < 0.01). Ammonium persulphate inhalation at high concentrations impairs the nervous NANC inhibitory control in the guinea pig airways. This may represent a novel mechanism contributing to persulphate-induced asthma. Copyright 2009 S. Karger AG, Basel.

Presynaptic Proteins as Markers of the Neurotoxic Activity of BmjeTX-I and BmjeTX-II Toxins from Bothrops marajoensis (Marajó Lancehead) Snake Venom.

PubMed

Lisboa, Antonio; Melaré, Rodolfo; Franco, Junia R B; Bis, Carolina V; Gracia, Marta; Ponce-Soto, Luis A; Marangoni, Sérgio; Rodrigues-Simioni, Léa; da Cruz-Höfling, Maria Alice; Rocha, Thalita

2016-01-01

Neuromuscular preparations exposed to B. marajoensis venom show increases in the frequency of miniature end-plate potentials and twitch tension facilitation followed by presynaptic neuromuscular paralysis, without evidences of muscle damage. Considering that presynaptic toxins interfere into the machinery involved in neurotransmitter release (synaptophysin, synaptobrevin, and SNAP25 proteins), the main objective of this communication is to analyze, by immunofluorescence and western blotting, the expression of the synaptic proteins, synaptophysin, synaptobrevin, and SNAP25 and by myography, light, and transmission electron microscopy the pathology of motor nerve terminals and skeletal muscle fibres of chick biventer cervicis preparations (CBC) exposed in vitro to BmjeTX-I and BmjeTX-II toxins from B. marajoensis venom. CBC incubated with toxins showed irreversible twitch tension blockade and unaffected KCl- and ACh-evoked contractures, and the positive colabelling of acetylcholine receptors confirmed that their action was primarily at the motor nerve terminal. Hypercontraction and loose myofilaments and synaptic vesicle depletion and motor nerve damage indicated that the toxins displayed both myotoxic and neurotoxic effect. The blockade resulted from interference on synaptophysin, synaptobrevin, and SNAP25 proteins leading to the conclusion that BmjeTX-I and BmjeTX-II affected neurotransmitter release machinery by preventing the docking of synaptic vesicles to the axolemma of the nerve terminal.

Different role of TTX-sensitive voltage-gated sodium channel (NaV 1) subtypes in action potential initiation and conduction in vagal airway nociceptors.

PubMed

Kollarik, M; Sun, H; Herbstsomer, R A; Ru, F; Kocmalova, M; Meeker, S N; Undem, B J

2018-04-15

The action potential initiation in the nerve terminals and its subsequent conduction along the axons of afferent nerves are not necessarily dependent on the same voltage-gated sodium channel (Na V 1) subunits. The action potential initiation in jugular C-fibres within airway tissues is not blocked by TTX; nonetheless, conduction of action potentials along the vagal axons of these nerves is often dependent on TTX-sensitive channels. This is not the case for nodose airway Aδ-fibres and C-fibres, where both action potential initiation and conduction is abolished by TTX or selective Na V 1.7 blockers. The difference between the initiation of action potentials within the airways vs. conduction along the axons should be considered when developing Na V 1 blocking drugs for topical application to the respiratory tract. The action potential (AP) initiation in the nerve terminals and its subsequent AP conduction along the axons do not necessarily depend on the same subtypes of voltage-gated sodium channels (Na V 1s). We evaluated the role of TTX-sensitive and TTX-resistant Na V 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Almost all of the jugular neurons expressed the TTX-sensitive channel Na V 1.7 along with TTX-resistant Na V 1.8 and Na V 1.9. Tracheal nodose neurons also expressed Na V 1.7 but, less frequently, Na V 1.8 and Na V 1.9. Na V 1.6 were expressed in ∼40% of the jugular and 25% of nodose tracheal neurons. Other Na V 1 α subunits were only rarely expressed. Single fibre recordings were made from the vagal nodose and jugular nerve fibres innervating the trachea or lung in the isolated perfused vagally-innervated preparations that allowed for selective drug delivery to the nerve terminal compartment (AP initiation) or to the desheathed vagus nerve (AP conduction). AP initiation in jugular C-fibres was unaffected by TTX, although it was inhibited by Na V 1.8 blocker (PF-01247324) and abolished by combination of TTX and PF-01247324. However, AP conduction in the majority of jugular C-fibres was abolished by TTX. By contrast, both AP initiation and conduction in nodose nociceptors was abolished by TTX or selective Na V 1.7 blockers. Distinction between the effect of a drug with respect to inhibiting AP in the nerve terminals within the airways vs. at conduction sites along the vagus nerve is relevant to therapeutic strategies involving inhaled Na V 1 blocking drugs. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

Mechanisms underlying electrical and mechanical responses of the bovine retractor penis to inhibitory nerve stimulation and to an inhibitory extract.

PubMed Central

Byrne, N. G.; Muir, T. C.

1985-01-01

The response of the bovine retractor penis (BRP) to stimulation of non-adrenergic, non-cholinergic (NANC) inhibitory nerves and to an inhibitory extract prepared from this muscle have been studied using intracellular microelectrode, sucrose gap and conventional mechanical recording techniques. Both inhibitory nerve stimulation and inhibitory extract hyperpolarized the membrane potential and relaxed spontaneous or guanethidine (3 X 10(-5) M)-induced tone. These effects were accompanied by an increase in membrane resistance. Following membrane potential displacement from an average value of -53 +/- 7 mV (n = 184; Byrne & Muir, 1984) inhibitory potentials to nerve stimulation were abolished at approximately -30 mV; there was no evidence of reversal. Displacement by inward hyperpolarizing current over the range -45 to -60 mV increased the inhibitory response to nerve stimulation and to inhibitory extract; at more negative potential values (above approximately -60 mV) the inhibitory potential decreased and was abolished (approximately -103 mV). There was no evidence of reversal. Removal of [K+]o reversibly reduced hyperpolarization to nerve stimulation and inhibitory extract. No enhancement was observed. Increasing the [K+]o to 20 mM reduced the inhibitory potential to nerve stimulation but this was restored by passive membrane hyperpolarization. Inhibitory potentials were obtained at membrane potential values exceeding that of the estimated EK (-49 mV). [Cl-]o-free or [Cl-]o-deficient solutions reduced and abolished (after some 20-25 min) the hyperpolarization produced by inhibitory nerve stimulation or inhibitory extract. The inhibitory potential amplitude following nerve stimulation was not restored by passive displacement of the membrane potential from -26 to -104 mV approximately. Ouabain (1-5 X 10(-5) M) reduced then (45-60 min later) abolished the inhibitory potential to nerve stimulation. The effects of this drug on the extract were not investigated. It is concluded that the inhibitory response to nerve stimulation and extract in the BRP may involve several ionic species. However, unlike that in gastrointestinal muscles the NANC response in the BRP is accompanied by an increased membrane resistance and does not primarily involve K+. The underlying mechanisms for the inhibitory response to both NANC nerve stimulation and inhibitory extract appear to be similar, compatible with the view that the latter may contain the inhibitory transmitter released from these nerves in this tissue. PMID:4027462

MELANOPHORE BANDS AND AREAS DUE TO NERVE CUTTING, IN RELATION TO THE PROTRACTED ACTIVITY OF NERVES

PubMed Central

Parker, G. H.

1941-01-01

1. When appropriate chromatic nerves are cut caudal bands, cephalic areas, and the pelvic fins of the catfish Ameiurus darken. In pale fishes all these areas will sooner or later blanch. By recutting their nerves all such blanched areas will darken again. 2. These observations show that the darkening of caudal bands, areas, and fins on cutting their nerves is not due to paralysis (Brücke), to the obstruction of central influences such as inhibition (Zoond and Eyre), nor to vasomotor disturbances (Hogben), but to activities emanating from the cut itself. 3. The chief agents concerned with the color changes in Ameiurus are three: intermedin from the pituitary gland, acetylcholine from the dispersing nerves (cholinergic fibers), and adrenalin from the concentrating nerves (adrenergic fibers). The first two darken the fish; the third blanches it. In darkening the dispersing nerves appear to initiate the process and to be followed and substantially supplemented by intermedin. 4. Caudal bands blanch by lateral invasion, cephalic areas by lateral invasion and internal disintegration, and pelvic fins by a uniform process of general loss of tint equivalent to internal disintegration. 5. Adrenalin may be carried in such an oil as olive oil and may therefore act as a lipohumor; it is soluble in water and hence may act as a hydrohumor. In lateral invasion (caudal bands, cephalic areas) it probably acts as a lipohumor and in internal disintegration (cephalic areas, pelvic fins) it probably plays the part of a hydrohumor. 6. The duration of the activity of dispersing nerves after they had been cut was tested by means of the oscillograph, by anesthetizing blocks, and by cold-blocks. The nerves of Ameiurus proved to be unsatisfactory for oscillograph tests. An anesthetizing block, magnesium sulfate, is only partly satisfactory. A cold-block, 0°C., is successful to a limited degree. 7. By means of a cold-block it can be shown that dispersing autonomic nerve fibers in Ameiurus can continue in activity for at least 6½ hours. It is not known how much longer they may remain active. So far as the duration of their activity is concerned dispersing nerve fibers in this fish are unlike other types of nerve fibers usually studied. PMID:19873231

Semi-quantitative ultrastructural analysis of the localization and neuropeptide content of gonadotropin releasing hormone nerve terminals in the median eminence throughout the estrous cycle of the rat.

PubMed

Prevot, V; Dutoit, S; Croix, D; Tramu, G; Beauvillain, J C

1998-05-01

The ultrastructural appearance of gonadotropin releasing hormone-immunoreactive elements was studied in the external zone of the median eminence of adult female Wistar rats. On the one hand, the purpose of the study was to determine the distribution of gonadotropin releasing hormone terminals towards the parenchymatous basal lamina at the level of hypothalamo-hypophyseal portal vessels, throughout the estrous cycle. On the other hand, we have semi-quantified the gonadotropin releasing hormone content in nerve terminals or preterminals during this physiological condition. A morphometric study was coupled to a colloidal 15 mn gold postembedding immunocytochemistry procedure. Animals were killed at 09.00 on diestrus II, 0.900, 10.00, 13.00, 17.00 and 18.00 on proestrus and 09.00 on estrus (n = 4-8 rats/group). A preliminary light microscopic study was carried out to identify an antero-posterior part of median eminence strongly immunostained by anti-gonadotropin releasing hormone antibodies but which was, in addition, easily spotted. This last condition was necessary to make a good comparison between each animal. Contacts between gonadotropin releasing hormone nerve terminals and the basal lamina were observed only the day of proestrus. Such contacts, however, were rare and in the great majority of cases, gonadotropin releasing hormone terminals are separated from basal lamina by tanycytic end feet. The morphometric analysis showed no significant variation in average distance between gonadotropin releasing hormone terminals and capillaries throughout the estrous cycle. Consequently, it did not appear that a large neuroglial plasticity exists during the estrous cycle. However, the observation of contacts only on proestrus together with some ultrastructural images evoke the possibility of a slight plasticity. The semi-quantitative results show that the content of gonadotropin releasing hormone in the nerve endings presented two peaks on proestrus: one at 09.00 (23 +/- 5 particles/micrograms2, P < 0.03) before the onset of luteinizing hormone surge, and the second at 18.00 (16 +/- 2 particles/micrograms2, P < 0.01) concomitantly with the luteinizing hormone surge, when compared to baseline values on proestrus 10.00 (8 +/- particles/micrograms2).

Functional maturation of motor nerve terminals in the avian iris: ultrastructure, transmitter metabolism and synaptic reliability

PubMed Central

Pilar, Guillermo; Tuttle, Jeremy; Vaca, Ken

1981-01-01

1. The transformation of easily fatigued embryonic neuromuscular junctions into highly reliable mature terminals was examined by studying functional and morphological changes during development of the avian iris. The mature ability to follow repetitive electrical nerve stimulation was correlated with the rate of acetylcholine (ACh) synthesis and choline uptake, and with the fine structure of the nerve terminals and the post-synaptic elements. 2. The terminals of the ciliary nerve of the chick initially form functional synaptic contacts with the iris muscle at embryonic St. 34-40. At the onset of this period, no Na+-dependent high affinity choline uptake can be demonstrated, and the low level of ACh synthesis present is sensitive to Na+ removal. At St. 36 [3H]ACh synthesis begins to increase, the increment being Na+-dependent. 3. ACh synthesis in the embryonic iris was insensitive to a conditioning [K+]o depolarization even as late as St. 43. Just before hatching, depolarization elicits some augmentation in synthesis, but by 2 days ex ovo this release-induced response has increased by an order of magnitude. 4. Concurrently with the acquisition of the ability to respond to depolarization with accelerated synthesis, neuromuscular transmission in the iris becomes reliable and secure during stimulation at 20 Hz. Embryonic junctions rapidly block during such stimulation, and the failure is shown to be presynaptic in origin, resulting most probably from failure to sustain adequate levels of transmitter release. 5. Ultrastructural examination of the developing ciliary terminals revealed few synaptic vesicles at early stages, and a dearth of other specializations. The sequence of development from these small structurally undistinguished endings to large en plaque junctions completely filled with vesicles was reconstructed and compared to other neuromuscular junctions. Morphological maturation appears progressive with little evidence of discontinuity signalling functional status, but it is only after the terminals enlarge and become closely packed with vesicles that mature synaptic reliability is found. 6. The temporal correlation between responsiveness of transmitter synthesis to depolarization and reliable neuromuscular transmission suggests that modulation of neurotransmitter metabolism in response to demand signals the achievement of junctional maturity. ImagesABPlate 2Plate 3Plate 4 PMID:6279822

The metabotropic glutamate receptor activates the lipid kinase PI3K in Drosophila motor neurons through the calcium/calmodulin-dependent protein kinase II and the nonreceptor tyrosine protein kinase DFak.

PubMed

Chun-Jen Lin, Curtis; Summerville, James B; Howlett, Eric; Stern, Michael

2011-07-01

Ligand activation of the metabotropic glutamate receptor (mGluR) activates the lipid kinase PI3K in both the mammalian central nervous system and Drosophila motor nerve terminal. In several subregions of the mammalian brain, mGluR-mediated PI3K activation is essential for a form of synaptic plasticity termed long-term depression (LTD), which is implicated in neurological diseases such as fragile X and autism. In Drosophila larval motor neurons, ligand activation of DmGluRA, the sole Drosophila mGluR, similarly mediates a PI3K-dependent downregulation of neuronal activity. The mechanism by which mGluR activates PI3K remains incompletely understood in either mammals or Drosophila. Here we identify CaMKII and the nonreceptor tyrosine kinase DFak as critical intermediates in the DmGluRA-dependent activation of PI3K at Drosophila motor nerve terminals. We find that transgene-induced CaMKII inhibition or the DFak(CG1) null mutation each block the ability of glutamate application to activate PI3K in larval motor nerve terminals, whereas transgene-induced CaMKII activation increases PI3K activity in motor nerve terminals in a DFak-dependent manner, even in the absence of glutamate application. We also find that CaMKII activation induces other PI3K-dependent effects, such as increased motor axon diameter and increased synapse number at the larval neuromuscular junction. CaMKII, but not PI3K, requires DFak activity for these increases. We conclude that the activation of PI3K by DmGluRA is mediated by CaMKII and DFak.

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons.

PubMed

Gervasi, Noreen M; Scott, Shane S; Aschrafi, Armaz; Gale, Jenna; Vohra, Sanah N; MacGibeny, Margaret A; Kar, Amar N; Gioio, Anthony E; Kaplan, Barry B

2016-06-01

Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3'UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal. Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Central Projections of Antennal and Labial Palp Sensory Neurons in the Migratory Armyworm Mythimna separata

PubMed Central

Ma, Bai-Wei; Zhao, Xin-Cheng; Berg, Bente G.; Xie, Gui-Ying; Tang, Qing-Bo; Wang, Gui-Rong

2017-01-01

The oriental armyworm, Mythimna separata (Walker), is a polyphagous, migratory pest relying on olfactory cues to find mates, locate nectar, and guide long-distance flight behavior. In the present study, a combination of neuroanatomical techniques were utilized on this species, including backfills, confocal microscopy, and three-dimensional reconstructions, to trace the central projections of sensory neurons from the antenna and the labial pit organ, respectively. As previously shown, the axons of the labial sensory neurons project via the ipsilateral labial nerve and terminate in three main areas of the central nervous system: (1) the labial-palp pit organ glomerulus of each antennal lobe, (2) the gnathal ganglion, and (3) the prothoracic ganglion of the ventral nerve cord. Similarly, the antennal sensory axons project to multiple areas of the central nervous system. The ipsilateral antennal nerve targets mainly the antennal lobe, the antennal mechanosensory and motor center, and the prothoracic and mesothoracic ganglia. Specific staining experiments including dye application to each of the three antennal segments indicate that the antennal lobe receives input from flagellar olfactory neurons exclusively, while the antennal mechanosensory and motor center is innervated by mechanosensory neurons from the whole antenna, comprising the flagellum, pedicle, and scape. The terminals in the mechanosensory and motor center are organized in segregated zones relating to the origin of neurons. The flagellar mechanosensory axons target anterior zones, while the pedicular and scapal axons terminate in posterior zones. In the ventral nerve cord, the processes from the antennal sensory neurons terminate in the motor area of the thoracic ganglia, suggesting a close connection with motor neurons. Taken together, the numerous neuropils innervated by axons both from the antenna and labial palp indicate the multiple roles these sensory organs serve in insect behavior. PMID:29209176

Neuro-muscular transmission in blood vessels: phasic and tonic components. An in-vitro study of mesenteric arteries of the rat.

PubMed

Sjöblom-Widfeldt, N

1990-01-01

For many years noradrenaline was considered to be the exclusive transmitter released from sympathetic nerves. However, during recent years both ATP and NPY have been suggested to be co-transmitters to noradrenaline in these nerves. The present study aimed to investigate the functional relationship between these suggested transmitters during nerve stimulation with different frequencies and in different extracellular calcium concentrations. Also the importance of the pattern of nerve stimulation and the potentiation of the neurogenic response after a period of high-frequency nerve stimulation were investigated. Contractions caused by nerve stimulation and applied agonists were investigated in segments of small mesenteric arteries from rat. The biophysical, electrophysiological, and pharmacological properties of these vessels are well characterized in previous studies. The rapid contraction caused by a single nerve stimulus, the "single twitch", and the initial, phasic contraction caused by high-frequency nerve stimulation were only slightly affected by alpha-adrenoceptor blockade with prazosin, whereas the tonic response to high-frequency stimulation was markedly reduced. The phasic responses and those to low-frequency nerve stimulation thus appear to be due mainly to a non-adrenergic transmitter. After inhibiting the response to exogenous ATP by alpha beta-methylene ATP, the response to single impulses and to low-frequency nerve stimulation were markedly reduced, while those to high-frequency stimulation were unaffected. This suggests that ATP acts as a true transmitter in sympathetic nerves, being responsible mainly for rapid responses to low-frequency stimulation, and for the initial part of responses to high-frequency stimulation. When alpha beta-methylene ATP and prazosin were given in combination, no contraction was obtained during nerve stimulation at any frequency. However, if in this situation a contraction was induced by e.g. exogenous vasopressin, field stimulation caused a further, slow contraction. This additional response was undoubtedly neurogenic, but required high-frequency nerve stimulation. The response to nerve stimulation was found to be calcium-dependent, the calcium-dependency being more pronounced at low than at high stimulation frequencies. A continuous, high-frequency (8-16 Hz) nerve stimulation could greatly (5-15 fold) enhance the response to subsequent low-frequency nerve stimulation. This potentiation increased with the frequency of the conditioning stimulation and, within limits, with the number of impulses delivered. Also the extracellular calcium concentration during the conditioning stimulation determined the magnitude of the potentiation. This post-tetanic potentiation has many characteristics in common with the post-tetanic potentiation studied in the central and somatomotor nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)

Origin and pharmacological response of atrial tachyarrhythmias induced by activation of mediastinal nerves in canines.

PubMed

Armour, J Andrew; Richer, Louis-Philippe; Pagé, Pierre; Vinet, Alain; Kus, Teresa; Vermeulen, Michel; Nadeau, Réginald; Cardinal, René

2005-03-31

We sought to determine the sites of origin of atrial tachyarrhythmias induced by activating mediastinal nerves, as well as the response of such arrhythmias to autonomic modulation. Under general anaesthesia, atrioventricular block was induced after thoracotomy in 19 canines. Brief trains of 5 electrical stimuli were delivered to right-sided mediastinal nerves during the atrial refractory period. Unipolar electrograms were recorded from 191 right and left atrial epicardial sites under several conditions, i.e. (i) with intact nervous systems and following (ii) acute decentralization of the intrathoracic nervous system or administration of (iii) atropine, (iv) timolol, (v) hexamethonium. Concomitant right atrial endocardial mapping was performed in 7 of these dogs. Mediastinal nerve stimulation consistently initiated bradycardia followed by atrial tachyarrhythmias. In the initial tachyarrhythmia beats, early epicardial breakthroughs were identified in the right atrial free wall (28/50 episodes) or Bachmann bundle region (22/50), which corresponded to endocardial sites of origin associated with the right atrial subsidiary pacemaker complex, i.e. the crista terminalis and dorsal locations including the right atrial aspect of the interatrial septum. Neuronally induced responses were eliminated by atropine, modified by timolol and unaffected by acute neuronal decentralization. After hexamethonium, responses to extra-pericardial but not intra-pericardial nerve stimulation were eliminated. It is concluded that concomitant activation of cholinergic and adrenergic efferent intrinsic cardiac neurons induced by right-sided efferent neuronal stimulation initiates atrial tachyarrhythmias that originate from foci anatomically related to the right atrial pacemaker complex and tissues underlying major atrial ganglionated plexuses.

Three variations of the laryngeal nerve in the same patient: a case report

PubMed Central

2011-01-01

Introduction A non-recurrent course is a rare anatomic variation of the inferior laryngeal nerve (ILN). Bilateral extra-laryngeal bifurcation of the ILN seldom occurs before its laryngeal entry. Anastomosis between the ILN and cervical sympathetic chain is another rare anatomic feature. The prevalence of extra-laryngeal branching of the non-recurrent nerve is unknown. We present an example of triple anatomic variations of ILNs in the same patient, and also two anatomic variations in the same nerve. Case presentation A 56-year-old Caucasian man with a large toxic multi-nodular goiter was surgically treated with total thyroidectomy. Both his right and left ILNs were identified, fully exposed and preserved along their cervical courses. We discovered many variations during bilateral exploration of the two ILNs. His right ILN was non-recurrent. This non-recurrent ILN showed a terminal division before laryngeal entry. The left nerve had a usual course as a recurrent laryngeal nerve (RLN) at his tracheaesophageal groove. We also discovered bifurcation of his RLN beginning at a neurovascular (RLN and inferior thyroid artery) crossing point. Anterior and posterior branches of both nerves entered his larynx separately. The sympathetic inferior laryngeal anastomotic branch (SILAB) between the posterior branch of his left ILN and the cervical sympathetic chain was established in the distal part of the nerve before laryngeal entry. Conclusion A non-recurrent nerve and extra-laryngeal branching of the ILN are two different variations. The coincidence of a right non-recurrent ILN and bilateral bifurcation of both nerves is a very interesting feature. SILAB is a rare additional finding as a third anatomic variation in the same patient. Extra-laryngeal terminal division of a non-recurrent ILN is an extremely unusual anatomic finding. Two anatomic variations have occurred in the same nerve, like "the variation of the variation". PMID:21722360

Prostanoids-induced dispersion in the melanophores of a carp Labeo rohita (Ham.).

PubMed

Ovais, M; Ahmed, Fraz; Mubashshir, Md; Sumoona, Safia

2014-02-01

Effects of three prostaglandins (i.e., prostanoids) and one of its precursors, arachidonic acid, were examined on the melanophores of the fish Labeo rohita (Ham.). PGE₁, PGE₂, PGF(2α) and arachidonic acid elicit a concentration-related dispersion in the fish melanophores. In vitro analysis of melanophores was performed through incubation of the isolated fish scales in different agonists and antagonists solutions. Dispersal effect of prostanoids may be mediated directly through the typical receptors or indirectly through release of neurotransmitter substance(s) from the melanophore nerve endings. Denervation of fish melanophores rendered them insensitive to prostanoid (PGF(2α)). Propranolol and verapamil completely inhibited the dispersal effects of PGF(2α); theophylline and indomethacine blocked the effects of higher concentrations of PGF(2α). During dispersing influence of PGF(2α), a free flux of Ca²⁺ ions was required and the indirectly released substance(s) from melanophore nerve endings would be the catecholamines of adrenergic and purinergic in nature.

Regional Differences in Rat Vaginal Smooth Muscle Contractility and Morphology

PubMed Central

Skoczylas, Laura C.; Jallah, Zegbeh; Sugino, Yoshio; Stein, Suzan E.; Feola, Andrew; Yoshimura, Naoki

2013-01-01

The objective of this study was to define the regional differences in rat vaginal smooth muscle contractility and morphology. We evaluated circumferential segments from the proximal, middle, and distal rat vagina (n = 21) in vitro. Contractile responses to carbachol, phenylephrine, potassium chloride, and electrical field stimulation (EFS) were measured. Immunohistochemical analyses were also performed. The dose–response curves for carbachol- and phenylephrine-dependent contractions were different in the distal (P = .05, P = .04) compared to the proximal/middle regions. Adjusted for region-dependent changes in contractility, the distal vagina generated lower force in response to carbachol and higher force in response to phenylephrine. There was less force with increasing EFS frequency in the distal (P = .03), compared to the proximal/middle regions. Cholinergic versus adrenergic nerves were more frequent in the proximal region (P = .03). In summary, the results indicate that functional and morphological differences in smooth muscle and nerve fibers of the distal versus proximal/middle regions of the vagina exist. PMID:23298869

Daily Electrical Muscle Stimulation Enhances Functional Recovery Following Nerve Transection and Repair in Rats.

PubMed

Willand, Michael P; Chiang, Cameron D; Zhang, Jennifer J; Kemp, Stephen W P; Borschel, Gregory H; Gordon, Tessa

2015-08-01

Incomplete recovery following surgical reconstruction of damaged peripheral nerves is common. Electrical muscle stimulation (EMS) to improve functional outcomes has not been effective in previous studies. To evaluate the efficacy of a new, clinically translatable EMS paradigm over a 3-month period following nerve transection and immediate repair. Rats were divided into 6 groups based on treatment (EMS or no treatment) and duration (1, 2, or 3 months). A tibial nerve transection injury was immediately repaired with 2 epineurial sutures. The right gastrocnemius muscle in all rats was implanted with intramuscular electrodes. In the EMS group, the muscle was electrically stimulated with 600 contractions per day, 5 days a week. Terminal measurements were made after 1, 2, or 3 months. Rats in the 3-month group were assessed weekly using skilled and overground locomotion tests. Neuromuscular junction reinnervation patterns were also examined. Muscles that received daily EMS had significantly greater numbers of reinnervated motor units with smaller average motor unit sizes. The majority of muscle endplates were reinnervated by a single axon arising from a nerve trunk with significantly fewer numbers of terminal sprouts in the EMS group, the numbers being small. Muscle mass and force were unchanged but EMS improved behavioral outcomes. Our results demonstrated that EMS using a moderate stimulation paradigm immediately following nerve transection and repair enhances electrophysiological and behavioral recovery. © The Author(s) 2014.

[Beta]-Adrenergic Receptor Activation Rescues Theta Frequency Stimulation-Induced LTP Deficits in Mice Expressing C-Terminally Truncated NMDA Receptor GluN2A Subunits

ERIC Educational Resources Information Center

Moody, Teena D.; Watabe, Ayako M.; Indersmitten, Tim; Komiyama, Noboru H.; Grant, Seth G. N.; O'Dell, Thomas J.

2011-01-01

Through protein interactions mediated by their cytoplasmic C termini the GluN2A and GluN2B subunits of NMDA receptors (NMDARs) have a key role in the formation of NMDAR signaling complexes at excitatory synapses. Although these signaling complexes are thought to have a crucial role in NMDAR-dependent forms of synaptic plasticity such as long-term…

Neuropeptide Y in the adult and fetal human pineal gland.

PubMed

Møller, Morten; Phansuwan-Pujito, Pansiri; Badiu, Corin

2014-01-01

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be colocalized with noradrenaline in sympathetic nerve terminals. The peptide has been demonstrated to be present in sympathetic nerve fibers innervating the pineal gland in many mammalian species. In this investigation, we show by use of immunohistochemistry that neuropeptide Y is present in nerve fibers of the adult human pineal gland. The fibers are classical neuropeptidergic fibers endowed with large boutons en passage and primarily located in a perifollicular position with some fibers entering the pineal parenchyma inside the follicle. The distance from the immunoreactive terminals to the pinealocytes indicates a modulatory function of neuropeptide Y for pineal physiology. Some of the immunoreactive fibers might originate from neurons located in the brain and be a part of the central innervation of the pineal gland. In a series of human fetuses, neuropeptide Y-containing nerve fibers was present and could be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is different from most rodents, where the innervation starts postnatally.

Neuropeptide Y in the Adult and Fetal Human Pineal Gland

PubMed Central

Møller, Morten; Phansuwan-Pujito, Pansiri

2014-01-01

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be colocalized with noradrenaline in sympathetic nerve terminals. The peptide has been demonstrated to be present in sympathetic nerve fibers innervating the pineal gland in many mammalian species. In this investigation, we show by use of immunohistochemistry that neuropeptide Y is present in nerve fibers of the adult human pineal gland. The fibers are classical neuropeptidergic fibers endowed with large boutons en passage and primarily located in a perifollicular position with some fibers entering the pineal parenchyma inside the follicle. The distance from the immunoreactive terminals to the pinealocytes indicates a modulatory function of neuropeptide Y for pineal physiology. Some of the immunoreactive fibers might originate from neurons located in the brain and be a part of the central innervation of the pineal gland. In a series of human fetuses, neuropeptide Y-containing nerve fibers was present and could be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is different from most rodents, where the innervation starts postnatally. PMID:24757681

Modulation of the release of ( sup 3 H)norepinephrine from the base and body of the rat urinary bladder by endogenous adrenergic and cholinergic mechanisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Somogyi, G.T.; de Groat, W.C.

Modulation of (3H)NE release was studied in rat urinary bladder strips prelabeled with (3H)NE. (3H)NE uptake occurred in strips from the bladder base and body, but was very prominent in the base where the noradrenergic innervation is most dense. Electrical field stimulation markedly increased (3H)NE outflow from the superfused tissue. The quantity of (3H)NE release was approximately equal during three consecutive periods of stimulation. Activation of presynaptic muscarinic receptors by 1.0 microM oxotremorine reduced (3H)NE release to 46% of the control. Atropine (1 microM) blocked the effect of oxotremorine and increased the release to 147% of predrug control levels. Activationmore » of presynaptic alpha-2 adrenoceptors by 1 microM clonidine reduced (3H)NE release to 55% of control. Yohimbine blocked the action of clonidine and increased the release to 148% of control. The release of (3H)NE from the bladder base and body was increased by both 1 microM atropine (to 167% and 174% of control, respectively) and 1 microM yohimbine (to 286% and 425% of control, respectively). Atropine and yohimbine administered in combination had similar facilitatory effects as when administered alone. We conclude that the release of (3H)NE from adrenergic nerve endings in electrically stimulated bladder strips is modulated via endogenous transmitters acting on both muscarinic and alpha-2 adrenergic presynaptic receptors and that the latter provide the most prominent control.« less

The Scaffolding Protein, Grb2-associated Binder-1, in Skeletal Muscles and Terminal Schwann Cells Regulates Postnatal Neuromuscular Synapse Maturation

PubMed Central

Park, So Young; Jang, So Young; Shin, Yoon Kyoung; Jung, Dong Keun; Yoon, Byeol A; Kim, Jong Kook; Jo, Young Rae; Lee, Hye Jeong

2017-01-01

The vertebrate neuromuscular junction (NMJ) is considered as a “tripartite synapse” consisting of a motor axon terminal, a muscle endplate, and terminal Schwann cells that envelope the motor axon terminal. The neuregulin 1 (NRG1)-ErbB2 signaling pathway plays an important role in the development of the NMJ. We previously showed that Grb2-associated binder 1 (Gab1), a scaffolding mediator of receptor tyrosine kinase signaling, is required for NRG1-induced peripheral nerve myelination. Here, we determined the role of Gab1 in the development of the NMJ using muscle-specific conditional Gab1 knockout mice. The mutant mice showed delayed postnatal maturation of the NMJ. Furthermore, the selective loss of the gab1 gene in terminal Schwann cells produced delayed synaptic elimination with abnormal morphology of the motor endplate, suggesting that Gab1 in both muscles and terminal Schwann cells is required for proper NMJ development. Gab1 in terminal Schwann cells appeared to regulate the number and process elongation of terminal Schwann cells during synaptic elimination. However, Gab2 knockout mice did not show any defects in the development of the NMJ. Considering the role of Gab1 in postnatal peripheral nerve myelination, our findings suggest that Gab1 is a pleiotropic and important component of NRG1 signals during postnatal development of the peripheral neuromuscular system. PMID:28680299

The Scaffolding Protein, Grb2-associated Binder-1, in Skeletal Muscles and Terminal Schwann Cells Regulates Postnatal Neuromuscular Synapse Maturation.

PubMed

Park, So Young; Jang, So Young; Shin, Yoon Kyoung; Jung, Dong Keun; Yoon, Byeol A; Kim, Jong Kook; Jo, Young Rae; Lee, Hye Jeong; Park, Hwan Tae

2017-06-01

The vertebrate neuromuscular junction (NMJ) is considered as a "tripartite synapse" consisting of a motor axon terminal, a muscle endplate, and terminal Schwann cells that envelope the motor axon terminal. The neuregulin 1 (NRG1)-ErbB2 signaling pathway plays an important role in the development of the NMJ. We previously showed that Grb2-associated binder 1 (Gab1), a scaffolding mediator of receptor tyrosine kinase signaling, is required for NRG1-induced peripheral nerve myelination. Here, we determined the role of Gab1 in the development of the NMJ using muscle-specific conditional Gab1 knockout mice. The mutant mice showed delayed postnatal maturation of the NMJ. Furthermore, the selective loss of the gab1 gene in terminal Schwann cells produced delayed synaptic elimination with abnormal morphology of the motor endplate, suggesting that Gab1 in both muscles and terminal Schwann cells is required for proper NMJ development. Gab1 in terminal Schwann cells appeared to regulate the number and process elongation of terminal Schwann cells during synaptic elimination. However, Gab2 knockout mice did not show any defects in the development of the NMJ. Considering the role of Gab1 in postnatal peripheral nerve myelination, our findings suggest that Gab1 is a pleiotropic and important component of NRG1 signals during postnatal development of the peripheral neuromuscular system.

RGS2 is a feedback inhibitor of melatonin production in the pineal gland

PubMed Central

Matsuo, Masahiro; Coon, Steven L.; Klein, David C.

2014-01-01

The 24-h rhythmic production of melatonin by the pineal gland is essential for coordinating circadian physiology. Melatonin production increases at night in response to the release of norepinephrine from sympathetic nerve processes which innervate the pineal gland. This signal is transduced through G-protein-coupled adrenergic receptors. Here, we found that the abundance of regulator of G-protein signaling 2 (RGS2) increases at night, that expression is increased by norepinephrine and that this protein has a negative feedback effect on melatonin production. These data are consistent with the conclusion that RGS2 functions on a daily basis to negatively modulate melatonin production. PMID:23523917

Palisade endings: cholinergic sensory organs or effector organs?

PubMed

Blumer, Roland; Konakci, Kadriye Zeynep; Pomikal, Christine; Wieczorek, Grazyna; Lukas, Julius-Robert; Streicher, Johannes

2009-03-01

This study aims to complement the authors' prior findings on palisade endings in extraocular muscles (EOMs) of monkeys, and to clarify whether palisade endings are cholinergic motor or cholinergic sensory. Macaque monkeys (Macaca fascicularis, n = 10) of both sexes were analyzed using three-dimensional (3D) reconstructions, confocal laser scanning microscopy (CLSM), and conventional/immuno transmission electron microscopy (TEM). For CLSM, we used three combinations of triple fluorescent labeling. EOM wholemounts were labeled with cholinergic markers, including choline acetyltransferase (ChAT), choline transporter (ChT), vesicular acetylcholine transporter (VAChT), and a classical postsynaptic marker for motor terminals, namely alpha-bungarotoxin. Muscle fibers were counterstained with phalloidin. 3D reconstructions were done of triple-labeled palisade endings. For immuno TEM, tissue was labeled with antibody against ChAT. Concordant with prior findings, the authors demonstrated that palisade endings at the muscle fiber tips arose from nerve fibers that are ChAT-positive. In 25% of the cases, axons forming palisade endings established multiple neuromuscular contacts outside the palisade complex. Such additional neuromuscular contacts were motor terminals, as demonstrated by alpha-bungarotoxin binding. All palisade endings established nerve terminals on the tendon. In 40% of the palisade endings, nerve terminals were observed on the muscle fiber as well. Neurotendinous contacts and neuromuscular contacts in palisade endings were ChT/ChAT/VAChT-immunoreactive. Neuromuscular contacts exhibited structural features of motor terminals and were also alpha-bungarotoxin positive. The present study ascertained that palisade endings are cholinergic motor organs. Therefore, it was concluded that palisade endings are not candidates to provide eye-position signals.

Ionotropic and metabotropic receptor mediated airway sensory nerve activation.

PubMed

Lee, Min-Goo; Kollarik, Marian; Chuaychoo, Benjamas; Undem, Bradley J

2004-01-01

There are several receptors capable of inducing activating generator potentials in cough-associated afferent terminals in the airways. The chemical receptors leading to generator potentials can be subclassified into ionotropic and metabotropic types. An ionotropic receptor has an agonist-binding domain, and also serves directly as an ion channel that is opened upon binding of the agonist. Examples of ionotropic receptors found in airway sensory nerve terminals include receptors for serotonin (5-HT3 receptors), ATP (P2X receptors), acetylcholine (nicotinic receptors), receptors for capsaicin and related vanilloids (TRPV1 receptors), and acid receptors (acid sensing ion channels). Afferent nerve terminals can also be depolarized via activation of metabotropic or G-protein coupled receptors (GPCRs). Among the GPCRs that can lead to activation of airway afferent fibers include bradykinin B2 and adenosine A1 receptors. The signaling events leading to GPCR-mediated membrane depolarization are more complex than that seen with ionotropic receptors. The GPCR-mediated effects are thought to occur through classical second messenger systems such as activation of phospholipase C. This may lead to membrane depolarization through interaction with specific ionotropic receptors (such as TRPV1) and/or various types of calcium activated channels.

Morphologically mixed chemical-electrical synapses formed by primary afferents in rodent vestibular nuclei as revealed by immunofluorescence detection of connexin36 and vesicular glutamate transporter-1

PubMed Central

Nagy, James I.; Bautista, Wendy; Blakley, Brian; Rash, John E.

2013-01-01

Axon terminals forming mixed chemical/electrical synapses in the lateral vestibular nucleus of rat were described over forty years ago. Because gap junctions formed by connexins are the morphological correlate of electrical synapses, and with demonstrations of widespread expression of the gap junction protein connexin36 (Cx36) in neurons, we investigated the distribution and cellular localization of electrical synapses in the adult and developing rodent vestibular nuclear complex, using immunofluorescence detection of Cx36 as a marker for these synapses. In addition, we examined Cx36 localization in relation to that of the nerve terminal marker vesicular glutamate transporter-1 (vglut-1). An abundance of immunolabelling for Cx36 in the form of Cx36-puncta was found in each of the four major vestibular nuclei of adult rat and mouse. Immunolabelling was associated with somata and initial dendrites of medium and large neurons, and was absent in vestibular nuclei of Cx36 knockout mice. Cx36-puncta were seen either dispersed or aggregated into clusters on the surface of neurons, and were never found to occur intracellularly. Nearly all Cx36-puncta were localized to large nerve terminals immunolabelled for vglut-1. These terminals and their associated Cx36-puncta were substantially depleted after labyrinthectomy. Developmentally, labelling for Cx36 was already present in the vestibular nuclei at postnatal day 5, where it was only partially co-localized with vglut-1, and did not become fully associated with vglut-1-positive terminals until postnatal day 20 to 25. The results show that vglut-1-positive primary afferent nerve terminals form mixed synapses throughout the vestibular nuclear complex, that the gap junction component of these synapses contain Cx36, that multiple Cx36-containing gap junctions are associated with individual vglut-1 terminals and that the development of these mixed synapses is protracted over several postnatal weeks. PMID:23912039

Schwann Cells in Neuromuscular Junction Formation and Maintenance.

PubMed

Barik, Arnab; Li, Lei; Sathyamurthy, Anupama; Xiong, Wen-Cheng; Mei, Lin

2016-09-21

The neuromuscular junction (NMJ) is a tripartite synapse that is formed by motor nerve terminals, postjunctional muscle membranes, and terminal Schwann cells (TSCs) that cover the nerve-muscle contact. NMJ formation requires intimate communications among the three different components. Unlike nerve-muscle interaction, which has been well characterized, less is known about the role of SCs in NMJ formation and maintenance. We show that SCs in mice lead nerve terminals to prepatterned AChRs. Ablating SCs at E8.5 (i.e., prior nerve arrival at the clusters) had little effect on aneural AChR clusters at E13.5, suggesting that SCs may not be necessary for aneural clusters. SC ablation at E12.5, a time when phrenic nerves approach muscle fibers, resulted in smaller and fewer nerve-induced AChR clusters; however, SC ablation at E15.5 reduced AChR cluster size but had no effect on cluster density, suggesting that SCs are involved in AChR cluster maturation. Miniature endplate potential amplitude, but not frequency, was reduced when SCs were ablated at E15.5, suggesting that postsynaptic alterations may occur ahead of presynaptic deficits. Finally, ablation of SCs at P30, after NMJ maturation, led to NMJ fragmentation and neuromuscular transmission deficits. Miniature endplate potential amplitude was reduced 3 d after SC ablation, but both amplitude and frequency were reduced 6 d after. Together, these results indicate that SCs are not only required for NMJ formation, but also necessary for its maintenance; and postsynaptic function and structure appeared to be more sensitive to SC ablation. Neuromuscular junctions (NMJs) are critical for survival and daily functioning. Defects in NMJ formation during development or maintenance in adulthood result in debilitating neuromuscular disorders. The role of Schwann cells (SCs) in NMJ formation and maintenance was not well understood. We genetically ablated SCs during development and after NMJ formation to investigate the consequences of the ablation. This study reveals a critical role of SCs in NMJ formation as well as maintenance. Copyright © 2016 the authors 0270-6474/16/369770-12$15.00/0.

Nerve-mediated descending inhibition in the proximal colon of the rabbit.

PubMed

Julé, Y

1980-12-01

1. Descending inhibition in the rabbit proximal colon, evoked by distension, was studied in vivo by recording extracellularly electrical activity from pressure electrodes placed on the serosa. 2. Distention produced, blow the level of the balloon, a brief hyperpolarization of smooth muscle fibres which could be recorded up to 20 cm from the point of distension. 3. This hyperpolarization like that produced by vagal stimulation (inhibitory junction potentials) persisted in the presence of sympathetic blocking agents and atropine, and was produced by non-adrenergic non-cholinergic intramural neurones. 4. In the presence of vagally evoked excitatory junction potentials (e.j.p.s), distension produced a transient inhibition of e.j.p.s, in addition to the hyperpolarization of smooth muscle. 5. The inhibition of these e.j.p.s persisted in the presence of sympathetic blocking agents, but in contrast to the hyperpolarization of smooth muscle produced by distension alone, was modulated by drugs interfering with 5-HT synthesis, re-uptake and activity. 6. The results indicate that descending inhibition in the rabbit proximal colon was produced by two distinct neuronal non-adrenergic inhibitory mechanisms exerted simultaneously on the smooth muscle and on the cholinergic excitatory pathways which innervate it.

Nerve-mediated descending inhibition in the proximal colon of the rabbit.

PubMed Central

Julé, Y

1980-01-01

1. Descending inhibition in the rabbit proximal colon, evoked by distension, was studied in vivo by recording extracellularly electrical activity from pressure electrodes placed on the serosa. 2. Distention produced, blow the level of the balloon, a brief hyperpolarization of smooth muscle fibres which could be recorded up to 20 cm from the point of distension. 3. This hyperpolarization like that produced by vagal stimulation (inhibitory junction potentials) persisted in the presence of sympathetic blocking agents and atropine, and was produced by non-adrenergic non-cholinergic intramural neurones. 4. In the presence of vagally evoked excitatory junction potentials (e.j.p.s), distension produced a transient inhibition of e.j.p.s, in addition to the hyperpolarization of smooth muscle. 5. The inhibition of these e.j.p.s persisted in the presence of sympathetic blocking agents, but in contrast to the hyperpolarization of smooth muscle produced by distension alone, was modulated by drugs interfering with 5-HT synthesis, re-uptake and activity. 6. The results indicate that descending inhibition in the rabbit proximal colon was produced by two distinct neuronal non-adrenergic inhibitory mechanisms exerted simultaneously on the smooth muscle and on the cholinergic excitatory pathways which innervate it. PMID:6454779

Deficient functional recovery after facial nerve crush in rats is associated with restricted rearrangements of synaptic terminals in the facial nucleus.

PubMed

Hundeshagen, G; Szameit, K; Thieme, H; Finkensieper, M; Angelov, D N; Guntinas-Lichius, O; Irintchev, A

2013-09-17

Crush injuries of peripheral nerves typically lead to axonotmesis, axonal damage without disruption of connective tissue sheaths. Generally, human patients and experimental animals recover well after axonotmesis and the favorable outcome has been attributed to precise axonal reinnervation of the original peripheral targets. Here we assessed functionally and morphologically the long-term consequences of facial nerve axonotmesis in rats. Expectedly, we found that 5 months after crush or cryogenic nerve lesion, the numbers of motoneurons with regenerated axons and their projection pattern into the main branches of the facial nerve were similar to those in control animals suggesting precise target reinnervation. Unexpectedly, however, we found that functional recovery, estimated by vibrissal motion analysis, was incomplete at 2 months after injury and did not improve thereafter. The maximum amplitude of whisking remained substantially, by more than 30% lower than control values even 5 months after axonotmesis. Morphological analyses showed that the facial motoneurons ipsilateral to injury were innervated by lower numbers of glutamatergic terminals (-15%) and cholinergic perisomatic boutons (-26%) compared with the contralateral non-injured motoneurons. The structural deficits were correlated with functional performance of individual animals and associated with microgliosis in the facial nucleus but not with polyinnervation of muscle fibers. These results support the idea that restricted CNS plasticity and insufficient afferent inputs to motoneurons may substantially contribute to functional deficits after facial nerve injuries, possibly including pathologic conditions in humans like axonotmesis in idiopathic facial nerve (Bell's) palsy. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Atropine and Other Anticholinergic Drugs

DTIC Science & Technology

2007-01-01

parasympathetic est concern, along with their chemical names and nerves and muscarinic and nicotinic choliner - two-letter military designations, are tabun (o...that hydrolyzes the cholin - tions, tremor, convulsions, electrical seizures and ergic neurotransmitter acetylcholine (ACh), that loss of respiratory... cholin - depress salivation, bronchial secretions and ergic synaptic nerve terminals, this leads to very sweating, increase heart rate, produce pupilary

Crystal Structure of Oligomeric β1-Adrenergic G Protein- Coupled Receptors in Ligand-Free Basal State

PubMed Central

Huang, Jianyun; Chen, Shuai; Zhang, J. Jillian; Huang, Xin-Yun

2013-01-01

G protein-coupled receptors (GPCRs) mediate transmembrane signaling. Before ligand binding, GPCRs exist in a basal state. Crystal structures of several GPCRs bound with antagonists or agonists have been solved. However, the crystal structure of the ligand-free basal state of a GPCR, the starting point of GPCR activation and function, has not been determined. Here we report the X-ray crystal structure of the first ligand-free basal state of a GPCR in a lipid membrane-like environment. Oligomeric turkey β1-adrenergic receptors display two alternating dimer interfaces. One interface involves the transmembrane domain (TM) 1, TM2, the C-terminal H8, and the extracellular loop 1. The other interface engages residues from TM4, TM5, the intracellular loop 2 and the extracellular loop 2. Structural comparisons show that this ligand-free state is in an inactive conformation. This provides the structural information regarding GPCR dimerization and oligomerization. PMID:23435379

Anatomy and Neurophysiology of Cough

PubMed Central

Canning, Brendan J.; Chang, Anne B.; Bolser, Donald C.; Smith, Jaclyn A.; Mazzone, Stuart B.; Adams, Todd M.; Altman, Kenneth W.; Barker, Alan F.; Birring, Surinder S.; Blackhall, Fiona; Bolser, Donald, C.; Boulet, Louis-Philippe; Braman, Sidney S.; Brightling, Christopher; Callahan-Lyon, Priscilla; Canning, Brendan; Chang, Anne Bernadette; Coeytaux, Remy; Cowley, Terrie; Davenport, Paul; Diekemper, Rebecca L.; Ebihara, Satoru; El Solh, Ali A.; Escalante, Patricio; Feinstein, Anthony; Field, Stephen K.; Fisher, Dina; French, Cynthia T.; Gibson, Peter; Gold, Philip; Grant, Cameron; Harding, Susan M.; Harnden, Anthony; Hill, Adam T.; Irwin, Richard S.; Kahrilas, Peter J.; Keogh, Karina A.; Lane, Andrew P.; Lewis, Sandra Zelman; Lim, Kaiser; Malesker, Mark A.; Mazzone, Peter; Mazzone, Stuart; Molasiotis, Alex; Murad, M. Hassan; Newcombe, Peter; Nguyen, Huong Q.; Oppenheimer, John; Prezant, David; Pringsheim, Tamara; Restrepo, Marcos I.; Rosen, Mark; Rubin, Bruce; Ryu, Jay H.; Smith, Jaclyn; Tarlo, Susan M.; Turner, Ronald B.; Vertigan, Anne; Wang, Gang; Weir, Kelly

2014-01-01

Bronchopulmonary C-fibers and a subset of mechanically sensitive, acid-sensitive myelinated sensory nerves play essential roles in regulating cough. These vagal sensory nerves terminate primarily in the larynx, trachea, carina, and large intrapulmonary bronchi. Other bronchopulmonary sensory nerves, sensory nerves innervating other viscera, as well as somatosensory nerves innervating the chest wall, diaphragm, and abdominal musculature regulate cough patterning and cough sensitivity. The responsiveness and morphology of the airway vagal sensory nerve subtypes and the extrapulmonary sensory nerves that regulate coughing are described. The brainstem and higher brain control systems that process this sensory information are complex, but our current understanding of them is considerable and increasing. The relevance of these neural systems to clinical phenomena, such as urge to cough and psychologic methods for treatment of dystussia, is high, and modern imaging methods have revealed potential neural substrates for some features of cough in the human. PMID:25188530

Nerve Entrapment Syndromes at the Wrist and Elbow by Sonography.

PubMed

Klauser, Andrea S; Buzzegoli, Tommaso; Taljanovic, Mihra S; Strobl, Sylvia; Rauch, Stefan; Teh, James; Wanschitz, Julia; Löscher, Wolfgang; Martinoli, Carlo

2018-07-01

Nerve entrapment syndromes of the upper extremity are associated with structural abnormalities or by an intrinsic abnormality of the nerve. Nerve entrapment syndromes generally have a typical clinical presentation, and findings on physical examination and in conjunction with electrodiagnostic studies imaging is used to evaluate the cause, severity, and etiology of the entrapment. With the development of high-frequency linear array transducers (12-24 MHz), ultrasound (US) is incomparable in terms of spatial resolution to depict morphological aspects and changes in nerves. US can identify the abnormalities causing entrapment, such as fibrous bands, ganglia, anomalous muscles, and osseous deformities, with the advantage of dynamic assessment under active and passive examination. US is a unique diagnostic modality that allows superb visualization of both large and small peripheral terminal nerve branches of the upper extremity and enables the correct diagnosis of various nerve entrapment syndromes. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Light microscopic image analysis system to quantify immunoreactive terminal area apposed to nerve cells.

PubMed

Wu, L C; D'Amelio, F; Fox, R A; Polyakov, I; Daunton, N G

1997-06-06

The present report describes a desktop computer-based method for the quantitative assessment of the area occupied by immunoreactive terminals in close apposition to nerve cells in relation to the perimeter of the cell soma. This method is based on Fast Fourier Transform (FFT) routines incorporated in NIH-Image public domain software. Pyramidal cells of layer V of the somatosensory cortex outlined by GABA immunolabeled terminals were chosen for our analysis. A Leitz Diaplan light microscope was employed for the visualization of the sections. A Sierra Scientific Model 4030 CCD camera was used to capture the images into a Macintosh Centris 650 computer. After preprocessing, filtering was performed on the power spectrum in the frequency domain produced by the FFT operation. An inverse FFT with filter procedure was employed to restore the images to the spatial domain. Pasting of the original image to the transformed one using a Boolean logic operation called 'AND'ing produced an image with the terminals enhanced. This procedure allowed the creation of a binary image using a well-defined threshold of 128. Thus, the terminal area appears in black against a white background. This methodology provides an objective means of measurement of area by counting the total number of pixels occupied by immunoreactive terminals in light microscopic sections in which the difficulties of labeling intensity, size, shape and numerical density of terminals are avoided.

Light microscopic image analysis system to quantify immunoreactive terminal area apposed to nerve cells

NASA Technical Reports Server (NTRS)

Wu, L. C.; D'Amelio, F.; Fox, R. A.; Polyakov, I.; Daunton, N. G.

1997-01-01

The present report describes a desktop computer-based method for the quantitative assessment of the area occupied by immunoreactive terminals in close apposition to nerve cells in relation to the perimeter of the cell soma. This method is based on Fast Fourier Transform (FFT) routines incorporated in NIH-Image public domain software. Pyramidal cells of layer V of the somatosensory cortex outlined by GABA immunolabeled terminals were chosen for our analysis. A Leitz Diaplan light microscope was employed for the visualization of the sections. A Sierra Scientific Model 4030 CCD camera was used to capture the images into a Macintosh Centris 650 computer. After preprocessing, filtering was performed on the power spectrum in the frequency domain produced by the FFT operation. An inverse FFT with filter procedure was employed to restore the images to the spatial domain. Pasting of the original image to the transformed one using a Boolean logic operation called 'AND'ing produced an image with the terminals enhanced. This procedure allowed the creation of a binary image using a well-defined threshold of 128. Thus, the terminal area appears in black against a white background. This methodology provides an objective means of measurement of area by counting the total number of pixels occupied by immunoreactive terminals in light microscopic sections in which the difficulties of labeling intensity, size, shape and numerical density of terminals are avoided.

Structural evidence that botulinum toxin blocks neuromuscular transmission by impairing the calcium influx that normally accompanies nerve depolarization

PubMed Central

1981-01-01

Taking advantage of the fact that nerve terminal mitochondria swell and sequester calcium during repetitive nerve stimulation, we here confirm that this change is caused by calcium influx into the nerve and use this fact to show that botulinum toxin abolishes such calcium influx. The optimal paradigm for producing the mitochondrial changes in normal nerves worked out to be 5 min of stimulation at 25 Hz in frog Ringer's solution containing five time more calcium than normal. Applying this same stimulation paradigm to botulinum-intoxicated nerves produced no mitochondrial changes at all. Only when intoxicated nerves were stimulated in 4-aminopyridine (which grossly exaggerates calcium currents in normal nerves) or when they were soaked in black widow spider venom (which is a nerve-specific calcium ionophore) could nerve mitochondria be induced to swell and accumulate calcium. These results indicate that nerve mitochondria are not damaged directly by the toxin and point instead to a primary inhibition of the normal depolarization- evoked calcium currents that accompany nerve activity. Because these currents normally provide the calcium that triggers transmitter secretion from the nerve, this demonstration of their inhibition helps to explain how botulinum toxin paralyzes. PMID:6259176

Acute effects of moclobemide and deprenyl on 5-HT synthesis rates in the rat brain: An autoradiographic study.

PubMed

Nishi, Kyoko; Mück-Seler, Dorotea; Hasegawa, Shu; Watanabe, Arata; Diksic, Mirko

2006-10-16

Serotonin (5-HT), norepinephrine (NE) and dopamine (DA) released from nerve terminals in the brain are primarily removed from the synaptic cleft by a reuptake mechanism. In part, the homeostasis is maintained by monoamine oxidase (MAO) deamination achieved primarily intracellularly. The present study's aim was to examine the effect of the acute administration of the MAO inhibitors, moclobemide (a MAO-A inhibitor) and deprenyl (a MAO-B inhibitor), on 5-HT synthesis rates, measured in discrete regions of the rat brain by an autoradiographic method, using alpha-[14C]methyl-l-tryptophan as a tracer. MAO inhibitors have different effects on 5-HT synthesis rates in the cell bodies and areas of the nerve terminals. Moclobemide (10 mg/kg, i.p. 30 min before the tracer injection) and deprenyl (3 mg/kg, i.p. 2 h before the tracer injection) decreased the 5-HT synthesis rates in the dorsal (-18% and -22%) and median (-22% and -33%) raphe, respectively. Moclobemide also significantly decreased 5-HT synthesis in the entire nerve terminal areas investigated. The reductions were between 23% (cingulate cortex) and 50% (locus coeruleus). Deprenyl did not significantly affect 5-HT synthesis in the nerve terminals. The present results suggest that MAO-A, and to a lesser extent, MAO-B, are involved in the regulation of 5-HT synthesis in the rat brain. The mechanism(s) of MAO inhibitors' action on 5-HT synthesis in the raphe nuclei are probably related to an increase in the extraneuronal 5-HT concentration and also to the interaction between the serotonergic and catecholaminergic neurons. The reduction of 5-HT synthesis in the raphe nuclei likely occurs by an action of extracellular 5-HT via the dendritic autoreceptors with a possible contribution from the action of extracellular DA and NE. In the terminal regions, the most likely mechanism is via the presynaptic autoreceptors through which elevated extraneuronal 5-HT acts on synthesis control. However, there is also a possibility that the elevation in intraneuronal 5-HT directly inhibits its synthesis, especially following deprenyl treatment. A great influence of moclobemide on 5-HT synthesis could be related to its antidepressant action.

Handlebar palsy--a compression syndrome of the deep terminal (motor) branch of the ulnar nerve in biking.

PubMed

Capitani, Daniel; Beer, Serafin

2002-10-01

We describe 3 patients who developed a severe palsy of the intrinsic ulnar supplied hand muscles after bicycle riding. Clinically and electrophysiologically all showed an isolated lesion of the deep terminal motor branch of the ulnar nerve leaving the hypothenar muscle and the distal sensory branch intact. This type of lesion at the canal of Guyon is quite unusual, caused in the majority of cases by chronic external pressure over the ulnar palm. In earlier reports describing this lesion in bicycle riders, most patients experienced this lesion after a long distance ride. Due to the change of riding position and shape of handlebars (horn handle) in recent years, however, even a single bicycle ride may be sufficient to cause a lesion of this ulnar branch. Especially in downhill riding, a large part of the body weight is supported by the hand on the corner of the handlebar leading to a high load at Guyon's canal. As no sensory fibres are affected, the patients are not aware of the ongoing nerve compression until a severe lesion develops. Individual adaptation of the handlebar and riding position seems to be crucial for prevention of this type of nerve lesion.

Effect of endogenous tachykinins on neuro-effector transmission of vagal nerve in guinea-pig tracheal tissue.

PubMed

Aizawa, H; Miyazaki, N; Inoue, H; Ikeda, T; Shigematsu, N

1990-01-01

To elucidate the effect of endogenous tachykinins on neuro-effector transmission of vagal nerves, we performed in vitro experiments using guinea-pig tracheal smooth muscle. The subthreshold dose (the highest dose which did not induce any smooth muscle contraction) of capsaicin (10(-8) to 10(-7) M) increased the amplitudes of contractions evoked by electrical field stimulation (EFS) significantly, but not those by acetylcholine (ACh). The inhibitor of neutral endopeptidase, phosphoramidon (10(-7) to 10(-6) M), increased the contractions evoked by EFS significantly. The inhibitor of cholinesterase, physostigmine (10(-6) to 10(-5) M), induced smooth muscle contractions, but such contractions were inhibited by atropine, suggesting the spontaneous release of ACh from the vagal nerve terminals. The subthreshold dose of substance P or capsaicin increased the contractions evoked by physostigmine. These results indicated that endogenous tachykinins increase the spontaneous ACh release as well as the ACh release in response to vagal stimulation from the nerve terminals. Furthermore, it is suggested that the excitatory effects of the tachykinins on the vagal neuro-effector transmission may be modulated by neutral endopeptidase in the guinea pig.

A comparison of epithalamic, hypothalamic and spinal neurosecretory terminals.

PubMed

Vigh-Teichmann, I; Vigh, B

1979-01-01

Nerve endings of epithalamic, hypothalamic and spinal neurosecretory areas were studied by light and electron microscopy in various vertebrates (from fishes up to mammals) including the lancelet. Areas investigated were the pineal organ, the pulvinar corporis pinealis, the neurohypophysis, the median eminence, the urophysis, the terminal filum and the medullo-spinal neurosecretory zones. We found that in all these areas the neurosecretory endings have common structures, which we call synaptic hemidesmosomes or neurohormonal terminals. These are characterized by accumulation of vesicles, and dense projections in a terminal on the basal lamina of the surface of the nervous tissue. A critical review of the literature suggests that a considerble neuroendocrine activity is associated with synaptic hemidesmosomes as special neurohormonal effector structures of the nerve cells. The cell-to-cell synapses formed by neurosecretory cells are discussed in connection with the dual capacity of these cells to function as both endocrine and "ordinary# neuronal elements. The importance of the external cerebrospinal fluid (CSF) space for the transport of materials released in the so-called neurohemal areas, is stressed.

Selective Deletion of Sodium Salt Taste during Development Leads to Expanded Terminal Fields of Gustatory Nerves in the Adult Mouse Nucleus of the Solitary Tract.

PubMed

Sun, Chengsan; Hummler, Edith; Hill, David L

2017-01-18

Neuronal activity plays a key role in the development of sensory circuits in the mammalian brain. In the gustatory system, experimental manipulations now exist, through genetic manipulations of specific taste transduction processes, to examine how specific taste qualities (i.e., basic tastes) impact the functional and structural development of gustatory circuits. Here, we used a mouse knock-out model in which the transduction component used to discriminate sodium salts from other taste stimuli was deleted in taste bud cells throughout development. We used this model to test the hypothesis that the lack of activity elicited by sodium salt taste impacts the terminal field organization of nerves that carry taste information from taste buds to the nucleus of the solitary tract (NST) in the medulla. The glossopharyngeal, chorda tympani, and greater superficial petrosal nerves were labeled to examine their terminal fields in adult control mice and in adult mice in which the α-subunit of the epithelial sodium channel was conditionally deleted in taste buds (αENaC knockout). The terminal fields of all three nerves in the NST were up to 2.7 times greater in αENaC knock-out mice compared with the respective field volumes in control mice. The shapes of the fields were similar between the two groups; however, the density and spread of labels were greater in αENaC knock-out mice. Overall, our results show that disruption of the afferent taste signal to sodium salts disrupts the normal age-dependent "pruning" of all terminal fields, which could lead to alterations in sensory coding and taste-related behaviors. Neural activity plays a major role in the development of sensory circuits in the mammalian brain. To date, there has been no direct test of whether taste-elicited neural activity has a role in shaping central gustatory circuits. However, recently developed genetic tools now allow an assessment of how specific taste stimuli, in this case sodium salt taste, play a role in the maturation of the terminal fields in the mouse brainstem. We found that the specific deletion of sodium salt taste during development produced terminal fields in adults that were dramatically larger than in control mice, demonstrating for the first time that sodium salt taste-elicited activity is necessary for the normal maturation of gustatory inputs into the brain. Copyright © 2017 the authors 0270-6474/17/370660-13$15.00/0.

Selective Deletion of Sodium Salt Taste during Development Leads to Expanded Terminal Fields of Gustatory Nerves in the Adult Mouse Nucleus of the Solitary Tract

PubMed Central

Sun, Chengsan; Hummler, Edith

2017-01-01

Neuronal activity plays a key role in the development of sensory circuits in the mammalian brain. In the gustatory system, experimental manipulations now exist, through genetic manipulations of specific taste transduction processes, to examine how specific taste qualities (i.e., basic tastes) impact the functional and structural development of gustatory circuits. Here, we used a mouse knock-out model in which the transduction component used to discriminate sodium salts from other taste stimuli was deleted in taste bud cells throughout development. We used this model to test the hypothesis that the lack of activity elicited by sodium salt taste impacts the terminal field organization of nerves that carry taste information from taste buds to the nucleus of the solitary tract (NST) in the medulla. The glossopharyngeal, chorda tympani, and greater superficial petrosal nerves were labeled to examine their terminal fields in adult control mice and in adult mice in which the α-subunit of the epithelial sodium channel was conditionally deleted in taste buds (αENaC knockout). The terminal fields of all three nerves in the NST were up to 2.7 times greater in αENaC knock-out mice compared with the respective field volumes in control mice. The shapes of the fields were similar between the two groups; however, the density and spread of labels were greater in αENaC knock-out mice. Overall, our results show that disruption of the afferent taste signal to sodium salts disrupts the normal age-dependent “pruning” of all terminal fields, which could lead to alterations in sensory coding and taste-related behaviors. SIGNIFICANCE STATEMENT Neural activity plays a major role in the development of sensory circuits in the mammalian brain. To date, there has been no direct test of whether taste-elicited neural activity has a role in shaping central gustatory circuits. However, recently developed genetic tools now allow an assessment of how specific taste stimuli, in this case sodium salt taste, play a role in the maturation of the terminal fields in the mouse brainstem. We found that the specific deletion of sodium salt taste during development produced terminal fields in adults that were dramatically larger than in control mice, demonstrating for the first time that sodium salt taste-elicited activity is necessary for the normal maturation of gustatory inputs into the brain. PMID:28100747

Co-administration of betulinic acid and methamphetamine causes toxicity to dopaminergic and serotonergic nerve terminals in the striatum of late adolescent rats

PubMed Central

Killinger, Bryan; Shah, Mrudang; Moszczynska, Anna

2013-01-01

Psychostimulant methamphetamine (METH) is toxic to dopaminergic and serotonergic striatal nerve terminals in adult, but not in adolescent, brain. Betulinic acid (BA) and its derivatives are promising anti-HIV agents with some toxic properties. Many METH users, particularly young men, are HIV-positive; therefore, they might be treated with BA or its derivative for HIV infection. It is not known whether BA, or any of its derivatives, is neurotoxic in combination with METH in adolescent brain. The present study investigated the effects of BA and binge METH in the striatum in late adolescent rats. BA or METH alone did not decrease the levels of dopaminergic or serotonergic markers in the striatum whereas BA and METH together decreased these markers in a BA dose-dependent manner. BA and METH combination also caused decreases in the levels of mitochondrial complex I in the same manner; BA alone only slightly decreased the levels of the enzyme in striatal synaptosomes. BA or METH alone increased cytochrome c. METH alone decreased parkin, increased complex II and striatal BA levels. These results suggest that METH in combination with BA can be neurotoxic to dopaminergic and serotonergic striatal nerve terminals in late adolescent brain via mitochondrial dysfunction and parkin deficit. PMID:24151877

Enhancement by vasopressin of adrenergic responses in human mesenteric arteries.

PubMed

Medina, P; Noguera, I; Aldasoro, M; Vila, J M; Flor, B; Lluch, S

1997-03-01

Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether subpressor concentrations of vasopressin could modify the constrictor responses to norepinephrine and electrical stimulation of the perivascular nerves in human mesenteric arteries. Human mesenteric artery rings (3-3.5 mm long, 0.8-1.2 mm OD) were obtained from 38 patients undergoing abdominal operations. The arterial rings were suspended in organ bath chambers for isometric recording of tension. Vasopressin (3 x 10(-11) M) enhanced the contractions elicited by electrical stimulation at 2, 4, and 8 Hz (by 100, 100, and 72%, respectively) and produced a leftward shift of the concentration-response curves to norepinephrine (half-maximal effective concentration decreased from 2.2 x 10(-6) to 5.0 x 10(-7) M; P < 0.05) without any alteration in maximal contractions. Vasopressin also potentiated KCl- and calcium-induced contractions. The V1-receptor antagonist 1-[beta-mercapto-beta,beta-cyclopentamethylenepropionic acid-2-O-methyl-tyrosine, 8-arginine]vasopressin (10(-6) M) prevented the potentiation evoked by vasopressin in all cases. The calcium antagonist nifedipine (10(-6) M) did not affect the potentiation of electrical stimulation and norepinephrine induced by vasopressin but abolished KCl-induced contractions. The results suggest that vasopressin, in addition to its direct vasoconstrictor effect, strongly potentiates the responses to adrenergic stimulation and KCl depolarization. Both the direct and indirect effects of vasopressin appear to be mediated by V1-receptor stimulation. The amplifying effect of vasopressin on constrictor responses may be relevant in those clinical situations characterized by increased plasma vasopressin levels.

Circulating gonadotropins and ovarian adiponectin system are modulated by acupuncture independently of sex steroid or β-adrenergic action in a female hyperandrogenic rat model of polycystic ovary syndrome.

PubMed

Maliqueo, Manuel; Benrick, Anna; Alvi, Asif; Johansson, Julia; Sun, Miao; Labrie, Fernand; Ohlsson, Claes; Stener-Victorin, Elisabet

2015-09-05

Acupuncture with combined manual and low-frequency electrical stimulation, or electroacupuncture (EA), reduces endocrine and reproductive dysfunction in women with polycystic ovary syndrome (PCOS), likely by modulating sympathetic nerve activity or sex steroid synthesis. To test this hypothesis, we induced PCOS in rats by prepubertal implantation of continuous-release letrozole pellets (200 µg/day) or vehicle. Six weeks later, rats were treated for 5-6 weeks with low-frequency EA 5 days/week, subcutaneous injection of 17β-estradiol (2.0 µg) every fourth day, or a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg/kg) 5 days/week. Letrozole controls were handled without needle insertion or injected with sesame oil every fourth day. Estrous cyclicity, ovarian morphology, sex steroids, gonadotropins, insulin-like growth factor I, bone mineral density, and gene and protein expression in ovarian tissue were measured. Low-frequency EA induced estrous-cycle changes, decreased high levels of circulating luteinizing hormone (LH) and the LH/follicle-stimulating hormone (FSH) ratio, decreased high ovarian gene expression of adiponectin receptor 2, and increased expression of adiponectin receptor 2 protein and phosphorylation of ERK1/2. EA also increased cortical bone mineral density. Propranolol decreased ovarian expression of Foxo3, Srd5a1, and Hif1a. Estradiol decreased circulating LH, induced estrous cycle changes, and decreased ovarian expression of Adipor1, Foxo3, and Pik3r1. Further, total bone mineral density was higher in the letrozole-estradiol group. Thus, EA modulates the circulating gonadotropin levels independently of sex steroids or β-adrenergic action and affects the expression of ovarian adiponectin system. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Failure of systemic hypoxia to blunt α-adrenergic vasoconstriction in the human forearm

PubMed Central

Dinenno, Frank A; Joyner, Michael J; Halliwill, John R

2003-01-01

Systemic hypoxia in humans evokes forearm vasodilatation despite significant reflex increases in sympathetic vasoconstrictor nerve activity and noradrenaline spillover. We sought to determine whether post-junctional α-adrenergic vasoconstrictor responsiveness to endogenous noradrenaline release is blunted during systemic hypoxia. To do so, we conducted a two-part study in healthy young adults. In protocol 1, we measured forearm blood flow (FBF; venous occlusion plethysmography) and calculated the vascular conductance (FVC) responses to brachial artery infusions of two doses of tyramine (evokes endogenous noradrenaline release) in 10 adults during normoxia and mild systemic hypoxia (85 % O2 saturation; pulse oximetry of the earlobe). Systemic hypoxia evoked significant forearm vasodilatation as indicated by the increases in FBF and FVC (∼20–23 %; P < 0.05). The low and high doses of tyramine evoked significant reductions in FVC (vasoconstriction) that were similar in magnitude during normoxia (−29 ± 3 and −53 ± 4 %) and mild hypoxia (−35 ± 4 and −58 ± 3 %; P = 0.33). In protocol 2, forearm vasoconstrictor responses to the high dose of tyramine were determined in eight young adults during normoxia and during graded levels of systemic hypoxia (85, 80 and 75 % O2 saturation). The reductions in FVC were similar during normoxia (−59 ± 2 %) and the three levels of hypoxia (85 % O2 saturation, −64 ± 3 %; 80 % O2 saturation, −62 ± 1 %; 75 % O2 saturation, −61 ± 3 %; P = 0.37). In both protocols, the tyramine-induced increases in deep venous noradrenaline concentrations were similar during normoxia and all levels of hypoxia. Our results demonstrate that post-junctional α-adrenergic receptor vasoconstrictor responsiveness to endogenous noradrenaline release is not blunted during mild-to-moderate systemic hypoxia in healthy humans. PMID:12730336

Effect of peripheral nerve injury on receptive fields of cells in the cat spinal cord.

PubMed

Devor, M; Wall, P D

1981-06-20

When the sciatic and saphenous nerves are cut and ligated in adult cats, the immediate effect is the production of a completely anesthetic foot and a region in medial lumbar dorsal horn where almost all cells have lost their natural receptive fields (RFs). Beginning at about 1 week and maturing by 4 weeks, some 40% of cells in the medial dorsal horn gain a novel RF on proximal skin, that is, upper and lower leg, thigh, lower back, or perineum. This new RF is supplied by intact proximal nerves and not by sciatic and saphenous nerve fibers that sprouted in the periphery. During the period of switching of RFs from distal to proximal skin there was no gross atrophy of dorsal horn grey matter and no Fink-Heimer stainable degeneration of central arbors and terminals of peripherally axotomized afferents. In intact animals medial dorsal horn cells showed no sign of response to mechanical stimulation of proximal skin. RFs of some of the cells had spontaneous variations in size and sensitivity, but these were not nearly sufficient to explain the large shifts observed after chronic nerve section. Tetanic electrical stimulation of skin or peripheral nerves often caused RFs to shrink, but never to expand. Although natural stimuli of proximal skin would not excite medial dorsal horn cells in intact or acutely deafferented animals, it was found that electrical stimulation of proximal nerves did excite many of these cells, often at short latencies. In the discussion we justify our working hypothesis that the appearance of novel RFs is due to the strengthening or unmasking of normally present but ineffective afferent terminals, rather than to long-distance sprouting of new afferent arbors within the spinal cord.

Intralaryngeal neuroanatomy of the recurrent laryngeal nerve of the rabbit

PubMed Central

Ryan, Stephen; McNicholas, Walter T; O'Regan, Ronan G; Nolan, Philip

2003-01-01

We undertook this study to determine the detailed neuroanatomy of the terminal branches of the recurrent laryngeal nerve (RLN) in the rabbit to facilitate future neurophysiological recordings from identified branches of this nerve. The whole larynx was isolated post mortem in 17 adult New Zealand White rabbits and prepared using a modified Sihler's technique, which stains axons and renders other tissues transparent so that nerve branches can be seen in whole mount preparations. Of the 34 hemi-laryngeal preparations processed, 28 stained well and these were dissected and used to characterize the neuroanatomy of the RLN. In most cases (23/28) the posterior cricoarytenoid muscle (PCA) was supplied by a single branch arising from the RLN, though in five PCA specimens there were two or three separate branches to the PCA. The interarytenoid muscle (IA) was supplied by two parallel filaments arising from the main trunk of the RLN rostral to the branch(es) to the PCA. The lateral cricoarytenoid muscle (LCA) commonly received innervation from two fine twigs branching from the RLN main trunk and travelling laterally towards the LCA. The remaining fibres of the RLN innervated the thyroarytenoid muscle (TA) and comprised two distinct branches, one supplying the pars vocalis and the other branching extensively to supply the remainder of the TA. No communicating anastomosis between the RLN and superior laryngeal nerve within the larynx was found. Our results suggest it is feasible to make electrophysiological recordings from identified terminal branches of the RLN supplying laryngeal adductor muscles separate from the branch or branches to the PCA. However, the very small size of the motor nerves to the IA and LCA suggests that it would be very difficult to record selectively from the nerve supply to individual laryngeal adductor muscles. PMID:12739619

The Effects of Renal Denervation on Renal Hemodynamics and Renal Vasculature in a Porcine Model

PubMed Central

Verloop, Willemien L.; Hubens, Lisette E. G.; Spiering, Wilko; Doevendans, Pieter A.; Goldschmeding, Roel; Bleys, Ronald L. A. W.; Voskuil, Michiel

2015-01-01

Rationale Recently, the efficacy of renal denervation (RDN) has been debated. It is discussed whether RDN is able to adequately target the renal nerves. Objective We aimed to investigate how effective RDN was by means of functional hemodynamic measurements and nerve damage on histology. Methods and Results We performed hemodynamic measurements in both renal arteries of healthy pigs using a Doppler flow and pressure wire. Subsequently unilateral denervation was performed, followed by repeated bilateral hemodynamic measurements. Pigs were terminated directly after RDN or were followed for 3 weeks or 3 months after the procedure. After termination, both treated and control arteries were prepared for histology to evaluate vascular damage and nerve damage. Directly after RDN, resting renal blood flow tended to increase by 29±67% (P = 0.01). In contrast, renal resistance reserve increased from 1.74 (1.28) to 1.88 (1.17) (P = 0.02) during follow-up. Vascular histopathology showed that most nerves around the treated arteries were located outside the lesion areas (8±7 out of 55±25 (14%) nerves per pig were observed within a lesion area). Subsequently, a correlation was noted between a more impaired adventitia and a reduction in renal resistance reserve (β: -0.33; P = 0.05) at three weeks of follow-up. Conclusion Only a small minority of renal nerves was targeted after RDN. Furthermore, more severe adventitial damage was related to a reduction in renal resistance in the treated arteries at follow-up. These hemodynamic and histological observations may indicate that RDN did not sufficiently target the renal nerves. Potentially, this may explain the significant spread in the response after RDN. PMID:26587981

Altered vesicular glutamate transporter distributions in the mouse cochlear nucleus following cochlear insult

PubMed Central

Heeringa, Amarins N.; Stefanescu, Roxana A.; Raphael, Yehoash; Shore, Susan E.

2015-01-01

Vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) have distinct distributions in the cochlear nucleus that correspond to the sources of the labeled terminals. VGLUT1 is mainly associated with terminals of auditory nerve fibers, whereas VGLUT2 is mainly associated with glutamatergic terminals deriving from other sources that project to the cochlear nucleus (CN), including somatosensory and vestibular terminals. Previous studies in guinea pig have shown that cochlear damage results in a decrease of VGLUT1-labeled puncta and an increase in VGLUT2-labeled puncta. This indicates cross-modal compensation that is of potential importance in somatic tinnitus. To examine whether this effect is consistent across species and to provide a background for future studies, using transgenesis, the current study examines VGLUT expression profiles upon cochlear insult by intracochlear kanamycin injections in the mouse. Intracochlear kanamycin injections abolished ipsilateral ABR responses in all animals and reduced ipsilateral spiral ganglion neuron densities in animals that were sacrificed after four weeks, but not in animals that were sacrificed after three weeks. In all unilaterally deafened animals, VGLUT1 density was decreased in CN regions that receive auditory nerve fiber terminals, i.e. in the deep layer of the dorsal cochlear nucleus (DCN), in the interstitial region where the auditory nerve enters the CN, and in the magnocellular region of the antero- and posteroventral CN. In contrast, density of VGLUT2 expression was upregulated in the fusiform cell layer of the DCN and in the granule cell lamina, which are known to receive somatosensory and vestibular terminals. These results show that a cochlear insult induces cross-modal compensation in the cochlear nucleus of the mouse, confirming previous findings in guinea pig, and that these changes are not dependent on the occurrence of spiral ganglion neuron degeneration. PMID:26705736

Altered vesicular glutamate transporter distributions in the mouse cochlear nucleus following cochlear insult.

PubMed

Heeringa, A N; Stefanescu, R A; Raphael, Y; Shore, S E

2016-02-19

Vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) have distinct distributions in the cochlear nucleus that correspond to sources of the labeled terminals. VGLUT1 is mainly associated with terminals of auditory nerve fibers, whereas VGLUT2 is mainly associated with glutamatergic terminals deriving from other sources that project to the cochlear nucleus (CN), including somatosensory and vestibular terminals. Previous studies in guinea pig have shown that cochlear damage results in a decrease of VGLUT1-labeled puncta and an increase in VGLUT2-labeled puncta. This indicates cross-modal compensation that is of potential importance in somatic tinnitus. To examine whether this effect is consistent across species and to provide a background for future studies, using transgenesis, the current study examines VGLUT expression profiles upon cochlear insult by intracochlear kanamycin injections in the mouse. Intracochlear kanamycin injections abolished ipsilateral ABR responses in all animals and reduced ipsilateral spiral ganglion neuron densities in animals that were sacrificed after four weeks, but not in animals that were sacrificed after three weeks. In all unilaterally deafened animals, VGLUT1 density was decreased in CN regions that receive auditory nerve fiber terminals, i.e., in the deep layer of the dorsal cochlear nucleus (DCN), in the interstitial region where the auditory nerve enters the CN, and in the magnocellular region of the antero- and posteroventral CN. In contrast, density of VGLUT2 expression was upregulated in the fusiform cell layer of the DCN and in the granule cell lamina, which are known to receive somatosensory and vestibular terminals. These results show that a cochlear insult induces cross-modal compensation in the cochlear nucleus of the mouse, confirming previous findings in guinea pig, and that these changes are not dependent on the occurrence of spiral ganglion neuron degeneration. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

HTDP-2, a new synthetic compound, inhibits glutamate release through reduction of voltage-dependent Ca²⁺ influx in rat cerebral cortex nerve terminals.

PubMed

Lin, Tzu-Yu; Lu, Cheng-Wei; Huang, Shu-Kuei; Chou, Shang-Shing Peter; Kuo, Yuh-Chi; Chou, Shiu-Huey; Tzeng, Woan-Fang; Leu, Chieh-Yih; Huang, Rwei-Fen S; Liew, Yih-Fong; Wang, Su-Jane

2011-01-01

The present study was aimed at investigating the effect of trans-6-(4-chlorobutyl)-5-hydroxy-4-(phenylthio)-1-tosyl-5,6-dihydropyridine-2(1H)-one (HTDP-2), a novel synthetic compound, on the release of endogenous glutamate in rat cerebrocortical nerve terminals (synaptosomes) and exploring the possible mechanism. The release of glutamate was evoked by the K⁺ channel blocker 4-aminopyridine (4-AP) and measured by an on-line enzyme-coupled fluorimetric assay. We also used a membrane potential-sensitive dye to assay nerve terminal excitability and depolarization, and a Ca²⁺ indicator, Fura-2-acetoxymethyl ester, to monitor cytosolic Ca²⁺ concentrations ([Ca²⁺](c)). HTDP-2 inhibited the release of glutamate evoked by 4-AP in a concentration-dependent manner. Inhibition of glutamate release by HTDP-2 was prevented by the chelating intraterminal Ca²⁺ ions, and by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to the glutamate transporter inhibitor DL-threo-β-benzyloxyaspartate. HTDP-2 did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization whereas it decreased the 4-AP-induced increase in [Ca²⁺](c). Furthermore, the inhibitory effect of HTDP-2 on the evoked glutamate release was abolished by the N-, and P/Q-type Ca²⁺ channel blocker ω-conotoxin MVIIC, but not by the ryanodine receptor blocker dantrolene, or the mitochondrial Na⁺/Ca²⁺ exchanger blocker CGP37157. Based on these results, we suggest that, in rat cerebrocortical nerve terminals, HTDP-2 decreases voltage-dependent Ca²⁺ channel activity and, in so doing, inhibits the evoked glutamate release. Copyright © 2011 S. Karger AG, Basel.

Under stressful conditions activation of the ionotropic P2X7 receptor differentially regulates GABA and glutamate release from nerve terminals of the rat cerebral cortex.

PubMed

Barros-Barbosa, Aurora R; Oliveira, Ângela; Lobo, M Graça; Cordeiro, J Miguel; Correia-de-Sá, Paulo

2018-01-01

γ-Aminobutyric acid (GABA) and glutamate (Glu) are the main inhibitory and excitatory neurotransmitters in the central nervous system (CNS), respectively. Fine tuning regulation of extracellular levels of these amino acids is essential for normal brain activity. Recently, we showed that neocortical nerve terminals from patients with epilepsy express higher amounts of the non-desensitizing ionotropic P2X7 receptor. Once activated by ATP released from neuronal cells, the P2X7 receptor unbalances GABAergic vs. glutamatergic neurotransmission by differentially interfering with GABA and Glu uptake. Here, we investigated if activation of the P2X7 receptor also affects [ 3 H]GABA and [ 14 C]Glu release measured synchronously from isolated nerve terminals (synaptosomes) of the rat cerebral cortex. Data show that activation of the P2X7 receptor consistently increases [ 14 C]Glu over [ 3 H]GABA release from cortical nerve terminals, but the GABA/Glu ratio depends on extracellular Ca 2+ concentrations. While the P2X7-induced [ 3 H]GABA release is operated by a Ca 2+ -dependent pathway when external Ca 2+ is available, this mechanism shifts towards the reversal of the GAT1 transporter in low Ca 2+ conditions. A different scenario is verified regarding [ 14 C]Glu outflow triggered by the P2X7 receptor, since the amino acid seems to be consistently released through the recruitment of connexin-containing hemichannels upon P2X7 activation, both in the absence and in the presence of external Ca 2+ . Data from this study add valuable information suggesting that ATP, via P2X7 activation, not only interferes with the high-affinity uptake of GABA and Glu but actually favors the release of these amino acids through distinct molecular mechanisms amenable to differential therapeutic control. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [3H]GABA from rat brain nerve terminals.

PubMed

Borisova, T; Pozdnyakova, N; Shaitanova, E; Gerus, I; Dudarenko, M; Haufe, G; Kukhar, V

2017-01-15

Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (β-i-Bu-GABA), i.e. β-polyfluoroalkyl-GABAs (FGABAs), with substituents: β-CF 3 -β-OH (1), β-CF 3 (2); β-CF 2 CF 2 H (3), are able to increase the initial rate of [ 3 H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100μM) on the ambient level and exocytotic release of [ 3 H]GABA in nerve terminals and compared with those of pregabalin (100μM). It was shown that FGABAs 1-3 did not influence the ambient level of [ 3 H]GABA in the synaptosomal preparations, and this parameter was also not altered by pregabalin. During blockage of GABA transporters GAT1 by specific inhibitor NO-711, FGABAs and pregabalin also did not change ambient [ 3 H]GABA in synaptosomal preparations. Exocytotic release of [ 3 H]GABA from synaptosomes decreased in the presence of FGABAs 1-3 and pregabalin, and the effects of FGABAs 1 &3 were more significant than those of FGABAs 2 and pregabalin. FGABAs 1-3/pregabalin-induced decrease in exocytotic release of [ 3 H]GABA from synaptosomes was not a result of changes in the potential of the plasma membrane. Therefore, new synthesized FGABAs 1 &3 were able to decrease exocytotic release of [ 3 H]GABA from nerve terminals more effectively in comparison to pregabalin. Absence of unspecific side effects of FGABAs 1 &3 on the membrane potential makes these compounds perspective for medical application. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immunohistochemical localization of FMRFamide-containing neurons and nerve fibers in the ganglia and the gonad wall of the scallop, Pecten maximus (L).

PubMed

Henry, M; Benlinmame, N; Belhsen, O K; Jule, Y; Mathieu, M

1995-02-01

The Phe-Met-Arg-Phe NH2 (FMRFamide)-like immunoreactivity was detected in neurons of the cerebro-pedal and visceral ganglia of the scallop Pecten maximus using immunohistochemical techniques. FMRFamide-like immunoreactivity was also found in nerve fibers localized in the connective tissue and the epithelial wall of the gonad. Electron microscopy study carried out on the gonads indicates the existence of numerous nerve fibers crossing the connective tissue; nerve terminals apposed to highly secretory cells were seen in the gonad wall. All in all, the present immunohistochemical and electron microscopic data suggest that FMRFamide might play an unusual secretagogue role in the gonad wall.

Substance P released from intrinsic airway neurons contributes to ozone-enhanced airway hyperresponsiveness in ferret trachea.

PubMed

Wu, Zhong-Xin; Satterfield, Brian E; Dey, Richard D

2003-08-01

Exposure to ozone (O3) induces airway hyperresponsiveness mediated partly through the release of substance P (SP) from nerve terminals in the airway wall. Although substantial evidence suggests that SP is released by sensory nerves, SP is also present in neurons of airway ganglia. The purpose of this study was to investigate the role of intrinsic airway neurons in O3-enhanced airway responsiveness in ferret trachea. To remove the effects of sensory innervation, segments of ferret trachea were maintained in culture conditions for 24 h before in vitro exposure to 2 parts/million of O3 or air for 1 h. Sensory nerve depletion was confirmed by showing that capsaicin did not affect tracheal smooth muscle responsiveness to cholinergic agonist or contractility responses to electrical field stimulation (EFS). Contractions of isolated tracheal smooth muscle to EFS were significantly increased after in vitro O3 exposure, but the constrictor response to cholinergic agonist was not altered. Pretreatment with CP-99994, an antagonist of the neurokinin 1 receptor, attenuated the increased contraction to EFS after O3 exposure but had no effect in the air exposure group. The number of SP-positive neurons in longitudinal trunk ganglia, the extent of SP innervation to superficial muscular plexus nerve cell bodies, and SP nerve fiber density in tracheal smooth muscle all increased significantly after O3 exposure. The results show that release of SP from intrinsic airway neurons contributes to O3-enhanced tracheal smooth muscle responsiveness by facilitating acetylcholine release from cholinergic nerve terminals.

Biophysical characterization of interactions between the C-termini of peripheral nerve claudins and the PDZ₁ domain of zonula occludens.

PubMed

Wu, Jiawen; Peng, Dungeng; Zhang, Yang; Lu, Zhenwei; Voehler, Markus; Sanders, Charles R; Li, Jun

2015-03-27

Our recent study has shown that cellular junctions in myelin and in the epi-/perineruium that encase nerve fibers regulate the permeability of the peripheral nerves. This permeability may affect propagation of the action potential. Direct interactions between the PDZ₁ domain of zonula occludens (ZO₁ or ZO₂) and the C-termini of claudins are known to be crucial for the formation of tight junctions. Using the purified PDZ₁ domain of ZO₂ and a variety of C-terminal mutants of peripheral nerve claudins (claudin-1, claudin-2, claudin-3, claudin-5 in epi-/perineurium; claudin-19 in myelin), we have utilized NMR spectroscopy to determine specific roles of the 3 C-terminal claudin residues (position -2, -1, 0) for their interactions with PDZ₁ of ZO₂. In contrast to the canonical model that emphasizes the importance of residues at the -2 and 0 positions, our results demonstrate that, for peripheral nerve claudins, the residue at position -1 plays a critical role in association with PDZ₁, while the side-chain of residue 0 plays a significant but lesser role. Surprisingly, claudin-19, the most abundant claudin in myelin, exhibited no binding to ZO₂. These findings reveal that the binding mechanism of claudin/ZO in epi-/perineurium is distinct from the canonical interactions between non-ZO PDZ-containing proteins with their ligands. This observation provides the molecular basis for a strategy to develop drugs that target tight junctions in the epi-/perineurium of peripheral nerves. Published by Elsevier Inc.

Rehabilitation, Using Guided Cerebral Plasticity, of a Brachial Plexus Injury Treated with Intercostal and Phrenic Nerve Transfers.

PubMed

Dahlin, Lars B; Andersson, Gert; Backman, Clas; Svensson, Hampus; Björkman, Anders

2017-01-01

Recovery after surgical reconstruction of a brachial plexus injury using nerve grafting and nerve transfer procedures is a function of peripheral nerve regeneration and cerebral reorganization. A 15-year-old boy, with traumatic avulsion of nerve roots C5-C7 and a non-rupture of C8-T1, was operated 3 weeks after the injury with nerve transfers: (a) terminal part of the accessory nerve to the suprascapular nerve, (b) the second and third intercostal nerves to the axillary nerve, and (c) the fourth to sixth intercostal nerves to the musculocutaneous nerve. A second operation-free contralateral gracilis muscle transfer directly innervated by the phrenic nerve-was done after 2 years due to insufficient recovery of the biceps muscle function. One year later, electromyography showed activation of the biceps muscle essentially with coughing through the intercostal nerves, and of the transferred gracilis muscle by deep breathing through the phrenic nerve. Voluntary flexion of the elbow elicited clear activity in the biceps/gracilis muscles with decreasing activity in intercostal muscles distal to the transferred intercostal nerves (i.e., corresponding to eighth intercostal), indicating cerebral plasticity, where neural control of elbow flexion is gradually separated from control of breathing. To restore voluntary elbow function after nerve transfers, the rehabilitation of patients operated with intercostal nerve transfers should concentrate on transferring coughing function, while patients with phrenic nerve transfers should focus on transferring deep breathing function.

Microsurgical anatomy of the trochlear nerve.

PubMed

Joo, Wonil; Rhoton, Albert L

2015-10-01

The trochlear nerve is the cranial nerve with the longest intracranial course, but also the thinnest. It is the only nerve that arises from the dorsal surface of the brainstem and decussates in the superior medullary velum. After leaving the dorsal surface of the brainstem, it courses anterolaterally around the lateral surface of the brainstem and then passes anteriorly just beneath the free edge of the tentorium. It passes forward to enter the cavernous sinus, traverses the superior orbital fissure and terminates in the superior oblique muscle in the orbit. Because of its small diameter and its long course, the trochlear nerve can easily be injured during surgical procedures. Therefore, precise knowledge of its surgical anatomy and its neurovascular relationships is essential for approaching and removing complex lesions of the orbit and the middle and posterior fossae safely. This review describes the microsurgical anatomy of the trochlear nerve and is illustrated with pictures involving the nerve and its surrounding connective and neurovascular structures. © 2015 Wiley Periodicals, Inc.

Mu-opiate receptor and Beta-endorphin expression in nerve endings and keratinocytes in human skin.

PubMed

Bigliardi-Qi, M; Sumanovski, L T; Büchner, S; Rufli, T; Bigliardi, P L

2004-01-01

We have previously shown that human epidermal keratinocytes express a functionally active micro-opiate receptor, which adds a new dimension to the recently developed research in neuroimmunodermatology and neurogenic inflammation in skin diseases. Human keratinocytes specifically bind and also produce beta-endorphin, the endogenous micro-opiate receptor ligand. Using confocal imaging microscopy, we could now demonstrate that micro-opiate receptors are not only expressed in keratinocytes, but also on unmyelinated peripheral nerve fibers in the dermis and epidermis. Some of the peripheral nerve fibers also express the ligand beta-endorphin. The keratinocytes positive for beta-endorphin staining are clustered around the terminal ends of the unmyelinated nerve fibers. Therefore the opiate receptor system seems to be crucial in the direct communication between nerves and skin. The keratinocytes can influence the unmyelinated nerve fibers in the epidermis directly via secreting beta-endorphin. On the other hand, nerve fibers can also secrete beta-endorphin and influence the migration, differentiation and probably also the cytokine production pattern of keratinocytes.

Flow Cytometric Analysis of Presynaptic Nerve Terminals Isolated from Rats Subjected to Hypergravity

NASA Astrophysics Data System (ADS)

Borisova, Tatiana

2008-06-01

Flow cytometric studies revealed an insignificant decrease in cell size heterogeneity and cytoplasmic granularity of rat brain nerve terminals (synaptosomes) isolated from animals subjected to centrifuge-induced hypergravity as compared to control ones. The analysis of plasma membrane potential using the potentiometric optical dye rhodamine 6G showed a decrease in fluorescence intensity by 10 % at steady state level in hypergravity synaptosomes. To monitor synaptic vesicle acidification we used pH-sensitive fluorescent dye acridine orange and demonstrated a lower fluorescence intensity level at steady state (10%) after hypergravity as compared to controls. Thus, exposure to hypergravity resulted in depolarization of the synaptosomal plasma membrane and diminution in synaptic vesicle acidification that may be a cause leading to altered synaptic neurotransmission.

Synaptic Activity and Muscle Contraction Increases PDK1 and PKCβI Phosphorylation in the Presynaptic Membrane of the Neuromuscular Junction.

PubMed

Hurtado, Erica; Cilleros, Víctor; Just, Laia; Simó, Anna; Nadal, Laura; Tomàs, Marta; Garcia, Neus; Lanuza, Maria A; Tomàs, Josep

2017-01-01

Conventional protein kinase C βI (cPKCβI) is a conventional protein kinase C (PKC) isoform directly involved in the regulation of neurotransmitter release in the neuromuscular junction (NMJ). It is located exclusively at the nerve terminal and both synaptic activity and muscle contraction modulate its protein levels and phosphorylation. cPKCβI molecular maturation includes a series of phosphorylation steps, the first of which is mediated by phosphoinositide-dependent kinase 1 (PDK1). Here, we sought to localize PDK1 in the NMJ and investigate the hypothesis that synaptic activity and muscle contraction regulate in parallel PDK1 and cPKCβI phosphorylation in the membrane fraction. To differentiate the presynaptic and postsynaptic activities, we abolished muscle contraction with μ-conotoxin GIIIB (μ-CgTx-GIIIB) in some experiments before stimulation of the phrenic nerve (1 Hz, 30 min). Then, we analyzed total and membrane/cytosol fractions of skeletal muscle by Western blotting. Results showed that PDK1 is located exclusively in the nerve terminal of the NMJ. After nerve stimulation with and without coincident muscle contraction, total PDK1 and phosphorylated PDK1 (pPDK1) protein levels remained unaltered. However, synaptic activity specifically enhanced phosphorylation of PDK1 in the membrane, an important subcellular location for PDK1 function. This increase in pPDK1 coincides with a significant increase in the phosphorylation of its substrate cPKCβI also in the membrane fraction. Moreover, muscle contraction maintains PDK1 and pPDK1 but increases cPKCβI protein levels and its phosphorylation. Thus, even though PDK1 activity is maintained, pcPKCβI levels increase in concordance with total cPKCβI. Together, these results indicate that neuromuscular activity could induce the membrane targeting of pPDK1 in the nerve terminal of the NMJ to promote the phosphorylation of the cPKCβI, which is involved in ACh release.

Synaptic Activity and Muscle Contraction Increases PDK1 and PKCβI Phosphorylation in the Presynaptic Membrane of the Neuromuscular Junction

PubMed Central

Hurtado, Erica; Cilleros, Víctor; Just, Laia; Simó, Anna; Nadal, Laura; Tomàs, Marta; Garcia, Neus; Lanuza, Maria A.; Tomàs, Josep

2017-01-01

Conventional protein kinase C βI (cPKCβI) is a conventional protein kinase C (PKC) isoform directly involved in the regulation of neurotransmitter release in the neuromuscular junction (NMJ). It is located exclusively at the nerve terminal and both synaptic activity and muscle contraction modulate its protein levels and phosphorylation. cPKCβI molecular maturation includes a series of phosphorylation steps, the first of which is mediated by phosphoinositide-dependent kinase 1 (PDK1). Here, we sought to localize PDK1 in the NMJ and investigate the hypothesis that synaptic activity and muscle contraction regulate in parallel PDK1 and cPKCβI phosphorylation in the membrane fraction. To differentiate the presynaptic and postsynaptic activities, we abolished muscle contraction with μ-conotoxin GIIIB (μ-CgTx-GIIIB) in some experiments before stimulation of the phrenic nerve (1 Hz, 30 min). Then, we analyzed total and membrane/cytosol fractions of skeletal muscle by Western blotting. Results showed that PDK1 is located exclusively in the nerve terminal of the NMJ. After nerve stimulation with and without coincident muscle contraction, total PDK1 and phosphorylated PDK1 (pPDK1) protein levels remained unaltered. However, synaptic activity specifically enhanced phosphorylation of PDK1 in the membrane, an important subcellular location for PDK1 function. This increase in pPDK1 coincides with a significant increase in the phosphorylation of its substrate cPKCβI also in the membrane fraction. Moreover, muscle contraction maintains PDK1 and pPDK1 but increases cPKCβI protein levels and its phosphorylation. Thus, even though PDK1 activity is maintained, pcPKCβI levels increase in concordance with total cPKCβI. Together, these results indicate that neuromuscular activity could induce the membrane targeting of pPDK1 in the nerve terminal of the NMJ to promote the phosphorylation of the cPKCβI, which is involved in ACh release. PMID:28890686

Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain.

PubMed

Shelukhina, Irina; Mikhailov, Nikita; Abushik, Polina; Nurullin, Leniz; Nikolsky, Evgeny E; Giniatullin, Rashid

2017-01-01

Parasympathetic innervation of meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in meninges, origin place for headache, are almost unknown. Using electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons. Both ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in meninges. Both nicotine and carbachol induced intracellular Ca 2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors. Trigeminal nerve terminals in meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which could be activated by the ACh released from parasympathetic nerves. These receptors represent a potential target for novel therapeutic interventions in trigeminal pain and probably in migraine.

A study of the action of amlodipine on adrenergically regulated sodium handling by the kidney in normotensive and hypertensive rats.

PubMed Central

Johns, E. J.

1988-01-01

1. An investigation was undertaken to examine the effect of calcium channel blockade, induced by amlodipine, on the ability of the renal sympathetic nerves to cause an antidiuresis and anti-natriuresis in normotensive Sprague Dawley and spontaneously hypertensive rats anaesthetized with pentobarbitone. 2. Low frequency renal nerve stimulation in normotensive rats, which did not change renal blood flow, caused a 15% reduction in glomerular filtration rate and was associated with falls in urine flow of 37%, absolute sodium excretion of 47%, and fractional sodium excretion of 38%. The magnitude of these renal excretory changes was unaffected by prior administration of amlodipine at either 200 micrograms kg-1 plus 50 micrograms kg-1 h-1 or 400 micrograms kg-1 plus 100 micrograms kg-1 h-1. Amlodipine given in the higher dose, decreased basal levels of blood pressure and increased basal urine flow and sodium excretion. 3. In spontaneously hypertensive rats, renal nerve stimulation minimally affected renal haemodynamics but decreased urine flow, absolute and fractional sodium excretion by 29%, 31% and 24%, respectively. 4. Similar renal nerve stimulation in spontaneously hypertensive rats given amlodipine at 200 micrograms kg-1 plus 50 micrograms kg-1 h-1 or 400 micrograms kg-1 plus 100 micrograms kg-1 h-1 caused minimal changes in renal haemodynamics and in the excretion of water and sodium. The higher dose of drug resulted in decreased blood pressure and increased basal rates of urine flow and sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2967097

The effect of inhaled K+ channel openers on bronchoconstriction and airway microvascular leakage in anaesthetised guinea pigs.

PubMed

Kidney, J C; Lotvall, J O; Lei, Y; Chung, K F; Barnes, P J

1996-01-18

Since orally administered K+ channel openers may have cardiovascular side effects, it is possible that inhaled administration would be preferred for the treatment of asthma. We have investigated whether inhaled levcromakalim and HOE 234 inhibit histamine-induced bronchoconstriction and airway plasma exudation in anaesthetised guinea pigs. We have also investigated whether inhaled HOE 234 inhibits the bronchoconstriction and plasma exudation induced by vagus nerve stimulation, which is due to the release of tachykinins from sensory nerves. Lung resistance was measured by airway resistance (RL) computed from airway and transpulmonary pressures and plasma exudation by measurement of Evans blue dye extravasation. Inhaled levcromakalim (25 mu g/ml) had a short duration of action, being effective against histamine-induced bronchoconstriction 2 min after pretreatment, but not at 10 min. Inhaled HOE 234 (25 mu g/ml) was similarly effective against histamine-induced bronchoconstriction but had a longer duration of action. Inhaled levcromakalim partially attenuated histamine-induced plasma extravasation in small airways, but not in the trachea or main bronchi, whereas inhaled HOE 234 had no effect. HOE 234 protected against non-adrenergic non-cholinergic nerve-induced bronchoconstriction, but had no effect on neurogenic- or substance P-induced plasma extravasation in the airway. Inhaled K+ channel openers protect against induced bronchoconstriction, but provide little or no protection against plasma exudation, possibly because of an increase in airway blood flow. In addition, inhaled HOE 234 had no effect on neurogenic leakage, suggesting that its vagal inhibitory effect on bronchoconstriction was on airway smooth muscle, rather than on release of neuropeptides from sensory nerves.

Distribution and cellular localization of imidazoleacetic acid-ribotide, an endogenous ligand at imidazol(in)e and adrenergic receptors, in rat brain

PubMed Central

Friedrich, Victor L.; Martinelli, Giorgio P.; Prell, George D.; Holstein, Gay R.

2007-01-01

Imidazoleacetic acid-ribotide (IAA-RP) is a putative neurotransmitter/modulator recently discovered in mammalian brain. The present study examines the distribution of IAA-RP in the rat CNS using a highly specific antiserum raised in rabbit against IAA-RP with immunostaining of aldehyde-fixed rat CNS. IAA-RP-immunoreactive neurons were present throughout the neuraxis; neuroglia were not labeled. In each region, only a subset of the neuronal pool was immunostained. In the forebrain, ribotide-immunolabeled neurons were common in neocortex, in hippocampal formation, and in subcortical structures including basal ganglia, thalamus and hypothalamus. Labeling was prominent limbic areas including olfactory bulb, basal forebrain, pyriform cortex and amygdala. In the mid- and hindbrain, immunolabled neurons were concentrated in specific nuclei and, in some areas, in specific subregions of those nuclei. Structures of the motor system, including cranial nerve motor nuclei, precerebellar nuclei, the substantia nigra, and the red nucleus were clearly labeled. Staining was intense in cells and/or puncta in the rostral and caudal ventrolateral medullary reticular formation, nucleus tractus solitarius and the caudal vestibular nuclear complex. Within neurons, the ribotide was found predominantly in somata and dendrites; some myelinated axons and occasional synaptic terminals were also immunostained. These data indicate that IAA-RP contributes to the neurochemical phenotype of many neuronal populations further support our suggestion that, in autonomic structures, the IAA-RP may serve as a chemical mediator in complex circuits involved in blood pressure regulation and, more generally, sympathetic drive. PMID:17210242

Communicating branches between lingual and hypoglossal nerve: observation using Sihler's staining technique.

PubMed

Iwanaga, Joe; Watanabe, Koichi; Saga, Tsuyoshi; Tabira, Yoko; Nakamura, Moriyoshi; Fisahn, Christian; Tubbs, R Shane; Kusukawa, Jingo; Yamaki, Koh-Ichi

2017-07-01

Many dental procedures are at risk of injuring the lingual nerve. We performed this study to better elucidate the microanatomy that exists between the ipsilateral lingual and hypoglossal nerves so that iatrogenic injury can be avoided. Adult human cadaveric tongues (ten sides) underwent Sihler's staining to identify the microanatomy between the lingual and hypoglossal nerves. The lingual nerve entered the middle part of the anterior two-thirds of the tongue from its lateral side and divided into two to four thick branches. These branches were then disseminated to the anterior, middle, and posterior parts of the anterior two-thirds of the tongue via 7-14 thin nerve bundles as terminal branches. The hypoglossal nerve entered the tongue at the posterior border of its anterior two-thirds and traveled forward to the apex of the tongue on all sides. All specimens were found to have communicating branches between the lingual and hypoglossal nerves at its anterior, middle, and posterior thirds. Our results indicate that the ipsilateral lingual and hypoglossal nerves constantly have three connections on each side between them. This knowledge might aid the dentist in minimizing iatrogenic nerve injury.

Neurovascular control of blood pressure is influenced by aging, sex, and sex hormones.

PubMed

Baker, Sarah E; Limberg, Jacqueline K; Ranadive, Sushant M; Joyner, Michael J

2016-12-01

In this review, we highlight that the relationship between muscle sympathetic nerve activity (MSNA) and mean arterial pressure is complex, differs by sex, and changes with age. In young men there is an inverse relationship between MSNA and cardiac output where high MSNA is compensated for by low cardiac output. This inverse relationship is not seen in older men. In young women sympathetic vasoconstriction is offset by β-adrenoreceptor mediated vasodilation, limiting the ability of young women to maintain blood pressure in response to orthostatic stress. However, β-mediated dilation in women is attenuated with age, leading to unopposed α-adrenergic vasoconstriction and a rise in the direct transduction of MSNA into increases in blood pressure. We propose that these changes with age and menopausal status are major contributing factors in the increased prevalence of hypertension in older women. In addition to aging, we highlight that changes in sex hormones in young women (across the menstrual cycle, with oral contraceptive use, or with pregnancy) influence MSNA and the transduction of MSNA into increases in blood pressure. It is likely that the β-adrenergic receptors and/or changes in baroreflex sensitivity play a large role in these sex differences and changes with alterations in sex hormones. Copyright © 2016 the American Physiological Society.

Cerebral Autoregulation Is Minimally Influenced by the Superior Cervical Ganglion in Two- Week-Old Lambs, and Absent in Preterm Lambs Immediately Following Delivery

PubMed Central

Czynski, Adam J.; Terry, Michael H.; Deming, Douglas D.; Power, Gordon G.; Buchholz, John N.; Blood, Arlin B.

2013-01-01

Cerebral vessels in the premature newborn brain are well supplied with adrenergic nerves, stemming from the superior cervical ganglia (SCG), but their role in regulation of blood flow remains uncertain. To test this function twelve premature or two-week-old lambs were instrumented with laser Doppler flow probes in the parietal cortices to measure changes in blood flow during changes in systemic blood pressure and electrical stimulation of the SCG. In lambs delivered prematurely at ∼129 days gestation cerebral perfusion and driving pressure demonstrated a direct linear relationship throughout the physiologic range, indicating lack of autoregulation. In contrast, in lambs two-weeks of age, surgical removal of one SCG resulted in ipsilateral loss of autoregulation during pronounced hypertension. Electrical stimulation of one SCG elicited unilateral increases in cerebral resistance to blood flow in both pre-term and two-week-old lambs, indicating functioning neural pathways in the instrumented, anesthetized lambs. We conclude cerebral autoregulation is non-functional in preterm lambs following cesarean delivery. Adrenergic control of cerebral vascular resistance becomes effective in newborn lambs within two-weeks after birth but SCG-dependent autoregulation is essential only during pronounced hypertension, well above the normal range of blood pressure. PMID:24349256

Adrenergic mediation of the intestinal antisecretory action of opiates administered into the central nervous system.

PubMed

Brown, D R; Miller, R J

1984-10-01

The antisecretory effects of the stable enkephalin analogs, [D-Ala2-Met5] enkephalinamide (DAMA) and [D-Ala2-D-Leu5] enkephalin, and the opiate drug morphine were evaluated on fluid secretion induced by cholera toxin in isolated loops of the jejunum and proximal and distal ileum in anesthetized rats. Intracerebroventricular administration of DAMA (0.03-3 micrograms) or [D-Ala2-D-Leu5] enkephalin (1.0-10 micrograms) dose-dependently reduced secretion in the jejunum without affecting fluid movement in the other small intestinal segments. Morphine in doses up to 30 micrograms i.c.v. had no significant antisecretory effects. Intravenous administration of DAMA, at doses up to 3000 micrograms/kg, had little effect on intestinal fluid accumulation. The antisecretory action of DAMA (3 micrograms i.c.v.) was completely blocked by pretreatment with the alpha adrenergic antagonist phentolamine and after peripheral sympathectomy induced by guanethidine. In contrast, DAMA activity was preserved in adrenal demedullated rats. DAMA had no significant effects upon mean arterial blood pressure or on blood acid-base balance. These results suggest that the antisecretory effects of opiates are, at least partly, mediated at sites within the central nervous system. These actions are probably a consequence of increased activity in sympathetic nerve fibers innervating the upper small intestine.

Resting sympathetic activity is associated with the sympathetically mediated component of energy expenditure following a meal.

PubMed

Limberg, Jacqueline K; Malterer, Katherine R; Matzek, Luke J; Levine, James A; Charkoudian, Nisha; Miles, John M; Joyner, Michael J; Curry, Timothy B

2017-08-01

Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following β -adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic β -adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and β -blockade (AUC P ropranolol -AUC S aline , β -REE) and as a percent (%) of control (AUC P ropranolol ÷AUC S aline  × 100). β -REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: β -REE R  =   -0.58, P =  0.03; %REE R  = -0.56, P =  0.04; NE: β -REE R  = -0.55, P  = 0.0535; %REE R  = -0.54, P  = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Neural modulation of salt secretion in teleostopercular epithelium by 2-adrenergic receptors and inositol 1,4,5-trisphosphate

PubMed

Marshall; Duquesnay; Gillis; Bryson; Liedtke

1998-05-21

Opercular epithelia from seawater-adapted killifish (Fundulus heteroclitus) were dissected with the nerve intact, mounted in Ussing-style membrane chambers and bathed in symmetrical saline solutions. Nerve stimulation rapidly inhibited transepithelial current (a measure of Cl- secretion rate) by 27.3+/-3.3 % (N=22), and the effect could be sustained for more than 10 min using intermittent pulse trains at 10 Hz. The effect was blocked in a dose-dependent manner by yohimbine, but not by propranolol, atropine or tubocurarine, indicating mediation by 2-adrenergic receptors. The effect was also present, but significantly diminished, in opercular membranes from animals that had been transferred to sea water for 48 h (18+/-8.6 % inhibition, N=14). The resting current and the effect were absent in membranes from freshwater-adapted animals. The addition of clonidine (1.0 micromol l-1 serosal side) started to inhibit Cl- current after 40-60 s; immediately before this, at 30 s, there was a significant rise (P<0.05, N=14) in tissue inositol 1,4,5, -trisphosphate (InsP3) level, but no change at later times, compared with LiCl-treated control membranes and measured by radiolabeled receptor assay. The results indicate that seawater-adapted killifish can decrease their Cl- secretion rate through the action of the sympathetic nervous system, a response appropriate for the entry of estuarine fish to fresh water, and that the effect is mediated by 2-adrenoceptors via InsP3. The results imply that euryhaline fish entering fresh water can undergo an autonomic reflex reduction in salt secretion that does not require a stress response.

Terminal changes in hereditary sensory and autonomic neuropathy: a long-term follow-up of a sporadic case.

PubMed

Lee, Sang-Soo; Lee, Sung-Hyun; Han, Seol-Heui

2003-07-01

We describe terminal changes in a long-term follow-up of a 51-year-old man with sporadic hereditary sensory and autonomic neuropathy (HSAN). From the age of 15 years onwards, he suffered from multiple painless ulcers of his feet and fingers, necessitating amputation. Neurological studies revealed almost complete sensory loss affecting all modalities in the upper and lower limbs, minimal involvement of motor fibers, and areflexia. A neurophysiological abnormality involved an absence of sensory action potentials with relatively normal motor nerve conduction velocities. Biopsy of the sural nerve showed almost total loss of myelinated fibers with a mild decrease in unmyelinated fibers. Despite the late onset of the disease, the progressive course, and the lancinating pain, the terminal features of this patient, which involved a selective loss of myelinated fibers and widespread sensory loss, seem to be symptomatic of HSAN II, the progressive form of autosomal recessive sensory neuropathy, and emphasize the clinical heterogeneity of HSAN.

A rare case of recurrent vasodepressive attacks of 2-hours duration: analysis of the mechanism by muscle sympathetic nerve activity recording.

PubMed

Yatomi, A; Iguchi, A; Uemura, K; Sakamoto, N; Iwase, S; Mano, T

1989-03-01

Muscle sympathetic nerve activity was recorded in a 57-year-old male patient suffering from severe hypotensive attacks with bradycardia for 10 years. Continuous blood pressure recording demonstrated frequent drastic falls in pressure. Disappearance and reappearance of muscle sympathetic nerve activity coincided with the onset and termination of attacks. Awakening from sleep or emotional and/or cardiovascular stress seems to trigger hypotension. Cardiac pacemaker was not useful in limiting the attack, because right ventricular pacing caused abrupt falls in both blood pressure and heart rate.

Evidence for recycling of synaptic vesicle membrane during transmitter release at the frog neuromuscular junction.

PubMed

Heuser, J E; Reese, T S

1973-05-01

When the nerves of isolated frog sartorius muscles were stimulated at 10 Hz, synaptic vesicles in the motor nerve terminals became transiently depleted. This depletion apparently resulted from a redistribution rather than disappearance of synaptic vesicle membrane, since the total amount of membrane comprising these nerve terminals remained constant during stimulation. At 1 min of stimulation, the 30% depletion in synaptic vesicle membrane was nearly balanced by an increase in plasma membrane, suggesting that vesicle membrane rapidly moved to the surface as it might if vesicles released their content of transmitter by exocytosis. After 15 min of stimulation, the 60% depletion of synaptic vesicle membrane was largely balanced by the appearance of numerous irregular membrane-walled cisternae inside the terminals, suggesting that vesicle membrane was retrieved from the surface as cisternae. When muscles were rested after 15 min of stimulation, cisternae disappeared and synaptic vesicles reappeared, suggesting that cisternae divided to form new synaptic vesicles so that the original vesicle membrane was now recycled into new synaptic vesicles. When muscles were soaked in horseradish peroxidase (HRP), this tracerfirst entered the cisternae which formed during stimulation and then entered a large proportion of the synaptic vesicles which reappeared during rest, strengthening the idea that synaptic vesicle membrane added to the surface was retrieved as cisternae which subsequently divided to form new vesicles. When muscles containing HRP in synaptic vesicles were washed to remove extracellular HRP and restimulated, HRP disappeared from vesicles without appearing in the new cisternae formed during the second stimulation, confirming that a one-way recycling of synaptic membrane, from the surface through cisternae to new vesicles, was occurring. Coated vesicles apparently represented the actual mechanism for retrieval of synaptic vesicle membrane from the plasma membrane, because during nerve stimulation they proliferated at regions of the nerve terminals covered by Schwann processes, took up peroxidase, and appeared in various stages of coalescence with cisternae. In contrast, synaptic vesicles did not appear to return directly from the surface to form cisternae, and cisternae themselves never appeared directly connected to the surface. Thus, during stimulation the intracellular compartments of this synapse change shape and take up extracellular protein in a manner which indicates that synaptic vesicle membrane added to the surface during exocytosis is retrieved by coated vesicles and recycled into new synaptic vesicles by way of intermediate cisternae.

EVIDENCE FOR RECYCLING OF SYNAPTIC VESICLE MEMBRANE DURING TRANSMITTER RELEASE AT THE FROG NEUROMUSCULAR JUNCTION

PubMed Central

Heuser, J. E.; Reese, T. S.

1973-01-01

When the nerves of isolated frog sartorius muscles were stimulated at 10 Hz, synaptic vesicles in the motor nerve terminals became transiently depleted. This depletion apparently resulted from a redistribution rather than disappearance of synaptic vesicle membrane, since the total amount of membrane comprising these nerve terminals remained constant during stimulation. At 1 min of stimulation, the 30% depletion in synaptic vesicle membrane was nearly balanced by an increase in plasma membrane, suggesting that vesicle membrane rapidly moved to the surface as it might if vesicles released their content of transmitter by exocytosis. After 15 min of stimulation, the 60% depletion of synaptic vesicle membrane was largely balanced by the appearance of numerous irregular membrane-walled cisternae inside the terminals, suggesting that vesicle membrane was retrieved from the surface as cisternae. When muscles were rested after 15 min of stimulation, cisternae disappeared and synaptic vesicles reappeared, suggesting that cisternae divided to form new synaptic vesicles so that the original vesicle membrane was now recycled into new synaptic vesicles. When muscles were soaked in horseradish peroxidase (HRP), this tracerfirst entered the cisternae which formed during stimulation and then entered a large proportion of the synaptic vesicles which reappeared during rest, strengthening the idea that synaptic vesicle membrane added to the surface was retrieved as cisternae which subsequently divided to form new vesicles. When muscles containing HRP in synaptic vesicles were washed to remove extracellular HRP and restimulated, HRP disappeared from vesicles without appearing in the new cisternae formed during the second stimulation, confirming that a one-way recycling of synaptic membrane, from the surface through cisternae to new vesicles, was occurring. Coated vesicles apparently represented the actual mechanism for retrieval of synaptic vesicle membrane from the plasma membrane, because during nerve stimulation they proliferated at regions of the nerve terminals covered by Schwann processes, took up peroxidase, and appeared in various stages of coalescence with cisternae. In contrast, synaptic vesicles did not appear to return directly from the surface to form cisternae, and cisternae themselves never appeared directly connected to the surface. Thus, during stimulation the intracellular compartments of this synapse change shape and take up extracellular protein in a manner which indicates that synaptic vesicle membrane added to the surface during exocytosis is retrieved by coated vesicles and recycled into new synaptic vesicles by way of intermediate cisternae. PMID:4348786

Inhibitory effects of HgCl2 on excitation-secretion coupling at the motor nerve terminal and excitation-contraction coupling in the muscle cell.

PubMed

Røed, A; Herlofson, B B

1994-12-01

1. Indirect and direct twitch (0.1-Hz) stimulation of the rat phrenic nerve-diaphragm disclosed that the inhibitory effect of HgCl2, 3.7 x 10(-5) M, on the neuromuscular transmission and in the muscle cell, was accelerated by 10-sec periods of 50-Hz tetanic stimulation every 10 min. This activity-dependent enhancement suggested an inhibitory mechanism of HgCl2 related to the development of fatigue, like membrane depolarization or decreased excitability, decreased availability of transmitter, or interference with the factors controlling excitation-secretion coupling of the nerve terminal, i.e. (Ca2+)0 or (Ca2+)i, and excitation-contraction coupling in the muscle cell, i.e., (Ca2+)i. 2. During both indirect and direct stimulation, HgCl2-induced inhibition was enhanced markedly by pretreatment with caffeine, which releases Ca2+ from endoplasmic and sarcoplasmic reticulum in the nerve terminal and muscle cell, respectively. This caffeine-induced enhancement was completely antagonized by dantrolene, which inhibits the caffeine-induced release. However, dantrolene alone did not antagonize the HgCl2-induced inhibition. 3. Since caffeine depletes the intracellular Ca2+ stores of the smooth endoplasmic reticulum, HgCl2 probably inhibits by binding to SH groups of transport proteins conveying the messenger function of (Ca2+)i. In the muscle cell this leads to inhibition of contraction. In the nerve terminal, an additional enhancement of the HgCl2-induced inhibition, by inhibiting reuptake of choline by TEA and tetanic stimulation, suggested that HgCl2 inhibited a (Ca2+)i signal necessary for this limiting factor in resynthesis of acetylcholine. 4. The (Ca2+)0 signal necessary for stimulus-induced release of acetylcholine was not affected by HgCl2. Hyperpolarization in K(+)-free solution antagonized the inhibitory effect of HgCl2 at indirect stimulation, and Ca(2+)-free solution enhanced the inhibitory effect at direct stimulation. K+ depolarization, membrane electric field increase with high Ca2+, membrane stabilization with lidocaine, and half-threshold stimulation, did not change the inhibitory effect of HgCl CH3HgCl. 1.85 x 10(-5) M, disclosed a synergistic interaction with caffeine during direct, but not during indirect, stimulation.

Sound damage and gentamicin treatment produce different patterns of damage to the efferent innervation of the chick cochlea.

PubMed

Ofsie, M S; Hennig, A K; Messana, E P; Cotanche, D A

1997-11-01

Both sound exposure and gentamicin treatment cause damage to sensory hair cells in the peripheral chick auditory organ, the basilar papilla. This induces a regeneration response which replaces hair cells and restores auditory function. Since functional recovery requires the re-establishment of connections between regenerated hair cells and the central nervous system, we have investigated the effects of sound damage and gentamicin treatment on the neuronal elements within the cochlea. Whole-mount preparations of basilar papillae were labeled with phalloidin to label the actin cytoskeleton and antibodies to neurofilaments, choline acetyltransferase, and synapsin to label neurons; and examined by confocal laser scanning microscopy. When chicks are treated with gentamicin or exposed to acoustic overstimulation, the transverse nerve fibers show no changes from normal cochleae assayed in parallel. Efferent nerve terminals, however, disappear from areas depleted of hair cells following acoustic trauma. In contrast, efferent nerve endings are still present in the areas of hair cell loss following gentamicin treatment, although their morphological appearance is greatly altered. These differences in the response of efferent nerve terminals to sound exposure versus gentamicin treatment may account, at least in part, for the discrepancies reported in the time of recovery of auditory function.

Corneal nerve regeneration. Correlation between morphology and restoration of sensitivity.

PubMed

de Leeuw, A M; Chan, K Y

1989-09-01

Corneal nerve regeneration was determined in albino rabbits after deepithelialization of the cornea using heptanol. Regeneration was monitored up to 10 weeks by measuring corneal tactile sensitivity using an esthesiometer and by examining stromal and intraepithelial nerve patterns following gold chloride impregnation and acetylcholinesterase staining. Tactile sensitivity was much reduced, possibly absent, up to 2 weeks after wounding. From 2.5-4 weeks, sensitivity recovered rapidly to 60% of prewounding levels and remained unchanged thereafter. In control corneas, a distinct orientation of the basoepithelial leashes towards the nasal-most limbus was observed in the central two-thirds of the cornea. Three days after wounding, neurites that were oriented radially towards the wound center extended into the periphery of the wound area from just beyond the wound margin. At 1 week, regenerating axons were present as single neurites and in the form of modified leashes, mainly at the periphery of the wound area but also more towards the center. At 3 weeks, neurites, regenerated leashes and networks of terminals with terminal endings were found throughout the regenerated epithelium. Regional changes in the orientation of the regenerated leashes were observed also. No further change in the intraepithelial nerve pattern was detectable thereafter up to 10 weeks after wounding. It was concluded that partial restoration of tactile sensitivity following deepithelialization of the cornea is a function of the establishment of a near-normal nerve pattern in the regenerated epithelium and is correlated with the subnormal neural density observed in a previous study.

Innervation of the rabbit cardiac ventricles.

PubMed

Pauziene, Neringa; Alaburda, Paulius; Rysevaite-Kyguoliene, Kristina; Pauza, Audrys G; Inokaitis, Hermanas; Masaityte, Aiste; Rudokaite, Gabriele; Saburkina, Inga; Plisiene, Jurgita; Pauza, Dainius H

2016-01-01

The rabbit is widely used in experimental cardiac physiology, but the neuroanatomy of the rabbit heart remains insufficiently examined. This study aimed to ascertain the architecture of the intrinsic nerve plexus in the walls and septum of rabbit cardiac ventricles. In 51 rabbit hearts, a combined approach involving: (i) histochemical acetylcholinesterase staining of intrinsic neural structures in total cardiac ventricles; (ii) immunofluorescent labelling of intrinsic nerves, nerve fibres (NFs) and neuronal somata (NS); and (iii) transmission electron microscopy of intrinsic ventricular nerves and NFs was used. Mediastinal nerves access the ventral and lateral surfaces of both ventricles at a restricted site between the root of the ascending aorta and the pulmonary trunk. The dorsal surface of both ventricles is supplied by several epicardial nerves extending from the left dorsal ganglionated nerve subplexus on the dorsal left atrium. Ventral accessing nerves are thicker and more numerous than dorsal nerves. Intrinsic ventricular NS are rare on the conus arteriosus and the root of the pulmonary trunk. The number of ventricular NS ranged from 11 to 220 per heart. Four chemical phenotypes of NS within ventricular ganglia were identified, i.e. ganglionic cells positive for choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), and biphenotypic, i.e. positive for both ChAT/nNOS and for ChAT/tyrosine hydroxylase. Clusters of small intensely fluorescent cells are distributed within or close to ganglia on the root of the pulmonary trunk, but not on the conus arteriosus. The largest and most numerous intrinsic nerves proceed within the epicardium. Scarce nerves were found near myocardial blood vessels, but the myocardium contained only a scarce meshwork of NFs. In the endocardium, large numbers of thin nerves and NFs proceed along the bundle of His and both its branches up to the apex of the ventricles. The endocardial meshwork of fine NFs was approximately eight times denser than the myocardial meshwork. Adrenergic NFs predominate considerably in all layers of the ventricular walls and septum, whereas NFs of other neurochemical phenotypes were in the minority and their amount differed between the epicardium, myocardium and endocardium. The densities of NFs positive for nNOS and ChAT were similar in the epicardium and endocardium, but NFs positive for nNOS in the myocardium were eight times more abundant than NFs positive for ChAT. Potentially sensory NFs positive for both calcitonin gene-related peptide and substance P were sparse in the myocardial layer, but numerous in epicardial nerves and particularly abundant within the endocardium. Electron microscopic observations demonstrate that intrinsic ventricular nerves have a distinctive morphology, which may be attributed to remodelling of the peripheral nerves after their access into the ventricular wall. In conclusion, the rabbit ventricles display complex structural organization of intrinsic ventricular nerves, NFs and ganglionic cells. The results provide a basic anatomical background for further functional analysis of the intrinsic nervous system in the cardiac ventricles. © 2015 Anatomical Society.

Surface targeting of the dopamine transporter involves discrete epitopes in the distal C terminus but does not require canonical PDZ domain interactions.

PubMed

Bjerggaard, Christian; Fog, Jacob U; Hastrup, Hanne; Madsen, Kenneth; Loland, Claus J; Javitch, Jonathan A; Gether, Ulrik

2004-08-04

The human dopamine transporter (hDAT) contains a C-terminal type 2 PDZ (postsynaptic density 95/Discs large/zona occludens 1) domain-binding motif (LKV) known to interact with PDZ domain proteins such as PICK1 (protein interacting with C-kinase 1). As reported previously, we found that, after deletion of this motif, hDAT was retained in the endoplasmic reticulum (ER) of human embryonic kidney (HEK) 293 and Neuro2A cells, suggesting that PDZ domain interactions might be critical for hDAT targeting. Nonetheless, substitution of LKV with SLL, the type 1 PDZ-binding sequence from the beta2-adrenergic receptor, did not disrupt plasma membrane targeting. Moreover, the addition of an alanine to the hDAT C terminus (+Ala), resulting in an LKVA termination sequence, or substitution of LKV with alanines (3xAla_618-620) prevented neither plasma membrane targeting nor targeting into sprouting neurites of differentiated N2A cells. The inability of +Ala and 3xAla_618-620 to bind PDZ domains was confirmed by lack of colocalization with PICK1 in cotransfected HEK293 cells and by the inability of corresponding C-terminal fusion proteins to pull down purified PICK1. Thus, although residues in the hDAT C terminus are indispensable for proper targeting, PDZ domain interactions are not required. By progressive substitutions with beta2-adrenergic receptor sequence, and by triple-alanine substitutions in the hDAT C terminus, we examined the importance of epitopes preceding the LKV motif. Substitution of RHW(615-617) with alanines caused retention of the transporter in the ER despite preserved ability of this mutant to bind PICK1. We propose dual roles of the hDAT C terminus: a role independent of PDZ interactions for ER export and surface targeting, and a not fully clarified role involving PDZ interactions with proteins such as PICK1.

How the optic nerve allocates space, energy capacity, and information

PubMed Central

Perge, Janos A.; Koch, Kristin; Miller, Robert; Sterling, Peter; Balasubramanian, Vijay

2009-01-01

Fiber tracts should use space and energy efficiently because both resources constrain neural computation. We found for a myelinated tract (optic nerve) that astrocytes use nearly 30% of the space and more than 70% of the mitochondria, establishing the significance of astrocytes for the brain’s space and energy budgets. Axons are mostly thin with a skewed distribution peaking at 0.7µm, near the lower limit set by channel noise. This distribution is matched closely by the distribution of mean firing rates measured under naturalistic conditions, suggesting that firing rate increases proportionally with axon diameter. In axons thicker than 0.7µm mitochondria occupy a constant fraction of axonal volume -- thus, mitochondrial volumes rise as the diameter squared. These results imply a law of diminishing returns: twice the information rate requires more than twice the space and energy capacity. We conclude that the optic nerve conserves space and energy by sending most information at low rates over fine axons with small terminal arbors, and sending some information at higher rates over thicker axons with larger terminal arbors – but only where more bits/s are needed for a specific purpose. Thicker axons seem to be needed, not for their greater conduction velocity (nor other intrinsic electrophysiological purpose), but instead to support larger terminal arbors and more active zones that transfer information synaptically at higher rates. PMID:19535603

High affinity choline uptake (HACU) and choline acetyltransferase (ChAT) activity in neuronal cultures for mechanistic and drug discovery studies

PubMed Central

Ray, Balmiki; Bailey, Jason A.; Simon, Jay R.; Lahiri, Debomoy K.

2012-01-01

Acetylcholine (ACh) is the neurotransmitter used by cholinergic neurons at the neuromuscular junction and in parasympathetic nerve terminals in the periphery, as well as important memory-related circuits in the brain and also takes part in several critical functions. ACh is synthesized from choline and acetyl coenzyme-A by the enzyme choline acetyltransferase (ChAT). The formation of acetylcholine in cholinergic nerve terminals requires both the transport of choline into the cells from the extracellular space, and the activity of ChAT. High affinity choline uptake (HACU) represents the majority of choline uptake into the nerve terminal, and is the acutely regulated, rate-limiting step in ACh synthesis. The HACU component of choline uptake can be differentiated from non-specific choline uptake by inhibition of the choline transporter with hemicholinium. Several methods have been described previously to measure HACU and ChAT simultaneously in synaptosomes, but a well-documented protocol for cultured cells is lacking. We describe a procedure to simultaneously measure HACU and ChAT in cultured cells by simple radionuclide-based techniques. In this procedure we have quantitatively determined HACU and ChAT activity in cholinergically differentiated human neuroblastoma (SK-N-SH) cells. These simple methods can be used for neurochemical and drug discovery studies relevant to several disorders including Alzheimer’s disease, myasthenia gravis, and cardiovascular disease. PMID:22752895

No consistent bioenergetic defects in presynaptic nerve terminals isolated from mouse models of Alzheimer’s disease

PubMed Central

Choi, Sung W.; Gerencser, Akos A.; Ng, Ryan; Flynn, James M.; Melov, Simon; Danielson, Steven R.; Gibson, Bradford W.; Nicholls, David G.; Bredesen, Dale E.; Brand, Martin D.

2012-01-01

Depressed cortical energy supply and impaired synaptic function are predominant associations of Alzheimer’s disease (AD). To test the hypothesis that presynaptic bioenergetic deficits are associated with the progression of AD pathogenesis, we compared bioenergetic variables of cortical and hippocampal presynaptic nerve terminals (synaptosomes) from commonly used mouse models with AD-like phenotypes (J20 age 6 months, Tg2576 age 16 months and APP/PS age 9 and 14 months) to age-matched controls. No consistent bioenergetic deficiencies were detected in synaptosomes from the three models, only APP/PS cortical synaptosomes from 14 month old mice showed an increase in respiration associated with proton leak. J20 mice were chosen for a highly stringent investigation of mitochondrial function and content. There were no significant differences in the quality of the synaptosomal preparations or the mitochondrial volume fraction. Furthermore, respiratory variables, calcium handling, and membrane potentials of synaptosomes from symptomatic J20 mice under calcium-imposed stress were not consistently impaired. The recovery of marker proteins during synaptosome preparation was the same, ruling out the possibility that the lack of functional bioenergetic defects in synaptosomes from J20 mice was due to the selective loss of damaged synaptosomes during sample preparation. Our results support the conclusion that the intrinsic bioenergetic capacities of presynaptic nerve terminals are maintained in these symptomatic AD mouse models. PMID:23175831

Stimuli of Sensory-Motor Nerves Terminate Arterial Contractile Effects of Endothelin-1 by CGRP and Dissociation of ET-1/ETA-Receptor Complexes

PubMed Central

Meens, Merlijn J. P. M. T.; Compeer, Matthijs G.; Hackeng, Tilman M.; van Zandvoort, Marc A.; Janssen, Ben J. A.; De Mey, Jo G. R.

2010-01-01

Background Endothelin-1 (ET-1), a long-acting paracrine mediator, is implicated in cardiovascular diseases but clinical trials with ET-receptor antagonists were not successful in some areas. We tested whether the quasi-irreversible receptor-binding of ET-1 (i) limits reversing effects of the antagonists and (ii) can be selectively dissociated by an endogenous counterbalancing mechanism. Methodology/Principal findings In isolated rat mesenteric resistance arteries, ETA-antagonists, endothelium-derived relaxing factors and synthetic vasodilators transiently reduced contractile effects of ET-1 but did not prevent persistent effects of the peptide. Stimuli of peri-vascular vasodilator sensory-motor nerves such as capsaicin not only reduced but also terminated long-lasting effects of ET-1. This was prevented by CGRP-receptor antagonists and was mimicked by exogenous calcitonin gene-related peptide (CGRP). Using 2-photon laser scanning microscopy in vital intact arteries, capsaicin and CGRP, but not ETA-antagonism, were observed to promote dissociation of pre-existing ET-1/ETA-receptor complexes. Conclusions Irreversible binding and activation of ETA-receptors by ET-1 (i) occur at an antagonist-insensitive site of the receptor and (ii) are selectively terminated by endogenously released CGRP. Hence, natural stimuli of sensory-motor nerves that stimulate release of endogenous CGRP can be considered for therapy of diseases involving ET-1. PMID:20532232

Ultrastructural and cytochemical evidence for single impulse initiation zones in vestibular macular nerve fibers of rat

NASA Technical Reports Server (NTRS)

Ross, Muriel D.; Chee, Oliver; Black, Samuel; Cutler, Lynn

1991-01-01

Cupric ion-ferricyanide labeling methods and related ferrocyanide-stained tissues were used to locate the characterize, at the ultrastructural level, presumptive impulse initiation zones in the three types of vestibular macular nerve fibers. Large-diameter, M-type vestibular nerve fibers terminate in a calyx at the heminode, and labeling is coextensive with the base of the calyx. Intermediate, M/U-type nerve fibers have short, unmyelinated preterminal segments that sometimes bifurcate intamacularly, and small-diameter, U-type nerve fibers have long, unmyelinated preterminal axons and up to three branches. Preterminals of these nerve fibers display ultrastructural heterogeneity that is correlated with labeling patterns for sodium channels and/or associated polyanionic sites. They have a nodelike ultrastructure and label heavily from near the heminode to the base of the macula. Their intramacular branches, less organized ultrastructurally, label only slightly. Results indicate that vestibular nerve fibers have one impulse initiation zone, located near the heminode, that varies in length according to nerve fiber type. Structural heterogeneity may favor impulse conduction in the central direction, and length of the impulse initiation zone could influence nerve discharge patterns.

Visual neuroscience before the neuron.

PubMed

Wade, Nicholas J

2004-01-01

Visual neuroscience is considered to be a contemporary concern, based in large part on relating characteristics of neural functioning to visual experience. It presupposes a detailed knowledge of neural activity for which the neuron doctrine is a fundamental tenet. However, long before either the neuron doctrine had been advanced or the nerve cell had been described, attempts were made to estimate the dimensions of nerve fibres from measures of visual resolution. In the seventeenth century, the microscopes of Hooke and van Leeuwenhoek were unable to resolve structures as small as nerves adequately. However, it was not Hooke's microscope that led to an estimate of the dimensions of nerve fibres but his experiments on the limits of visual resolution. Hooke determined that a separation of one minute of arc was the minimum that could normally be seen. Descartes had earlier speculated that the retina consisted of the terminations of fibres of the optic nerve, and that their size defined the limits of what could be seen. Estimates of the diameters of nerve fibres were made on the basis of human visual acuity by Porterfield in 1738; he calculated the diameters of nerve fibres in the retina as one 7200th part of an inch (0.0035 mm), based on the resolution of one minute of arc as the minimum visible. In the same year, Jurin questioned the reliability of such estimates because of variations in visual resolution with different stimuli. The measurement of visual acuity was refined by Mayer in 1755, with dots, gratings, and grids used as stimuli. In the 1830s, Treviranus fused the microscopic and acuity approaches to determine the dimensions of nerve fibres. His indirect estimates of the dimensions of retinal fibres were close to those derived from microscopic observation. However, the suggestion that the retina consisted of terminations of nerve fibres influenced his detailed illustrations of its microscopic structure. Contrary to the situation that obtained after the microscopic structure of the retina had been established, a function of vision (acuity) was used to determine the dimensions of the structures (retinal elements) that were thought to mediate it.

Identification of the visceral pain pathway activated by noxious colorectal distension in mice.

PubMed

Kyloh, Melinda; Nicholas, Sarah; Zagorodnyuk, Vladimir P; Brookes, Simon J; Spencer, Nick J

2011-01-01

In patients with irritable bowel syndrome, visceral pain is evoked more readily following distension of the colorectum. However, the identity of extrinsic afferent nerve pathway that detects and transmits visceral pain from the colorectum to the spinal cord is unclear. In this study, we identified which extrinsic nerve pathway(s) underlies nociception from the colorectum to the spinal cord of rodents. Electromyogram recordings were made from the transverse oblique abdominal muscles in anesthetized wild type (C57BL/6) mice and acute noxious intraluminal distension stimuli (100-120 mmHg) were applied to the terminal 15 mm of colorectum to activate visceromotor responses (VMRs). Lesioning the lumbar colonic nerves in vivo had no detectable effect on the VMRs evoked by colorectal distension. Also, lesions applied to the right or left hypogastric nerves failed to reduce VMRs. However, lesions applied to both left and right branches of the rectal nerves abolished VMRs, regardless of whether the lumbar colonic or hypogastric nerves were severed. Electrical stimulation applied to either the lumbar colonic or hypogastric nerves in vivo, failed to elicit a VMR. In contrast, electrical stimulation (2-5 Hz, 0.4 ms, 60 V) applied to the rectum reliably elicited VMRs, which were abolished by selective lesioning of the rectal nerves. DiI retrograde labeling from the colorectum (injection sites 9-15 mm from the anus, measured in unstretched preparations) labeled sensory neurons primarily in dorsal root ganglia (DRG) of the lumbosacral region of the spinal cord (L6-S1). In contrast, injection of DiI into the mid to proximal colon (injection sites 30-75 mm from the anus, measured in unstretched preparations) labeled sensory neurons in DRG primarily of the lower thoracic level (T6-L2) of the spinal cord. The visceral pain pathway activated by acute noxious distension of the terminal 15 mm of mouse colorectum is transmitted predominantly, if not solely, through rectal/pelvic afferent nerve fibers to the spinal cord. The sensory neurons of this spinal afferent pathway lie primarily in the lumbosacral region of the spinal cord, between L6 and S1.

Autologous transplantation with fewer fibers repairs large peripheral nerve defects

PubMed Central

Deng, Jiu-xu; Zhang, Dian-yin; Li, Ming; Weng, Jian; Kou, Yu-hui; Zhang, Pei-xun; Han, Na; Chen, Bo; Yin, Xiao-feng; Jiang, Bao-guo

2017-01-01

Peripheral nerve injury is a serious disease and its repair is challenging. A cable-style autologous graft is the gold standard for repairing long peripheral nerve defects; however, ensuring that the minimum number of transplanted nerve attains maximum therapeutic effect remains poorly understood. In this study, a rat model of common peroneal nerve defect was established by resecting a 10-mm long right common peroneal nerve. Rats receiving transplantation of the common peroneal nerve in situ were designated as the in situ graft group. Ipsilateral sural nerves (10–30 mm long) were resected to establish the one sural nerve graft group, two sural nerves cable-style nerve graft group and three sural nerves cable-style nerve graft group. Each bundle of the peroneal nerve was 10 mm long. To reduce the barrier effect due to invasion by surrounding tissue and connective-tissue overgrowth between neural stumps, small gap sleeve suture was used in both proximal and distal terminals to allow repair of the injured common peroneal nerve. At three months postoperatively, recovery of nerve function and morphology was observed using osmium tetroxide staining and functional detection. The results showed that the number of regenerated nerve fibers, common peroneal nerve function index, motor nerve conduction velocity, recovery of myodynamia, and wet weight ratios of tibialis anterior muscle were not significantly different among the one sural nerve graft group, two sural nerves cable-style nerve graft group, and three sural nerves cable-style nerve graft group. These data suggest that the repair effect achieved using one sural nerve graft with a lower number of nerve fibers is the same as that achieved using the two sural nerves cable-style nerve graft and three sural nerves cable-style nerve graft. This indicates that according to the ‘multiple amplification’ phenomenon, one small nerve graft can provide a good therapeutic effect for a large peripheral nerve defect. PMID:29323049

Alterations in Corneal Sensory Nerves During Homeostasis, Aging, and After Injury in Mice Lacking the Heparan Sulfate Proteoglycan Syndecan-1.

PubMed

Pal-Ghosh, Sonali; Tadvalkar, Gauri; Stepp, Mary Ann

2017-10-01

To determine the impact of the loss of syndecan 1 (SDC1) on intraepithelial corneal nerves (ICNs) during homeostasis, aging, and in response to 1.5-mm trephine and debridement injury. Whole-mount corneas are used to quantify ICN density and thickness over time after birth and in response to injury in SDC1-null and wild-type (WT) mice. High-resolution three-dimensional imaging is used to visualize intraepithelial nerve terminals (INTs), axon fragments, and lysosomes in corneal epithelial cells using antibodies against growth associated protein 43 (GAP43), βIII tubulin, and LAMP1. Quantitative PCR was performed to quantify expression of SDC1, SDC2, SDC3, and SDC4 in corneal epithelial mRNA. Phagocytosis was assessed by quantifying internalization of fluorescently labeled 1-μm latex beads. Intraepithelial corneal nerves innervate the corneas of SDC1-null mice more slowly. At 8 weeks, ICN density is less but thickness is greater. Apically projecting intraepithelial nerve terminals and lysosome-associated membrane glycoprotein 1 (LAMP1) are also reduced in unwounded SDC1-null corneas. Quantitative PCR and immunofluorescence studies show that SDC3 expression and localization are increased in SDC1-null ICNs. Wild-type and SDC1-null corneas lose ICN density and thickness as they age. Recovery of axon density and thickness after trephine but not debridement wounds is slower in SDC1-null corneas compared with WT. Experiments assessing phagocytosis show reduced bead internalization by SDC1-null epithelial cells. Syndecan-1 deficiency alters ICN morphology and homeostasis during aging, reduces epithelial phagocytosis, and impairs reinnervation after trephine but not debridement injury. These data provide insight into the mechanisms used by sensory nerves to reinnervate after injury.

New transmitters and new targets in the autonomic nervous system.

PubMed

Barajas-López, C; Huizinga, J D

1993-12-01

Several recent findings have made research into the autonomic nervous system even more exciting, such as the revelation that nitric oxide is a major neurotransmitter, the delineation of the physiological roles for purines and vasoactive intestinal peptide, and the discovery that the interstitial cells of Cajal are major target cells for enteric innervation. Nitric oxide is probably the major neurotransmitter evoking inhibitory junction potentials in smooth muscle. ATP is a mediator of non-adrenergic non-cholinergic enteric innervation, as well as being a fast neurotransmitter in peripheral and autonomic neuro-neuronal synapses. The interactions between enteric nerves and both immune cells and interstitial cells of Cajal (as pacemaker cells of gut smooth muscle) are forcing a rethink of many aspects of gut physiology.

Identification of a negative regulatory region for the exchange activity and characterization of T332I mutant of Rho guanine nucleotide exchange factor 10 (ARHGEF10).

PubMed

Chaya, Taro; Shibata, Satoshi; Tokuhara, Yasunori; Yamaguchi, Wataru; Matsumoto, Hiroshi; Kawahara, Ichiro; Kogo, Mikihiko; Ohoka, Yoshiharu; Inagaki, Shinobu

2011-08-26

The T332I mutation in Rho guanine nucleotide exchange factor 10 (ARHGEF10) was previously found in persons with slowed nerve conduction velocities and thin myelination of peripheral nerves. However, the molecular and cellular basis of the T332I mutant is not understood. Here, we show that ARHGEF10 has a negative regulatory region in the N terminus, in which residue 332 is located, and the T332I mutant is constitutively active. An N-terminal truncated ARHGEF10 mutant, ARHGEF10 ΔN (lacking amino acids 1-332), induced cell contraction that was inhibited by a Rho kinase inhibitor Y27632 and had higher GEF activity for RhoA than the wild type. The T332I mutant also showed the phenotype similar to the N-terminal truncated mutant. These data suggest that the ARHGEF10 T332I mutation-associated phenotype observed in the peripheral nerves is due to activated GEF activity of the ARHGEF10 T332I mutant.

Identification of a Negative Regulatory Region for the Exchange Activity and Characterization of T332I Mutant of Rho Guanine Nucleotide Exchange Factor 10 (ARHGEF10)*

PubMed Central

Chaya, Taro; Shibata, Satoshi; Tokuhara, Yasunori; Yamaguchi, Wataru; Matsumoto, Hiroshi; Kawahara, Ichiro; Kogo, Mikihiko; Ohoka, Yoshiharu; Inagaki, Shinobu

2011-01-01

The T332I mutation in Rho guanine nucleotide exchange factor 10 (ARHGEF10) was previously found in persons with slowed nerve conduction velocities and thin myelination of peripheral nerves. However, the molecular and cellular basis of the T332I mutant is not understood. Here, we show that ARHGEF10 has a negative regulatory region in the N terminus, in which residue 332 is located, and the T332I mutant is constitutively active. An N-terminal truncated ARHGEF10 mutant, ARHGEF10 ΔN (lacking amino acids 1–332), induced cell contraction that was inhibited by a Rho kinase inhibitor Y27632 and had higher GEF activity for RhoA than the wild type. The T332I mutant also showed the phenotype similar to the N-terminal truncated mutant. These data suggest that the ARHGEF10 T332I mutation-associated phenotype observed in the peripheral nerves is due to activated GEF activity of the ARHGEF10 T332I mutant. PMID:21719701

Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to "Biased Opioids"?

PubMed

Root-Bernstein, Robert; Turke, Miah; Subhramanyam, Udaya K Tiruttani; Churchill, Beth; Labahn, Joerg

2018-01-17

Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.

Neuropathy in non-freezing cold injury (trench foot).

PubMed Central

Irwin, M S; Sanders, R; Green, C J; Terenghi, G

1997-01-01

Non-freezing cold injury (trench foot) is characterized, in severe cases, by peripheral nerve damage and tissue necrosis. Controversy exists regarding the susceptibility of nerve fibre populations to injury as well as the mechanism of injury. Clinical and histological studies (n = 2) were conducted in a 40-year-old man with severe non-freezing cold injury in both feet. Clinical sensory tests, including two-point discrimination and pressure, vibration and thermal thresholds, indicated damage to large and small diameter nerves. On immunohistochemical assessment, terminal cutaneous nerve fibres within the plantar skin stained much less than in a normal control whereas staining to von Willebrand factor pointed to increased vascularity in all areas. The results indicate that all nerve populations (myelinated and unmyelinated) were damaged, possibly in a cycle of ischaemia and reperfusion. Images Figure 1 a Figure 1 b Figure 2 a Figure 2 b Figure 3 a Figure 3 b PMID:9306996

Active uptake system for substance P carboxy-terminal heptapeptide (5-11) into a fraction from rabbit enriched in glial cells.

PubMed

Inoue, A; Nakata, Y; Yajima, H; Segawa, T

1984-10-01

In the present study, we demonstrated the existence of an active uptake system for substance P carboxy-terminal heptapeptide, (5-11)SP. When a fraction from rabbit brain enriched in glial cells was incubated with [3H] (5-11)SP, an uptake of [3H](5-11)SP was observed. The uptake system has the properties of an active transport mechanism. Kinetic analysis indicated two components of [3H](5-11)SP uptake, one representing a high and the other a low affinity transport system. After unilateral ablation of the striatum, approximately 30% of the high affinity [3H](5-11)SP uptake capacity of substantia nigra slices disappeared. The subcellular distribution of the high affinity uptake indicated that [3H] 5-hydroxytryptamine was taken up mostly into the P2B fraction (synaptosomal fraction), whereas [3H](5-11)SP was taken up into the P2A fraction (myelin fraction) to the same extent as into the P2B fraction. These results suggest that when SP is released from nerve terminals, it is hydrolysed into (5-11)SP, which is in turn accumulated into glial cells as well as nerve terminals and that this high affinity uptake mechanism may play an important role in terminating the synaptic action of SP.

Supercharged end-to-side anterior interosseous to ulnar motor nerve transfer for intrinsic musculature reinnervation.

PubMed

Barbour, John; Yee, Andrew; Kahn, Lorna C; Mackinnon, Susan E

2012-10-01

Functional motor recovery after peripheral nerve injury is predominantly determined by the time to motor end plate reinnervation and the absolute number of regenerated motor axons that reach target. Experimental models have shown that axonal regeneration occurs across a supercharged end-to-side (SETS) nerve coaptation. In patients with a recovering proximal ulnar nerve injury, a SETS nerve transfer conceptually is useful to protect and preserve distal motor end plates until the native axons fully regenerate. In addition, for nerve injuries in which incomplete regeneration is anticipated, a SETS nerve transfer may be useful to augment the regenerating nerve with additional axons and to more quickly reinnervate target muscle. We describe our technique for a SETS nerve transfer of the terminal anterior interosseous nerve (AIN) to the pronator quadratus muscle (PQ) end-to-side to the deep motor fascicle of the ulnar nerve in the distal forearm. In addition, we describe our postoperative therapy regimen for these transfers and an evaluation tool for monitoring progressive muscle reinnervation. Although the AIN-to-ulnar motor group SETS nerve transfer was specifically designed for ulnar nerve injuries, we believe that the SETS procedure might have broad clinical utility for second- and third-degree axonotmetic nerve injuries, to augment partial recovery and/or "babysit" motor end plates until the native parent axons regenerate to target. We would consider all donor nerves currently utilized in end-to-end nerve transfers for neurotmetic injuries as candidates for this SETS technique. Copyright © 2012 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

The sensory-motor bridge neurorraphy: an anatomic study of feasibility between sensory branch of the musculocutaneous nerve and deep branch of the radial nerve.

PubMed

Goubier, Jean-Noel; Teboul, Frédéric

2011-05-01

Restoring elbow flexion remains the first step in the management of total palsy of the brachial plexus. Non avulsed upper roots may be grafted on the musculocutaneous nerve. When this nerve is entirely grafted, some motor fibres regenerate within the sensory fibres quota. Aiming potential utilization of these lost motor fibres, we attempted suturing the sensory branch of the musculocutaneous nerve onto the deep branch of the radial nerve. The objective of our study was to assess the anatomic feasibility of such direct suturing of the terminal sensory branch of the musculocutaneous nerve onto the deep branch of the radial nerve. The study was carried out with 10 upper limbs from fresh cadavers. The sensory branch of the musculocutaneous muscle was dissected right to its division. The motor branch of the radial nerve was identified and dissected as proximally as possible into the radial nerve. Then, the distance separating the two nerves was measured so as to assess whether direct neurorraphy of the two branches was feasible. The excessive distance between the two branches averaged 6 mm (1-13 mm). Thus, direct neurorraphy of the sensory branch of the musculocutaneous nerve and the deep branch of the radial nerve was possible. When the whole musculocutaneous nerve is grafted, some of its motor fibres are lost amongst the sensory fibres (cutaneous lateral antebrachial nerve). By suturing this sensory branch onto the deep branch of the radial nerve, "lost" fibres may be retrieved, resulting in restoration of digital extension. Copyright © 2011 Wiley-Liss, Inc.

Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?

PubMed Central

Turke, Miah; Subhramanyam, Udaya K. Tiruttani; Churchill, Beth; Labahn, Joerg

2018-01-01

Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists. PMID:29342106

Innervation pattern of the preocular human central retinal artery.

PubMed

Bergua, Antonio; Kapsreiter, Markus; Neuhuber, Winfried L; Reitsamer, Herbert A; Schrödl, Falk

2013-05-01

The central retinal artery (CRA) is the main vessel for inner retinal oxygen and nutrition supply. While the intraocular branches lack autonomic innervation, the innervation pattern of the extra-ocular part of this vessel along its course within the optic nerve is poorly investigated. This part however is essential for maintenance of retinal blood supply, in physiological and pathological conditions. Therefore, the aim of this study was the characterization of the autonomic innervation of the preocular CRA in humans with morphological methods. Meeting the Declaration of Helsinki, eyes of body or cornea donors were processed for single or double immunohistochemistry against tyrosine hydroxilase (TH), dopamine-β-hydroxylase (DBH), choline acetyl-transferase (ChAT), vesicular acetylcholine transporter (VAChT), neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal polypeptide (VIP), and cytochemistry for NADPH-diaphorase (NADPH-d). For documentation, light-, fluorescence-, and confocal laser-scanning microscopy were used. TH and DBH immunoreactive nerve fibres were detected in the CRA vessel wall, although a distinct perivascular plexus was missing. Further, nerve fibres immunoreactive for ChAT and VAChT were found, while CGRP, SP, and VIP were not detected. NADPH-d staining revealed scattered nerve fibres in the adventitia of the CRA and in close vicinity; however, nNOS-immunostaining could not confirm this finding. The CRA receives adrenergic and cholinergic innervations, indicating sympathetic and parasympathetic components, respectively. Remarkably, a peptidergic primary afferent innervation was missing. Since clinical results suggest an autoregulation of intraretinal vessels, further studies are needed to clarify the impact of CRA innervation for retinal perfusion. Copyright © 2012 Elsevier Ltd. All rights reserved.

Race and sex differences in cardiovascular α-adrenergic and β-adrenergic receptor responsiveness in men and women with high blood pressure

PubMed Central

Sherwood, Andrew; Hill, LaBarron K.; Blumenthal, James A.; Johnson, Kristy S.; Hinderliter, Alan L.

2018-01-01

Objective Hypertension is associated with unfavorable changes in adrenergic receptor responsiveness, but the relationship of race and sex to adrenergic receptor responsiveness in the development of cardiovascular disease is unclear. This study examined α-adrenergic and β-adrenergic receptor responsiveness in African-American and white men and women with untreated high blood pressure (BP) (HBP) and with normal BP. Methods and results The study sample comprised 161 African-American and white men and women in the age range 25–45 years. Isoproterenol, a nonselective β-adrenergic receptor agonist, was administered intravenously to determine the bolus dose required to increase heart rate by 25 bpm, an index of β-adrenergic receptor responsiveness. Similarly, phenylephrine, an α1-adrenergic receptor agonist, was administered to determine the bolus dose required to increase BP by 25 mmHg, an index of vascular α1-adrenergic receptor responsiveness. HBP (P <0.01), male sex (P =0.04), and higher BMI (P <0.01) were all associated with reduced β-adrenergic receptor responsiveness, with a similar trend observed for African-American race (P =0.07). Conversely, α1-adrenergic receptor responsiveness was increased in association with HBP (P <0.01), female sex (P <0.01), and African-American race (P <0.01). Conclusion In the early stages of hypertension, cardiovascular β-adrenergic receptors demonstrate blunted responsiveness, whereas conversely α1-adrenergic receptors exhibit increased responsiveness. This pattern of receptor changes is especially evident in men and African-Americans, is exacerbated by obesity, and may contribute to the development of cardiovascular disease. PMID:28306633

β1-adrenergic receptor stimulation by agonist Compound 49b restores insulin receptor signal transduction in vivo

PubMed Central

Jiang, Youde; Zhang, Qiuhua; Ye, Eun-Ah

2014-01-01

Purpose Determine whether Compound 49b treatment ameliorates retinal changes due to the lack of β2-adrenergic receptor signaling. Methods Using retinas from 3-month-old β2-adrenergic receptor-deficient mice, we treated mice with our novel β1-/β2-adrenergic receptor agonist, Compound 49b, to assess the effects of adrenergic agonists acting only on β1-adrenergic receptors due to the absence of β2-adrenergic receptors. Western blotting or enzyme-linked immunosorbent assay (ELISA) analyses were performed for β1- and β2-adrenergic receptors, as well as key insulin resistance proteins, including TNF-α, SOCS3, IRS-1Ser307, and IRTyr960. Analyses were also performed on key anti- and proapoptotic proteins: Akt, Bcl-xL, Bax, and caspase 3. Electroretinogram analyses were conducted to assess functional changes, while histological assessment was conducted for changes in retinal thickness. Results A 2-month treatment of β2-adrenergic receptor-deficient mice with daily eye drops of 1 mM Compound 49b, a novel β1- and β2-adrenergic receptor agonist, reversed the changes in insulin resistance markers (TNF-α and SOCS3) observed in untreated β2-adrenergic receptor-deficient mice, and concomitantly increased morphological integrity (retinal thickness) and functional responses (electroretinogram amplitude). These results suggest that stimulating β1-adrenergic receptors on retinal endothelial cells or Müller cells can compensate for the loss of β2-adrenergic receptor signaling on Müller cells, restore insulin signal transduction, reduce retinal apoptosis, and enhance retinal function. Conclusions Since our previous studies with β1-adrenergic receptor knockout mice confirmed that the reverse also occurs (β2-adrenergic receptor stimulation can compensate for the loss of β1-adrenergic receptor activity), it appears that increased activity in either of these pathways alone is sufficient to block insulin resistance–based retinal cell apoptosis. PMID:24966659

Innervation of the wrist joint and surgical perspectives of denervation.

PubMed

Van de Pol, Gerrit J; Koudstaal, Maarten J; Schuurman, Arnold H; Bleys, Ronald L A W

2006-01-01

Because our experience with the techniques used in denervation surgery of the wrist joint often has proven insufficient in treating chronic pain we conducted an anatomic study to clarify the exact contributions of the nerves supplying the wrist joint. Our goal was to reveal all periosteal and capsular nerve connections and if necessary adjust our technique used in denervation surgery. Innervation of the wrist joint was investigated by microdissection and histologic examination of 18 human wrists. An acetylcholinesterase method was used to identify the nerves, both in whole-mount preparations and in sections. We found that the main innervation to the wrist capsule and periosteal nerve network came from the anterior interosseous nerve, lateral antebrachial cutaneous nerve, and posterior interosseous nerve. The palmar cutaneous branch of the median nerve, the deep branch of the ulnar nerve, the superficial branch of the radial nerve, and the dorsal branch of the ulnar nerve also were found to have connections with the capsule. The periosteal nerve branches did not appear to play a major role in the innervation of the capsule and ligaments; here the specific articular nerve branches proved more important. The posterior and medial antebrachial cutaneous nerves did not connect to the wrist capsule or periosteum but rather terminated in the extensor and flexor retinaculum. Based on our findings we propose to denervate the wrist by making 2 incisions. With one palmar and one dorsal incision it should be possible to disconnect the periosteum from the capsule and interrupt the majority of the capsular nerve branches.

Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.

PubMed

Bassi, Gabriel S; do C Malvar, David; Cunha, Thiago M; Cunha, Fernando Q; Kanashiro, Alexandre

2016-08-01

Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.

Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

PubMed Central

Webb, Ian G.; Nishino, Yasuhiro; Clark, James E.; Murdoch, Colin; Walker, Simon J.; Makowski, Marcus R.; Botnar, Rene M.; Redwood, Simon R.; Shah, Ajay M.; Marber, Michael S.

2010-01-01

Aims Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3α and 9 of GSK-3β respectively, required for inactivation by upstream kinases. Methods and results Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. Conclusion Expression of inactivation-resistant GSK-3α/β does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3α/β, may enable a sustained cardiac response to chronic β-agonist stimulation while preventing pathological remodelling. PMID:20299330

Tertiary Oximes on Brain Acetylcholinesterase and Central Excitatory Effects of Nerve Agents

DTIC Science & Technology

2012-01-01

5 test doses of the oxime. Animals were euthanized 45 min after oxime treatment when blood and target tissues were collected. AChE activity was...the ability of MINA and DHAP to block or terminate nerve agent-induced electroencephalographic (EEG) seizure activity was evaluated. Animals...instrumented to record brain EEG activity were challenged with a seizure-inducing dose (2.0 x LD50) of GB, GF, or VX, and oxime was administered one min

The release of acetylcholine from post-ganglionic cell bodies in response to depolarization.

PubMed Central

Johnson, D A; Pilar, G

1980-01-01

1. Acetylcholine (Ach) release from parasympathetic ganglia cell somata was investigated in denervated avian ciliary ganglia. Three days after the input to the ganglion (the oculomotor nerve) was sectioned, all presynaptic nerve terminals had degenerated. 2. Denervated ganglia were shown to contain endogenous ACh and to be capable of synthesizing [3H]ACh from [3H]choline added to the incubation medium. 3. In response to depolarization induced by incubation in 50 mM-[K+]o, denervated ganglia released [3H]ACh into bath effluents in amounts approximately 15% of the non-denervated contralateral control. This release was shown to be Ca2+ dependent in both intact and denervated ganglia. 4. Antidromic electrical stimulation of ciliary nerves also elicited [3H]ACh release. Nicotine (1 microgram/microliter.) depolarized denervated ciliary ganglion cells and evoked release of the transmitter and this release was antagonized by curare. 5. It is concluded that the ganglionic cell bodies sysnthesized ACh and released the transmitter in response to K+ depolarization, antidromic stimulation and cholinergic agonists, despite the lack of morphological specializations usually associated with stimulus-induced release of neurotransmitter. The evidence suggests the existence of a mechanism of transmitter release which is Ca2+ dependent, probably from a cytoplasmic pool and therefore distinct from the usual vesicular release at the nerve terminal. Images Plate 1 Plate 2 PMID:6247485

Cytoarchitectonic study of the brain of a dwarf snakehead, Channa gachua (Ham.). I. The telencephalon.

PubMed

Baile, Vidya V; Patle, Pratap J

2011-12-01

Cytoarchitectonic pattern of the telencephalon of a dwarf snakehead, Channa gachua, is studied by serial transverse sections of the brain (Kluver and Barrera staining). On the anteriormost extremity of the telencephalon, olfactory bulbs terminate that are sessile. The olfactory bulbs comprise four concentric layers, which from outside toward the center are olfactory nerve layer, a glomerular layer, mitral cell layer, and internal cell layer. Large terminal nerve ganglion cells are prominently visible in the dorsomedial position where the bulbs terminate on the telencephalon. In all, 24 nuclei are identified in the telencephalon on ventral and dorsal areas and are named according to their position. Ventral telencephalon exhibits 11 nuclei. On the dorsal telencephalon, there are 13 nuclei. These again are named according to their position on dorsal, ventral, median, lateral, or posterior part. This study reported for the first time in this fish will be useful in tracing the neuronal system of Channa gachua and subsequent studies of the functional aspects of these nuclei in the regulation of reproductive cycle of this species.

The effects of lubrol WX on brain membrane Ca2+/Mg2+ ATPase and ATP-dependent Ca2+ uptake activity following acute and chronic ethanol.

PubMed

Ross, D H; Garrett, K M; Cardenas, H L

1985-02-01

Acute administration of ethanol (2.5 gm/kg, i.p.) to rats inhibits the cytosolic buffering of Ca2+ in nerve terminals. Ca2+ ATPase and ATP-dependent Ca2+ uptake are both inhibited 30 min after a single dose of ethanol. Chronic ethanol administration (6%, 14 days) did not inhibit Ca2+ ATPase but significantly stimulated ATP-dependent Ca2+ uptake. Lubrol WX treatment of acute ethanolic membranes reverses the inhibition of Ca2+ ATPase seen following ethanol. Lubrol WX treatment of chronic ethanolic membranes prevents the increase in ATP-dependent Ca2+ uptake seen in ethanolic membranes. Both acute and chronic ethanol-induced changes in Ca2+ transport within nerve terminals may involve lipid-dependent parameters of the membrane which may underlie neuronal adaptation.

The effects of combined application of inorganic Martian dust simulant and carbon dots on glutamate transport rat brain nerve terminals

NASA Astrophysics Data System (ADS)

Borisova, Tatiana; Krisanova, Natalia; Nazarova, Anastasiya; Borysov, Arseniy; Pastukhov, Artem; Pozdnyakova, Natalia; Dudarenko, Marina

2016-07-01

During inhalation, nano-/microsized particles are efficiently deposited in nasal, tracheobronchial, and alveolar regions and can be transported to the central nervous system (Oberdorster et al., 2004). Recently, the research team of this study found the minor fractions of nanoparticles with the size ~ 50 -60 nm in Lunar and Martian dust stimulants (JSC-1a and JSC, ORBITEC Orbital Technologies Corporation, Madison, Wisconsin), whereas the average size of the simulants was 1 mm and 4mm, respectively (Krisanova et al., 2013). Also, the research team of this study discovered new phenomenon - the neuromodulating and neurotoxic effect of carbon nano-sized particles - Carbon dots (C-dots), originated from ash of burned carbon-containing product (Borisova et al, 2015). The aims of this study was to analyse acute effects of upgraded stimulant of inorganic Martian dust derived from volcanic ash (JSC-1a/JSC, ORBITEC Orbital Technologies Corporation, Madison, Wisconsin) by the addition of carbon components, that is, carbon dots, on the key characteristic of synaptic neurotransmission. Acute administration of carbon-containing Martian dust analogue resulted in a significant decrease in transporter-mediated uptake of L-[14C]glutamate (the major excitatory neurotransmitter) by isolated rat brain nerve terminals. The ambient level of the neurotransmitter in the preparation of nerve terminals increased in the presence of carbon dot-contained Martian dust analogue. These effects were associated with action of carbon component of the upgraded Martian dust stimulant but not with its inorganic constituent.

Novel technique for repair of severed peripheral nerves in rats using polyurea crosslinked silica aerogel scaffold.

PubMed

Sabri, Firouzeh; Gerth, David; Tamula, George-Rudolph M; Phung, Thien-Chuong N; Lynch, Kyle J; Boughter, John D

2014-10-01

To design, synthesize, and test in vivo an aerogel-based top-open peripheral nerve scaffold to simultaneously support and guide multiple completely severed peripheral nerves in a rat model. Also, to explore options for immobilizing severed nerves on the aerogel material without the use of sutures resulting in reduced surgical time. A novel material and approach was developed for the reattachment of severed peripheral nerves. Nerve confinement and alignment in this case relies on the surface properties of a lightweight, highly porous, polyurea crosslinked silica aerogel scaffold. The distal and proximal ends of completely transected nerve terminals were positioned inside prefabricated "top-open" corrugated channels that cradled approximately two thirds of the circumference of the nerve trunk and connectivity of the severed nerves was evaluated using sciatic function index (SFI) technique for five months post-surgery on 10 female Sprague-Dawley rats then compared with the gold standard for peripheral nerve repair. The interaction of nerves with the surface of the scaffold was investigated also. Multichannel aerogel-based nerve support scaffold showed similar SFI recovery trend as the case suture repair technique. Usage of an adhesion-promoting coating reduced the friction between the nerve and the scaffold leading to slippage and lack of attachment between nerve and surface. The aerogel scaffold used in this study did not collapse under pressure during the incubation period and allowed for a rapid and non-invasive peripheral nerve repair approach without the demands of microsurgery on both time and surgical expertise. This technique may allow for simultaneous repair and reconnection of multiple severed nerves particularly relevant to nerve branching sites.

Race and sex differences in cardiovascular α-adrenergic and β-adrenergic receptor responsiveness in men and women with high blood pressure.

PubMed

Sherwood, Andrew; Hill, LaBarron K; Blumenthal, James A; Johnson, Kristy S; Hinderliter, Alan L

2017-05-01

Hypertension is associated with unfavorable changes in adrenergic receptor responsiveness, but the relationship of race and sex to adrenergic receptor responsiveness in the development of cardiovascular disease is unclear. This study examined α-adrenergic and ß-adrenergic receptor responsiveness in African-American and white men and women with untreated high blood pressure (BP) (HBP) and with normal BP. The study sample comprised 161 African-American and white men and women in the age range 25-45 years. Isoproterenol, a nonselective ß-adrenergic receptor agonist, was administered intravenously to determine the bolus dose required to increase heart rate by 25 bpm, an index of β-adrenergic receptor responsiveness. Similarly, phenylephrine, an α1-adrenergic receptor agonist, was administered to determine the bolus dose required to increase BP by 25 mmHg, an index of vascular α1-adrenergic receptor responsiveness. HBP (P < 0.01), male sex (P = 0.04), and higher BMI (P < 0.01) were all associated with reduced β-adrenergic receptor responsiveness, with a similar trend observed for African-American race (P = 0.07). Conversely, α1-adrenergic receptor responsiveness was increased in association with HBP (P < 0.01), female sex (P < 0.01), and African-American race (P < 0.01). In the early stages of hypertension, cardiovascular β-adrenergic receptors demonstrate blunted responsiveness, whereas conversely α1-adrenergic receptors exhibit increased responsiveness. This pattern of receptor changes is especially evident in men and African-Americans, is exacerbated by obesity, and may contribute to the development of cardiovascular disease.

Galanin regulates blood glucose level in the zebrafish: a morphological and functional study.

PubMed

Podlasz, P; Jakimiuk, A; Chmielewska-Krzesinska, M; Kasica, N; Nowik, N; Kaleczyc, J

2016-01-01

The present study has demonstrated the galaninergic innervation of the endocrine pancreas including sources of the galaninergic nerve fibers, and the influence of galanin receptor agonists on blood glucose level in the zebrafish. For the first time, a very abundant galaninergic innervation of the endocrine pancreas during development is shown, from the second day post-fertilization to adulthood. The fibers originated from ganglia consisting of galanin-IR, non-adrenergic (non-sensory) neurons located rostrally to the pancreatic tissue. The ganglia were found on the dorsal side of the initial part of the anterior intestinal segment, close to the intestinal branch of the vagus nerve. The galanin-IR neurons did not show immunoreactivity for applied antibodies against tyrosine hydroxylase, choline acetyltransferase, and vesicular acetylcholine transporter. Intraperitoneal injections of galanin analog NAX 5055 resulted in a statistically significant increase in the blood glucose level. Injections of another galanin receptor agonist, galnon, also caused a rise in blood glucose level; however, it was not statistically significant. The present findings suggest that, like in mammals, in the zebrafish galanin is involved in the regulation of blood glucose level. However, further studies are needed to elucidate the exact mechanism of the galanin action.

Correlation of ultrasound appearance, gross anatomy, and histology of the femoral nerve at the femoral triangle.

PubMed

Lonchena, Tiffany K; McFadden, Kathryn; Orebaugh, Steven L

2016-01-01

Correlation between ultrasound appearance, gross anatomic characteristics, and histologic structure of the femoral nerve (FN) is lacking. Utilizing cadavers, we sought to characterize the anatomy of the FN, and provide a quantitative measure of its branching. We hypothesize that at the femoral crease, the FN exists as a group of nerve branches, rather than a single nerve structure, and secondarily, that this transition into many branches is apparent on ultrasonography. Nineteen preserved cadavers were investigated. Ultrasonography was sufficient to evaluate the femoral nerve in nine specimens; gross dissection was utilized in all 19. Anatomic characteristics were recorded, including distances from the inguinal ligament to femoral crease, first nerve branch, and complete arborization of the nerve. The nerves from nine specimens were excised for histologic analysis. On ultrasound, the nerve became more flattened, widened, and less discrete as it coursed distally. Branching of the nerve was apparent in 12 of 18 images, with mean distance from inguinal ligament of 3.9 (1.0) cm. However, upon dissection, major branching of the femoral nerve occurred at 3.1 (1.0) cm distal to the inguinal ligament, well proximal to the femoral crease. Histologic analysis was consistent with findings at dissection. The femoral nerve arborizes into multiple branches between the inguinal ligament and the femoral crease. Initial branching is often high in the femoral triangle. As hypothesized, the FN exists as a closely associated group of nerve branches at the level of the femoral crease; however, the termination of the nerve into multiple branches is not consistently apparent on ultrasonography.

Heart-specific overexpression of choline acetyltransferase gene protects murine heart against ischemia through hypoxia-inducible factor-1α-related defense mechanisms.

PubMed

Kakinuma, Yoshihiko; Tsuda, Masayuki; Okazaki, Kayo; Akiyama, Tsuyoshi; Arikawa, Mikihiko; Noguchi, Tatsuya; Sato, Takayuki

2013-01-18

Murine and human ventricular cardiomyocytes rich in acetylcholine (Ach) receptors are poorly innervated by the vagus, compared with whole ventricular innervation by the adrenergic nerve. However, vagal nerve stimulation produces a favorable outcome even in the murine heart, despite relatively low ventricular cholinergic nerve density. Such a mismatch and missing link suggest the existence of a nonneuronal cholinergic system in ventricular myocardium. To examine the role of the nonneuronal cardiac cholinergic system, we generated choline acetyltransferase (ChAT)-expressing cells and heart-specific ChAT transgenic (ChAT-tg) mice. Compared with cardiomyocytes of wild-type (WT) mice, those of the ChAT-tg mice had high levels of ACh and hypoxia-inducible factor (HIF)-1α protein and augmented glucose uptake. These phenotypes were also reproduced by ChAT-overexpressing cells, which utilized oxygen less. Before myocardial infarction (MI), the WT and ChAT-tg mice showed similar hemodynamics; after MI, however, the ChAT-tg mice had better survival than did the WT mice. In the ChAT-tg hearts, accelerated angiogenesis at the ischemic area, and accentuated glucose utilization prevented post-MI remodeling. The ChAT-tg heart was more resistant to ischemia-reperfusion injury than was the WT heart. These results suggest that the activated cardiac ACh-HIF-1α cascade improves survival after MI. We conclude that de novo synthesis of ACh in cardiomyocytes is a pivotal mechanism for self-defense against ischemia.

Stress increases descending inhibition in mouse and human colon.

PubMed

Reed, D E; Zhang, Y; Beyak, M J; Lourenssen, S; Blennerhassett, M G; Paterson, W G; Vanner, S J

2016-04-01

A relationship between stress and the symptoms of irritable bowel syndrome (IBS) has been well established but the cellular mechanisms are poorly understood. Therefore, we investigated effects of stress and stress hormones on colonic descending inhibition and transit in mouse models and human tissues. Stress was applied using water avoidance stress (WAS) in the animal model or mimicked using stress hormones, adrenaline (5 nM), and corticosterone (1 μM). Intracellular recordings were obtained from colonic circular smooth muscle cells in isolated smooth muscle/myenteric plexus preparations and the inhibitory junction potential (IJP) was elicited by nerve stimulation or balloon distension oral to the site of recording. Water avoidance stress increased the number of fecal pellets compared to control (p < 0.05). WAS also caused a significant increase in IJP amplitude following balloon distension. Stress hormones also increased the IJP amplitude following nerve stimulation and balloon distension (p < 0.05) in control mice but had no effect in colons from stressed mice. No differences were observed with application of ATP between stress and control tissues, suggesting the actions of stress hormones were presynaptic. Stress hormones had a large effect in the nerve stimulated IJP in human colon (increased >50%). Immunohistochemical studies identified alpha and beta adrenergic receptor immunoreactivity on myenteric neurons in human colon. These studies suggest that WAS and stress hormones can signal via myenteric neurons to increase inhibitory neuromuscular transmission. This could lead to greater descending relaxation, decreased transit time, and subsequent diarrhea. © 2016 John Wiley & Sons Ltd.

A novel inositol phosphate selectively inhibits vasoconstriction evoked by the sympathetic co-transmitters neuropeptide Y (NPY) and adenosine triphosphate (ATP).

PubMed

Wahlestedt, C; Reis, D J; Yoo, H; Adamsson, M; Andersson, D; Edvinsson, L

1992-08-31

Postganglionic sympathetic nerves release norepinephrine (NE) as their primary neurotransmitter at vascular and other targets. However, much evidence supports involvement of additional messengers, co-transmitters, which are co-released with NE upon sympathetic nerve stimulation and thereby contribute to their actions, e.g., vasoconstriction. Two such putative co-transmitters, neuropeptide Y (NPY) and adenosine triphosphate (ATP) have been of particular interest since they fulfill several neurotransmitter criteria. Importantly, hitherto it has been difficult to antagonize vasoconstriction evoked by either NPY or ATP with agents that are devoid of intrinsic activity. The present study describes the ability of a novel inositol phosphate, D-myo-inositol 1,2,6-trisphosphate (Ins[1,2,6]P3; PP-56) to in vitro potently block vasoconstrictor responses elicited by NPY and ATP, but not by NE, as studied in guinea-pig isolated basilar artery. The action of Ins[1,2,6]P3 does not seem to occur through antagonism at NPY- or ATP-receptor recognition sites, labeled by 125I-peptide YY and 35S-gamma-ATP, respectively, in membranes of rat cultured vena cava vascular smooth muscle cells. However, it does involve inhibition of the influx of Ca2+ induced by either co-transmitter in these same vena cava cells. It is proposed that Ins[1,2,6]P3 may be a useful functional antagonist of non-adrenergic component(s) of the vasoconstrictor response to sympathetic nerve stimulation.

Pharmacotherapy for benign prostatic hyperplasia.

PubMed Central

Narayan, P; Indudhara, R

1994-01-01

Benign prostatic hyperplasia is a benign neoplasm of the prostate seen in men of advancing age. Microscopic evidence of the disorder is seen in about 70% of men by 70 years of age, whereas symptoms requiring some form of surgical intervention occur in 30% of men during their lifetime. Although the exact cause of benign prostatic hyperplasia is not clear, it is well recognized that high levels of intraprostatic androgens are required for the maintenance of prostatic growth. In recent years, extensive surveys of patients undergoing transurethral resection of the prostate reveal an 18% incidence of morbidity that has essentially not changed in the past 30 years. This procedure is also the second highest reimbursed surgical therapy under Medicare. These findings have resulted in an intensive search for alternative therapies for prostatic hyperplasia. An alternative that has now been well defined is the use of alpha-adrenergic blockers to relax the prostatic urethra. This is based on findings that a major component of benign prostatic hyperplasia symptoms is spasm of the prostatic urethra and bladder neck, which is mediated by the alpha-adrenergic nerves. A second approach is to block androgens involved in maintaining prostate growth. Several such drugs are now available for clinical use, and we discuss their side effects and use. We also include the newer recommendations on evaluating benign prostatic hyperplasia that are cost-effective yet comprehensive. Images PMID:7528957

Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

PubMed Central

Lorton, Dianne; Bellinger, Denise L.

2015-01-01

Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells. PMID:25768345

Cardiovascular control in Antarctic fish

NASA Astrophysics Data System (ADS)

Egginton, Stuart; Campbell, Hamish; Davison, William

2006-04-01

The capacity for synthesis and plasma levels of stress hormones in species with a range of activity patterns suggest that depressed catecholamine synthesis is typical of notothenioid fishes regardless of life style, although they are able to release extensive stores under conditions of extreme trauma. Cortisol does not appear to be an important primary stress hormone in these species. In general, vascular reactivity shows a modest α and β adrenergic tonus, but with greater potency for cholinergic and serotonergic vasoconstrictor agonists, although a dominance of vasodilatation over vasoconstriction is observed in one species. Vasomotor control mechanisms appear to be primarily a consequence of evolutionary lineage rather than low environmental temperature, but the pattern may be modified according to functional demand. These and other data confirm the cardiovascular system is dominated by cholinergic control: the heart apparently lacks adrenergic innervation, but receives inhibitory parasympathetic input that regulates heart rate (HR) by setting a resting vagal tonus. Oxygen consumption (MO 2) determined at rest and varied via specific dynamic action, in intact fish and fish that had undergone bilateral sectioning of the vagus nerve, show that HR is a good predictor of MO 2, and that the major influence on HR is the degree of vagal tone—these fish work by removing the brake rather than applying the accelerator. However, whether these traits actually represent adaptation to the Antarctic environment or merely represent ancestral characteristics and their relative phylogenetic position is at present unclear.

α2-adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression

PubMed Central

Lamkin, Donald M.; Sung, Ha Yeon; Yang, Gyu Sik; David, John M.; Ma, Jeffrey C.Y.; Cole, Steve W.; Sloan, Erica K.

2014-01-01

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology. PMID:25462899

Vas deferens neuro-effector junction: from kymographic tracings to structural biology principles.

PubMed

Navarrete, L Camilo; Barrera, Nelson P; Huidobro-Toro, J Pablo

2014-10-01

The vas deferens is a simple bioassay widely used to study the physiology of sympathetic neurotransmission and the pharmacodynamics of adrenergic drugs. The role of ATP as a sympathetic co-transmitter has gained increasing attention and furthered our understanding of its role in sympathetic reflexes. In addition, new information has emerged on the mechanisms underlying the storage and release of ATP. Both noradrenaline and ATP concur to elicit the tissue smooth muscle contractions following sympathetic reflexes or electrical field stimulation of the sympathetic nerve terminals. ATP and adenosine (its metabolic byproduct) are powerful presynaptic regulators of co-transmitter actions. In addition, neuropeptide Y, the third member of the sympathetic triad, is an endogenous modulator. The peptide plus ATP and/or adenosine play a significant role as sympathetic modulators of transmitter's release. This review focuses on the physiological principles that govern sympathetic co-transmitter activity, with special interest in defining the motor role of ATP. In addition, we intended to review the recent structural biology findings related to the topology of the P2X1R based on the crystallized P2X4 receptor from Danio rerio, or the crystallized adenosine A2A receptor as a member of the G protein coupled family of receptors as prototype neuro modulators. This review also covers structural elements of ectonucleotidases, since some members are found in the vas deferens neuro-effector junction. The allosteric principles that apply to purinoceptors are also reviewed highlighting concepts derived from receptor theory at the light of the current available structural elements. Finally, we discuss clinical applications of these concepts. Copyright © 2014 Elsevier B.V. All rights reserved.

Exaggerated coronary vasoconstriction limits muscle metaboreflex-induced increases in ventricular performance in hypertension

PubMed Central

Spranger, Marty D.; Kaur, Jasdeep; Sala-Mercado, Javier A.; Krishnan, Abhinav C.; Abu-Hamdah, Rania; Alvarez, Alberto; Machado, Tiago M.; Augustyniak, Robert A.

2017-01-01

Increases in myocardial oxygen consumption during exercise mainly occur via increases in coronary blood flow (CBF) as cardiac oxygen extraction is high even at rest. However, sympathetic coronary constrictor tone can limit increases in CBF. Increased sympathetic nerve activity (SNA) during exercise likely occurs via the action of and interaction among activation of skeletal muscle afferents, central command, and resetting of the arterial baroreflex. As SNA is heightened even at rest in subjects with hypertension (HTN), we tested whether HTN causes exaggerated coronary vasoconstriction in canines during mild treadmill exercise with muscle metaboreflex activation (MMA; elicited by reducing hindlimb blood flow by ~60%) thereby limiting increases in CBF and ventricular performance. Experiments were repeated after α1-adrenergic blockade (prazosin; 75 µg/kg) and in the same animals following induction of HTN (modified Goldblatt 2K1C model). HTN increased mean arterial pressure from 97.1 ± 2.6 to 132.1 ± 5.6 mmHg at rest and MMA-induced increases in CBF, left ventricular dP/dtmax, and cardiac output were markedly reduced to only 32 ± 13, 26 ± 11, and 28 ± 12% of the changes observed in control. In HTN, α1-adrenergic blockade restored the coronary vasodilation and increased in ventricular function to the levels observed when normotensive. We conclude that exaggerated MMA-induced increases in SNA functionally vasoconstrict the coronary vasculature impairing increases in CBF, which limits oxygen delivery and ventricular performance in HTN. NEW & NOTEWORTHY We found that metaboreflex-induced increases in coronary blood flow and ventricular contractility are attenuated in hypertension. α1-Adrenergic blockade restored these parameters toward normal levels. These findings indicate that the primary mechanism mediating impaired metaboreflex-induced increases in ventricular function in hypertension is accentuated coronary vasoconstriction. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/metaboreflex-induced-functional-coronary-vasoconstriction/. PMID:27769997

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

PubMed Central

Kostich, Walter; Hamman, Brian D.; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V.; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K.; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M.; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O’Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H.; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E.; Lentz, Kimberley A.; Santone, Kenneth S.; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K.; Nara, Susheel J.; Dzierba, Carolyn; Bronson, Joanne; Macor, John E.; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M.

2016-01-01

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans. PMID:27411717

Measuring Synaptic Vesicle Endocytosis in Cultured Hippocampal Neurons.

PubMed

Villarreal, Seth; Lee, Sung Hoon; Wu, Ling-Gang

2017-09-04

During endocytosis, fused synaptic vesicles are retrieved at nerve terminals, allowing for vesicle recycling and thus the maintenance of synaptic transmission during repetitive nerve firing. Impaired endocytosis in pathological conditions leads to decreases in synaptic strength and brain functions. Here, we describe methods used to measure synaptic vesicle endocytosis at the mammalian hippocampal synapse in neuronal culture. We monitored synaptic vesicle protein endocytosis by fusing a synaptic vesicular membrane protein, including synaptophysin and VAMP2/synaptobrevin, at the vesicular lumenal side, with pHluorin, a pH-sensitive green fluorescent protein that increases its fluorescence intensity as the pH increases. During exocytosis, vesicular lumen pH increases, whereas during endocytosis vesicular lumen pH is re-acidified. Thus, an increase of pHluorin fluorescence intensity indicates fusion, whereas a decrease indicates endocytosis of the labelled synaptic vesicle protein. In addition to using the pHluorin imaging method to record endocytosis, we monitored vesicular membrane endocytosis by electron microscopy (EM) measurements of Horseradish peroxidase (HRP) uptake by vesicles. Finally, we monitored the formation of nerve terminal membrane pits at various times after high potassium-induced depolarization. The time course of HRP uptake and membrane pit formation indicates the time course of endocytosis.

Sensory Innervation of the Nonspecialized Connective Tissues in the Low Back of the Rat

PubMed Central

Corey, Sarah M.; Vizzard, Margaret A.; Badger, Gary J.; Langevin, Helene M.

2011-01-01

Chronic musculoskeletal pain, including low back pain, is a worldwide debilitating condition; however, the mechanisms that underlie its development remain poorly understood. Pathological neuroplastic changes in the sensory innervation of connective tissue may contribute to the development of nonspecific chronic low back pain. Progress in understanding such potentially important abnormalities is hampered by limited knowledge of connective tissue's normal sensory innervation. The goal of this study was to evaluate and quantify the sensory nerve fibers terminating within the nonspecialized connective tissues in the low back of the rat. With 3-dimensional reconstructions of thick (30–80 μm) tissue sections we have for the first time conclusively identified sensory nerve fiber terminations within the collagen matrix of connective tissue in the low back. Using dye labeling techniques with Fast Blue, presumptive dorsal root ganglia cells that innervate the low back were identified. Of the Fast Blue-labeled cells, 60–88% also expressed calcitonin gene-related peptide (CGRP) immunoreactivity. Based on the immunolabeling with CGRP and the approximate size of these nerve fibers (≤2 μm) we hypothesize that they are Aδ or C fibers and thus may play a role in the development of chronic pain. PMID:21411968

Antibodies to ribosomal P proteins of Trypanosoma cruzi in Chagas disease possess functional autoreactivity with heart tissue and differ from anti-P autoantibodies in lupus.

PubMed

Kaplan, D; Ferrari, I; Bergami, P L; Mahler, E; Levitus, G; Chiale, P; Hoebeke, J; Van Regenmortel, M H; Levin, M J

1997-09-16

Anti-P antibodies present in sera from patients with chronic Chagas heart disease (cChHD) recognize peptide R13, EEEDDDMGFGLFD, which encompasses the C-terminal region of the Trypanosoma cruzi ribosomal P1 and P2 proteins. This peptide shares homology with the C-terminal region (peptide H13 EESDDDMGFGLFD) of the human ribosomal P proteins, which is in turn the target of anti-P autoantibodies in systemic lupus erythematosus (SLE), and with the acidic epitope, AESDE, of the second extracellular loop of the beta1-adrenergic receptor. Anti-P antibodies from chagasic patients showed a marked preference for recombinant parasite ribosomal P proteins and peptides, whereas anti-P autoantibodies from SLE reacted with human and parasite ribosomal P proteins and peptides to the same extent. A semi-quantitative estimation of the binding of cChHD anti-P antibodies to R13 and H13 using biosensor technology indicated that the average affinity constant was about 5 times higher for R13 than for H13. Competitive enzyme immunoassays demonstrated that cChHD anti-P antibodies bind to the acidic portions of peptide H13, as well as to peptide H26R, encompassing the second extracellular loop of the beta1 adrenoreceptor. Anti-P antibodies isolated from cChHD patients exert a positive chronotropic effect in vitro on cardiomyocytes from neonatal rats, which resembles closely that of anti-beta1 receptor antibodies isolated from the same patient. In contrast, SLE anti-P autoantibodies have no functional effect. Our results suggest that the adrenergic-stimulating activity of anti-P antibodies may be implicated in the induction of functional myocardial impairments observed in cChHD.

Antibodies to ribosomal P proteins of Trypanosoma cruzi in Chagas disease possess functional autoreactivity with heart tissue and differ from anti-P autoantibodies in lupus

PubMed Central

Kaplan, Dan; Ferrari, Ines; Bergami, Pablo Lopez; Mahler, Evelina; Levitus, Gabriela; Chiale, Pablo; Hoebeke, Johan; Van Regenmortel, Marc H. V.; Levin, Mariano J.

1997-01-01

Anti-P antibodies present in sera from patients with chronic Chagas heart disease (cChHD) recognize peptide R13, EEEDDDMGFGLFD, which encompasses the C-terminal region of the Trypanosoma cruzi ribosomal P1 and P2 proteins. This peptide shares homology with the C-terminal region (peptide H13 EESDDDMGFGLFD) of the human ribosomal P proteins, which is in turn the target of anti-P autoantibodies in systemic lupus erythematosus (SLE), and with the acidic epitope, AESDE, of the second extracellular loop of the β1-adrenergic receptor. Anti-P antibodies from chagasic patients showed a marked preference for recombinant parasite ribosomal P proteins and peptides, whereas anti-P autoantibodies from SLE reacted with human and parasite ribosomal P proteins and peptides to the same extent. A semi-quantitative estimation of the binding of cChHD anti-P antibodies to R13 and H13 using biosensor technology indicated that the average affinity constant was about 5 times higher for R13 than for H13. Competitive enzyme immunoassays demonstrated that cChHD anti-P antibodies bind to the acidic portions of peptide H13, as well as to peptide H26R, encompassing the second extracellular loop of the β1 adrenoreceptor. Anti-P antibodies isolated from cChHD patients exert a positive chronotropic effect in vitro on cardiomyocytes from neonatal rats, which resembles closely that of anti-β1 receptor antibodies isolated from the same patient. In contrast, SLE anti-P autoantibodies have no functional effect. Our results suggest that the adrenergic-stimulating activity of anti-P antibodies may be implicated in the induction of functional myocardial impairments observed in cChHD. PMID:9294205

Prevention and Treatment of Noise-Induced Tinnitus

DTIC Science & Technology

2012-07-01

process of completing the normative data base(s) of VGLUT1 , VAT and VGAT immunostaining in the rat AVCN and DCN that will allow assessment of changes under...our experimental conditions. Initial results indicate some loss of VGLUT1 immunolabeled auditory nerve terminals in the ventral cochlear nucleus...Research Accomplishments for TASK 3: Test the hypothesis that the loss of AN terminals (marked by VGLUT1 immunolabel) on neurons in the AVCN and

Tolazoline decreases survival time during microwave-induced lethal heat stress in anesthetized rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jauchem, J.R.; Chang, K.S.; Frei, M.R.

1996-03-01

Effects of {alpha}-adrenergic antagonists have been studied during environmental heating but not during microwave-induced heating. Tolazoline may exert some of its effects via {alpha}-adrenergic blockade. In the present study, ketamine-anesthetized Sprague-Dawley rats were exposed to 2450-MHz microwaves at an average power density of 60 mW/cm{sup 2} (whole-body specific absorption rate of approximately 14 W/kg) until lethal temperatures were attained. The effects of tolazoline (10 mg/kg body weight) on physiological responses (including changes in body temperature, heart rate, blood pressure, and respiratory rate) were examined. Survival time was significantly shorter in the tolazoline group than in saline-treated animals. In general, heartmore » rate and blood pressure responses were similar to those that occur during environmental heat stress. Heart rate, however, was significantly elevated in animals that received tolazoline, both before and during terminal microwave exposure. It is possible that changes associated with the elevated heart rate (e.g., less cardiac filling) in tolazoline-treated animals resulted in greater susceptibility to microwave-induced heating and the lower survival time. 47 refs., 3 figs., 2 tabs.« less

The neglected cranial nerve: nervus terminalis (cranial nerve N).

PubMed

Vilensky, Joel A

2014-01-01

The nervus terminalis (NT; terminal nerve) was clearly identified as an additional cranial nerve in humans more than a century ago yet remains mostly undescribed in modern anatomy textbooks. The nerve is referred to as the nervus terminalis because in species initially examined its fibers were seen entering the brain in the region of the lamina terminalis. It has also been referred to as cranial nerve 0, but because there is no Roman symbol for zero, an N for the Latin word nulla is a better numerical designation. This nerve is very distinct in human fetuses and infants but also has been repeatedly identified in adult human brains. The NT fibers are unmyelinated and emanate from ganglia. The fibers pass through the cribriform plate medial to those of the olfactory nerve fila. The fibers end in the nasal mucosa and probably arise from autonomic/neuromodulatory as well as sensory neurons. The NT has been demonstrated to release luteinizing-releasing luteinizing hormone and is therefore thought to play a role in reproductive behavior. Based on the available evidence, the NT appears to be functional in adult humans and should be taught in medical schools and incorporated into anatomy/neuroanatomy textbooks. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

Abnormal afferent nerve endings in the soft palatal mucosa of sleep apnoics and habitual snorers.

PubMed

Friberg, D; Gazelius, B; Hökfelt, T; Nordlander, B

1997-07-23

Habitual snoring precedes obstructive sleep apnea (OSA), but the pathophysiological mechanisms behind progression are still unclear. The patency of upper airways depends on a reflexogen mechanism reacting on negative intrapharyngeal pressure at inspiration, probably mediated by mucosal receptors, i.e., via afferent nerve endings. Such nerves contain a specific nerve protein, protein-gene product 9.5 (PGP 9.5) and in some cases substance P (SP) and calcitonin gene-related (CGRP). Biopsies of the soft palatial mucosa were obtained from non-smoking men ten OSA patients, 11 habitual snorers and 11 non-snoring controls. The specimens were immunohistochemically analyzed for PGP 9.5, SP and CGRP. As compared to controls, an increased number of PGP-, SP- and CGRP-immunoreactive nerves were demonstrated in the mucosa in 9/10 OSA patients and 4/11 snorers, in addition to varicose nerve endings in the papillae and epithelium. Using double staining methodology, it could be shown that SP- and CGRP-like immunoreactivities (LIs) often coexisted in these fibres, as did CGRP- and PGP 9.5-LIs. The increased density in sensory nerve terminals are interpreted to indicate an afferent nerve lesion. Our results support the hypothesis of a progressive neurogenic lesion as a contributory factor to the collapse of upper airways during sleep in OSA patients.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

Our research efforts in the first funding year concentrated on animal and clinical studies validating {sup 11}C-hydroxyephedrine as a marker for norepinephrine uptake and storage in presynaptic sympathetic nerve terminals. In addition to kinetic studies in animals, the first clinical studies have been performed. {sup 11}C-hydroxyephedrine provides excellent image quality in the human heart with high myocardium to blood ratios. A canine model with transient intracoronary occlusion of the left anterior descending aorta was used to show decreased retention of tracer with ischemia. Clinical studies of patients with acute myocardial infarction showed an area of decreased retention of tracer exceedingmore » the infarct territory as defined by {sup 82}Rb blood flow imaging. We are also developing tracers for the parasympathetic nervous system. It appears that methyl-TRB is a specific tracer for this system. Studies of {sup 11}C- or {sup 18}F-benzovesamicol as a potential tracer for parasympathetic presynaptic nerve terminals are under way. (MHB)« less

Dynamin phosphorylation controls optimization of endocytosis for brief action potential bursts

PubMed Central

Armbruster, Moritz; Messa, Mirko; Ferguson, Shawn M; De Camilli, Pietro; Ryan, Timothy A

2013-01-01

Modulation of synaptic vesicle retrieval is considered to be potentially important in steady-state synaptic performance. Here we show that at physiological temperature endocytosis kinetics at hippocampal and cortical nerve terminals show a bi-phasic dependence on electrical activity. Endocytosis accelerates for the first 15–25 APs during bursts of action potential firing, after which it slows with increasing burst length creating an optimum stimulus for this kinetic parameter. We show that activity-dependent acceleration is only prominent at physiological temperature and that the mechanism of this modulation is based on the dephosphorylation of dynamin 1. Nerve terminals in which dynamin 1 and 3 have been replaced with dynamin 1 harboring dephospho- or phospho-mimetic mutations in the proline-rich domain eliminate the acceleration phase by either setting endocytosis at an accelerated state or a decelerated state, respectively. DOI: http://dx.doi.org/10.7554/eLife.00845.001 PMID:23908769

TRPA1 activation by lidocaine in nerve terminals results in glutamate release increase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piao, L.-H.; Fujita, Tsugumi; Jiang, C.-Y.

2009-02-20

We examined the effects of local anesthetics lidocaine and procaine on glutamatergic spontaneous excitatory transmission in substantia gelatinosa (SG) neurons in adult rat spinal cord slices with whole-cell patch-clamp techniques. Bath-applied lidocaine (1-5 mM) dose-dependently and reversibly increased the frequency but not the amplitude of spontaneous excitatory postsynaptic current (sEPSC) in SG neurons. Lidocaine activity was unaffected by the Na{sup +}-channel blocker, tetrodotoxin, and the TRPV1 antagonist, capsazepine, but was inhibited by the TRP antagonist, ruthenium red. In the same neuron, the TRPA1 agonist, allyl isothiocyanate, and lidocaine both increased sEPSC frequency. In contrast, procaine did not produce presynaptic enhancement.more » These results indicate that lidocaine activates TRPA1 in nerve terminals presynaptic to SG neurons to increase the spontaneous release of L-glutamate.« less

β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

PubMed Central

Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

2010-01-01

Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

Comparative proteomic analysis of differentially expressed proteins between peripheral sensory and motor nerves.

PubMed

He, Qianru; Man, Lili; Ji, Yuhua; Zhang, Shuqiang; Jiang, Maorong; Ding, Fei; Gu, Xiaosong

2012-06-01

Peripheral sensory and motor nerves have different functions and different approaches to regeneration, especially their distinct ability to accurately reinervate terminal nerve pathways. To understand the molecular aspects underlying these differences, the proteomics technique by coupling isobaric tags for relative and absolute quantitation (iTRAQ) with online two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) was used to investigate the protein profile of sensory and motor nerve samples from rats. A total of 1472 proteins were identified in either sensory or motor nerve. Of them, 100 proteins showed differential expressions between both nerves, and some of them were validated by quantitative real time RT-PCR, Western blot analysis, and immunohistochemistry. In the light of functional categorization, the differentially expressed proteins in sensory and motor nerves, belonging to a broad range of classes, were related to a diverse array of biological functions, which included cell adhesion, cytoskeleton, neuronal plasticity, neurotrophic activity, calcium-binding, signal transduction, transport, enzyme catalysis, lipid metabolism, DNA-binding, synaptosome function, actin-binding, ATP-binding, extracellular matrix, and commitment to other lineages. The relatively higher expressed proteins in either sensory or motor nerve were tentatively discussed in combination with their specific molecular characteristics. It is anticipated that the database generated in this study will provide a solid foundation for further comprehensive investigation of functional differences between sensory and motor nerves, including the specificity of their regeneration.

Neuroprotective effects of (-)-epigallocatechin-3-gallate (EGCG) against peripheral nerve transection-induced apoptosis.

PubMed

Kian, Kosar; Khalatbary, Ali Reza; Ahmadvand, Hassan; Karimpour Malekshah, Abbasali; Shams, Zahra

2018-01-02

Recent studies revealed the neuroprotective effects of epigallocatechin-3-gallate (EGCG) on a variety of neural injury models. The purpose of this study was to determine the neuroprotective effects of EGCG following sciatic nerve transection (SNT). Rats were randomly divided into four groups each as follows: Sham-operated group, SNT group, and Pre-EGCG (50-mg/kg, i.p., 30 minutes before nerve transection and followed for 3 days) and Post-EGCG (50-mg/kg, i.p., 1 hour after nerve transection and followed for 3 days) groups. Spinal cord segments of the sciatic nerve and related dorsal root ganglions were removed four weeks after nerve transection for the assessment of malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities, immunohistochemistry of caspase-3, cyclooxygenase-2 (COX-2), S100beta (S100B), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). MDA levels were significantly decreased, and SOD and CAT activities were significantly increased in EGCG-treated rats after nerve transection. Attenuated caspase-3 and COX-2 expression, and TUNEL reaction could be significantly detected in the EGCG-treated rats after nerve transection. Also, EGCG significantly increased S100B expression. We propose that EGCG may be effective in the protection of neuronal cells against retrograde apoptosis and may enhance neuronal survival time following nerve transection.

Identification of PN1, a Predominant Voltage-Dependent Sodium Channel Expressed Principally in Peripheral Neurons

NASA Astrophysics Data System (ADS)

Toledo-Aral, Juan J.; Moss, Brenda L.; He, Zhi-Jun; Koszowski, Adam G.; Whisenand, Teri; Levinson, Simon R.; Wolf, John J.; Silos-Santiago, Inmaculada; Halegoua, Simon; Mandel, Gail

1997-02-01

Membrane excitability in different tissues is due, in large part, to the selective expression of distinct genes encoding the voltage-dependent sodium channel. Although the predominant sodium channels in brain, skeletal muscle, and cardiac muscle have been identified, the major sodium channel types responsible for excitability within the peripheral nervous system have remained elusive. We now describe the deduced primary structure of a sodium channel, peripheral nerve type 1 (PN1), which is expressed at high levels throughout the peripheral nervous system and is targeted to nerve terminals of cultured dorsal root ganglion neurons. Studies using cultured PC12 cells indicate that both expression and targeting of PN1 is induced by treatment of the cells with nerve growth factor. The preferential localization suggests that the PN1 sodium channel plays a specific role in nerve excitability.

Comparative distribution of misonidazole and its amine metabolite in female Swiss Webster mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Born, J.L.; Hadley, W.M.

1985-06-01

The distribution of misonidazole and its terminal reduction product 1-(2-amino-1-imidazolyl)-3-methoxy-2-propanol (misoamine) were compared in female Swiss Webster mice to determine if either misonidazole or misoamine is distributed to peripheral nerves. Female Swiss Webster mice received a 100 mg/kg (5 ..mu..Ci/..mu..mole) i.p. dose of either /sup 3/H-misonidazole or /sup 3/H-miso-amine and the distribution of radioactivity was determined in various tissues including sciatic nerves and other myelinated nerves. Misonidazole produced higher initial tissue concentrations of radioactivity than did miso-amine. The relative tissue concentrations of radioactivity produced by misonidazole or miso-amine were similar, although not identical, 48 hours after administration of the drugs.more » Both sciatic and other myelinated nerves were found to retain radioactivity following the administration of either misonidazole or miso-amine.« less

Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism.

PubMed

Dienel, Gerald A; Cruz, Nancy F

2016-07-01

Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific β-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas β-receptor blockade 're-balances' the stoichiometry of oxygen-glucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential non-oxidative glucose utilization and glycogen turnover during brain activation. Aerobic glycolysis, the preferential up-regulation of glucose utilization (CMRglc ) compared with oxygen consumption (CMRO2 ) during brain activation, is blocked by propranolol. Epinephrine release from the adrenal gland stimulates vagus nerve signaling to the locus coeruleus, enhancing norepinephrine release in the brain, and regulation of astrocytic and neuronal metabolism to stimulate CMRglc more than CMRO2 . Propranolol suppresses CMRglc more than CMRO2 . © 2016 International Society for Neurochemistry.

Rate dependency and role of nitric oxide in the vascular response to direct cooling in human skin.

PubMed

Yamazaki, Fumio; Sone, Ryoko; Zhao, Kun; Alvarez, Guy E; Kosiba, Wojciech A; Johnson, John M

2006-01-01

Local cooling of nonglabrous skin without functional sympathetic nerves causes an initial vasodilation followed by vasoconstriction. To further characterize these responses to local cooling, we examined the importance of the rate of local cooling and the effect of nitric oxide synthase (NOS) inhibition in intact skin and in skin with vasoconstrictor function inhibited. Release of norepinephrine was blocked locally (iontophoresis) with bretylium tosylate (BT). Skin blood flow was monitored from the forearm by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as the ratio of LDF to blood pressure. Local temperature was controlled over 6.3 cm2 around the sites of LDF measurement. Local cooling was applied at -0.33 or -4 degrees C/min. At -4 degrees C/min, CVC increased (P < 0.05) at BT sites in the early phase. At -0.33 degrees C/min, there was no early vasodilator response, but there was a delay in the onset of vasoconstriction relative to intact skin. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) (intradermal microdialysis) decreased (P < 0.05) CVC by 28.3 +/- 3.8% at untreated sites and by 46.9 +/- 6.3% at BT-treated sites from the value before infusion. Rapid local cooling (-4 degrees C/min) to 24 degrees C decreased (P < 0.05) CVC at both untreated (saline) sites and L-NAME only sites from the precooling levels, but it transiently increased (P < 0.05) CVC at both BT + saline sites and BT + L-NAME sites in the early phase. After 35-45 min of local cooling, CVC decreased at BT + saline sites relative to the precooling levels (P < 0.05), but at BT + L-NAME sites CVC was not reduced below the precooling level (P = 0.29). These findings suggest that the rate of local cooling, but not functional NOS, is an important determinant of the early non-adrenergic vasodilator response to local cooling and that functional NOS, adrenergic nerves, as well as other mechanisms play roles in vasoconstriction during prolonged local cooling of skin.

Polyamine FTX-3.3 and polyamine amide sFTX-3.3 inhibit presynaptic calcium currents and acetylcholine release at mouse motor nerve terminals.

PubMed

Fatehi, M; Rowan, E G; Harvey, A L; Moya, E; Blagbrough, I S

1997-02-01

FTX-3.3 is the proposed structure of a calcium-channel blocking toxin that has been isolated from the funnel web spider (Agelenopsis aperta). The effects of FTX-3.3 and one of its analogues, sFTX-3.3, on acetylcholine release, on presynaptic currents at mouse motor nerve terminals and on whole-cell sodium currents in SK.N.SH cells (a human neuroblastoma cell line) have been studied. FTX-3.3 (10-30 microM) and sFTX-3.3 (100-300 microM) reversibly reduced release of acetylcholine by approximately 70-90% and 40-60%, respectively. FTX-3.3 (10 microM) blocked the fast component of presynaptic calcium currents by approximately 60%. sFTX-3.3 (100 microM) reduced the duration of the slow component of presynaptic calcium currents by about 50% of the control and also reduced presynaptic sodium current by approximately 20% of the control. sFTX-3.3 (100 microM) reduced whole-cell sodium current recorded from SK.N.SH cells by approximately 15%, whereas FTX-3.3, even at 200 microM, did not affect this current. Since the only difference in chemical structures of these toxins is that sFTX-3.3 has an amide function which is absent in FTX-3.3, the amide function may be responsible for the reduced potency and selectivity of sFTX-3.3. This study also provides further support for the existence of P-type calcium channels at mouse motor nerve terminals.

Strontium, barium, and manganese metabolism in isolated presynaptic nerve terminals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rasgado-Flores, H.; Sanchez-Armass, S.; Blaustein, M.P.

1987-06-01

To gain insight into the mechanisms by which the divalent cations Sr, Ba, and Mn affect neurotransmitter release from presynaptic nerve terminals, the authors examined the sequestration of these cations, ion comparison to Ca, by mitochondrial and nonmitochondrial organelles and the extrusion of these cations from isolated nerve terminals. Sequestration was studied in synaptosomes made leaky to small ions by treatment with saponin; efflux was examined in intact synaptosomes that were preloaded with the divalent cations by incubation in depolarizing (K rich) media. The selectivity sequence for ATP-dependent mitochondrial uptake that they observed was Mn>>Ca>Sr>>Ba, whereas that for the SERmore » was Ca greater than or equal to Mn>Sr>>Ba. When synaptosomes that were preloaded with divalent cations were incubated in Na- and Ca-free media, there was little efflux of /sup 45/Ca, /sup 133/Ba, /sup 85/Sr, or /sup 54/Mn. When the incubation was carried out in media containing Na without Ca, there was substantial stimulation of Ca and Sr efflux, but only slight stimulation of Ba or Mn efflux. In Na-free media, the addition of 1 mM Ca promoted the efflux of all four divalent cations, probably via Ca-divalent cation exchange. In summary, the sequestration and extrusion data suggest that, with equal loads, Mn will be buffered to the greatest extent, whereas Ba will be least well buffered. These results may help to explain why Mn has a very long-lasting effect on transmitter release, while the effect of Sr is much briefer.« less

Myosin Va Plays a Role in Nitrergic Smooth Muscle Relaxation in Gastric Fundus and Corpora Cavernosa of Penis

PubMed Central

Carew, Josephine A.; Goyal, Raj K.; Sullivan, Maryrose P.

2014-01-01

The intracellular motor protein myosin Va is involved in nitrergic neurotransmission possibly by trafficking of neuronal nitric oxide synthase (nNOS) within the nerve terminals. In this study, we examined the role of myosin Va in the stomach and penis, proto-typical smooth muscle organs in which nitric oxide (NO) mediated relaxation is critical for function. We used confocal microscopy and co-immunoprecipitation of tissue from the gastric fundus (GF) and penile corpus cavernosum (CCP) to localize myosin Va with nNOS and demonstrate their molecular interaction. We utilized in vitro mechanical studies to test whether smooth muscle relaxations during nitrergic neuromuscular neurotransmission is altered in DBA (dilute, brown, non-agouti) mice which lack functional myosin Va. Myosin Va was localized in nNOS-positive nerve terminals and was co-immunoprecipitated with nNOS in both GF and CCP. In comparison to C57BL/6J wild type (WT) mice, electrical field stimulation (EFS) of precontracted smooth muscles of GF and CCP from DBA animals showed significant impairment of nitrergic relaxation. An NO donor, Sodium nitroprusside (SNP), caused comparable levels of relaxation in smooth muscles of WT and DBA mice. These normal postjunctional responses to SNP in DBA tissues suggest that impairment of smooth muscle relaxation resulted from inhibition of NO synthesis in prejunctional nerve terminals. Our results suggest that normal physiological processes of relaxation of gastric and cavernosal smooth muscles that facilitate food accommodation and penile erection, respectively, may be disrupted under conditions of myosin Va deficiency, resulting in complications like gastroparesis and erectile dysfunction. PMID:24516539

The HIV-1 associated protein, Tat1–86, impairs dopamine transporters and interacts with cocaine to reduce nerve terminal function: a no-net-flux microdialysis study

PubMed Central

Ferris, Mark J.; Frederick-Duus, Danielle; Fadel, Jim; Mactutus, Charles F.; Booze, Rosemarie M.

2009-01-01

Injection drug use accounts for approximately one-third of HIV-infections in the United States. HIV associated proteins have been shown to interact with various drugs of abuse to incite concerted neurotoxicity. One common area for their interaction is the nerve terminal, including dopamine transporter (DAT) systems. However, results regarding DAT function and regulation in HIV-infection, regardless of drug use, are mixed. Thus, the present experiments were designed to explicitly control Tat and cocaine administration in an in vivo model in order to reconcile differences that exist in the literature to date. We examined Tat plus cocaine-induced alterations using no-net-flux microdialysis, which is sensitive to alterations in DAT function, in order to test the potential for DAT as an early mediator of HIV-induced oxidative stress and neurodegeneration in vivo. Within 5 hours of intra-accumbal administration of the HIV-associated protein, Tat, we noted a significant reduction in local DAT efficiency with little change in DA overflow/release dynamics. Further, at 48 hrs post-Tat administration, we demonstrated a concerted effect of the HIV-protein Tat with cocaine on both uptake and release function. Finally, we discuss the extent to which DAT dysfunction may be considered a predecessor to generalized nerve terminal dysfunction. Characterization of DAT dysfunction in vivo may provide an early pharamacotherapeutic target, which in turn may prevent or attenuate downstream mediators of neurotoxicity (i.e., reactive species) to DA systems occurring in NeuroAIDS. PMID:19344635

Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats.

PubMed

Martínez-Salamanca, Juan I; Zurita, Mercedes; Costa, Carla; Martínez-Salamanca, Eduardo; Fernández, Argentina; Castela, Angela; Vaquero, Jesús; Carballido, Joaquín; Angulo, Javier

2016-01-01

Novel effective therapeutic strategies are necessary for treating erectile dysfunction secondary to cavernous nerve injury (CNI). To functionally evaluate the benefits of long-term oral treatment with a phosphodiesterase type 5 inhibitor on the potential capacity of intracavernosal cell therapy to recover erectile function after CNI. Bilateral crush CNI (BCNI) was produced in anesthetized male rats. After BCNI, rats were treated with the phosphodiesterase type 5 inhibitor tadalafil (TAD; 5 mg/kg/d orally; BCNI + TAD), a single intracavernosal injection of bone marrow-derived mesenchymal stem cells (BMSCs; BCNI + BMSC), or dual therapy (BCNI + BMSC + TAD). Ex vivo function of the corpus cavernosum (CC) and in vivo intracavernosal pressure responses to CN electrical stimulation were evaluated 4 weeks after BCNI. Trichrome staining and terminal 2'-deoxyuridine-5'-triphosphate nick-end labeling assay were used for fibrosis and apoptosis determination, respectively, in the CC. In vivo erectile responses in anesthetized rats, ex vivo evaluation of endothelium-dependent relaxation, neurogenic relaxation and neurogenic contraction in CC strips, and histologic evaluation of fibrosis and apoptosis in cavernosal tissue. BCNI resulted in a marked decrease of erectile responses that were partly recovered in the BCNI + TAD and BCNI + BMSC groups. Complete recovery of erectile function was achieved only in the BCNI + BMSC + TAD group. Endothelium-dependent and nitric oxide donor-induced relaxations of the CC were not altered by BCNI or the treatments. BCNI resulted in enhanced neurogenic adrenergic contractions and impaired nitrergic relaxations of the CC. The BCNI + TAD group displayed diminished neurogenic contractions, whereas the BCNI + TAD and BCNI + BMSC groups showed partly recovered nitrergic responses. In the BCNI + BMSC + TAD group, neurogenic contractions were decreased and nitrergic relaxations were normalized. Cavernosal apoptosis and fibrosis were similarly prevented in the BCNI + TAD, BCNI + BMSC, and BCNI + BMSC + TAD groups. A dual strategy combining the intracavernosal injection of BMSCs and oral administration of TAD was superior to individual approaches in normalizing neurogenic control of cavernosal tone and preserving erectile function after CNI, suggesting the potential of this dual strategy in the future management of erectile dysfunction after radical prostatectomy. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Sinus Bradycardia in Habitual Cocaine Users.

PubMed

Franklin, Sona M; Thihalolipavan, Sudarone; Fontaine, John M

2017-05-15

Common physiological manifestations of cocaine are related to its adrenergic effects, due to inhibition of dopamine and norepinephrine uptake at the postsynaptic terminal. Few studies have documented bradycardia secondary to cocaine use, representing the antithesis of its adrenergic effects. We assessed the prevalence of sinus bradycardia (SB) in habitual cocaine users and postulated a mechanism for this effect. One hundred sixty-two patients with a history of cocaine use were analyzed and compared with age- and gender-matched controls. SB was defined as a rate of <60 beats/min and habitual cocaine use as 2 or more documented uses >30 days apart. Propensity score-matching analysis was applied to balance covariates between cocaine users and nonusers and reduce selection bias. Patients with a history of bradycardia, hypothyroidism, or concomitant beta-blocker use were excluded. Mean age of study patients was 44 ± 8 years. SB was observed in 43 of 162 (27%) cocaine users and in 9 of 149 (6%) nonusers (p = 0.0001). Propensity score-matching analysis matched 218 patients from both groups. Among matched patients SB was observed in 25 of 109 (23%) cocaine users and in 5 of 109 (5%) nonusers (p = 0.0001). Habitual cocaine use was an independent predictor of SB and associated with a sevenfold increase in the risk of SB (95% CI 2.52 to 19.74, p = 0.0002). In conclusion, habitual cocaine use is a strong predictor of SB and was unrelated to recency of use. A potential mechanism for SB may be related to cocaine-induced desensitization of the beta-adrenergic receptor secondary to continuous exposure. Symptomatic SB was not observed; thus, pacemaker therapy was not indicated. Copyright © 2017 Elsevier Inc. All rights reserved.

α1b-Adrenergic Receptor Localization and Relationship to the D1-Dopamine Receptor in the Rat Nucleus Accumbens.

PubMed

Mitrano, Darlene A; Jackson, Kelsey; Finley, Samantha; Seeley, Allison

2018-02-10

The α1-adrenergic receptors (α1ARs) have been implicated in numerous actions of the brain, including attention and wakefulness. Additionally, they have been identified as contributing to disorders of the brain, such as drug addiction, and recent work has shown a role of these receptors in relapse to psychostimulants. While some functionality is known, the actual subcellular localization of the subtypes of the α1ARs remains to be elucidated. Further, their anatomical relationship to receptors for other neurotransmitters, such as dopamine (DA), remains unclear. Therefore, using immunohistochemistry and electron microscopy techniques, this study describes the subcellular localization of the α1b-adrenergic receptor (α1bAR), the subtype most tied to relapse behaviors, as well as its relationship to the D1-dopamine receptor (D1R) in both the shell and core of the rat nucleus accumbens (NAc). Overall, α1bARs were found in unmyelinated axons and axon terminals with some labeling in dendrites. In accordance with other studies of the striatum, the D1R was found mainly in dendrites and spines; therefore, colocalization of the D1R with the α1bAR was rare postsynaptically. However, in the NAc shell, when the receptors were co-expressed in the same neuronal elements there was a trend for both receptors to be found on the plasma membrane, as opposed to the intracellular compartment. This study provides valuable anatomical information about the α1bAR and its relationship to the D1R and the regulation of DA and norepinephrine (NE) neurotransmission in the brain which have been examined previously. Published by Elsevier Ltd.

Loss of β-adrenergic-stimulated phosphorylation of CaV1.2 channels on Ser1700 leads to heart failure.

PubMed

Yang, Linghai; Dai, Dao-Fu; Yuan, Can; Westenbroek, Ruth E; Yu, Haijie; West, Nastassya; de la Iglesia, Horacio O; Catterall, William A

2016-12-06

L-type Ca 2+ currents conducted by voltage-gated calcium channel 1.2 (Ca V 1.2) initiate excitation-contraction coupling in the heart, and altered expression of Ca V 1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of Ca V 1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the Ca V 1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca 2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of Ca V 1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.

The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure.

PubMed

Ryan, John J; Archer, Stephen L

2014-06-20

The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary arterial hypertension. RV hypertrophy (RVH) triggered by pressure overload is initially compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients develop adaptive RVH (concentric with retained RV function), while others develop maladaptive RVH, characterized by dilatation, fibrosis, and RV failure. The differentiation of adaptive versus maladaptive RVH is imprecise, but adaptive RVH is associated with better functional capacity and survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis, adrenergic signaling, and metabolism than adaptive RVH, and these derangements often involve the left ventricle. Clinically, maladaptive RVH is characterized by increased N-terminal pro-brain natriuretic peptide levels, troponin release, elevated catecholamine levels, RV dilatation, and late gadolinium enhancement on MRI, increased (18)fluorodeoxyglucose uptake on positron emission tomography, and QTc prolongation on the ECG. In maladaptive RVH there is reduced inotrope responsiveness because of G-protein receptor kinase-mediated downregulation, desensitization, and uncoupling of β-adrenoreceptors. RV ischemia may result from capillary rarefaction or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with cancer including aerobic glycolysis (resulting from a forkhead box protein O1-mediated transcriptional upregulation of pyruvate dehydrogenase kinase), and glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of pyruvate dehydrogenase kinase, fatty acid oxidation, or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of metabolism, angiogenesis, adrenergic signaling, and phosphodiesterase-5 expression. The ability to restore RV function in experimental models challenges the dogma that RV failure is irreversible without regression of pulmonary vascular disease. © 2014 American Heart Association, Inc.

Src family kinases mediate the inhibition of substance P release in the rat spinal cord by μ-opioid receptors and GABAB receptors, but not α2 adrenergic receptors

PubMed Central

Zhang, Guohua; Chen, Wenling; Marvizón, Juan Carlos G.

2010-01-01

GABAB, μ-opioid, and adrenergic α2 receptors inhibit substance P release from primary afferent terminals in the dorsal horn. Studies in cell expression systems suggest that μ-opioid and GABAB receptors inhibit transmitter release from primary afferents by activating Src family kinases (SFKs), which then phosphorylate and inhibit voltage-gated calcium channels. This study investigated whether SFKs mediate the inhibition of substance P release by these three receptors. Substance P release was measured as neurokinin 1 receptor (NK1R) internalization in spinal cord slices and in vivo. In slices, NK1R internalization induced by high frequency dorsal root stimulation was inhibited by the μ-opioid agonist DAMGO and the GABAB agonist baclofen. This inhibition was reversed by the SFK inhibitor PP1. NK1R internalization induced by low frequency stimulation was also inhibited by DAMGO, but PP1 did not reverse this effect. In vivo, NK1R internalization induced by noxious mechanical stimulation of the hind paw was inhibited by intrathecal DAMGO and baclofen. This inhibition was reversed by intrathecal PP1, but not by the inactive PP1 analog PP3. PP1 produced no effect by itself. The α2 adrenergic agonists medetomidine and guanfacine produced a small but statistically significant inhibition of NK1R internalization induced by low frequency dorsal root stimulation. PP1 did not reverse the inhibition by guanfacine. These results show that SFKs mediate the inhibition of substance P release by μ-opioid and GABAB receptors, but not by α2 receptors, which is probably mediated by the binding of G protein βγ subunits to calcium channels. PMID:20726886

Distance between intramuscular nerve and artery in the extraocular muscles: a preliminary immunohistochemical study using elderly human cadavers.

PubMed

Kitamura, Kei; Cho, Kwang Ho; Jang, Hyung Suk; Murakami, Gen; Yamamoto, Masahito; Abe, Shin-Ichi

2017-01-01

Extraocular muscles are quite different from skeletal muscles in muscle fiber type and nerve supply; the small motor unit may be the most well known. As the first step to understanding the nerve-artery relationship, in this study we measured the distance from the arteriole (25-50 μm in thickness) to the nerve terminal twigs in extraocular muscles. With the aid of immunohistochemistry for nerves and arteries, we examined the arteriole-nerve distance at 10-15 sites in each of 68 extraocular muscles obtained from ten elderly cadavers. The oblique sections were nearly tangential to the muscle plate and included both global and orbital aspects of the muscle. In all muscles, the nerve twigs usually took a course parallel to muscle fibers, in contrast to most arterioles that crossed muscles. Possibly due to polyinnervation, an intramuscular nerve plexus was evident in four rectus and two oblique muscles. The arteriole-nerve distance usually ranged from 300 to 400 μm. However, individual differences were more than two times greater in each of seven muscles. Moreover, in each muscle the difference between sites sometimes reached 1 mm or more. The distance was generally shorter in the rectus and oblique muscles than in the levator palpebrae muscle, which reached statistical significance (p < 0.05). The differences in arteriole-nerve distances between sites within each muscle, between muscles, and between individuals might lead to an individual biological rhythm of fatigue in oculomotor performance.

Harmful impact on presynaptic glutamate and GABA transport by carbon dots synthesized from sulfur-containing carbohydrate precursor.

PubMed

Borisova, Tatiana; Dekaliuk, Mariia; Pozdnyakova, Natalia; Pastukhov, Artem; Dudarenko, Marina; Borysov, Arsenii; Vari, Sandor G; Demchenko, Alexander P

2017-07-01

Carbon nanoparticles that may be potent air pollutants with adverse effects on human health often contain heteroatoms including sulfur. In order to study in detail their effects on different physiological and biochemical processes, artificially produced carbon dots (CDs) with well-controlled composition that allows fluorescence detection may be of great use. Having been prepared from different types of organic precursors, CDs expose different atoms at their surface suggesting a broad variation of functional groups. Recently, we demonstrated neurotoxic properties of CDs synthesized from the amino acid β-alanine, and it is of importance to analyze whether CDs obtained from different precursors and particularly those exposing sulfur atoms induce similar neurotoxic effects. This study focused on synthesis of CDs from the sulfur-containing precursor thiourea-CDs (TU-CDs) with a size less than 10 nm, their characterization, and neuroactivity assessment. Neuroactive properties of TU-CDs were analyzed based on their effects on the key characteristics of glutamatergic and γ-aminobutyric acid (GABA) neurotransmission in isolated rat brain nerve terminals. It was observed that TU-CDs (0.5-1.0 mg/ml) attenuated the initial velocity of Na + -dependent transporter-mediated uptake and accumulation of L-[ 14 C]glutamate and [ 3 H]GABA by nerve terminals in a dose-dependent manner and increased the ambient level of the neurotransmitters. Starting from the concentration of 0.2 mg/ml, TU-CDs evoked a gradual dose-dependent depolarization of the plasma membrane of nerve terminals measured with the cationic potentiometric dye rhodamine 6G. Within the concentration range of 0.1-0.5 mg/ml, TU-CDs caused an "unphysiological" step-like increase in fluorescence intensity of the рН-sensitive fluorescent dye acridine orange accumulated by synaptic vesicles. Therefore, despite different surface properties and fluorescent features of CDs prepared from different starting materials (thiourea and β-alanine), their principal neurotoxic effects are analogous but displayed at a different level of efficiency. Sulfur-containing TU-CDs exhibit lower effects (by ~30%) on glutamate and GABA transport in the nerve terminals in comparison with sulfur-free β-alanine CDs. Our results suggest considering that an uncontrolled presence of carbon-containing particulate matter in the human environment may pose a toxicity risk for the central nervous system.

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity.

PubMed

Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Masseck, Olivia A; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

2017-04-25

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity

PubMed Central

Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

2017-01-01

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing. PMID:28396432

Synaptic Vesicle Mobility and Presynaptic F-Actin Are Disrupted in a N-ethylmaleimide–sensitive Factor Allele of Drosophila

PubMed Central

Nunes, Paula; Haines, Nicola; Kuppuswamy, Venkat; Fleet, David J.

2006-01-01

N-ethylmaleimide sensitive factor (NSF) can dissociate the soluble NSF attachment receptor (SNARE) complex, but NSF also participates in other intracellular trafficking functions by virtue of SNARE-independent activity. Drosophila that express a neural transgene encoding a dominant-negative form of NSF2 show an 80% reduction in the size of releasable synaptic vesicle pool, but no change in the number of vesicles in nerve terminal boutons. Here we tested the hypothesis that vesicles in the NSF2 mutant terminal are less mobile. Using a combination of genetics, pharmacology, and imaging we find a substantial reduction in vesicle mobility within the nerve terminal boutons of Drosophila NSF2 mutant larvae. Subsequent analysis revealed a decrease of filamentous actin in both NSF2 dominant-negative and loss-of-function mutants. Lastly, actin-filament disrupting drugs also decrease vesicle movement. We conclude that a factor contributing to the NSF mutant phenotype is a reduction in vesicle mobility, which is associated with decreased presynaptic F-actin. Our data are consistent with a model in which actin filaments promote vesicle mobility and suggest that NSF participates in establishing or maintaining this population of actin. PMID:16914524

β-Adrenergic Receptor Mediation of Stress-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Roles for β1 and β2 Adrenergic Receptors

PubMed Central

Vranjkovic, Oliver; Hang, Shona; Baker, David A.

2012-01-01

Stress can trigger the relapse of drug use in recovering cocaine addicts and reinstatement in rodent models through mechanisms that may involve norepinephrine release and β-adrenergic receptor activation. The present study examined the role of β-adrenergic receptor subtypes in the stressor-induced reinstatement of extinguished cocaine-induced (15 mg/kg i.p.) conditioned place preference in mice. Forced swim (6 min at 22°C) stress or activation of central noradrenergic neurotransmission by administration of the selective α2 adrenergic receptor antagonist 2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole (BRL-44,408) (10 mg/kg i.p.) induced reinstatement in wild-type, but not β- adrenergic receptor-deficient Adrb1/Adrb2 double-knockout, mice. In contrast, cocaine administration (15 mg/kg i.p.) resulted in reinstatement in both wild-type and β-adrenergic receptor knockout mice. Stress-induced reinstatement probably involved β2 adrenergic receptors. The β2 adrenergic receptor antagonist -(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI-118,551) (1 or 2 mg/kg i.p.) blocked reinstatement by forced swim or BRL-44,408, whereas administration of the nonselective β-adrenergic receptor agonist isoproterenol (2 or 4 mg/kg i.p.) or the β2 adrenergic receptor-selective agonist clenbuterol (2 or 4 mg/kg i.p.) induced reinstatement. Forced swim-induced, but not BRL-44,408-induced, reinstatement was also blocked by a high (20 mg/kg) but not low (10 mg/kg) dose of the β1 adrenergic receptor antagonist betaxolol, and isoproterenol-induced reinstatement was blocked by pretreatment with either ICI-118,551 or betaxolol, suggesting a potential cooperative role for β1 and β2 adrenergic receptors in stress-induced reinstatement. Overall, these findings suggest that targeting β-adrenergic receptors may represent a promising pharmacotherapeutic strategy for preventing drug relapse, particularly in cocaine addicts whose drug use is stress related. PMID:22593095

The β3-adrenergic receptor is dispensable for browning of adipose tissues.

PubMed

de Jong, Jasper M A; Wouters, René T F; Boulet, Nathalie; Cannon, Barbara; Nedergaard, Jan; Petrovic, Natasa

2017-06-01

Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β 3 -adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β 3 -adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β 3 -adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β 3 -adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression ( Ucp1 , Pgc1a , Dio2 , and Cidea ) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β 3 -adrenergic receptor. Experiments with the β 3 -adrenergic receptor agonist CL-316,243 verified the functional absence of β 3 -adrenergic signaling in these knockout mice. The β 3 -adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β 3 -adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells. Copyright © 2017 the American Physiological Society.

Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine β-hydroxylase knockout mice.

PubMed

Hu, Frances Y; Hanna, George M; Han, Wei; Mardini, Feras; Thomas, Steven A; Wyner, Abraham J; Kelz, Max B

2012-11-01

Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. Using dopamine β-hydroxylase knockout (Dbh) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators co-packaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend on inhibition of adrenergic neurotransmission.

Roles for the sympathetic nervous system, renal nerves, and CNS melanocortin-4 receptor in the elevated blood pressure in hyperandrogenemic female rats.

PubMed

Maranon, Rodrigo; Lima, Roberta; Spradley, Frank T; do Carmo, Jussara M; Zhang, Howei; Smith, Andrew D; Bui, Elizabeth; Thomas, R Lucas; Moulana, Mohadetheh; Hall, John E; Granger, Joey P; Reckelhoff, Jane F

2015-04-15

Women with polycystic ovary syndrome (PCOS) have hyperandrogenemia and increased prevalence of risk factors for cardiovascular disease, including elevated blood pressure. We recently characterized a hyperandrogenemic female rat (HAF) model of PCOS [chronic dihydrotestosterone (DHT) beginning at 4 wk of age] that exhibits similar characteristics as women with PCOS. In the present studies we tested the hypotheses that the elevated blood pressure in HAF rats is mediated in part by sympathetic activation, renal nerves, and melanocortin-4 receptor (MC4R) activation. Adrenergic blockade with terazosin and propranolol or renal denervation reduced mean arterial pressure (MAP by telemetry) in HAF rats but not controls. Hypothalamic MC4R expression was higher in HAF rats than controls, and central nervous system MC4R antagonism with SHU-9119 (1 nmol/h icv) reduced MAP in HAF rats. Taking a genetic approach, MC4R null and wild-type (WT) female rats were treated with DHT or placebo from 5 to 16 wk of age. MC4R null rats were obese and had higher MAP than WT control rats, and while DHT increased MAP in WT controls, DHT failed to further increase MAP in MC4R null rats. These data suggest that increases in MAP with chronic hyperandrogenemia in female rats are due, in part, to activation of the sympathetic nervous system, renal nerves, and MC4R and may provide novel insights into the mechanisms responsible for hypertension in women with hyperandrogenemia such as PCOS. Copyright © 2015 the American Physiological Society.

Heart‐Specific Overexpression of Choline Acetyltransferase Gene Protects Murine Heart Against Ischemia Through Hypoxia‐Inducible Factor‐1α–Related Defense Mechanisms

PubMed Central

Kakinuma, Yoshihiko; Tsuda, Masayuki; Okazaki, Kayo; Akiyama, Tsuyoshi; Arikawa, Mikihiko; Noguchi, Tatsuya; Sato, Takayuki

2013-01-01

Background Murine and human ventricular cardiomyocytes rich in acetylcholine (Ach) receptors are poorly innervated by the vagus, compared with whole ventricular innervation by the adrenergic nerve. However, vagal nerve stimulation produces a favorable outcome even in the murine heart, despite relatively low ventricular cholinergic nerve density. Such a mismatch and missing link suggest the existence of a nonneuronal cholinergic system in ventricular myocardium. Methods and Results To examine the role of the nonneuronal cardiac cholinergic system, we generated choline acetyltransferase (ChAT)–expressing cells and heart‐specific ChAT transgenic (ChAT‐tg) mice. Compared with cardiomyocytes of wild‐type (WT) mice, those of the ChAT‐tg mice had high levels of ACh and hypoxia‐inducible factor (HIF)‐1α protein and augmented glucose uptake. These phenotypes were also reproduced by ChAT‐overexpressing cells, which utilized oxygen less. Before myocardial infarction (MI), the WT and ChAT‐tg mice showed similar hemodynamics; after MI, however, the ChAT‐tg mice had better survival than did the WT mice. In the ChAT‐tg hearts, accelerated angiogenesis at the ischemic area, and accentuated glucose utilization prevented post‐MI remodeling. The ChAT‐tg heart was more resistant to ischemia–reperfusion injury than was the WT heart. Conclusions These results suggest that the activated cardiac ACh‐HIF‐1α cascade improves survival after MI. We conclude that de novo synthesis of ACh in cardiomyocytes is a pivotal mechanism for self‐defense against ischemia. PMID:23525439

Neuronal BDNF Signaling Is Necessary for the Effects of Treadmill Exercise on Synaptic Stripping of Axotomized Motoneurons

PubMed Central

Krakowiak, Joey; Liu, Caiyue; Papudesu, Chandana; Ward, P. Jillian; Wilhelm, Jennifer C.; English, Arthur W.

2015-01-01

The withdrawal of synaptic inputs from the somata and proximal dendrites of spinal motoneurons following peripheral nerve injury could contribute to poor functional recovery. Decreased availability of neurotrophins to afferent terminals on axotomized motoneurons has been implicated as one cause of the withdrawal. No reduction in contacts made by synaptic inputs immunoreactive to the vesicular glutamate transporter 1 and glutamic acid decarboxylase 67 is noted on axotomized motoneurons if modest treadmill exercise, which stimulates the production of neurotrophins by spinal motoneurons, is applied after nerve injury. In conditional, neuron-specific brain-derived neurotrophic factor (BDNF) knockout mice, a reduction in synaptic contacts onto motoneurons was noted in intact animals which was similar in magnitude to that observed after nerve transection in wild-type controls. No further reduction in coverage was found if nerves were cut in knockout mice. Two weeks of moderate daily treadmill exercise following nerve injury in these BDNF knockout mice did not affect synaptic inputs onto motoneurons. Treadmill exercise has a profound effect on synaptic inputs to motoneurons after peripheral nerve injury which requires BDNF production by those postsynaptic cells. PMID:25918648

Nitrergic nerves derived from the pterygopalatine ganglion innervate arteries irrigating the cerebrum but not the cerebellum and brain stem in monkeys.

PubMed

Ayajiki, Kazuhide; Kobuchi, Shuhei; Tawa, Masashi; Okamura, Tomio

2012-01-01

The functional roles of the nitrergic nerves innervating the monkey cerebral artery were evaluated in a tension-response study examining isolated arteries in vitro and cerebral angiography in vivo. Nicotine produced relaxation of arteries by stimulation of nerve terminals innervating isolated monkey arteries irrigating the cerebrum, cerebellum and brain stem. Relaxation of arteries induced by nicotine was abolished by treatment with N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor, and was restored by addition of L-arginine. Cerebral angiography showed that electrical stimulation of the unilateral greater petrosal nerve, which connects to the pterygopalatine ganglion via the parasympathetic ganglion synapse, produced vasodilatation of the anterior, middle and posterior cerebral arteries in the stimulated side. However, stimulation failed to produce vasodilatation of the superior and anterior-inferior cerebellar arteries and the basilar artery in anesthetized monkeys. Therefore, nitrergic nerves derived from the pterygopalatine ganglion appear to regulate cerebral vasomotor function. In contrast, circulation in the cerebellum and brain stem might be regulated by nitrergic nerves originating not from the pterygopalatine ganglion, but rather from an unknown ganglion (or ganglia).

Interplay between mast cells, enterochromaffin cells, and sensory signaling in the aging human bowel.

PubMed

Yu, Y; Daly, D M; Adam, I J; Kitsanta, P; Hill, C J; Wild, J; Shorthouse, A; Grundy, D; Jiang, W

2016-10-01

Advanced age is associated with a reduction in clinical visceral pain perception. However, the underlying mechanisms remain largely unknown. Previous studies have suggested that an abnormal interplay between mast cells, enterochromaffin (EC) cells, and afferent nerves contribute to nociception in gastrointestinal disorders. The aim of this study was to investigate how aging affects afferent sensitivity and neuro-immune association in the human bowel. Mechanical and chemical sensitivity of human bowel afferents were examined by ex vivo afferent nerve recordings. Age-related changes in the density of mast cells, EC cells, sensory nerve terminals, and mast cell-nerve micro-anatomical association were investigated by histological and immune staining. Human afferents could be broadly classified into subpopulations displaying mechanical and chemical sensitivity, adaptation, chemo-sensitization, and recruitment. Interestingly human bowel afferent nerve sensitivity was attenuated with age. The density of substance P-immunoreactive (SP-IR) nerve varicosities was also reduced with age. In contrast, the density of ileal and colonic mucosal mast cells was increased with age, as was ileal EC cell number. An increased proportion of mast cells was found in close apposition to SP-IR nerves. Afferent sensitivity in human bowel was reduced with advancing age. Augmentation of mast cells and EC cell numbers and the mast cell-nerve association suggest a compensatory mechanism for sensory neurodegeneration. © 2016 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.

Nerve growth factor reduces apoptotic cell death in rat facial motor neurons after facial nerve injury.

PubMed

Hui, Lian; Yuan, Jing; Ren, Zhong; Jiang, Xuejun

2015-01-01

To assess the effects of nerve growth factor (NGF) on motor neurons after induction of a facial nerve lesion, and to compare the effects of different routes of NGF injection on motor neuron survival. This study was carried out in the Department of Otolaryngology Head & Neck Surgery, China Medical University, Liaoning, China from October 2012 to March 2013. Male Wistar rats (n = 65) were randomly assigned into 4 groups: A) healthy controls; B) facial nerve lesion model + normal saline injection; C) facial nerve lesion model + NGF injection through the stylomastoid foramen; D) facial nerve lesion model + intraperitoneal injection of NGF. Apoptotic cell death was detected using the terminal deoxynucleotidyl transferase dUTP nick end-labeling assay. Expression of caspase-3 and p53 up-regulated modulator of apoptosis (PUMA) was determined by immunohistochemistry. Injection of NGF significantly reduced cell apoptosis, and also greatly decreased caspase-3 and PUMA expression in injured motor neurons. Group C exhibited better efficacy for preventing cellular apoptosis and decreasing caspase-3 and PUMA expression compared with group D (p<0.05). Our findings suggest that injections of NGF may prevent apoptosis of motor neurons by decreasing caspase-3 and PUMA expression after facial nerve injury in rats. The NGF injected through the stylomastoid foramen demonstrated better protective efficacy than when injected intraperitoneally.

Parasympathetic control of Na, K transport in perfused submaxillary duct of the rat.

PubMed

Schneyer, L H

1977-07-01

The effects of stimulating the parasympathetic innervation to rat submaxillary gland on ductal transport of Na, K, water, and transepithelial PD, were tested in the main excretory duct during perfusion through its lumen. During nerve stimulation, transepithelial PD was consistently decreased, usually by about 15 mV, and this decrease could be blocked by atropine but not by adrenergic blocking agents. Net flux of Na, K, or water was not significantly changed during stimulation. One-way flux of Na from the lumen also was unaffected. The decrease in PD during stimulation was not affected by substituting isethionate for Cl or increasing [K] in the luminal perfusion medium. It is concluded that parasympathetic effects are exerted on the ductal cells, but that these probably do not involve conductance changes at the luminal membrane.

Effects of HCM cTnI Mutation R145G on Troponin Structure and Modulation by PKA Phosphorylation Elucidated by Molecular Dynamics Simulations

PubMed Central

Lindert, Steffen; Cheng, Yuanhua; Kekenes-Huskey, Peter; Regnier, Michael; McCammon, J. Andrew

2015-01-01

Cardiac troponin (cTn) is a key molecule in the regulation of human cardiac muscle contraction. The N-terminal cardiac-specific peptide of the inhibitory subunit of troponin, cTnI (cTnI1-39), is a target for phosphorylation by protein kinase A (PKA) during β-adrenergic stimulation. We recently presented evidence indicating that this peptide interacts with the inhibitory peptide (cTnl137–147) when S23 and S24 are phosphorylated. The inhibitory peptide is also the target of the point mutation cTnI-R145G, which is associated with hypertrophic cardiomyopathy (HCM), a disease associated with sudden death in apparently healthy young adults. It has been shown that both phosphorylation and this mutation alter the cTnC-cTnI (C-I) interaction, which plays a crucial role in modulating contractile activation. However, little is known about the molecular-level events underlying this modulation. Here, we computationally investigated the effects of the cTnI-R145G mutation on the dynamics of cTn, cTnC Ca2+ handling, and the C-I interaction. Comparisons were made with the cTnI-R145G/S23D/S24D phosphomimic mutation, which has been used both experimentally and computationally to study the cTnI N-terminal specific effects of PKA phosphorylation. Additional comparisons between the phosphomimic mutations and the real phosphorylations were made. For this purpose, we ran triplicate 150 ns molecular dynamics simulations of cTnI-R145G Ca2+-bound cTnC1-161-cTnI1-172-cTnT236-285, cTnI-R145G/S23D/S24D Ca2+-bound cTnC1-161-cTnI1-172-cTnT236-285, and cTnI-R145G/PS23/PS24 Ca2+-bound cTnC1-161-cTnI1-172-cTnT236-285, respectively. We found that the cTnI-R145G mutation did not impact the overall dynamics of cTn, but stabilized crucial Ca2+-coordinating interactions. However, the phosphomimic mutations increased overall cTn fluctuations and destabilized Ca2+ coordination. Interestingly, cTnI-R145G blunted the intrasubunit interactions between the cTnI N-terminal extension and the cTnI inhibitory peptide, which have been suggested to play a crucial role in modulating troponin function during β-adrenergic stimulation. These findings offer a molecular-level explanation for how the HCM mutation cTnI-R145G reduces the modulation of cTn by phosphorylation of S23/S24 during β-adrenergic stimulation. PMID:25606687

Effects of HCM cTnI mutation R145G on troponin structure and modulation by PKA phosphorylation elucidated by molecular dynamics simulations.

PubMed

Lindert, Steffen; Cheng, Yuanhua; Kekenes-Huskey, Peter; Regnier, Michael; McCammon, J Andrew

2015-01-20

Cardiac troponin (cTn) is a key molecule in the regulation of human cardiac muscle contraction. The N-terminal cardiac-specific peptide of the inhibitory subunit of troponin, cTnI (cTnI(1-39)), is a target for phosphorylation by protein kinase A (PKA) during β-adrenergic stimulation. We recently presented evidence indicating that this peptide interacts with the inhibitory peptide (cTnl(137-147)) when S23 and S24 are phosphorylated. The inhibitory peptide is also the target of the point mutation cTnI-R145G, which is associated with hypertrophic cardiomyopathy (HCM), a disease associated with sudden death in apparently healthy young adults. It has been shown that both phosphorylation and this mutation alter the cTnC-cTnI (C-I) interaction, which plays a crucial role in modulating contractile activation. However, little is known about the molecular-level events underlying this modulation. Here, we computationally investigated the effects of the cTnI-R145G mutation on the dynamics of cTn, cTnC Ca(2+) handling, and the C-I interaction. Comparisons were made with the cTnI-R145G/S23D/S24D phosphomimic mutation, which has been used both experimentally and computationally to study the cTnI N-terminal specific effects of PKA phosphorylation. Additional comparisons between the phosphomimic mutations and the real phosphorylations were made. For this purpose, we ran triplicate 150 ns molecular dynamics simulations of cTnI-R145G Ca(2+)-bound cTnC(1-161)-cTnI(1-172)-cTnT(236-285), cTnI-R145G/S23D/S24D Ca(2+)-bound cTnC(1-161)-cTnI(1-172)-cTnT(236-285), and cTnI-R145G/PS23/PS24 Ca(2+)-bound cTnC(1-161)-cTnI(1-172)-cTnT(236-285), respectively. We found that the cTnI-R145G mutation did not impact the overall dynamics of cTn, but stabilized crucial Ca(2+)-coordinating interactions. However, the phosphomimic mutations increased overall cTn fluctuations and destabilized Ca(2+) coordination. Interestingly, cTnI-R145G blunted the intrasubunit interactions between the cTnI N-terminal extension and the cTnI inhibitory peptide, which have been suggested to play a crucial role in modulating troponin function during β-adrenergic stimulation. These findings offer a molecular-level explanation for how the HCM mutation cTnI-R145G reduces the modulation of cTn by phosphorylation of S23/S24 during β-adrenergic stimulation. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Controversial therapeutics: the β-adrenergic antagonist and cocaine-associated cardiovascular complications dilemma.

PubMed

Schurr, James W; Gitman, Brenda; Belchikov, Yuly

2014-12-01

Cocaine abuse is associated with cardiovascular complications that include chest pain and myocardial infarction. Traditional therapy for these conditions includes a β-adrenergic antagonist. However, guidelines released in 2008 recommended against this treatment option because of the prevailing theory that cocaine will potentiate vasospasm secondary to unopposed α-adrenergic effects. Subsequently, further evidence and updated guidelines have become available, debunking this claim. Current literature is limited but suggests that β-adrenergic antagonists are harmful. Although case reports support a detrimental effect of β-adrenergic antagonists, the anecdotal data are inconsistent, and the conclusions from case studies are overruled by larger studies. The pharmacology, pathophysiology, and literature on the use of β-adrenergic antagonists in association with cocaine are reviewed. Future studies that focus on outcomes and different pharmacologic profiles of β-adrenergic antagonists are needed. © 2014 Pharmacotherapy Publications, Inc.

Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia.

PubMed

Spalink, Christy L; Barnes, Erin; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio

2017-08-01

To report the use of intranasal dexmedetomidine, an α 2 -adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. Case series. Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

Decreased catecholamine secretion from the adrenal medullae of chronically diabetic BB-Wistar rats

NASA Technical Reports Server (NTRS)

Wilke, R. A.; Riley, D. A.; Lelkes, P. I.; Hillard, C. J.

1993-01-01

Many humans with IDDM eventually lose the capacity to secrete epinephrine from their adrenal medullae. The mechanism for this pathological change is unknown. We hypothesized that this abnormality is attributable to neuropathic changes in the greater splanchnic nerves or in the chromaffin cells that they innervate. To study this hypothesis, we isolated rat adrenal glands, perfused them ex vivo, and measured the epinephrine content of the perfusate under various conditions of stimulation. We used transmural electrical stimulation (20-80 V, at 10 Hz) to induce epinephrine secretion indirectly by selectively activating residual splanchnic nerve terminals within the isolated glands. Under these conditions, epinephrine secretion was severely attenuated in glands from female BB-Wistar rats with diabetes of 4 mo duration compared with their age-matched, nondiabetic controls. These perfused diabetic adrenal medullae also demonstrated decreased catecholamine release in response to direct chromaffin cell depolarization with 20 mM K+, evidence that a functional alteration exists within the chromaffin cells themselves. Nonetheless, total catecholamine content of adrenal medullae from these diabetic rats was not significantly different from controls, indicating that the secretory defect was not simply attributable to a difference in the amount of catecholamines stored and available for release. Herein, we also provide histological evidence of degenerative changes within the cholinergic nerve terminals that innervate these glands.

Memantine Inhibits α3β2-nAChRs-Mediated Nitrergic Neurogenic Vasodilation in Porcine Basilar Arteries

PubMed Central

Wu, Celeste Yin-Chieh; Chen, Po-Yi; Chen, Mei-Fang; Kuo, Jon-Son; Lee, Tony Jer-Fu

2012-01-01

Memantine, an NMDA receptor antagonist used for treatment of Alzheimer’s disease (AD), is known to block the nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). In the present study, we examined by wire myography if memantine inhibited α3β2-nAChRs located on cerebral perivascular sympathetic nerve terminals originating in the superior cervical ganglion (SCG), thus, leading to inhibition of nicotine-induced nitrergic neurogenic dilation of isolated porcine basilar arteries. Memantine concentration-dependently blocked nicotine-induced neurogenic dilation of endothelium-denuded basilar arteries without affecting that induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, memantine significantly inhibited nicotine-elicited inward currents in Xenopous oocytes expressing α3β2-, α7- or α4β2-nAChR, and nicotine-induced calcium influx in cultured rat SCG neurons. These results suggest that memantine is a non-specific antagonist for nAChR. By directly inhibiting α3β2-nAChRs located on the sympathetic nerve terminals, memantine blocks nicotine-induced neurogenic vasodilation of the porcine basilar arteries. This effect of memantine is expected to reduce the blood supply to the brain stem and possibly other brain regions, thus, decreasing its clinical efficacy in the treatment of Alzheimer’s disease. PMID:22792283

Effects of hyperglycemia on rat cavernous nerve axons: a functional and ultrastructural study.

PubMed

Zotova, Elena G; Schaumburg, Herbert H; Raine, Cedric S; Cannella, Barbara; Tar, Moses; Melman, Arnold; Arezzo, Joseph C

2008-10-01

The present study explored parallel changes in the physiology and structure of myelinated (Adelta) and unmyelinated (C) small diameter axons in the cavernous nerve of rats associated with streptozotocin-induced hyperglycemia. Damage to these axons is thought to play a key role in diabetic autonomic neuropathy and erectile dysfunction, but their pathophysiology has been poorly studied. Velocities in slow conducting fibers were measured by applying multiple unit procedures; histopathology was evaluated with both light and electron microscopy. To our knowledge, these are the initial studies of slow nerve conduction velocities in the distal segments of the cavernous nerve. We report that hyperglycemia is associated with a substantial reduction in the amplitude of the slow conducting response, as well as a slowing of velocities within this very slow range (< 2.5 m/s). Even with prolonged hyperglycemia (> 4 months), histopathological abnormalities were mild and limited to the distal segments of the cavernous nerve. Structural findings included dystrophic changes in nerve terminals, abnormal accumulations of glycogen granules in unmyelinated and preterminal axons, and necrosis of scattered smooth muscle fibers. The onset of slowing of velocity in the distal cavernous nerve occurred subsequent to slowing in somatic nerves in the same rats. The functional changes in the cavernous nerve anticipated and exceeded the axonal degeneration detected by morphology. The physiologic techniques outlined in these studies are feasible in most electrophysiologic laboratories and could substantially enhance our sensitivity to the onset and progression of small fiber diabetic neuropathy.

EFFECTS OF HYPERGLYCEMIA ON RAT CAVERNOUS NERVE AXONS: A FUNCTIONAL AND ULTRASTRUCTURAL STUDY

PubMed Central

Zotova, Elena G.; Schaumburg, Herbert H.; Raine, Cedric S.; Cannella, Barbara; Tar, Moses; Melman, Arnold; Arezzo, Joseph C.

2008-01-01

The present study explored parallel changes in the physiology and structure of myelinated (Aδ) and unmyelinated (C) small diameter axons in the cavernous nerve of rats associated with streptozotocin-induced hyperglycemia. Damage to these axons is thought to play a key role in diabetic autonomic neuropathy and erectile dysfunction, but their pathophysiology has been poorly studied. Velocities in slow conducting fibers were measured by applying multiple unit procedures; histopathology was evaluated with both light and electron microscopy. To our knowledge, these are the initial studies of slow nerve conduction velocities in the distal segments of the cavernous nerve. We report that hyperglycemia is associated with a substantial reduction in the amplitude of the slow conducting response, as well as a slowing of velocities within this very slow range (<2.5 m/sec). Even with prolonged hyperglycemia (> 4 months), histopathological abnormalities were mild and limited to the distal segments of the cavernous nerve. Structural findings included dystrophic changes in nerve terminals, abnormal accumulations of glycogen granules in unmyelinated and preterminal axons, and necrosis of scattered smooth muscle fibers. The onset of slowing of velocity in the distal cavernous nerve occurred subsequent to slowing in somatic nerves in the same rats. The functional changes in the cavernous nerve anticipated and exceeded the axonal degeneration detected by morphology. The physiologic techniques outlined in these studies are feasible in most electrophysiologic laboratories and could substantially enhance our sensitivity to the onset and progression of small fiber diabetic neuropathy. PMID:18687329

Beta-adrenergic signaling promotes tumor angiogenesis and prostate cancer progression through HDAC2-mediated suppression of thrombospondin-1.

PubMed

Hulsurkar, M; Li, Z; Zhang, Y; Li, X; Zheng, D; Li, W

2017-03-01

Chronic behavioral stress and beta-adrenergic signaling have been shown to promote cancer progression, whose underlying mechanisms are largely unclear, especially the involvement of epigenetic regulation. Histone deacetylase-2 (HDAC2), an epigenetic regulator, is critical for stress-induced cardiac hypertrophy. It is unknown whether it is necessary for beta-adrenergic signaling-promoted cancer progression. Using xenograft models, we showed that chronic behavioral stress and beta-adrenergic signaling promote angiogenesis and prostate cancer progression. HDAC2 was induced by beta-adrenergic signaling in vitro and in mouse xenografts. We next uncovered that HDAC2 is a direct target of cAMP response element-binding protein (CREB) that is activated by beta-adrenergic signaling. Notably, HDAC2 is necessary for beta-adrenergic signaling to induce angiogenesis. We further demonstrated that, upon CREB activation, HDAC2 represses thrombospondin-1 (TSP1), a potent angiogenesis inhibitor, through epigenetic regulation. Together, these data establish a novel pathway that HDAC2 and TSP1 act downstream of CREB activation in beta-adrenergic signaling to promote cancer progression.

Mood states, sympathetic activity, and in vivo beta-adrenergic receptor function in a normal population.

PubMed

Yu, Bum-Hee; Kang, Eun-Ho; Ziegler, Michael G; Mills, Paul J; Dimsdale, Joel E

2008-01-01

The purpose of this study was to examine the relationship between mood states and beta-adrenergic receptor function in a normal population. We also examined if sympathetic nervous system activity is related to mood states or beta-adrenergic receptor function. Sixty-two participants aged 25-50 years were enrolled in this study. Mood states were assessed using the Profile of Mood States (POMS). Beta-adrenergic receptor function was determined using the chronotropic 25 dose isoproterenol infusion test. Level of sympathetic nervous system activity was estimated from 24-hr urine norepinephrine excretion. Higher tension-anxiety, depression-dejection, and anger-hostility were related to decreased beta-adrenergic receptor sensitivity (i.e., higher chronotropic 25 dose values), but tension-anxiety was the only remaining independent predictor of beta-adrenergic receptor function after controlling for age, gender, ethnicity, and body mass index (BMI). Urinary norepinephrine excretion was unrelated to either mood states or beta-adrenergic receptor function. These findings replicate previous reports that anxiety is related to decreased (i.e., desensitized) beta-adrenergic receptor sensitivity, even after controlling for age, gender, ethnicity, and body mass index.

β2-Adrenergic Receptor Knockout Mice Exhibit A Diabetic Retinopathy Phenotype

PubMed Central

Jiang, Youde; Zhang, Qiuhua; Liu, Li; Tang, Jie; Kern, Timothy S.; Steinle, Jena J.

2013-01-01

There is considerable evidence from our lab and others for a functional link between β-adrenergic receptor and insulin receptor signaling pathways in retina. Furthermore, we hypothesize that this link may contribute to lesions similar to diabetic retinopathy in that the loss of adrenergic input observed in diabetic retinopathy may disrupt normal anti-apoptotic insulin signaling, leading to retinal cell death. Our studies included assessment of neural retina function (ERG), vascular degeneration, and Müller glial cells (which express only β1 and β2-adrenergic receptor subtypes). In the current study, we produced β2-adrenergic receptor knockout mice to examine this deletion on retinal neurons and vasculature, and to identify specific pathways through which β2-adrenergic receptor modulates insulin signaling. As predicted from our hypothesis, β2-adrenergic receptor knockout mice display certain features similar to diabetic retinopathy. In addition, loss of β2-adrenergic input resulted in an increase in TNFα, a key inhibitor of insulin receptor signaling. Increased TNFα may be associated with insulin-dependent production of the anti-apoptotic factor, Akt. Since the effects occurred in vivo under normal glucose conditions, we postulate that aspects of the diabetic retinopathy phenotype might be triggered by loss of β2-adrenergic receptor signaling. PMID:23894672

alpha-Adrenergic-mediated activation of human reconstituted fibrinogen receptor (integrin alphaIIbbeta3) in Chinese hamster ovary cells.

PubMed

Butta, Nora; Larrucea, Susana; Gonzalez-Manchon, Consuelo; Alonso, Sonia; Parrilla, Roberto

2004-12-01

This work reports the functional studies of CHO cells coexpressing alpha-adrenergic (alphaAR) and human fibrinogen (Fg) receptors (integrin alphaIIbbeta3). Stimulation of these cells with alpha-agonists produced a transient rise in the free cytosolic calcium (Ca(++)) accompanied by enhanced binding to soluble Fg, and these effects were prevented by specific alphaAR antagonists. The alpha-adrenergic-induced activation of alphaIIbbeta3 in CHO-alphaIIbbeta3-alphaAR increased the rate of adhesion and extension of cells onto Fg coated plates, and also induced a soluble Fg- and alphaIIbbeta3-dependent formation of cell aggregates, whereas no effects were observed by the stimulation of CHO-alphaIIbbeta3 cells. alpha-Adrenergic antagonists, the ligand mimetic peptide RGDS, pertussis toxin (PTX), or EDTA, they all prevented the alpha-adrenergic stimulation of adhesion and aggregation. However, inhibition of PKC prevented the alpha-adrenergic stimulation of cell adherence, whereas blocking the intracellular Ca(++) mobilization impeded the stimulation of cell aggregation. The alpha-adrenergic activation was associated with phosphorylation of a protein of approximately 100 kDa and proteins of the MAPK family. The former was selectively phosphorylated by alpha-adrenergic stimulation whereas the latter were phosphorylated by the binding of cells to Fg and markedly intensified by alpha-adrenergic stimulation.

Investigating β-adrenergic-induced cardiac hypertrophy through computational approach: classical and non-classical pathways.

PubMed

Khalilimeybodi, Ali; Daneshmehr, Alireza; Sharif-Kashani, Babak

2018-07-01

The chronic stimulation of β-adrenergic receptors plays a crucial role in cardiac hypertrophy and its progression to heart failure. In β-adrenergic signaling, in addition to the well-established classical pathway, Gs/AC/cAMP/PKA, activation of non-classical pathways such as Gi/PI3K/Akt/GSK3β and Gi/Ras/Raf/MEK/ERK contribute in cardiac hypertrophy. The signaling network of β-adrenergic-induced hypertrophy is very complex and not fully understood. So, we use a computational approach to investigate the dynamic response and contribution of β-adrenergic mediators in cardiac hypertrophy. The proposed computational model provides insights into the effects of β-adrenergic classical and non-classical pathways on the activity of hypertrophic transcription factors CREB and GATA4. The results illustrate that the model captures the dynamics of the main signaling mediators and reproduces the experimental observations well. The results also show that despite the low portion of β2 receptors out of total cardiac β-adrenergic receptors, their contribution in the activation of hypertrophic mediators and regulation of β-adrenergic-induced hypertrophy is noticeable and variations in β1/β2 receptors ratio greatly affect the ISO-induced hypertrophic response. The model results illustrate that GSK3β deactivation after β-adrenergic receptor stimulation has a major influence on CREB and GATA4 activation and consequent cardiac hypertrophy. Also, it is found through sensitivity analysis that PKB (Akt) activation has both pro-hypertrophic and anti-hypertrophic effects in β-adrenergic signaling.

The Course of the Terminal Posterior Interosseous Nerve and Its Relationship with Wrist Arthroscopy Portals

PubMed Central

Pan, Yongwei; Hung, Leung-kim

2016-01-01

Purpose The terminal branches of the posterior interosseous nerve (PIN) are the main articular branch on the dorsal aspect of the wrist. Its relationship to dorsal wrist arthroscopic portals has not yet been elucidated. The purpose of this study was to quantitatively describe the anatomical relationships between the dorsal wrist arthroscopic portals and the PIN. Methods Dorsal wrist arthroscopic portals were established in 28 cadaver extremities, after which the limbs were dissected. Measurements were taken from the portals to the PIN. Results The PIN passed ulnar to the 3/4 portal with a mean distance of 4.8 mm (range: 1.2–12.0, standard deviation [SD] = 2.6). The PIN passed radial to the 4/5 portal with a mean interval of 9.0 mm (range: 3.8–12.7, SD = 2.3). The main trunk of PIN or its closest terminal branch was a mean of 7.2 mm (range: 0.0–13.2 mm, SD = 3.1) radial to the midcarpal radial (MCR) portal. In 2 of the 28 specimens, one terminal branch of PIN lay directly over this portal. The distance between the midcarpal ulnar (MCU) portal and the PIN or its closest terminal branch was only a mean of 1.6 mm (range: 0–6.4 mm, SD = 2.0). In 15 of the 28 specimens, the PIN lay directly over the MCU portal, or the portal was located between the terminal branches of PIN. Conclusion The MCU portal was the most precarious, due to the close proximity of PIN and its terminal branches. The 3/4 and MCR portals were also at risk, while the 4/5 portal was relatively safe for the PIN. PMID:27777824

Functional subcellular distribution of β1- and β2-adrenergic receptors in rat ventricular cardiac myocytes

PubMed Central

Cros, Caroline; Brette, Fabien

2013-01-01

β-adrenergic stimulation is a key regulator of cardiac function. The localization of major cardiac adrenergic receptors (β1 and β2) has been investigated using biochemical and biophysical approaches and has led to contradictory results. This study investigates the functional subcellular localization of β1- and β2-adrenergic receptors in rat ventricular myocytes using a physiological approach. Ventricular myocytes were isolated from the hearts of rat and detubulated using formamide. Physiological cardiac function was measured as Ca2+ transient using Fura-2-AM and cell shortening. Selective activation of β1- and β2-adrenergic receptors was induced with isoproterenol (0.1 μmol/L) and ICI-118,551 (0.1 μmol/L); and with salbutamol (10 μmol/L) and atenolol (1 μmol/L), respectively. β1- and β2-adrenergic stimulations induced a significant increase in Ca2+ transient amplitude and cell shortening in intact rat ventricular myocytes (i.e., surface sarcolemma and t-tubules) and in detubulated cells (depleted from t-tubules, surface sarcolemma only). Both β1- and β2-adrenergic receptors stimulation caused a greater effect on Ca2+ transient and cell shortening in detubulated myocytes than in control myocytes. Quantitative analysis indicates that β1-adrenergic stimulation is ∼3 times more effective at surface sarcolemma compared to t-tubules, whereas β2- adrenergic stimulation occurs almost exclusively at surface sarcolemma (∼100 times more effective). These physiological data demonstrate that in rat ventricular myocytes, β1-adrenergic receptors are functionally present at surface sarcolemma and t-tubules, while β2-adrenergic receptors stimulation occurs only at surface sarcolemma of cardiac cells. PMID:24303124

Hypnotic Hypersensitivity to Volatile Anesthetics and Dexmedetomidine in Dopamine β-Hydroxylase Knockout Mice

PubMed Central

Hu, Frances Y.; Hanna, George M.; Han, Wei; Mardini, Feras; Thomas, Steven A.; Wyner, Abraham J.; Kelz, Max B.

2012-01-01

BACKGROUND Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. METHODS Using dopamine β-hydroxylase (Dbh−/−) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. RESULTS We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators copackaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh−/− mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh−/− mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh−/− mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. CONCLUSIONS Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend upon inhibition of adrenergic neurotransmission. PMID:23042227

Stimulation of postsynapse adrenergic α2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder.

PubMed

Kawaura, Kazuaki; Karasawa, Jun-ichi; Chaki, Shigeyuki; Hikichi, Hirohiko

2014-08-15

A 5-trial inhibitory avoidance test using spontaneously hypertensive rat (SHR) pups has been used as an animal model of attention deficit hyperactivity disorder (ADHD). However, the roles of noradrenergic systems, which are involved in the pathophysiology of ADHD, have not been investigated in this model. In the present study, the effects of adrenergic α2 receptor stimulation, which has been an effective treatment for ADHD, on attention/cognition performance were investigated in this model. Moreover, neuronal mechanisms mediated through adrenergic α2 receptors were investigated. We evaluated the effects of both clonidine, a non-selective adrenergic α2 receptor agonist, and guanfacine, a selective adrenergic α2A receptor agonist, using a 5-trial inhibitory avoidance test with SHR pups. Juvenile SHR exhibited a shorter transfer latency, compared with juvenile Wistar Kyoto (WKY) rats. Both clonidine and guanfacine significantly prolonged the transfer latency of juvenile SHR. The effects of clonidine and guanfacine were significantly blocked by pretreatment with an adrenergic α2A receptor antagonist. In contrast, the effect of clonidine was not attenuated by pretreatment with an adrenergic α2B receptor antagonist, or an adrenergic α2C receptor antagonist, while it was attenuated by a non-selective adrenergic α2 receptor antagonist. Furthermore, the effects of neither clonidine nor guanfacine were blocked by pretreatment with a selective noradrenergic neurotoxin. These results suggest that the stimulation of the adrenergic α2A receptor improves the attention/cognition performance of juvenile SHR in the 5-trial inhibitory avoidance test and that postsynaptic, rather than presynaptic, adrenergic α2A receptor is involved in this effect. Copyright © 2014 Elsevier B.V. All rights reserved.

Patterns of fast synaptic cholinergic activation of neurons in the celiac ganglia of cats.

PubMed

Niel, J P; Clerc, N; Jule, Y

1988-12-01

Fast nicotinic transmission was studied in vitro in neurons of isolated cat celiac ganglia. In the absence of nerve stimulation, neurons could be classified into three types: silent neurons, synaptically activated neurons, and spontaneously discharging neurons. In all three types, fast synaptic activation could be obtained in single neurons by stimulating with a single pulse both the splanchnic nerves or one of the peripheral nerves connected to the ganglia. During repetitive nerve stimulation, a gradual depression of the central and peripheral fast nicotinic activation occurred, which was not affected by phentolamine plus propranolol, domperidone, atropine, or naloxone. Repetitive nerve stimulation was followed by a long lasting discharge of excitatory postsynaptic potentials and action potentials that decreased gradually with time. This discharge, which was probably due to presynaptic or prejunctional facilitation of acetylcholine release from cholinergic terminals, was reduced by the application of phentolamine plus propranolol, domperidone, or atropine and increased with naloxone. The existence of the mechanisms described in this study reflects the complexity of the integrative processes at work in neurons of the cat celiac ganglia that involve fast synaptic cholinergic activation.

Effect of the alkaloid (-)cathinone on the release of radioactivity from rabbit atria prelabelled with /sup 3/H-norepinephrine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalix, P.

1983-02-14

In certain countries of East Africa and the Arab Peninsula, fresh leaves of the khat shrub are used as a stimulant. The effect of the plant material can be explained by the presence of the phenylalklamine alkaloid (-)cathinone in the leaves, since this substance has been shown to have an amphetamine-like releasing effect on CNS tissue prelabelled with /sup 3/H-dopamine. Characteristically, the chewing of khat is accompanied by sympathomimetic effects, especially at the cardiovascular level. To test whether these might be due to release of neurotransmitter from adrenergic nerve endings, the effect of (-)cathinone on the efflux of radioactivity frommore » isolated rabbit atrium tissue prelabelled with /sup 3/H-norepinephrine was investigated. It was found that, at concentrations below 1 ..mu..M, (-)cathinone caused an immediate increase of efflux. The effect was dose-dependent and was potentiated by pretreatment of the rabbits with reserpine. Preincubation of the tissue with desipramine and cocaine prevented the induction of release by (-)cathinone. The results indicate that the alkaloid (-)cathinone has an amphetamine-like releasing effect on noradrenergic nerve endings and they suggest that the cardiovascular symptoms observed during khat consumption are due to release of neurotransmitter from physiologicl storage sites.« less

The role of substance P release in the lung with esophageal acid.

PubMed

Kohrogi, H; Hamamoto, J; Kawano, O; Iwagoe, H; Fujii, K; Hirata, N; Ando, M

2001-12-03

To investigate whether tachykinins are released in the airways by stimulating the esophagus, airway plasma extravasation induced by intraesophageal hydrochloric acid (HCl) in the presence or absence of the neutral endopeptidase (NEP) inhibitor phosphoramidon and the neurokinin-1-receptor antagonist FK888 was studied in anesthetized guinea pigs. Airway plasma extravasation also was studied in the presence of the NEP inhibitor in guinea pigs pretreated with capsaicin or bilateral vagotomy. Propranolol and atropine were used in all animals to block adrenergic and cholinergic nerve effects. Airway plasma leakage was evaluated by measuring extravasated Evans blue dye. One normal HCl infusion into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation induced by HCl infusion into the esophagus in the trachea and main bronchi, and FK888 significantly inhibited extravasation in a dose-related manner. In capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilaterally vagotomized animals. These results suggest that locally acting substances are released by intraesophageal HCl stimulation that cause airway plasma extravasation. These substances are generated through activation of neural pathways, including some that traffic through the vagus nerves that link the esophagus or airways.

Anatomical Variability in the Termination of the Basilar Artery in the Human Cadaveric Brain.

PubMed

Gunnal, Sandhya; Farooqui, Mujeebuddin; Wabale, Rajendra

2015-01-01

The basilar artery (BA) is the prominent median vessel of the vertebrobasilar circulation and usually terminates into two posterior cerebral arteries forming the posterior angle of the Circle of Willis (CW). To tackle different variations of CW, basilar artery acts as a guideline for neuroradiologists and neurosurgeons. Basilar termination is the most frequent site of aneurysm. Abnormalities at the site of termination may compress the oculomotor nerve. Variations at the termination may complicate surgeries at the base of brain. The present study aims to add to the knowledge regarding the termination pattern of the BA. 170 BA terminations were studied. Morphological variations in the termination pattern were noted. Frequency of variations in termination patterns was recorded. Dimensions of BA were measured. Data were analyzed. Morphological variations in termination were seen in 17.64%. Bifurcation, Trifurcation, Quadrifurcation, Pentafurcation and Nonfurcation of BA was seen in 82.35%, 5.29%, 5.88%, 3.52% and 2.94% respectively. BA associated with aneurysm and Fenestration was seen in 3.52% and 1.17% respectively. Mean length and diameter of BA was 30.27 mm and 4.8 mm respectively. Awareness of these anatomical variations in termination patterns of BA is important in neurovascular procedures.

High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of β2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts.

PubMed

Fu, Qin; Hu, Yuting; Wang, Qingtong; Liu, Yongming; Li, Ning; Xu, Bing; Kim, Sungjin; Chiamvimonvat, Nipavan; Xiang, Yang K

2017-03-15

Patients with diabetes show a blunted cardiac inotropic response to β-adrenergic stimulation despite normal cardiac contractile reserve. Acute insulin stimulation impairs β-adrenergically induced contractile function in isolated cardiomyocytes and Langendorff-perfused hearts. In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high-fat diet (HFD) feeding on the cardiac β 2 -adrenergic receptor signalling and the impacts on cardiac contractile function. We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β-adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β 2 -adrenergic receptor phosphorylation at protein kinase A and G-protein receptor kinase sites in the myocardium. The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications. Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high-fat diet (HFD) on the insulin-adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD-fed mice displayed a significant elevation of phosphorylation of the β 2 -adrenergic receptor (β 2 AR) at both the protein kinase A site serine 261/262 and the G-protein-coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD-fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β 2 AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD-fed mice. Together, these data indicate that HFD promotes phosphorylation of the β 2 AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin-adrenergic signalling network might be effective in prevention of cardiac complications in diabetes. © 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

High‐fat diet induces protein kinase A and G‐protein receptor kinase phosphorylation of β2‐adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts

PubMed Central

Hu, Yuting; Wang, Qingtong; Liu, Yongming; Li, Ning; Xu, Bing; Kim, Sungjin; Chiamvimonvat, Nipavan

2017-01-01

Key points Patients with diabetes show a blunted cardiac inotropic response to β‐adrenergic stimulation despite normal cardiac contractile reserve.Acute insulin stimulation impairs β‐adrenergically induced contractile function in isolated cardiomyocytes and Langendorff‐perfused hearts.In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high‐fat diet (HFD) feeding on the cardiac β2‐adrenergic receptor signalling and the impacts on cardiac contractile function.We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β‐adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2‐adrenergic receptor phosphorylation at protein kinase A and G‐protein receptor kinase sites in the myocardium.The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications. Abstract Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high‐fat diet (HFD) on the insulin–adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD‐fed mice displayed a significant elevation of phosphorylation of the β2‐adrenergic receptor (β2AR) at both the protein kinase A site serine 261/262 and the G‐protein‐coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD‐fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β2AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD‐fed mice. Together, these data indicate that HFD promotes phosphorylation of the β2AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin–adrenergic signalling network might be effective in prevention of cardiac complications in diabetes. PMID:27983752

Adrenergic modulation of hepatotoxicity.

PubMed

Roberts, S M; DeMott, R P; James, R C

1997-01-01

Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for potentiation to occur. The importance of dose timing has not been evaluated for adrenergic potentiation of methylphenidate hepatotoxicity, but it is clear that this interaction is based on yet a third mechanism. While only three hepatotoxicants of the group I type have been examined in detail, the diversity of receptor types and mechanisms involved suggest that this phenomenon may be relevant for a wide variety of hepatotoxic drugs and chemicals. This interaction is also of interest because factors or events that lead to increased adrenergic stimulation are common in everyday life. Most over-the-counter cold and allergy preparations contain sympathomimetic drugs, and many prescription drugs produce adrenergic effects as either an extension of the intended therapeutic effect or as a side effect. Stress and some disease states can also lead to significant increases in peripheral adrenergic activity, creating the potential for increased susceptibility to hepatic injury from exposure to certain drugs or chemicals. Cocaine and bromobenzene represent group II, chemicals whose hepatotoxicity is diminished by cotreatment with adrenergic antagonist drugs. In the case of cocaine, adrenergic antagonist cotreatment was capable of reducing serum alanine aminotransferase activities by approximately 50%. For bromobenzene, the protection afforded by adrenergic antagonist cotreatment was more profound, with minimal hepatic lesions resulting from doses of bromobenzene that otherwise produced lethal hepatic necrosis. For the chemicals in group II, experimental observations are consistent with a phenomenon in which adrenergic potentiation of toxicity is supplied by the hepatotoxicant itself. Both cocaine and bromobenzene, in hepatotoxic doses increase endogenous catecholamine levels. When the effects of the elevated catecholamines are removed with the appropriate adrenergic antagonist, much lower toxicity (presumably due only to the direct hepatotoxic effects of the drug or chemical) is obse

Hibernating myocardium results in partial sympathetic denervation and nerve sprouting.

PubMed

Fernandez, Stanley F; Ovchinnikov, Vladislav; Canty, John M; Fallavollita, James A

2013-01-15

Hibernating myocardium due to chronic repetitive ischemia is associated with regional sympathetic nerve dysfunction and spontaneous arrhythmic death in the absence of infarction. Although inhomogeneity in regional sympathetic innervation is an acknowledged substrate for sudden death, the mechanism(s) responsible for these abnormalities in viable, dysfunctional myocardium (i.e., neural stunning vs. sympathetic denervation) and their association with nerve sprouting are unknown. Accordingly, markers of sympathetic nerve function and nerve sprouting were assessed in subendocardial tissue collected from chronically instrumented pigs with hibernating myocardium (n = 18) as well as sham-instrumented controls (n = 7). Hibernating myocardium exhibited evidence of partial sympathetic denervation compared with the normally perfused region and sham controls, with corresponding regional reductions in tyrosine hydroxylase protein (-32%, P < 0.001), norepinephrine uptake transport protein (-25%, P = 0.01), and tissue norepinephrine content (-45%, P < 0.001). Partial denervation induced nerve sprouting with regional increases in nerve growth factor precursor protein (31%, P = 0.01) and growth associated protein-43 (38%, P < 0.05). All of the changes in sympathetic nerve markers were similar in animals that developed sudden death (n = 9) compared with electively terminated pigs with hibernating myocardium (n = 9). In conclusion, sympathetic nerve dysfunction in hibernating myocardium is most consistent with partial sympathetic denervation and is associated with regional nerve sprouting. The extent of sympathetic remodeling is similar in animals that develop sudden death compared with survivors; this suggests that sympathetic remodeling in hibernating myocardium is not an independent trigger for sudden death. Nevertheless, sympathetic remodeling likely contributes to electrical instability in combination with other factors.

Hibernating myocardium results in partial sympathetic denervation and nerve sprouting

PubMed Central

Fernandez, Stanley F.; Ovchinnikov, Vladislav; Canty, John M.

2013-01-01

Hibernating myocardium due to chronic repetitive ischemia is associated with regional sympathetic nerve dysfunction and spontaneous arrhythmic death in the absence of infarction. Although inhomogeneity in regional sympathetic innervation is an acknowledged substrate for sudden death, the mechanism(s) responsible for these abnormalities in viable, dysfunctional myocardium (i.e., neural stunning vs. sympathetic denervation) and their association with nerve sprouting are unknown. Accordingly, markers of sympathetic nerve function and nerve sprouting were assessed in subendocardial tissue collected from chronically instrumented pigs with hibernating myocardium (n = 18) as well as sham-instrumented controls (n = 7). Hibernating myocardium exhibited evidence of partial sympathetic denervation compared with the normally perfused region and sham controls, with corresponding regional reductions in tyrosine hydroxylase protein (−32%, P < 0.001), norepinephrine uptake transport protein (−25%, P = 0.01), and tissue norepinephrine content (−45%, P < 0.001). Partial denervation induced nerve sprouting with regional increases in nerve growth factor precursor protein (31%, P = 0.01) and growth associated protein-43 (38%, P < 0.05). All of the changes in sympathetic nerve markers were similar in animals that developed sudden death (n = 9) compared with electively terminated pigs with hibernating myocardium (n = 9). In conclusion, sympathetic nerve dysfunction in hibernating myocardium is most consistent with partial sympathetic denervation and is associated with regional nerve sprouting. The extent of sympathetic remodeling is similar in animals that develop sudden death compared with survivors; this suggests that sympathetic remodeling in hibernating myocardium is not an independent trigger for sudden death. Nevertheless, sympathetic remodeling likely contributes to electrical instability in combination with other factors. PMID:23125211

Autoregulation of Neuromuscular Transmission by Nerve Terminals.

DTIC Science & Technology

1985-09-01

prejunctional cholinoceptor. Nicotine, carbachol , ACh and suberyl- dicholine have been used as agonists. 1 , 2 Neostigmine (NEO) and related acetylcholinesterase...bromide, aminopyridine, aBGT, DFP, nicotine, carnitine, dTC, physostigmine and carbachol . A one-way analysis of variance of these data indicated a lack

Structure activity relationship of synaptic and junctional neurotransmission.

PubMed

Goyal, Raj K; Chaudhury, Arun

2013-06-01

Chemical neurotransmission may include transmission to local or remote sites. Locally, contact between 'bare' portions of the bulbous nerve terminal termed a varicosity and the effector cell may be in the form of either synapse or non-synaptic contact. Traditionally, all local transmissions between nerves and effector cells are considered synaptic in nature. This is particularly true for communication between neurons. However, communication between nerves and other effectors such as smooth muscles has been described as nonsynaptic or junctional in nature. Nonsynaptic neurotransmission is now also increasingly recognized in the CNS. This review focuses on the relationship between structure and function that orchestrate synaptic and junctional neurotransmissions. A synapse is a specialized focal contact between the presynaptic active zone capable of ultrafast release of soluble transmitters and the postsynaptic density that cluster ionotropic receptors. The presynaptic and the postsynaptic areas are separated by the 'closed' synaptic cavity. The physiological hallmark of the synapse is ultrafast postsynaptic potentials lasting milliseconds. In contrast, junctions are juxtapositions of nerve terminals and the effector cells without clear synaptic specializations and the junctional space is 'open' to the extracellular space. Based on the nature of the transmitters, postjunctional receptors and their separation from the release sites, the junctions can be divided into 'close' and 'wide' junctions. Functionally, the 'close' and the 'wide' junctions can be distinguished by postjunctional potentials lasting ~1s and tens of seconds, respectively. Both synaptic and junctional communications are common between neurons; however, junctional transmission is the rule at many neuro-non-neural effectors. Published by Elsevier B.V.

Structure activity relationship of synaptic and junctional neurotransmission

PubMed Central

Goyal, Raj K; Chaudhury, Arun

2013-01-01

Chemical neurotransmission may include transmission to local or remote sites. Locally, contact between ‘bare’ portions of the bulbous nerve terminal termed a varicosity and the effector cell may be in the form of either synapse or non-synaptic contact. Traditionally, all local transmissions between nerves and effector cells are considered synaptic in nature. This is particularly true for communication between neurons. However, communication between nerves and other effectors such as smooth muscles has been described as nonsynaptic or junctional in nature. Nonsynaptic neurotransmission is now also increasing recognized in the CNS. This review focuses on the relationship between structure and function that orchestrate synaptic and junctional neurotransmissions. A synapse is a specialized focal contact between the presynaptic active zone capable for ultrafast release of soluble transmitters and the postsynaptic density that cluster ionotropic receptors. The presynaptic and the postsynaptic areas are separated by the ‘closed’ synaptic cavity. The physiological hallmark of the synapse is ultrafast postsynaptic potentials lasting in milliseconds. In contrast, junctions are juxtapositions of nerve terminals and the effector cells without clear synaptic specializations and the junctional space is ‘open’ to the extracellular space. Based on the nature of the transmitters, postjunctional receptors and their separation from the release sites, the junctions can be divided into ‘close’ and ‘wide’ junctions. Functionally, the ‘close’ and the ‘wide’ junctions can be distinguished by postjunctional potentials lasting ~1 second and 10s of seconds, respectively. Both synaptic and junctional communications are common between neurons; however, junctional transmission is the rule at many neuro-non-neural effectors. PMID:23535140

Specificity and impact of adrenergic projections to the midbrain dopamine system

PubMed Central

Mejias-Aponte, Carlos A.

2016-01-01

Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson’s disease and substance abuse. Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release. Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. PMID:26820641

Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson’s Disease Patients

PubMed Central

Mu, Liancai; Chen, Jingming; Sobotka, Stanislaw; Nyirenda, Themba; Benson, Brian; Gupta, Fiona; Sanders, Ira; Adler, Charles H.; Caviness, John N.; Shill, Holly A.; Sabbagh, Marwan; Samanta, Johan E.; Sue, Lucia I.; Beach, Thomas G.

2015-01-01

Dysphagia is common in Parkinson’s disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia. PMID:26041249

Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson's Disease Patients.

PubMed

Mu, Liancai; Chen, Jingming; Sobotka, Stanislaw; Nyirenda, Themba; Benson, Brian; Gupta, Fiona; Sanders, Ira; Adler, Charles H; Caviness, John N; Shill, Holly A; Sabbagh, Marwan; Samanta, Johan E; Sue, Lucia I; Beach, Thomas G

2015-08-01

Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

PubMed

Gross, Noah B; Duncker, Patrick C; Marshall, John F

2011-11-01

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. Copyright © 2011 Wiley-Liss, Inc.

Nucleus of the solitary tract in the C57BL/6J mouse: Subnuclear parcellation, chorda tympani nerve projections, and brainstem connections.

PubMed

Ganchrow, Donald; Ganchrow, Judith R; Cicchini, Vanessa; Bartel, Dianna L; Kaufman, Daniel; Girard, David; Whitehead, Mark C

2014-05-01

The nucleus of the solitary tract (NST) processes gustatory and related somatosensory information rostrally and general viscerosensory information caudally. To compare its connections with those of other rodents, this study in the C57BL/6J mouse provides a subnuclear cytoarchitectonic parcellation (Nissl stain) of the NST into rostral, intermediate, and caudal divisions. Subnuclei are further characterized by NADPH staining and P2X2 immunoreactivity (IR). Cholera toxin subunit B (CTb) labeling revealed those NST subnuclei receiving chorda tympani nerve (CT) afferents, those connecting with the parabrachial nucleus (PBN) and reticular formation (RF), and those interconnecting NST subnuclei. CT terminals are densest in the rostral central (RC) and medial (M) subnuclei; less dense in the rostral lateral (RL) subnucleus; and sparse in the ventral (V), ventral lateral (VL), and central lateral (CL) subnuclei. CTb injection into the PBN retrogradely labels cells in the aforementioned subnuclei; RC and M providing the largest source of PBN projection neurons. Pontine efferent axons terminate mainly in V and rostral medial (RM) subnuclei. CTb injection into the medullary RF labels cells and axonal endings predominantly in V at rostral and intermediate NST levels. Small CTb injections within the NST label extensive projections from the rostral division to caudal subnuclei. Projections from the caudal division primarily interconnect subnuclei confined to the caudal division of the NST; they also connect with the area postrema. P2X2 -IR identifies probable vagal nerve terminals in the central (Ce) subnucleus in the intermediate/caudal NST. Ce also shows intense NADPH staining and does not project to the PBN. Copyright © 2013 Wiley Periodicals, Inc.

Nucleus of the solitary tract in the C57BL/6J mouse: Subnuclear parcellation, chorda tympani nerve projections, and brainstem connections

PubMed Central

Ganchrow, Donald; Ganchrow, Judith R; Cicchini, Vanessa; Bartel, Dianna L; Kaufman, Daniel; Girard, David; Whitehead, Mark C

2013-01-01

The nucleus of the solitary tract (NST) processes gustatory and related somatosensory information rostrally and general viscerosensory information caudally. To compare its connections with those of other rodents, this study in the C57BL/6J mouse provides a subnuclear cytoarchitectonic parcellation (Nissl stain) of the NST into rostral, intermediate, and caudal divisions. Subnuclei are further characterized by NADPH staining and P2X2 immunoreactivity (IR). Cholera toxin subunit B (CTb) labeling revealed those NST subnuclei receiving chorda tympani nerve (CT) afferents, those connecting with the parabrachial nucleus (PBN) and reticular formation (RF), and those interconnecting NST subnuclei. CT terminals are densest in the rostral central (RC) and medial (M) subnuclei; less dense in the rostral lateral (RL) subnucleus; and sparse in the ventral (V), ventral lateral (VL), and central lateral (CL) subnuclei. CTb injection into the PBN retrogradely labels cells in the aforementioned subnuclei; RC and M providing the largest source of PBN projection neurons. Pontine efferent axons terminate mainly in V and rostral medial (RM) subnuclei. CTb injection into the medullary RF labels cells and axonal endings predominantly in V at rostral and intermediate NST levels. Small CTb injections within the NST label extensive projections from the rostral division to caudal subnuclei. Projections from the caudal division primarily interconnect subnuclei confined to the caudal division of the NST; they also connect with the area postrema. P2X2-IR identifies probable vagal nerve terminals in the central (Ce) subnucleus in the intermediate/caudal NST. Ce also shows intense NADPH staining and does not project to the PBN. J. Comp. Neurol. 522:1565–1596, 2014. PMID:24151133

Visualization of endosome dynamics in living nerve terminals with four-dimensional fluorescence imaging.

PubMed

Stewart, Richard S; Kiss, Ilona M; Wilkinson, Robert S

2014-04-16

Four-dimensional (4D) light imaging has been used to study behavior of small structures within motor nerve terminals of the thin transversus abdominis muscle of the garter snake. Raw data comprises time-lapse sequences of 3D z-stacks. Each stack contains 4-20 images acquired with epifluorescence optics at focal planes separated by 400-1,500 nm. Steps in the acquisition of image stacks, such as adjustment of focus, switching of excitation wavelengths, and operation of the digital camera, are automated as much as possible to maximize image rate and minimize tissue damage from light exposure. After acquisition, a set of image stacks is deconvolved to improve spatial resolution, converted to the desired 3D format, and used to create a 4D "movie" that is suitable for variety of computer-based analyses, depending upon the experimental data sought. One application is study of the dynamic behavior of two classes of endosomes found in nerve terminals-macroendosomes (MEs) and acidic endosomes (AEs)-whose sizes (200-800 nm for both types) are at or near the diffraction limit. Access to 3D information at each time point provides several advantages over conventional time-lapse imaging. In particular, size and velocity of movement of structures can be quantified over time without loss of sharp focus. Examples of data from 4D imaging reveal that MEs approach the plasma membrane and disappear, suggesting that they are exocytosed rather than simply moving vertically away from a single plane of focus. Also revealed is putative fusion of MEs and AEs, by visualization of overlap between the two dye-containing structures as viewed in each three orthogonal projections.

Calcium channel blockers and transmitter release at the normal human neuromuscular junction.

PubMed

Protti, D A; Reisin, R; Mackinley, T A; Uchitel, O D

1996-05-01

Transmitter release evoked by nerve stimulation is highly dependent on Ca2+ entry through voltage-activated plasma membrane channels. Calcium influx may be modified in some neuromuscular diseases like Lambert-Eaton syndrome and amyotrophic lateral sclerosis. We studied the pharmacologic sensitivity of the transmitter release process to different calcium channel blockers in normal human muscles and found that funnel web toxin and omega-Agatoxin-IVA, both P-type calcium channel blockers, blocked nerve-elicited muscle action potentials and inhibited evoked synaptic transmission. The transmitter release was not affected either by nitrendipine, an L-type channel blocker, or omega-Conotoxin-GVIA, an N-type channel blocker. The pharmacologic profile of neuromuscular transmission observed in normal human muscles indicates that P-like channels mediate transmitter release at the motor nerve terminals.

Ultrastructural identification of noradrenergic nerve terminals and vasopressin-containing neurons of the paraventricular nucleus in the same thin section.

PubMed

Silverman, A J; Hou-Yu, A; Oldfield, B J

1983-09-01

Since many peptidergic cell groups receive a diverse and complex monoaminergic innervation, we have developed a double-label procedure to visualize a peptide and a catecholamine in the same ultrathin section. Radiolabeled norepinephrine (NE) is applied locally and its reuptake into NE terminals is demonstrated by ultrastructural radioautography. Controls in this and other studies demonstrate that the NE labels only NE (and possibly epinephrine) terminals and not dopaminergic or serotonergic terminals. In the same tissue, vasopressin is localized by immunocytochemistry on unembedded sections that are subsequently embedded in epoxy resins for thin sectioning. The procedure as described here shows that NE terminals in the periventricular zone of the paraventricular nucleus of the hypothalamus innervate both vasopressin-positive and vasopressin-negative structures. This technique is useful in determining the chemical connectivity of the hypothalamus.

The thoracic muscular system and its innervation in third instar Calliphora vicina Larvae. II. Projection patterns of the nerves associated with the pro- and mesothorax and the pharyngeal complex.

PubMed

Schoofs, Andreas; Hanslik, Ulrike; Niederegger, Senta; Heinzel, Hans-Georg; Spiess, Roland

2010-08-01

We describe the anatomy of the nerves that project from the central nervous system (CNS) to the pro- and mesothoracic segments and the cephalopharyngeal skeleton (CPS) for third instar Calliphora larvae. Due to the complex branching pattern we introduce a nomenclature that labels side branches of first and second order. Two fine nerves that were not yet described are briefly introduced. One paired nerve projects to the ventral arms (VAs) of the CPS. The second, an unpaired nerve, projects to the ventral surface of the cibarial part of the esophagus (ES). Both nerves were tentatively labeled after the structures they innervate. The antennal nerve (AN) innervates the olfactory dorsal organ (DO). It contains motor pathways that project through the frontal connectives (FC) to the frontal nerve (FN) and innervate the cibarial dilator muscles (CDM) which mediate food ingestion. The maxillary nerve (MN) innervates the sensory terminal organ (TO), ventral organ (VO), and labial organ (LO) and comprises the motor pathways to the mouth hook (MH) elevator, MH depressor, and the labial retractor (LR) which opens the mouth cavity. An anastomosis of unknown function exists between the AN and MN. The prothoracic accessory nerve (PaN) innervates a dorsal protractor muscle of the CPS and sends side branches to the aorta and the bolwig organ (BO) (stemmata). In its further course, this nerve merges with the prothoracic nerve (PN). The architecture of the PN is extremely complex. It innervates a set of accessory pharyngeal muscles attached to the CPS and the body wall musculature of the prothorax. Several anastomoses exist between side branches of this nerve which were shown to contain motor pathways. The mesothoracic nerve (MeN) innervates a MH accessor and the longitudinal and transversal body wall muscles of the second segment. J. Morphol. 271:969-979, 2010. (c) 2010 Wiley-Liss, Inc.

Anti-β1-adrenergic receptor autoantibodies in patients with chronic Chagas heart disease

PubMed Central

Labovsky, V; Smulski, C R; Gómez, K; Levy, G; Levin, M J

2007-01-01

Chronic Chagas heart disease (cChHD), a chronic manifestation of the Trypanosoma cruzi infection, is characterized by high antibody levels against the C-terminal region of the ribosomal P proteins (i.e. peptide R13, EEEDDDMGFGLFD) which bears similarity with the second extracellular loop of β1-adrenergic receptor (β1-AR, peptide H26R HWWRAESDEARRCYNDPKCCDFVTNR). Because it has not been demonstrated clearly that IgGs from cChHD patients bind to native human β1-AR, the aim of this study was to investigate further the physical interaction between cChHD IgGs and the human β1-AR. Immunofluorescence assays demonstrated the binding of these antibodies to the receptor expressed on stably transfected cells, together with a β1-AR agonist-like effect. In addition, immunoadsorption of the serum samples from cChHD patients with a commercially available matrix, containing peptides representing the first and the second extracellular loop of the β1-AR, completely abolished reactivity against the H26R peptide and the physiological response to the receptor. The follow-up of this specificity after in vitro immunoadsorption procedures suggests that this treatment might be used to diminish significantly the serum levels of anti-β1-AR antibodies in patients with Chagas heart disease. PMID:17419712

β-adrenergic receptor responsiveness in aging heart and clinical implications

PubMed Central

Ferrara, Nicola; Komici, Klara; Corbi, Graziamaria; Pagano, Gennaro; Furgi, Giuseppe; Rengo, Carlo; Femminella, Grazia D.; Leosco, Dario; Bonaduce, Domenico

2014-01-01

Elderly healthy individuals have a reduced exercise tolerance and a decreased left ventricle inotropic reserve related to increased vascular afterload, arterial-ventricular load mismatching, physical deconditioning and impaired autonomic regulation (the so called “β-adrenergic desensitization”). Adrenergic responsiveness is altered with aging and the age-related changes are limited to the β-adrenergic receptor density reduction and to the β-adrenoceptor-G-protein(s)-adenylyl cyclase system abnormalities, while the type and level of abnormalities change with species and tissues. Epidemiological studies have shown an high incidence and prevalence of heart failure in the elderly and a great body of evidence correlate the changes of β-adrenergic system with heart failure pathogenesis. In particular it is well known that: (a) levels of cathecolamines are directly correlated with mortality and functional status in heart failure, (b) β1-adrenergic receptor subtype is down-regulated in heart failure, (c) heart failure-dependent cardiac adrenergic responsiveness reduction is related to changes in G proteins activity. In this review we focus on the cardiovascular β-adrenergic changes involvement in the aging process and on similarities and differences between aging heart and heart failure. PMID:24409150

Fibroblast Growth Factor 22 Contributes to the Development of Retinal Nerve Terminals in the Dorsal Lateral Geniculate Nucleus

PubMed Central

Singh, Rishabh; Su, Jianmin; Brooks, Justin; Terauchi, Akiko; Umemori, Hisashi; Fox, Michael A.

2012-01-01

At least three forms of signaling between pre- and postsynaptic partners are necessary during synapse formation. First, “targeting” signals instruct presynaptic axons to recognize and adhere to the correct portion of a postsynaptic target cell. Second, trans-synaptic “organizing” signals induce differentiation in their synaptic partner so that each side of the synapse is specialized for synaptic transmission. Finally, in many regions of the nervous system an excess of synapses are initially formed, therefore “refinement” signals must either stabilize or destabilize the synapse to reinforce or eliminate connections, respectively. Because of both their importance in processing visual information and their accessibility, retinogeniculate synapses have served as a model for studying synaptic development. Molecular signals that drive retinogeniculate “targeting” and “refinement” have been identified, however, little is known about what “organizing” cues are necessary for the differentiation of retinal axons into presynaptic terminals. To identify such “organizing” cues, we used microarray analysis to assess whether any target-derived “synaptic organizers” were enriched in the mouse dorsal lateral geniculate nucleus (dLGN) during retinogeniculate synapse formation. One candidate “organizing” molecule enriched in perinatal dLGN was FGF22, a secreted cue that induces the formation of excitatory nerve terminals in muscle, hippocampus, and cerebellum. In FGF22 knockout mice, the development of retinal terminals in dLGN was impaired. Thus, FGF22 is an important “organizing” cue for the timely development of retinogeniculate synapses. PMID:22363257

GLUT4 Mobilization Supports Energetic Demands of Active Synapses.

PubMed

Ashrafi, Ghazaleh; Wu, Zhuhao; Farrell, Ryan J; Ryan, Timothy A

2017-02-08

The brain is highly sensitive to proper fuel availability as evidenced by the rapid decline in neuronal function during ischemic attacks and acute severe hypoglycemia. We previously showed that sustained presynaptic function requires activity-driven glycolysis. Here, we provide strong evidence that during action potential (AP) firing, nerve terminals rely on the glucose transporter GLUT4 as a glycolytic regulatory system to meet the activity-driven increase in energy demands. Activity at synapses triggers insertion of GLUT4 into the axonal plasma membrane driven by activation of the metabolic sensor AMP kinase. Furthermore, we show that genetic ablation of GLUT4 leads to an arrest of synaptic vesicle recycling during sustained AP firing, similar to what is observed during acute glucose deprivation. The reliance on this biochemical regulatory system for "exercising" synapses is reminiscent of that occurring in exercising muscle to sustain cellular function and identifies nerve terminals as critical sites of proper metabolic control. Copyright © 2017 Elsevier Inc. All rights reserved.

Recycling of Kinesin-1 Motors by Diffusion after Transport

PubMed Central

Blasius, T. Lynne; Reed, Nathan; Slepchenko, Boris M.; Verhey, Kristen J.

2013-01-01

Kinesin motors drive the long-distance anterograde transport of cellular components along microtubule tracks. Kinesin-dependent transport plays a critical role in neurogenesis and neuronal function due to the large distance separating the soma and nerve terminal. The fate of kinesin motors after delivery of their cargoes is unknown but has been postulated to involve degradation at the nerve terminal, recycling via retrograde motors, and/or recycling via diffusion. We set out to test these models concerning the fate of kinesin-1 motors after completion of transport in neuronal cells. We find that kinesin-1 motors are neither degraded nor returned by retrograde motors. By combining mathematical modeling and experimental analysis, we propose a model in which the distribution and recycling of kinesin-1 motors fits a “loose bucket brigade” where individual motors alter between periods of active transport and free diffusion within neuronal processes. These results suggest that individual kinesin-1 motors are utilized for multiple rounds of transport. PMID:24098765

Reduced 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)-Initiated Oxidative DNA Damage and Neurodegeneration in Prostaglandin H Synthase-1 Knockout Mice

PubMed Central

2010-01-01

The neurodegenerative potential of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and underlying mechanisms are under debate. Here, we show that MDMA is a substrate for CNS prostaglandin H synthase (PHS)-catalyzed bioactivation to a free radical intermediate that causes reactive oxygen species (ROS) formation and neurodegenerative oxidative DNA damage. In vitro PHS-1-catalyzed bioactivation of MDMA stereoselectively produced free radical intermediate formation and oxidative DNA damage that was blocked by the PHS inhibitor eicosatetraynoic acid. In vivo, MDMA stereoselectively caused gender-independent DNA oxidation and dopaminergic nerve terminal degeneration in several brain regions, dependent on regional PHS-1 levels. Conversely, MDMA-initiated striatal DNA oxidation, nerve terminal degeneration, and motor coordination deficits were reduced in PHS-1 +/− and −/− knockout mice in a gene dose-dependent fashion. These results confirm the neurodegenerative potential of MDMA and provide the first direct evidence for a novel molecular mechanism involving PHS-catalyzed formation of a neurotoxic MDMA free radical intermediate. PMID:22778832

Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex

PubMed Central

Su, Jianmin; Chen, Jiang; Lippold, Kumiko; Monavarfeshani, Aboozar; Carrillo, Gabriela Lizana; Jenkins, Rachel

2016-01-01

Inhibitory synapses comprise only ∼20% of the total synapses in the mammalian brain but play essential roles in controlling neuronal activity. In fact, perturbing inhibitory synapses is associated with complex brain disorders, such as schizophrenia and epilepsy. Although many types of inhibitory synapses exist, these disorders have been strongly linked to defects in inhibitory synapses formed by Parvalbumin-expressing interneurons. Here, we discovered a novel role for an unconventional collagen—collagen XIX—in the formation of Parvalbumin+ inhibitory synapses. Loss of this collagen results not only in decreased inhibitory synapse number, but also in the acquisition of schizophrenia-related behaviors. Mechanistically, these studies reveal that a proteolytically released fragment of this collagen, termed a matricryptin, promotes the assembly of inhibitory nerve terminals through integrin receptors. Collectively, these studies not only identify roles for collagen-derived matricryptins in cortical circuit formation, but they also reveal a novel paracrine mechanism that regulates the assembly of these synapses. PMID:26975851

Innervation of arteriovenous anastomoses in the sheep tongue: immunocytochemical evidence for coexistence of neural transmitters.

PubMed Central

Molyneux, G S; Haller, C J

1988-01-01

In this study structural and immunocytochemical evidence has shown that arterial vessels, particularly AVAs, are associated with nerves containing peptidergic vasodilators, viz. VIP, CGRP and SP. The presence of VIP-like immunoreactivity in both P-type and C-type nerves is evidence of the coexistence of VIP and acetylcholine in cholinergic nerves and suggests the action of VIP in maintaining the opening of AVAs in heat stress conditions. The evidence for the co-existence of CGRP and SP is more direct as immunoreactivity for both peptides has been demonstrated in serial sections of the same nerve terminal. Although SP is a potent vasodilator there is little evidence of its role in thermoregulation; however it may be involved in a local axon reflex and cause antidromic vasodilatation of local vessels particularly AVAs. Images Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 4 Fig. 5 Fig. 1 Fig. 2 Fig. 3 PMID:2461925

Peripheral innervation patterns of vestibular nerve afferents in the bullfrog utriculus

NASA Technical Reports Server (NTRS)

Baird, Richard A.; Schuff, N. R.

1994-01-01

Vestibular nerve afferents innervating the bullfrog utriculus differ in their response dynamics and sensitivity to natural stimulation. They also supply hair cells that differ markedly in hair bundle morphology. To examine the peripheral innervation patterns of individual utricular afferents more closely, afferent fibers were labeled by the extracellular injection of horseradish peroxidase (HRP) into the vestibular nerve after sectioning the vestibular nerve medial to Scarpa's ganglion to allow the degeneration of sympathetic and efferent fibers. The peripheral arborizations of individual afferents were then correlated with the diameters of their parent axons, the regions of the macula they innervate, and the number and type of hair cells they supply. The utriculus is divided by the striola, a narrow zone of distinctive morphology, into media and lateral parts. Utiricular afferents were classified as striolar or extrastriolar according to the epithelial entrance of their parent axons and the location of their terminal fields. In general, striolar afferents had thicker parent axons, fewer subepithelial bifurcations, larger terminal fields, and more synaptic endings than afferents in extrstriolar regions. Afferents in a juxtastriolar zone, immediately adjacent to the medial striola, had innervation patterns transitional between those in the striola and more peripheral parts of the medial extrastriola. moast afferents innervated only a single macular zone. The terminal fields of striolar afferents, with the notable exception of a few afferents with thin parent axons, were generally confined to one side of the striola. Hair cells in the bullfrog utriculus have perviously been classified into four types based on hair bundle morphology. Afferents in the extrastriolar and juxtastriolar zones largely or exclusively innervated Type B hair cells, the predominant hair cell type in the utricular macula. Striolar afferents supplied a mixture of four hair cell types, but largely contacted Type B and Type C hair cells, particularly on the outer rows of the medial striola. Afferents supplying more central striolar regions innervated fewer Type B and larger numbers of Type E and Type F hair cells. Striolar afferents with thin parent axons largely supplied Type E hair cells with bulbed kniocilia in the innermost striolar rows.

Effect of cochlear nerve electrocautery on the adult cochlear nucleus.

PubMed

Iseli, Claire E; Merwin, William H; Klatt-Cromwell, Cristine; Hutson, Kendall A; Ewend, Matthew G; Adunka, Oliver F; Fitzpatrick, Douglas C; Buchman, Craig A

2015-04-01

Electrocauterization and subsequent transection of the cochlear nerve induce greater injury to the cochlear nucleus than sharp transection alone. Some studies show that neurofibromatosis Type 2 (NF2) patients fit with auditory brainstem implants (ABIs) fail to achieve speech perception abilities similar to ABI recipients without NF2. Reasons for these differences remain speculative. One hypothesis posits poorer performance to surgically induced trauma to the cochlear nucleus from electrocautery. Sustained electrosurgical depolarization of the cochlear nerve may cause excitotoxic-induced postsynaptic nuclear injury. Equally plausible is that cautery in the vicinity of the cochlear nucleus induces necrosis. The cochlear nerve was transected in anesthetized adult gerbils sharply with or without bipolar electrocautery at varying intensities. Gerbils were perfused at 1, 3, 5, and 7 days postoperatively; their brainstem and cochleas were embedded in paraffin and sectioned at 10 μm. Alternate sections were stained with flourescent markers for neuronal injury or Nissl substance. In additional experiments, anterograde tracers were applied directly to a sectioned eighth nerve to verify that fluorescent-labeled profiles seen were terminating auditory nerve fibers. Cochlear nerve injury was observed from 72 hours postoperatively and was identical across cases regardless of surgical technique. Postsynaptic cochlear nucleus injury was not seen after distal transection of the nerve. By contrast, proximal transection was associated with trauma to the cochlear nucleus. Distal application of bipolar electrocautery seems safe for the cochlear nucleus. Application near the root entry zone must be used cautiously because this may compromise nuclear viability needed to support ABI stimulation.

The use of targeted muscle reinnervation for improved myoelectric prosthesis control in a bilateral shoulder disarticulation amputee.

PubMed

Kuiken, T A; Dumanian, G A; Lipschutz, R D; Miller, L A; Stubblefield, K A

2004-12-01

A novel method for the control of a myoelectric upper limb prosthesis was achieved in a patient with bilateral amputations at the shoulder disarticulation level. Four independently controlled nerve-muscle units were created by surgically anastomosing residual brachial plexus nerves to dissected and divided aspects of the pectoralis major and minor muscles. The musculocutaneous nerve was anastomosed to the upper pectoralis major; the median nerve was transferred to the middle pectoralis major region; the radial nerve was anastomosed to the lower pectoralis major region; and the ulnar nerve was transferred to the pectoralis minor muscle which was moved out to the lateral chest wall. After five months, three nerve-muscle units were successful (the musculocutaneous, median and radial nerves) in that a contraction could be seen, felt and a surface electromyogram (EMG) could be recorded. Sensory reinnervation also occurred on the chest in an area where the subcutaneous fat was removed. The patient was fitted with a new myoelectric prosthesis using the targeted muscle reinnervation. The patient could simultaneously control two degrees-of-freedom with the experimental prosthesis, the elbow and either the terminal device or wrist. Objective testing showed a doubling of blocks moved with a box and blocks test and a 26% increase in speed with a clothes pin moving test. Subjectively the patient clearly preferred the new prosthesis. He reported that it was easier and faster to use, and felt more natural.

Dietary correlates associated with the mental foramen in primates: implications for interpreting the fossil record.

PubMed

Muchlinski, Magdalena N; Deane, Andrew S

2016-07-01

The mandibular nerve is a sensory and motor nerve that innervates the muscles of mastication, the lower dentition, and the lower lip and surrounding structures. Although this nerve contains both efferent and afferent fibers, the mental nerve, a terminal branch of the mandibular nerve, is a strictly sensory nerve that exits the mental foramen and innervates the lower lip, the skin overlaying the mandible, and the oral mucosa around the mandible. Osteological foramina are often used as proxies for nerve cross section area and they often correlate well with some aspect of a primate's ecology (e.g., optic foramen and visual acuity). The primary objective of this study is to explore the correlation between the mental foramen and dietary preference among primates. The mental foramen of 40 primate species (n = 180) was measured from 3-D surface models of the mandible. Both conventional and phylogenetic tests indicate that although frugivores have larger mental foramina than folivores, the differences were not significant. These results show that while structures like the infraorbital foramen correlate well with diet and touch sensitivity, the mental foramen does not. Based on these findings, the mental foramen is not a suggested morphological character for interpreting of the fossil record. J. Morphol. 277:978-985, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Hypertonic enhancement of transmitter release from frog motor nerve terminals: Ca2+ independence and role of integrins

NASA Technical Reports Server (NTRS)

Kashani, A. H.; Chen, B. M.; Grinnell, A. D.

2001-01-01

Hyperosmotic solutions cause markedly enhanced spontaneous quantal release of neurotransmitter from many nerve terminals. The mechanism of this enhancement is unknown. We have investigated this phenomenon at the frog neuromuscular junction with the aim of determining the degree to which it resembles the modulation of release by stretch, which has been shown to be mediated by mechanical tension on integrins.The hypertonicity enhancement, like the stretch effect, does not require Ca2+ influx or release from internal stores, although internal release may contribute to the effect. The hypertonicity effect is sharply reduced (but not eliminated) by peptides containing the RGD sequence, which compete with native ligands for integrin bonds.There is co-variance in the magnitude of the stretch and osmotic effects; that is, individual terminals exhibiting a large stretch effect also show strong enhancement by hypertonicity, and vice versa. The stretch and osmotic enhancements also can partially occlude each other.There remain some clear-cut differences between osmotic and stretch forms of modulation: the larger range of enhancement by hypertonic solutions, the relative lack of effect of osmolarity on evoked release, and the reported higher temperature sensitivity of osmotic enhancement. Nevertheless, our data strongly implicate integrins in a significant fraction of the osmotic enhancement, possibly acting via the same mechanism as stretch modulation.

Terminal Schwann Cells Participate in Neuromuscular Synapse Remodeling during Reinnervation following Nerve Injury

PubMed Central

Kang, Hyuno; Tian, Le; Mikesh, Michelle; Lichtman, Jeff W.

2014-01-01

Schwann cells (SCs) at neuromuscular junctions (NMJs) play active roles in synaptic homeostasis and repair. We have studied how SCs contribute to reinnervation of NMJs using vital imaging of mice whose motor axons and SCs are transgenically labeled with different colors of fluorescent proteins. Motor axons most commonly regenerate to the original synaptic site by following SC-filled endoneurial tubes. During the period of denervation, SCs at the NMJ extend elaborate processes from the junction, as shown previously, but they also retract some processes from territory they previously occupied within the endplate. The degree of this retraction depends on the length of the period of denervation. We show that the topology of the remaining SC processes influences the branching pattern of regenerating axon terminals and the redistribution of acetylcholine receptors (AChRs). Upon arriving at the junction, regenerating axons follow existing SC processes within the old synaptic site. Some of the AChR loss that follows denervation is correlated with failure of portions of the old synaptic site that lack SC coverage to be reinnervated. New AChR clustering is also induced by axon terminals that follow SC processes extended during denervation. These observations show that SCs participate actively in the remodeling of neuromuscular synapses following nerve injury by their guidance of axonal reinnervation. PMID:24790203

Effect of Stimulation of Neurotransmitter Systems on Heart Rate Variability and β-Adrenergic Responsiveness of Erythrocytes in Outbred Rats.

PubMed

Kur'yanova, E V; Tryasuchev, A V; Stupin, V O; Teplyi, D L

2017-05-01

We studied heart rate variability and β-adrenergic responsiveness of erythrocytes and changes in these parameters in response to single administration of β-adrenoblocker propranolol (2 mg/kg) in outbred male rats against the background of activation of the noradrenergic, serotonergic, and dopaminergic neurotransmitter systems achieved by 4-fold injections maprotiline (10 mg/kg), 5-hydroxytryptophan (50 mg/kg) combined with fluoxetine (3 mg/kg), and L-DOPA (20 mg/kg) with amantadine (20 mg/kg), respectively. Stimulation of the noradrenergic system moderately enhanced the heart rhythm rigidity and β-adrenergic responsiveness of erythrocytes. In addition, it markedly augmented the moderating effect of subsequently administered propranolol on LF and VLF components in the heart rate variability and reversed the effect of propranolol on β-adrenergic responsiveness of erythrocytes. Stimulation of the serotonergic system dramatically decreased all components in the heart rate variability and pronouncedly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol slightly restored all components in the heart rate variability and decreased β-adrenergic responsiveness of erythrocytes to the control level. Stimulation of the dopaminergic system made the heart rate more rigid due to decrease of all components in the heart rate variability; in addition, it slightly but significantly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol produced no significant effects on all components in the heart rate variability and on β-adrenergic responsiveness of erythrocytes. Stimulation of noradrenergic, serotonergic, and dopaminergic neurotransmitter systems produced unidirectional and consorted effects on heart rate variability and β-adrenergic responsiveness of erythrocytes, although the magnitudes of these effects were different. Probably, the changes in the heart rate variability in rats with stimulated neurotransmitter systems results from modification of the cellular sensitivity in peripheral organs to adrenergic influences. However, the differences in the reactions to β-adrenoblocker attest to specificity of the mechanisms underlying the changes in membrane reception and adrenergic pathways in every experimental model employed in this study.

In vitro assessment of induced phrenic nerve cryothermal injury.

PubMed

Goff, Ryan P; Bersie, Stephanie M; Iaizzo, Paul A

2014-10-01

Phrenic nerve injury, both left and right, is considered a significant complication of cryoballoon ablation for treatment of drug-refractory atrial fibrillation, and functional recovery of the phrenic nerve can take anywhere from hours to months. The purpose of this study was to focus on short periods of cooling to determine the minimal amount of cooling that may terminate nerve function related to cryo ablation. Left and/or right phrenic nerves were dissected from the pericardium and connective tissue of swine (n = 35 preparations). Nerves were placed in a recording chamber modified with a thermocouple array. This apparatus was placed in a digital water bath to maintain an internal chamber temperature of 37°C. Nerves were stimulated proximally with a 1-V, 0.1-ms square wave. Bipolar compound action potentials were recorded proximal and distal to the site of ablation both before and after ablation, then analyzed to determine changes in latency, amplitude, and duration. Temperatures were recorded at a rate of 5 Hz, and maximum cooling rates were calculated. Phrenic nerves were found to elicit compound action potentials upon stimulation for periods up to 4 hours minimum. Average conduction velocity was 56.7 ± 14.7 m/s preablation and 49.8 ± 16.6 m/s postablation (P = .17). Cooling to mild subzero temperatures ceased production of action potentials for >1 hour. Taking into account the data presented here, previous publications, and a conservative stance, during cryotherapy applications, cooling of the nerve to below 4°C should be avoided whenever possible. Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Sex differences and the effects of ovariectomy on the β-adrenergic contractile response

PubMed Central

McIntosh, Victoria J.; Chandrasekera, P. Charukeshi

2011-01-01

The presence of sex differences in myocardial β-adrenergic responsiveness is controversial, and limited studies have addressed the mechanism underlying these differences. Studies were performed using isolated perfused hearts from male, intact female and ovariectomized female mice to investigate sex differences and the effects of ovarian hormone withdrawal on β-adrenergic receptor function. Female hearts exhibited blunted contractile responses to the β-adrenergic receptor agonist isoproterenol (ISO) compared with males but not ovariectomized females. There were no sex differences in β1-adrenergic receptor gene or protein expression. To investigate the role of adenylyl cyclase, phosphodiesterase, and the cAMP-signaling cascade in generating sex differences in the β-adrenergic contractile response, dose-response studies were performed in isolated perfused male and female hearts using forskolin, 3-isobutyl-1-methylxanthine (IBMX), and 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (CPT-cAMP). Males showed a modestly enhanced contractile response to forskolin at 300 nM and 5 μM compared with females, but there were no sex differences in the response to IBMX or CPT-cAMP. The role of the A1 adenosine receptor (A1AR) in antagonizing the β-adrenergic contractile response was investigated using both the A1AR agonist 2-chloro-N6-cyclopentyl-adenosine and A1AR knockout (KO) mice. Intact females showed an enhanced A1AR anti-adrenergic effect compared with males and ovariectomized females. The β-adrenergic contractile response was potentiated in both male and female A1ARKO hearts, with sex differences no longer present above 1 nM ISO. The β-adrenergic contractile response is greater in male hearts than females, and minor differences in the action of adenylyl cyclase or the A1AR may contribute to these sex differences. PMID:21685268

Linear ordered collagen scaffolds loaded with collagen-binding basic fibroblast growth factor facilitate recovery of sciatic nerve injury in rats.

PubMed

Ma, Fukai; Xiao, Zhifeng; Chen, Bing; Hou, Xianglin; Dai, Jianwu; Xu, Ruxiang

2014-04-01

Natural biological functional scaffolds, consisting of biological materials filled with promoting elements, provide a promising strategy for the regeneration of peripheral nerve defects. Collagen conduits have been used widely due to their excellent biological properties. Linear ordered collagen scaffold (LOCS) fibers are good lumen fillers that can guide nerve regeneration in an ordered direction. In addition, basic fibroblast growth factor (bFGF) is important in the recovery of nerve injury. However, the traditional method for delivering bFGF to the lesion site has no long-term effect because of its short half-life and rapid diffusion. Therefore, we fused a specific collagen-binding domain (CBD) peptide to the N-terminal of native basic fibroblast growth factor (NAT-bFGF) to retain bFGF on the collagen scaffolds. In this study, a natural biological functional scaffold was constructed using collagen tubes filled with collagen-binding bFGF (CBD-bFGF)-loaded LOCS to promote regeneration in a 5-mm rat sciatic nerve transection model. Functional evaluation, histological investigation, and morphometric analysis indicated that the natural biological functional scaffold retained more bFGF at the injury site, guided axon growth, and promoted nerve regeneration as well as functional restoration.

Serial neurophysiological and neurophysiological examinations for delayed facial nerve palsy in a patient with Fisher syndrome.

PubMed

Umekawa, Motoyuki; Hatano, Keiko; Matsumoto, Hideyuki; Shimizu, Takahiro; Hashida, Hideji

2017-05-27

The patient was a 47-year-old man who presented with diplopia and gait instability with a gradual onset over the course of three days. Neurological examinations showed ophthalmoplegia, diminished tendon reflexes, and truncal ataxia. Tests for anti-GQ1b antibodies and several other antibodies to ganglioside complex were positive. We made a diagnosis of Fisher syndrome. After administration of intravenous immunoglobulin, the patient's symptoms gradually improved. However, bilateral facial palsy appeared during the recovery phase. Brain MRI showed intensive contrast enhancement of bilateral facial nerves. During the onset phase of facial palsy, the amplitude of the compound muscle action potential (CMAP) in the facial nerves was preserved. During the peak phase, the facial CMAP amplitude was within the lower limit of normal values, or mildly decreased. During the recovery phase, the CMAP amplitude was normalized, and the R1 and R2 responses of the blink reflex were prolonged. The delayed facial nerve palsy improved spontaneously, and the enhancement on brain MRI disappeared. Serial neurophysiological and neuroradiological examinations suggested that the main lesions existed in the proximal part of the facial nerves and the mild lesions existed in the facial nerve terminals, probably due to reversible conduction failure.

Expression of mammalian beta-adrenergic receptors in Xenopus laevis oocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bahouth, S.W.; Malbon, C.C.

1987-05-01

Xenopus laevis oocytes are a useful transcription and expression system for DNA and RNA, respectively. Total cellular RNA was extracted from mouse lymphoma S49 cells and poly(A)/sup +/mRNA prepared by affinity chromatography of RNA on oligo(dT) cellulose. The membranes of S49 cells contain beta-adrenergic receptors that display pharmacological characteristics of beta/sub 2/-subtype. Xenopus laevis oocytes were injected with 50 ng of mRNA/oocyte. Expression of beta-adrenergic receptors in oocytes incubated for 30 hr after microinjection was assessed in membranes by radioligand binding using (/sup 3/H) dihydroalprenolol. The injected oocytes displayed 0.34 fmol receptor/oocyte as compared to 0.02 fmol receptor/oocyte in themore » control oocytes. The affinity of beta-adrenergic receptors in injected oocytes for this radioligand was 2 nM, a value similar to the affinity of beta-adrenergic receptors for DHA in S49 cell membranes. The potency of beta-adrenergic agonists in competing for DHA binding to oocytes membranes was isoproterenol > epinephrine > norepineprine, indicating that the expressed beta-adrenergic receptors were of the beta/sub 2/-subtype. The K/sub I/ of these agonists for the beta-adrenergic receptor in oocyte membranes was 0.03, 0.15 and 1.2 ..mu..M, respectively. The role of post-translational modification in dictating receptor subtype is analyzed using mRNA of beta/sub 1/- as well as beta/sub 2/-adrenergic receptors.« less

Effect of Prazosin and Naltrexone on Script Induced Alcohol Craving in Veterans with Alcohol Use Disorders with and without Co-occurring PTSD

DTIC Science & Technology

2015-01-01

status, moderate medication response. 15. SUBJECT TERMS Alcohol Drinking, Drinking Behavior, Naltrexone, Prazosin, Adrenergic Agents, Adrenergice ...primates and humans express α1 adrenergic receptors. Given the interplay of the noradrenergic system with craving-related brain systems, blocking α1...Antagonists, Adrenergic alpha-1 receptor antagonists, Adrenergic alpha- antagonists, Antihypertensive agents, Narcotic antagonists, Therapeutic uses

Modeling the Effects of β1-Adrenergic Receptor Blockers and Polymorphisms on Cardiac Myocyte Ca2+ Handling

PubMed Central

Amanfu, Robert K.

2014-01-01

β-Adrenergic receptor blockers (β-blockers) are commonly used to treat heart failure, but the biologic mechanisms governing their efficacy are still poorly understood. The complexity of β-adrenergic signaling coupled with the influence of receptor polymorphisms makes it difficult to intuit the effect of β-blockers on cardiac physiology. While some studies indicate that β-blockers are efficacious by inhibiting β-adrenergic signaling, other studies suggest that they work by maintaining β-adrenergic responsiveness. Here, we use a systems pharmacology approach to test the hypothesis that in ventricular myocytes, these two apparently conflicting mechanisms for β-blocker efficacy can occur concurrently. We extended a computational model of the β1-adrenergic pathway and excitation-contraction coupling to include detailed receptor interactions for 19 ligands. Model predictions, validated with Ca2+ and Förster resonance energy transfer imaging of adult rat ventricular myocytes, surprisingly suggest that β-blockers can both inhibit and maintain signaling depending on the magnitude of receptor stimulation. The balance of inhibition and maintenance of β1-adrenergic signaling is predicted to depend on the specific β-blocker (with greater responsiveness for metoprolol than carvedilol) and β1-adrenergic receptor Arg389Gly polymorphisms. PMID:24867460

The Sense of Smell Impacts Metabolic Health and Obesity.

PubMed

Riera, Celine E; Tsaousidou, Eva; Halloran, Jonathan; Follett, Patricia; Hahn, Oliver; Pereira, Mafalda M A; Ruud, Linda Engström; Alber, Jens; Tharp, Kevin; Anderson, Courtney M; Brönneke, Hella; Hampel, Brigitte; Filho, Carlos Daniel de Magalhaes; Stahl, Andreas; Brüning, Jens C; Dillin, Andrew

2017-07-05

Olfactory inputs help coordinate food appreciation and selection, but their role in systemic physiology and energy balance is poorly understood. Here we demonstrate that mice upon conditional ablation of mature olfactory sensory neurons (OSNs) are resistant to diet-induced obesity accompanied by increased thermogenesis in brown and inguinal fat depots. Acute loss of smell perception after obesity onset not only abrogated further weight gain but also improved fat mass and insulin resistance. Reduced olfactory input stimulates sympathetic nerve activity, resulting in activation of β-adrenergic receptors on white and brown adipocytes to promote lipolysis. Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory performance in mice and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals. Copyright © 2017 Elsevier Inc. All rights reserved.

[Effect of different therapy options on bronchial contraction in rats with modeled obstructive pulmonary disease].

PubMed

Kuzubova, N A; Fedin, A N; Lebedeva, E S; Platonova, I S

2014-09-01

In the model of chronic obstructive pulmonary disease, produced in rats by 60-day exposure to nitrogen dioxide, the effect of different options of combination therapy (corticosteroids, anticholinergics, adrenergic agonists) on the functional state of the bronchi was studied. The contractile activity of strips of the bronchi caused by nerve or smooth muscle stimulation was evaluated. Corticosteroid monotherapy resulted in deterioration of the functional state of the bronchial wall neuromuscular apparatus due to corticosteroid resistance, evolving under the influence of long-term exposure to nitrogen dioxide. Application of M-anticholinergic tiotropium had a beneficial effect on the functional state of the bronchi smooth muscles, leading to the full restoration of the bronchial wall contractile activity and removal the morphological manifestations of inflammatory lung tissue remodeling. Most effective in terms of impact on the functional state of the bronchial wall neuromuscular apparatus was corticosteroid therapy combined with M-cholinolytik or beta2-adrenoagonist.

Effect of bedrest on circadian rhythms of plasma renin, aldosterone, and cortisol

NASA Technical Reports Server (NTRS)

Chavarri, M.; Ganguly, A.; Luetscher, J. A.; Zager, P. G.

1977-01-01

Previous studies of normal men after 5 d of bedrest showed that circulatory instability on head-up tilt or standing is preceded by increased plasma renin activity (PRA) at bedrest. In the present study, the circadian rhythms of PRA, aldosterone, and cortisol have been observed in five normal men on a constant diet. In ambulatory controls, PRA and aldosterone increased normally after standing. On the third morning of bedrest, PRA was higher than before, and at noon, PRA was higher than in standing controls. The nocturnal peaks of PRA resulting from episodic renin secretion during sleep were higher after bedrest. Plasma aldosterone was also increased by bedrest. The findings are compatible with the theory that intermittent beta-adrenergic nerve activity during sleep is increased after bedrest, but other factors, such as loss of body sodium and a lower plasma volume, may also be involved.

[Anesthetic management using esmolol for arthroscopic synovectomy in a patient with thyroid storm].

PubMed

Torigoe, Kei; Suzuki, Hiroto; Nakajima, Waka; Takahashi, Minori; Aoyagi, Mitsuo

2010-02-01

We report a case of a 47-year-old woman with past medical history of Graves disease who presented with thyroid storm, a state of physiologic decompensation due to severe thyrotoxicosis, and arthritis purulenta. Antithyroid therapy ameliorated thyrotoxicosis in 4 days, and arthroscopic synovectomy of the right knee was performed. Anesthesia was induced with intravenous propofol. Esmolol, an ultra-short-acting beta blocker listed in national drug tariff of Japan for intraoperative continuous iv infusion in March 2008, was also administered to control heart rate. Then, laryngeal mask airway was inserted and echo-guided femoral nerve block was done with ropivacaine. Anesthesia was maintained with i.v. infusion of propofol and fentanyl. Short episode of supraventricular tachycardia occurred twice, but each tachycardia disappered in about a half minute. The postoperative course was uneventful. Esmolol probably acted to prevent intraoperative tachycardia due to increased beta-adrenergic tone.

Treatment of Gastrointestinal Sphincters Spasms with Botulinum Toxin A

PubMed Central

Brisinda, Giuseppe; Sivestrini, Nicola; Bianco, Giuseppe; Maria, Giorgio

2015-01-01

Botulinum toxin A inhibits neuromuscular transmission. It has become a drug with many indications. The range of clinical applications has grown to encompass several neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum toxin A provides benefit in diseases of the gastrointestinal tract. Although toxin blocks cholinergic nerve endings in the autonomic nervous system, it has also been shown that it does not block non-adrenergic non-cholinergic responses mediated by nitric oxide. This has promoted further interest in using botulinum toxin A as a treatment for overactive smooth muscles and sphincters. The introduction of this therapy has made the treatment of several clinical conditions easier, in the outpatient setting, at a lower cost and without permanent complications. This review presents current data on the use of botulinum toxin A in the treatment of pathological conditions of the gastrointestinal tract. PMID:26035487

Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury

PubMed Central

Moss, Andrew; Ingram, Rachel; Koch, Stephanie; Theodorou, Andria; Low, Lucie; Baccei, Mark; Hathway, Gareth J; Costigan, Michael; Salton, Stephen R; Fitzgerald, Maria

2008-01-01

Background The role of the neurotrophin regulated polypeptide, VGF, has been investigated in a rat spared injury model of neuropathic pain. This peptide has been shown to be associated with synaptic strengthening and learning in the hippocampus and while it is known that VGFmRNA is upregulated in dorsal root ganglia following peripheral nerve injury, the role of this VGF peptide in neuropathic pain has yet to be investigated. Results Prolonged upregulation of VGF mRNA and protein was observed in injured dorsal root ganglion neurons, central terminals and their target dorsal horn neurons. Intrathecal application of TLQP-62, the C-terminal active portion of VGF (5–50 nmol) to naïve rats caused a long-lasting mechanical and cold behavioral allodynia. Direct actions of 50 nM TLQP-62 upon dorsal horn neuron excitability was demonstrated in whole cell patch recordings in spinal cord slices and in receptive field analysis in intact, anesthetized rats where significant actions of VGF were upon spontaneous activity and cold evoked responses. Conclusion VGF expression is therefore highly modulated in nociceptive pathways following peripheral nerve injury and can cause dorsal horn cell excitation and behavioral hypersensitivity in naïve animals. Together the results point to a novel and powerful role for VGF in neuropathic pain. PMID:19077191

Arousal From Sleep and Sympathetic Excitation During Wakefulness.

PubMed

Taylor, Keri S; Murai, Hisayoshi; Millar, Philip J; Haruki, Nobuhiko; Kimmerly, Derek S; Morris, Beverley L; Tomlinson, George; Bradley, T Douglas; Floras, John S

2016-12-01

Obstructive apnea during sleep elevates the set point for efferent sympathetic outflow during wakefulness. Such resetting is attributed to hypoxia-induced upregulation of peripheral chemoreceptor and brain stem sympathetic function. Whether recurrent arousal from sleep also influences daytime muscle sympathetic nerve activity is unknown. We therefore tested, in a cohort of 48 primarily nonsleepy, middle-aged, male (30) and female (18) volunteers (age: 59±1 years, mean±SE), the hypothesis that the frequency of arousals from sleep (arousal index) would relate to daytime muscle sympathetic burst incidence, independently of the frequency of apnea or its severity. Polysomnography identified 24 as having either no or mild obstructive sleep apnea (apnea-hypopnea index <15 events/h) and 24 with moderate-to-severe obstructive sleep apnea (apnea-hypopnea index >15 events/h). Burst incidence correlated significantly with arousal index (r=0.53; P<0.001), minimum oxygen saturation (r=-0.43; P=0.002), apnea-hypopnea index (r=0.41; P=0.004), age (r=0.36; P=0.013), and body mass index (r=0.33; P=0.022) but not with oxygen desaturation index (r=0.28; P=0.056). Arousal index was the single strongest predictor of muscle sympathetic nerve activity burst incidence, present in all best subsets regression models. The model with the highest adjusted R 2 (0.456) incorporated arousal index, minimum oxygen saturation, age, body mass index, and oxygen desaturation index but not apnea-hypopnea index. An apnea- and hypoxia-independent effect of sleep fragmentation on sympathetic discharge during wakefulness could contribute to intersubject variability, age-related increases in muscle sympathetic nerve activity, associations between sleep deprivation and insulin resistance or insomnia and future cardiovascular events, and residual adrenergic risk with persistence of hypertension should therapy eliminate obstructive apneas but not arousals. © 2016 American Heart Association, Inc.

N-substituted imidazolines and ethylenediamines and their action on alpha- and beta-adrenergic receptors.

PubMed

Hamada, A; Yaden, E L; Horng, J S; Ruffolo, R R; Patil, P N; Miller, D D

1985-09-01

A series of N-substituted imidazolines and ethylenediamines were synthesized and examined for their activity in alpha- and beta-adrenergic systems. The length of the intermediate side chain between the catechol and imidazoline ring or the amine of the ethylenediamine segment was shown to affect the adrenergic activity. N-[2-(3,4-Dihydroxyphenyl)ethyl]imidazoline hydrochloride (2) and N-[2-(3,4-dihydroxyphenyl)ethyl]ethylenediamine dihydrochloride (4), both with two methylene groups between the catechol and amine segment, were found to be somewhat selective for alpha 2-adrenergic receptors while 1-(3,4-dihydroxybenzyl)imidazoline hydrochloride (1) and N-2-(3,4-dihydroxybenzyl)ethylenediamine dihydrochloride (3), both with one methylene group between the catechol and amine segment, were more selective for alpha1-adrenergic receptors in a pithed rat model. Of the four compounds examined, only compound 2 showed significant direct activity on beta1- and beta2-adrenergic receptors.

Effect of noxious electrical stimulation of the peroneal nerve on stretch reflex activity of the hamstring muscle in rats: possible implications of neuronal mechanisms in the development of tight hamstrings in lumbar disc herniation.

PubMed

Hirayama, Jiro; Yamagata, Masatsune; Takahashi, Kazuhisa; Moriya, Hideshige

2005-05-01

The effect of noxious electrical stimulation of the peroneal nerve on the stretch reflex electromyogram activity of the hamstring muscle (semitendinous) was studied. To verify the following hypothetical mechanisms underlying tight hamstrings in lumbar disc herniation: stretch reflex muscle activity of hamstrings is increased by painful inputs from an injured spinal nerve root and the increased stretch reflex muscle activity is maintained by central sensitization. It is reported that stretch reflex activity of the trunk muscles is induced by noxious stimulation of the sciatic nerve and maintained by central sensitization. In spinalized rats (transected spinal cord), the peroneal nerve was stimulated electrically as a conditioning stimulus. Stretch reflex electromyogram activity of the semitendinous muscle was recorded before and after the conditioning stimulus. Even after electrical stimulation was terminated, an increased stretch reflex activity of the hamstring muscle was observed. It is likely that a central sensitization mechanism at the spinal cord level was involved in the increased reflex activity. Central sensitization may play a part in the neuronal mechanisms of tight hamstrings in lumbar disc herniation.

Schwann Cell Phenotype Changes in Aging Human Dental Pulp.

PubMed

Couve, E; Lovera, M; Suzuki, K; Schmachtenberg, O

2018-03-01

Schwann cells are glial cells that support axonal development, maintenance, defense, and regeneration in the peripheral nervous system. There is limited knowledge regarding the organization, plasticity, and aging of Schwann cells within the dental pulp in adult permanent teeth. The present study sought to relate changes in the pattern of Schwann cell phenotypes between young and old adult teeth with neuronal, immune, and vascular components of the dental pulp. Schwann cells are shown to form a prominent glial network at the dentin-pulp interface, consisting of nonmyelinating and myelinating phenotypes, forming a multicellular neuroimmune interface in association with nerve fibers and dendritic cells. Schwann cell phenotypes are recognized by the expression of S100, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), Sox10, GAP43, and p75NTR markers. In young adult teeth, a dense population of nonmyelinating Schwann cells projects processes in close association with sensory nerve terminals through the odontoblast layer, reaching the adjacent predentin/dentin domain. While GAP43 and p75NTR are highly expressed in nonmyelinating Schwann cells from young adult teeth, the presence of these markers declines significantly in old adult teeth. Myelinated axons, identified by MBP expression, are mainly present at the Raschkow plexus and within nerve bundles in the dental pulp, but their density is significantly reduced in old adult versus young adult teeth. These data reveal age-related changes within the glial network of the dental pulp, in association with a reduction of coronal dental pulp innervation in old adult versus young adult teeth. The prominence of Schwann cells as a cellular component at the dentin-pulp interface supports the notion that their association with sensory nerve terminals and immune system components forms part of an integrated multicellular barrier for defense against pathogens and dentin repair.

An electrophysiological study on the effects of Pa-1G (a phospholipase A(2)) from the venom of king brown snake, Pseudechis australis, on neuromuscular function.

PubMed

Fatehi, M; Rowan, E G; Harvey, A L

2002-01-01

The effects of Pa-1G, a phospholipase A(2) (PLA(2)) from the venom of the Australian king brown snake (Pseudechis australis) were determined on the release of acetylcholine, muscle resting membrane potential and motor nerve terminal action potential at mouse neuromuscular junction. Intracellular recording from endplate regions of mouse triangularis sterni nerve-muscle preparations revealed that Pa-1G (800 nM) significantly reduced the amplitude of endplate potentials within 10 min exposure. The quantal content of endplate potentials was decreased to 58+/-6% of control after 30 min exposure to 800 nM Pa-1G. The toxin also caused a partial depolarisation of mouse muscle fibres within 60 min exposure. Extracellular recording of action potentials at motor nerve terminals showed that Pa-1G reduced the waveforms associated with both sodium and potassium conductances. To investigate whether this was a direct or indirect effect of the toxin on these ionic currents, whole cell patch clamp experiments were performed using human neuroblastoma (SK-N-SH) cells and B82 mouse fibroblasts stably transfected with rKv1.2. Patch clamp recording experiments confirmed that potassium currents sensitive to alpha-dendrotoxin recorded from B82 cells and sodium currents in SK-N-SH cells were not affected by the toxin. Since neither facilitation of acetylcholine release at mouse neuromuscular junction nor depression of potassium currents in B82 cells has been observed, the apparent blockade of potassium currents at mouse motor nerve endings induced by the toxin is unlikely to be due to a selective block of potassium channels.

A genetic polymorphism of the alpha2-adrenergic receptor increases autonomic responses to stress.

PubMed

Finley, J Clayton; O'Leary, Michael; Wester, Derin; MacKenzie, Steven; Shepard, Neil; Farrow, Stephen; Lockette, Warren

2004-06-01

We hypothesized that individual differences in autonomic responses to psychological, physiological, or environmental stresses are inherited, and exaggerated autonomic responsiveness may represent an intermediate phenotype that can contribute to the development of essential hypertension in humans over time. alpha(2)-Adrenergic receptors (alpha(2)-ARs), encoded by a gene on chromosome 10, are found in the central nervous system and also mediate release of norepinephrine from the presynaptic nerve terminals of the peripheral sympathetic nervous system and the exocytosis of epinephrine from the adrenal medulla. We postulated that, because this receptor mediates central and peripheral autonomic responsiveness to stress, genetic mutations in the gene encoding this receptor may explain contrasting activity of the autonomic nervous system among individuals. The restriction enzyme Dra I identifies a polymorphic site in the 3'-transcribed, but not translated, portion of the gene encoding the chromosome 10 alpha(2)-AR. Southern blotting of genomic DNA with a cDNA probe after restriction enzyme digestion results in fragments that are either 6.7 kb or 6.3 kb in size. Transfection studies of these two genotypes resulted in contrasting expression of a reporter gene, and it is suggested from these findings that this is a functional polymorphism. In a study of 194 healthy subjects, we measured autonomic responses to provocative motion, a fall in blood pressure induced by decreasing venous return and cardiac output, or exercise. Specifically, we measured reactions to 1) Coriolis stress, a strong stimulus that induces motion sickness in man; 2) heart rate responses to the fall in blood pressure induced by the application of graded lower body negative pressure; and 3) exercise-induced sweat secretion. In all of these paradigms of stress, subjective and objective evidence of increased autonomic responsiveness was found in those individuals harboring the 6.3-kb allele. Specifically, volunteers with the 6.3-kb allele had greater signs and symptoms of motion sickness mediated by the autonomic nervous system after off-axis rotation at increasing velocity (number of head movements a subject could complete during rotation before emesis +/- SE: 295 +/- 18 vs. 365 +/- 11; P = 0.001). They also had greater increases in heart rate in responses to the lower body negative pressure-induced fall in blood pressure (increase in heart rate +/- SE: 3.0 +/- 0.4 vs. 1.8 +/- 0.3; P = 0.012), and the 6.3-kb group had higher sweat sodium concentrations during exercise (mean sweat sodium concentration in meq/l over 30 min of exercise +/- SE: 43.2 +/- 7.1 vs. 27.6 +/- 3.4; P < 0.05). This single-nucleotide polymorphism may contribute to contrasting individual differences in autonomic responsiveness among healthy individuals.

Site(s) and ionic basis of α-autoinhibition and facilitation of [3H]noradrenaline secretion in guinea-pig vas deferens

PubMed Central

Alberts, P.; Bartfai, T.; Stjärne, L.

1981-01-01

1. Mechanisms controlling the secretion of [3H]noradrenaline from the noradrenergic nerves of guinea-pig isolated vas deferens, prelabelled by incubation with [3H]noradrenaline, were studied using (a) different modes of (extramural or transmural) electrical nerve stimulation (a total of 300 shocks of varying strength, and a duration of 2 msec) at 1-30 Hz, or (b) depolarizing concentrations of K+ (60-110 mm). 2. The fractional rise in efflux of 3H-labelled material (Δt) was used to measure the secretion of [3H]noradrenaline. 3. The dependence of [3H]noradrenaline secretion on the external Ca2+ concentration (1-8 mm) was essentially hyperbolic. Double reciprocal plot analysis (1/Δt vs. 1/Ca2+) of the data yields that blockade of α-autoinhibition (phentolamine 1 μm) does not increase the maximal secretory velocity, but does enhance the apparent affinity of the secretory mechanism for external Ca2+. Exogenous noradrenaline has (qualitatively) opposite effects. The interaction between α-autoinhibition and external Ca2+ thus shows a `competitive' pattern, indicating that restriction of the utilization of external Ca2+ is a major mechanism in α-autoinhibition of noradrenaline secretion, in this system. 4. Phenoxybenzamine (10 μm) and phentolamine (1 μm) increased the secretion of [3H]noradrenaline evoked by depolarization with K+ much less than that caused by electrical nerve stimulation (frequencies up to 10 Hz). Exogenous noradrenaline (1-5 μm) depressed the secretion evoked by both modes of stimulation. The results indicate that α-autoinhibition of [3H]noradrenaline secretion is mainly operative when the secretory stimulus requires conduction of nerve impulses between varicosities. 5. The frequency dependence of [3H]noradrenaline secretion was hyperbolic, both in the presence and in the absence of α-autoinhibition; at each frequency the secretion (Δt per shock) increased with the Ca2+ concentration in the medium (0·6-8 mm). Double reciprocal plot analysis (1/Δt vs. 1/frequency) of the data yields that the pattern of interaction between external Ca2+ and facilitation depends on the presence or absence of α-autoinhibition (phentolamine 1 μm); in the former case it is `non-competitive', in the latter `competitive'. Similar analysis of the effect of facilitation by increasing the length of stimulus trains (from 5 to 300 pulses) at a constant frequency (5 Hz), on the Ca2+ dependence of Δt (1/Δt vs. 1/Ca2+) in the absence of α-autoinhibition also yields that facilitation promotes utilization of external Ca2+. These results apparently imply that a rise in external Ca2+, in the presence of α-autoinhibition, augments the secretory response to electrical nerve stimulation mainly by promoting recruitment of active units (varicosities?), without markedly altering their `affinity' for facilitation. In the absence of autoinhibition (when all units are already recruited?), the results seem to imply that facilitation promotes depolarization-secretion coupling in each, by more efficient utilization of external Ca2+. 6. The pattern of interaction between α-autoinhibition and facilitation depends on the Ca2+ concentration in the medium. At or below the physiological level of Ca2+ in extracellular fluid (1·2 mm) it is `non-competitive', indicating that α-autoinhibition and facilitation act, at least in part, at separate targets under these conditions. At high (5·4 mm) external Ca2+ the pattern becomes almost purely `competitive', indicating that facilitation can, under suitable conditions, overcome all manifestations of α-autoinhibition. 7. The secretion evoked by electrical nerve stimulation (Δt per shock, at 1 or 10 Hz) increased with the strength of applied shocks, both when applied extra- or transmurally, in the presence or absence of α-autoinhibition. In the former case the rise in (Δt per shock) vs. (current strength) was hyperbolic, in the latter it followed a biphasic pattern. Double reciprocal plot analysis (1/Δt vs. 1/current) of the data yields a `non-competitive' pattern of interaction between facilitation or α-autoinhibition, and exogenous current, when stimulation was extramural. When it was transmural the pattern is `competitive'. The results seem to imply that hyperpolarization, or depolarization, of nerve terminals are major mechanisms whereby α-autoinhibition and facilitation, respectively, exert their effects on the secretory response to electrical nerve stimulation. 8. Neither activation of Na+, K+-ATPase, nor promotion of GCl appear to be critically involved in α-autoinhibition. Experiments with known blockers of GK (tetraethylammonium, 4-aminopyridine and Rb+) did not give support to the notion that promotion of K+ efflux is a mechanism whereby prejunctional α-adrenoceptors cause (hyperpolarization of nerve terminals and) autoinhibition of secretion. If α-autoinhibition does involve K+ channels in the nerve terminal membrane, then these must be different from the (voltage-sensitive) K+ channels blocked by the above mentioned inhibitors of K+ efflux. 9. The results are discussed in the context of a model that assumes that local control of noradrenaline secretion from noradrenergic nerves may be exerted both by control of invasion of terminals, and by control of depolarization—secretion coupling in each invaded varicosity. Under suitable conditions facilitation and α-autoinhibition may interact at both levels. It proposed that utilization of external Ca2+ plays a pivotal role for both, and that restriction of invasion of nerve terminal varicosities is the main effect of α-autoinhibition, while promotion of depolarization—secretion coupling is the main effect of facilitation, at physiological concentrations of Ca2+ in the medium. For the nerve the role of this dual control system is proposed to be to ensure `rotational' activation of varicosities, and for the effector cell of noradrenergic junctions, to increase the signal/noise ratio. PMID:6267264

T-Tubular Electrical Defects Contribute to Blunted β-Adrenergic Response in Heart Failure.

PubMed

Crocini, Claudia; Coppini, Raffaele; Ferrantini, Cecilia; Yan, Ping; Loew, Leslie M; Poggesi, Corrado; Cerbai, Elisabetta; Pavone, Francesco S; Sacconi, Leonardo

2016-09-03

Alterations of the β-adrenergic signalling, structural remodelling, and electrical failure of T-tubules are hallmarks of heart failure (HF). Here, we assess the effect of β-adrenoceptor activation on local Ca(2+) release in electrically coupled and uncoupled T-tubules in ventricular myocytes from HF rats. We employ an ultrafast random access multi-photon (RAMP) microscope to simultaneously record action potentials and Ca(2+) transients from multiple T-tubules in ventricular cardiomyocytes from a HF rat model of coronary ligation compared to sham-operated rats as a control. We confirmed that β-adrenergic stimulation increases the frequency of Ca(2+) sparks, reduces Ca(2+) transient variability, and hastens the decay of Ca(2+) transients: all these effects are similarly exerted by β-adrenergic stimulation in control and HF cardiomyocytes. Conversely, β-adrenergic stimulation in HF cells accelerates a Ca(2+) rise exclusively in the proximity of T-tubules that regularly conduct the action potential. The delayed Ca(2+) rise found at T-tubules that fail to conduct the action potential is instead not affected by β-adrenergic signalling. Taken together, these findings indicate that HF cells globally respond to β-adrenergic stimulation, except at T-tubules that fail to conduct action potentials, where the blunted effect of the β-adrenergic signalling may be directly caused by the lack of electrical activity.

Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation

PubMed Central

Baker, Candice N.; Gidus, Sarah A.; Price, George F.; Peoples, Jessica N. R.

2014-01-01

As development proceeds from the embryonic to fetal stages, cardiac energy demands increase substantially, and oxidative phosphorylation of ADP to ATP in mitochondria becomes vital. Relatively little, however, is known about the signaling mechanisms regulating the transition from anaerobic to aerobic metabolism that occurs during the embryonic period. The main objective of this study was to test the hypothesis that adrenergic hormones provide critical stimulation of energy metabolism during embryonic/fetal development. We examined ATP and ADP concentrations in mouse embryos lacking adrenergic hormones due to targeted disruption of the essential dopamine β-hydroxylase (Dbh) gene. Embryonic ATP concentrations decreased dramatically, whereas ADP concentrations rose such that the ATP/ADP ratio in the adrenergic-deficient group was nearly 50-fold less than that found in littermate controls by embryonic day 11.5. We also found that cardiac extracellular acidification and oxygen consumption rates were significantly decreased, and mitochondria were significantly larger and more branched in adrenergic-deficient hearts. Notably, however, the mitochondria were intact with well-formed cristae, and there was no significant difference observed in mitochondrial membrane potential. Maternal administration of the adrenergic receptor agonists isoproterenol or l-phenylephrine significantly ameliorated the decreases in ATP observed in Dbh−/− embryos, suggesting that α- and β-adrenergic receptors were effective modulators of ATP concentrations in mouse embryos in vivo. These data demonstrate that adrenergic hormones stimulate cardiac energy metabolism during a critical period of embryonic development. PMID:25516547

Bucindolol, a nonselective beta 1- and beta 2-adrenergic receptor antagonist, decreases beta-adrenergic receptor density in cultured embryonic chick cardiac myocyte membranes.

PubMed

Asano, K; Zisman, L S; Yoshikawa, T; Headley, V; Bristow, M R; Port, J D

2001-06-01

Bucindolol and carvedilol, nonselective beta1- and beta2-adrenergic receptor antagonists, have been widely used in clinical therapeutic trials of congestive heart failure. The aim of the current study was to investigate long-term effects of bucindolol or carvedilol on beta-adrenergic receptor protein and gene expression in cardiac myocytes. Embryonic chick cardiac myocytes were cultured and incubated with bucindolol (1 microM), carvedilol (1 microM), or norepinephrine (1 microM) for 24 h. 125I-iodocyanopindolol binding assays demonstrated that incubation with norepinephrine or bucindolol, but not carvedilol, significantly decreased beta-adrenergic receptor density in crude membranes prepared from the myocytes. Neither bucindolol nor carvedilol significantly stimulated adenylyl cyclase activity in membranes from drug-untreated cells. Unlike by norepinephrine, the receptor density reduction by bucindolol incubation was not accompanied by a change in beta1-adrenergic receptor messenger RNA abundance. A decrease in membrane beta-adrenergic receptor density without a change in cognate messenger RNA abundance was also observed in hamster DDT1 MF2 cell line incubated with bucindolol (1 microM, 24 h). We conclude that incubation with bucindolol, but not carvedilol, results in true reduction of beta-adrenergic receptor density in chick cardiac myocyte membranes by mechanisms that are distinct from those responsible for receptor density reduction by the agonist norepinephrine.

Dexmedetomidine (12.5 μg/mL) improves tissue distribution, anesthetic action, and hemodynamic effects of lidocaine after palatal infiltration in rats.

PubMed

Akimoto, Takuma; Hashimoto, Shuichi; Sunada, Katsuhisa

2016-09-01

Dexmedetomidine hydrochloride (DEX) is a α2-adrenergic receptor agonist that causes vasoconstriction by acting on α2B-adrenergic receptors in peripheral blood vessels. The authors aimed to determine the influence of DEX on tissue distribution, anesthetic action, and hemodynamic effects of lidocaine in rats. The investigators injected indigo carmine-containing (14)C-labeled lidocaine hydrochloride (2 %) without and with 3.1, 12.5, or 50 μg/mL DEX or 10 μg/mL epinephrine into the right palatal mucosa mesial to the maxillary first molar of specific pathogen-free male Wistar rats. Autoradiography and liquid scintillation counting were performed to evaluate (14)C-labeled lidocaine concentrations in the palatal mucosa, maxillary bone, maxillary nerve, and peripheral blood. Somatosensory-evoked potentials were measured to analyze anesthetic action, and blood pressure and pulse rate were measured to compare hemodynamic effects. DEX extended the tissue distribution of lidocaine in a concentration-dependent manner. Lidocaine with 12.5 μg/mL DEX had similar blood peak arrival time and peak-to-peak amplitude as lidocaine with 10 μg/mL epinephrine, but it reduced pulse rate. The results of this study suggest that 12.5 μg/mL DEX improves tissue distribution, anesthetic action, and hemodynamic effects of lidocaine in rats. Therefore, 12.5 μg/mL DEX may be a suitable alternative to epinephrine in lidocaine formulations, especially for patients with ischemic heart disease and hypertension.

LIMITED RECOVERY OF PINEAL FUNCTION AFTER REGENERATION OF PREGANGLIONIC SYMPATHETIC AXONS: EVIDENCE FOR LOSS OF GANGLIONIC SYNAPTIC SPECIFICITY

PubMed Central

Lingappa, Jaisri R.; Zigmond, Richard E.

2013-01-01

The cervical sympathetic trunks (CST) contain axons of preganglionic neurons that innervate the superior cervical ganglia (SCG). Since, regeneration of CST fibers can be extensive and can reestablish certain specific patterns of SCG connections, restoration of end organ function would be expected. This expectation was examined with respect to the pineal gland, an organ innervated by the two SCG. The activity of pineal serotonin N-acetyltransferase (NAT) exhibits a large circadian rhythm, with activity high at night, which is dependent on the gland’s sympathetic input. Thirty six hours after the CST were crushed bilaterally, nocturnal NAT was decreased by 99%. Three months later, enzyme activity had recovered only to 15% of control values, a recovery dependent on regeneration of CST fibers. Nevertheless, a small day-night rhythm was present in lesioned animals. Neither the density of the gland’s adrenergic innervation nor the ability of an adrenergic agonist to stimulate NAT activity was reduced in rats with regenerated CST. In addition, stimulation of the regenerated CST at a variety of frequencies was at least as effective in increasing NAT activity as seen with control nerves. These data suggest that the failure of pineal function to recover is not due to a quantitative deficit in the extent of reinnervation or in synaptic efficacy. Rather, we suggest that there is some loss of specificity in the synaptic connections made in the SCG during reinnervation, resulting in a loss of the central neuronal information necessary for directing a normal NAT rhythm and thus normal pineal function. PMID:23486957

Segmental arterial mediolysis--an iatrogenic vascular disorder induced by ractopamine.

PubMed

Slavin, Richard E; Yaeger, Micheal J

2012-01-01

Segmental arterial mediolysis, an uncommon arterial disorder most often occurring in the splanchnic muscular arteries of the abdomen, is a cause of catastrophic hemorrhages. Its histology and initial clinical presentations suggested that it represented a localized norepinephrine-induced vasospastic response to perturbations in vascular tone and blood volume distribution caused by coexisting vasoconstrictor conditions. However, later presentations were at odds with some aspects of this hypothesis. Nine greyhound dogs were administered a single dose of ractopamine. Two dogs developing persistent conduction abnormalities with biochemical evidence of heart injury were euthanized and necropsied--one 4 days and the other 17 days after dosage This report is based on findings and comparisons of the canine abdominal and coronary arteries to segmental arterial mediolysis. Lesions having features of early-injurious-stage segmental arterial mediolysis were identified in the canine arteries 4 days postractopamine, and arteries examined after 17 days showed alterations typically occurring in reparative-stage segmental arterial mediolysis. It is suspected that ractopamine, a Beta-2 adrenergic agonist, created segmental arterial mediolysis by neuromodulating the peripheral sympathetic nervous system to release norepinephrine from varicosities of efferent nerves serving splanchnic arteries that stimulate alpha-1 receptors to induce injury at the adventitial medial junction and medial muscle apoptosis. This finding and other cited examples suggest that segmental arterial mediolysis may be a disorder principally caused by iatrogenic or accidental exposure to alpha-1 adrenergic receptor agonists or Beta-2 agonists able to release norepinephrine from the peripheral nervous system. Copyright © 2012 Elsevier Inc. All rights reserved.

Side effects of cocaine abuse: multiorgan toxicity and pathological consequences.

PubMed

Riezzo, I; Fiore, C; De Carlo, D; Pascale, N; Neri, M; Turillazzi, E; Fineschi, V

2012-01-01

Cocaine is a powerful stimulant of the sympathetic nervous system by inhibiting catecholamine reuptake, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine (NE). It is known, from numerous studies, that cocaine causes irreversible structural changes on the brain, heart, lung and other organs such as liver and kidney and there are many mechanisms involved in the genesis of these damages. Some effects are determined by the overstimulation of the adrenergic system. Most of the direct toxic effects are mediated by oxidative stress and by mitochondrial dysfunction produced during the metabolism of noradrenaline or during the metabolism of norcocaina, as in cocaine-induced hepathotoxicity. Cocaine is responsible for the coronary arteries vasoconstriction, atherosclerotic phenomena and thrombus formation. In this way, cocaine favors the myocardial infarction. While the arrhythmogenic effect of cocaine is mediated by the action on potassium channel (blocking), calcium channels (enhances the function) and inhibiting the flow of sodium during depolarization. Moreover chronic cocaine use is associated with myocarditis, ventricular hypertrophy, dilated cardiomyopathy and heart failure. A variety of respiratory problems temporally associated with crack inhalation have been reported. Cocaine may cause changes in the respiratory tract as a result of its pharmacologic effects exerted either locally or systemically, its method of administration (smoking, sniffing, injecting), or its alteration of central nervous system neuroregulation of pulmonary function. Renal failure resulting from cocaine abuse has been also well documented. A lot of studies demonstrated a high incidence of congenital cardiovascular and brain malformations in offspring born to mothers with a history of cocaine abuse.

Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum.

PubMed

Lunardi, N; Oklopcic, A; Prillaman, M; Erisir, A; Jevtovic-Todorovic, V

2015-10-01

Exposure to general anesthesia (GA) during critical stages of brain development induces widespread neuronal apoptosis and causes long-lasting behavioral deficits in numerous animal species. Although several studies have focused on the morphological fate of neurons dying acutely by GA-induced developmental neuroapoptosis, the effects of an early exposure to GA on the surviving synapses remain unclear. The aim of this study is to study whether exposure to GA disrupts the fine regulation of the dynamic spatial organization and trafficking of synaptic vesicles in presynaptic terminals. We exposed postnatal day 7 (PND7) rat pups to a clinically relevant anesthetic combination of midazolam, nitrous oxide, and isoflurane and performed a detailed ultrastructural analysis of the synaptic vesicle architecture at presynaptic terminals in the subiculum of rats at PND 12. In addition to a significant decrease in the density of presynaptic vesicles, we observed a reduction of docked vesicles, as well as a reduction of vesicles located within 100 nm from the active zone, in animals 5 days after an initial exposure to GA. We also found that the synaptic vesicles of animals exposed to GA are located more distally with respect to the plasma membrane than those of sham control animals and that the distance between presynaptic vesicles is increased in GA-exposed animals compared to sham controls. We report that exposure of immature rats to GA during critical stages of brain development causes significant disruption of the strategic topography of presynaptic vesicles within the nerve terminals of the subiculum.

Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly.

PubMed

Rios, Jonathan J; Paria, Nandina; Burns, Dennis K; Israel, Bonnie A; Cornelia, Reuel; Wise, Carol A; Ezaki, Marybeth

2013-02-01

Macrodactyly is a discrete congenital anomaly consisting of enlargement of all tissues localized to the terminal portions of a limb, typically within a 'nerve territory'. The classic terminology for this condition is 'lipofibromatous hamartoma of nerve' or Type I macrodactyly. The peripheral nerve, itself, is enlarged both in circumference and in length. It is not related to neurofibromatosis (NF1), nor is it associated with vascular malformations, such as in the recently reported CLOVES syndrome. The specific nerve pathophysiology in this form of macrodactyly has not been well described and a genetic etiology for this specific form of enlargement is unknown. To identify the genetic cause of macrodactyly, we used whole-exome sequencing to identify somatic mutations present in the affected nerve of a single patient. We confirmed a novel mutation in PIK3CA (R115P) present in the patient's affected nerve tissue but not in blood DNA. Sequencing PIK3CA exons identified gain-of-function mutations (E542K, H1047L or H1047R) in the affected tissue of five additional unrelated patients; mutations were absent in blood DNA available from three patients. Immunocytochemistry confirmed AKT activation in cultured cells from the nerve of a macrodactyly patient. Additionally, we found that the most abnormal structure within the involved nerve in a macrodactylous digit is the perineurium, with additional secondary effects on the axon number and size. Thus, isolated congenital macrodactyly is caused by somatic activation of the PI3K/AKT cell-signaling pathway and is genetically and biochemically related to other overgrowth syndromes.

Distribution of CGRP and TRPV2 in Human Paranasal Sinuses.

PubMed

Sato, Tadasu; Sasahara, Nobuyuki; Kanda, Noriyuki; Sasaki, Yu; Yamaguma, Yu; Kokubun, Souichi; Yajima, Takehiro; Ichikawa, Hiroyuki

2017-01-01

Immunohistochemistry for protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP) and the transient receptor potential cation channel subfamily V member 2 (TRPV2) was performed on human paranasal sinuses. It was found that in the paranasal sinuses, mucous membranes contain PGP 9.5-immunoreactive (PGP 9.5-IR) nerve fibers. Such nerve fibers terminated around large blood vessels as fine varicosities. Isolated PGP 9.5-IR nerve fibers were scattered beneath the epithelium. Glandular tissues were also innervated by PGP 9.5-IR nerve fibers. These fibers were numerous in the maxillary and ethmoid sinuses, and relatively rare in the frontal and sphenoid sinuses. CGRP-IR nerve fibers were common in the maxillary sinus whereas TRPV2-IR nerve fibers were abundant in the ethmoid sinus. They were located around large blood vessels in the lamina propria. Many subepithelial nerve fibers contained TRPV2 immunoreactivity in the ethmoid sinus. CGRP- and TRPV2-IR nerve fibers were very infrequent in the frontal and sphenoid sinuses. In the human trigeminal ganglion (TG), sensory neurons contained CGRP or TRPV2 immunoreactivity. CGRP-IR TG neurons were more common than TRPV2-IR TG neurons. CGRP-IR TG neurons were of various cell body sizes, whereas TRPV2-IR TG neurons were mostly medium-to-large. In addition, human spinal and principal trigeminal sensory nuclei contained abundant CGRP- and TRPV2-IR varicosities. This study indicates that CGRP- and TRPV2-containing TG neurons probably innervate the paranasal sinus mucosae, and project into spinal and principal trigeminal sensory nuclei. © 2016 S. Karger AG, Basel.

Recruitment order of quadriceps motor units: femoral nerve vs. direct quadriceps stimulation.

PubMed

Rodriguez-Falces, Javier; Place, Nicolas

2013-12-01

To investigate potential differences in the recruitment order of motor units (MUs) in the quadriceps femoris when electrical stimulation is applied over the quadriceps belly versus the femoral nerve. M-waves and mechanical twitches were evoked using femoral nerve stimulation and direct quadriceps stimulation of gradually increasing intensity from 20 young, healthy subjects. Recruitment order was investigated by analysing the time-to-peak twitch and the time interval from the stimulus artefact to the M-wave positive peak (M-wave latency) for the vastus medialis (VM) and vastus lateralis (VL) muscles. During femoral nerve stimulation, time-to-peak twitch and M-wave latency decreased consistently (P < 0.05) with increasing stimulus intensity, whereas, during graded direct quadriceps stimulation, time-to-peak twitch and VL M-wave latency did not show a clear trend (P > 0.05). For the VM muscle, M-wave latency decreased with increasing stimulation level for both femoral nerve and direct quadriceps stimulation, whereas, for the VL muscle, the variation of M-wave latency with stimulus intensity was different for the two stimulation geometries (P < 0.05). Femoral nerve stimulation activated MUs according to the size principle, whereas the recruitment order during direct quadriceps stimulation was more complex, depending ultimately on the architecture of the peripheral nerve and its terminal branches below the stimulating electrodes for each muscle. For the VM, MUs were orderly recruited for both stimulation geometries, whereas, for the VL muscle, MUs were orderly recruited for femoral nerve stimulation, but followed no particular order for direct quadriceps stimulation.

ß-Adrenergic Stimulation Increases RyR2 Activity via Intracellular Ca2+ and Mg2+ Regulation

PubMed Central

Li, Jiao; Imtiaz, Mohammad S.; Beard, Nicole A.; Dulhunty, Angela F.; Thorne, Rick; vanHelden, Dirk F.; Laver, Derek R.

2013-01-01

Here we investigate how ß-adrenergic stimulation of the heart alters regulation of ryanodine receptors (RyRs) by intracellular Ca2+ and Mg2+ and the role of these changes in SR Ca2+ release. RyRs were isolated from rat hearts, perfused in a Langendorff apparatus for 5 min and subject to 1 min perfusion with 1 µM isoproterenol or without (control) and snap frozen in liquid N2 to capture their phosphorylation state. Western Blots show that RyR2 phosphorylation was increased by isoproterenol, confirming that RyR2 were subject to normal ß-adrenergic signaling. Under basal conditions, S2808 and S2814 had phosphorylation levels of 69% and 15%, respectively. These levels were increased to 83% and 60%, respectively, after 60 s of ß-adrenergic stimulation consistent with other reports that ß-adrenergic stimulation of the heart can phosphorylate RyRs at specific residues including S2808 and S2814 causing an increase in RyR activity. At cytoplasmic [Ca2+] <1 µM, ß-adrenergic stimulation increased luminal Ca2+ activation of single RyR channels, decreased luminal Mg2+ inhibition and decreased inhibition of RyRs by mM cytoplasmic Mg2+. At cytoplasmic [Ca2+] >1 µM, ß-adrenergic stimulation only decreased cytoplasmic Mg2+ and Ca2+ inhibition of RyRs. The Ka and maximum levels of cytoplasmic Ca2+ activation site were not affected by ß-adrenergic stimulation. Our RyR2 gating model was fitted to the single channel data. It predicted that in diastole, ß-adrenergic stimulation is mediated by 1) increasing the activating potency of Ca2+ binding to the luminal Ca2+ site and decreasing its affinity for luminal Mg2+ and 2) decreasing affinity of the low-affinity Ca2+/Mg2+ cytoplasmic inhibition site. However in systole, ß-adrenergic stimulation is mediated mainly by the latter. PMID:23533585

alpha1B-Adrenergic receptor phosphorylation and desensitization induced by transforming growth factor-beta.

PubMed Central

Romero-Avila, M Teresa; Flores-Jasso, C Fabián; García-Sáinz, J Adolfo

2002-01-01

Transforming growth factor-beta (TGF-beta) induced alpha(1B)-adrenergic receptor phosphorylation in Rat-1 fibroblasts stably expressing these adrenoceptors. This effect of TGF-beta was rapid, reaching a maximum within 30 min and decreasing thereafter, and concentration-dependent (EC(50) 0.3 pM). The phosphoinositide 3-kinase inhibitors wortmannin and LY294002, and the protein kinase C inhibitors staurosporine, Ro 318220 and bisindolylmaleimide, blocked the effect of this growth factor. alpha(1B)-Adrenergic receptor phosphorylation was associated with desensitization, as indicated by a reduction in the adrenergic-mediated production of [(3)H]inositol phosphates. Phosphorylation of alpha(1B)-adrenergic receptors by TGF-beta was also observed in Cos-1 cells transfected with the receptor. Co-transfection of the dominant-negative mutant of the regulatory subunit of phosphoinositide 3-kinase (Deltap85) inhibited the phosphorylation of alpha(1B)-adrenergic receptors induced by TGF-beta. Our results indicate that activation of TGF-beta receptors induces alpha(1B)-adrenergic receptor phosphorylation and desensitization. The data suggest that phosphoinositide 3-kinase and protein kinase C play key roles in this effect of TGF-beta. PMID:12234252

alpha1B-Adrenergic receptor phosphorylation and desensitization induced by transforming growth factor-beta.

PubMed

Romero-Avila, M Teresa; Flores-Jasso, C Fabián; García-Sáinz, J Adolfo

2002-12-01

Transforming growth factor-beta (TGF-beta) induced alpha(1B)-adrenergic receptor phosphorylation in Rat-1 fibroblasts stably expressing these adrenoceptors. This effect of TGF-beta was rapid, reaching a maximum within 30 min and decreasing thereafter, and concentration-dependent (EC(50) 0.3 pM). The phosphoinositide 3-kinase inhibitors wortmannin and LY294002, and the protein kinase C inhibitors staurosporine, Ro 318220 and bisindolylmaleimide, blocked the effect of this growth factor. alpha(1B)-Adrenergic receptor phosphorylation was associated with desensitization, as indicated by a reduction in the adrenergic-mediated production of [(3)H]inositol phosphates. Phosphorylation of alpha(1B)-adrenergic receptors by TGF-beta was also observed in Cos-1 cells transfected with the receptor. Co-transfection of the dominant-negative mutant of the regulatory subunit of phosphoinositide 3-kinase (Deltap85) inhibited the phosphorylation of alpha(1B)-adrenergic receptors induced by TGF-beta. Our results indicate that activation of TGF-beta receptors induces alpha(1B)-adrenergic receptor phosphorylation and desensitization. The data suggest that phosphoinositide 3-kinase and protein kinase C play key roles in this effect of TGF-beta.

The course of the superficial peroneal nerve in relation to the ankle position: anatomical study with ankle arthroscopic implications

PubMed Central

Golanó, Pau; Sierevelt, Inger N.; van Dijk, C. Niek

2010-01-01

Despite the fact that the superficial peroneal nerve is the only nerve in the human body that can be made visible; iatrogenic damage to this nerve is the most frequently reported complication in anterior ankle arthroscopy. One of the methods to visualize the nerve is combined ankle plantar flexion and inversion. In the majority of cases, the superficial peroneal nerve can be made visible. The portals for anterior ankle arthroscopy are however created with the ankle in the neutral or slightly dorsiflexed position and not in combined plantar flexion and inversion. The purpose of this study was to undertake an anatomical study to the course of the superficial peroneal nerve in different positions of the foot and ankle. We hypothesize that the anatomical localization of the superficial peroneal nerve changes with different foot and ankle positions. In ten fresh frozen ankle specimens, a window, only affecting the skin, was made at the level of the anterolateral portal for anterior ankle arthroscopy in order to directly visualize the superficial peroneal nerve, or if divided, its terminal branches. Nerve movement was assessed from combined 10° plantar flexion and inversion to 5° dorsiflexion, standardized by the Telos stress device. Also for the 4th toe flexion, flexion of all the toes and for skin tensioning possible nerve movement was determined. The mean superficial peroneal nerve movement was 2.4 mm to the lateral side when the ankle was moved from 10° plantar flexion and inversion to the neutral ankle position and 3.6 mm to the lateral side from 10° plantar flexion and inversion to 5° dorsiflexion. Both displacements were significant (P < 0.01). The nerve consistently moves lateral when the ankle is manoeuvred from combined plantar flexion and inversion to the neutral or dorsiflexed position. If visible, it is therefore advised to create the anterolateral portal medial from the preoperative marking, in order to prevent iatrogenic damage to the superficial peroneal nerve. PMID:20224993

β Subunits Control the Effects of Human Kv4.3 Potassium Channel Phosphorylation.

PubMed

Abbott, Geoffrey W

2017-01-01

The transient outward K + current, I to , activates early in the cardiac myocyte action potential, to begin repolarization. Human I to is generated primarily by two Kv4.3 potassium channel α subunit splice variants (Kv4.3L and Kv4.3S) that diverge only by a C-terminal, membrane-proximal, 19-residue stretch unique to Kv4.3L. Protein kinase C (PKC) phosphorylation of threonine 504 within the Kv4.3L-specific 19-residues mediates α-adrenergic inhibition of I to in human heart. Kv4.3 is regulated in human heart by various β subunits, including cytosolic KChIP2b and transmembrane KCNEs, yet their impact on the functional effects of human Kv4.3 phosphorylation has not been reported. Here, this gap in knowledge was addressed using human Kv4.3 splice variants, T504 mutants, and human β subunits. Subunits were co-expressed in Xenopus laevis oocytes and analyzed by two-electrode voltage-clamp, using phorbol 12-myristate 13-acetate (PMA) to stimulate PKC. Unexpectedly, KChIP2b removed the inhibitory effect of PKC on Kv4.3L (but not Kv4.3L threonine phosphorylation by PKC per-se ), while co-expression with KCNE2, but not KCNE4, restored PKC-dependent inhibition of Kv4.3L-KChIP2b to quantitatively resemble previously reported effects of α-adrenergic modulation of human ventricular I to . In addition, PKC accelerated recovery from inactivation of Kv4.3L-KChIP2b channels and, interestingly, of both Kv4.3L and Kv4.3S alone. Thus, β subunits regulate the response of human Kv4.3 to PKC phosphorylation and provide a potential mechanism for modifying the response of I to to α-adrenergic regulation in vivo .

β Subunits Control the Effects of Human Kv4.3 Potassium Channel Phosphorylation

PubMed Central

Abbott, Geoffrey W.

2017-01-01

The transient outward K+ current, Ito, activates early in the cardiac myocyte action potential, to begin repolarization. Human Ito is generated primarily by two Kv4.3 potassium channel α subunit splice variants (Kv4.3L and Kv4.3S) that diverge only by a C-terminal, membrane-proximal, 19-residue stretch unique to Kv4.3L. Protein kinase C (PKC) phosphorylation of threonine 504 within the Kv4.3L-specific 19-residues mediates α-adrenergic inhibition of Ito in human heart. Kv4.3 is regulated in human heart by various β subunits, including cytosolic KChIP2b and transmembrane KCNEs, yet their impact on the functional effects of human Kv4.3 phosphorylation has not been reported. Here, this gap in knowledge was addressed using human Kv4.3 splice variants, T504 mutants, and human β subunits. Subunits were co-expressed in Xenopus laevis oocytes and analyzed by two-electrode voltage-clamp, using phorbol 12-myristate 13-acetate (PMA) to stimulate PKC. Unexpectedly, KChIP2b removed the inhibitory effect of PKC on Kv4.3L (but not Kv4.3L threonine phosphorylation by PKC per-se), while co-expression with KCNE2, but not KCNE4, restored PKC-dependent inhibition of Kv4.3L-KChIP2b to quantitatively resemble previously reported effects of α-adrenergic modulation of human ventricular Ito. In addition, PKC accelerated recovery from inactivation of Kv4.3L-KChIP2b channels and, interestingly, of both Kv4.3L and Kv4.3S alone. Thus, β subunits regulate the response of human Kv4.3 to PKC phosphorylation and provide a potential mechanism for modifying the response of Ito to α-adrenergic regulation in vivo. PMID:28919864

Src family kinases mediate the inhibition of substance P release in the rat spinal cord by μ-opioid receptors and GABA(B) receptors, but not α2 adrenergic receptors.

PubMed

Zhang, Guohua; Chen, Wenling; Marvizón, Juan Carlos G

2010-09-01

GABA(B) , μ-opioid and adrenergic α(2) receptors inhibit substance P release from primary afferent terminals in the dorsal horn. Studies in cell expression systems suggest that μ-opioid and GABA(B) receptors inhibit transmitter release from primary afferents by activating Src family kinases (SFKs), which then phosphorylate and inhibit voltage-gated calcium channels. This study investigated whether SFKs mediate the inhibition of substance P release by these three receptors. Substance P release was measured as neurokinin 1 receptor (NK1R) internalization in spinal cord slices and in vivo. In slices, NK1R internalization induced by high-frequency dorsal root stimulation was inhibited by the μ-opioid agonist DAMGO and the GABA(B) agonist baclofen. This inhibition was reversed by the SFK inhibitor PP1. NK1R internalization induced by low-frequency stimulation was also inhibited by DAMGO, but PP1 did not reverse this effect. In vivo, NK1R internalization induced by noxious mechanical stimulation of the hind paw was inhibited by intrathecal DAMGO and baclofen. This inhibition was reversed by intrathecal PP1, but not by the inactive PP1 analog PP3. PP1 produced no effect by itself. The α(2) adrenergic agonists medetomidine and guanfacine produced a small but statistically significant inhibition of NK1R internalization induced by low-frequency dorsal root stimulation. PP1 did not reverse the inhibition by guanfacine. These results show that SFKs mediate the inhibition of substance P release by μ-opioid and GABA(B) receptors, but not by α(2) receptors, which is probably mediated by the binding of G protein βγ subunits to calcium channels. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd. No claim to original US government works.

Bayesian analysis of the kinetics of quantal transmitter secretion at the neuromuscular junction.

PubMed

Saveliev, Anatoly; Khuzakhmetova, Venera; Samigullin, Dmitry; Skorinkin, Andrey; Kovyazina, Irina; Nikolsky, Eugeny; Bukharaeva, Ellya

2015-10-01

The timing of transmitter release from nerve endings is considered nowadays as one of the factors determining the plasticity and efficacy of synaptic transmission. In the neuromuscular junction, the moments of release of individual acetylcholine quanta are related to the synaptic delays of uniquantal endplate currents recorded under conditions of lowered extracellular calcium. Using Bayesian modelling, we performed a statistical analysis of synaptic delays in mouse neuromuscular junction with different patterns of rhythmic nerve stimulation and when the entry of calcium ions into the nerve terminal was modified. We have obtained a statistical model of the release timing which is represented as the summation of two independent statistical distributions. The first of these is the exponentially modified Gaussian distribution. The mixture of normal and exponential components in this distribution can be interpreted as a two-stage mechanism of early and late periods of phasic synchronous secretion. The parameters of this distribution depend on both the stimulation frequency of the motor nerve and the calcium ions' entry conditions. The second distribution was modelled as quasi-uniform, with parameters independent of nerve stimulation frequency and calcium entry. Two different probability density functions for the distribution of synaptic delays suggest at least two independent processes controlling the time course of secretion, one of them potentially involving two stages. The relative contribution of these processes to the total number of mediator quanta released depends differently on the motor nerve stimulation pattern and on calcium ion entry into nerve endings.

Synthesis and pharmacological characterization of beta2-adrenergic agonist enantiomers: zilpaterol.

PubMed

Kern, Christopher; Meyer, Thorsten; Droux, Serge; Schollmeyer, Dieter; Miculka, Christian

2009-03-26

The beta-adrenergic agonist 1 (zilpaterol) is used as production enhancer in cattle. Binding experiments of separated enantiomers on recombinant human beta(2)-adrenergic and mu-opioid receptors and functional studies showed that the (-)-1 enantiomer accounts for essentially all the beta(2)-adrenergic agonist activity and that it exhibits less affinity toward the mu-opioid receptor than (+)-1, which is a mu-opioid receptor antagonist. X-ray crystallography revealed the absolute configuration of (-)-1 to be 6R,7R.

Bardoxolone Methyl Prevents Fat Deposition and Inflammation in Brown Adipose Tissue and Enhances Sympathetic Activity in Mice Fed a High-Fat Diet

PubMed Central

Dinh, Chi H. L.; Szabo, Alexander; Yu, Yinghua; Camer, Danielle; Zhang, Qingsheng; Wang, Hongqin; Huang, Xu-Feng

2015-01-01

Obesity results in changes in brown adipose tissue (BAT) morphology, leading to fat deposition, inflammation, and alterations in sympathetic nerve activity. Bardoxolone methyl (BARD) has been extensively studied for the treatment of chronic diseases. We present for the first time the effects of oral BARD treatment on BAT morphology and associated changes in the brainstem. Three groups (n = 7) of C57BL/6J mice were fed either a high-fat diet (HFD), a high-fat diet supplemented with BARD (HFD/BARD), or a low-fat diet (LFD) for 21 weeks. BARD was administered daily in drinking water. Interscapular BAT, and ventrolateral medulla (VLM) and dorsal vagal complex (DVC) in the brainstem, were collected for analysis by histology, immunohistochemistry and Western blot. BARD prevented fat deposition in BAT, demonstrated by the decreased accumulation of lipid droplets. When administered BARD, HFD mice had lower numbers of F4/80 and CD11c macrophages in the BAT with an increased proportion of CD206 macrophages, suggesting an anti-inflammatory effect. BARD increased phosphorylation of tyrosine hydroxylase in BAT and VLM. In the VLM, BARD increased energy expenditure proteins, including beta 3-adrenergic receptor (β3-AR) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Overall, oral BARD prevented fat deposition and inflammation in BAT, and stimulated sympathetic nerve activity. PMID:26066016

Bardoxolone Methyl Prevents Fat Deposition and Inflammation in Brown Adipose Tissue and Enhances Sympathetic Activity in Mice Fed a High-Fat Diet.

PubMed

Dinh, Chi H L; Szabo, Alexander; Yu, Yinghua; Camer, Danielle; Zhang, Qingsheng; Wang, Hongqin; Huang, Xu-Feng

2015-06-09

Obesity results in changes in brown adipose tissue (BAT) morphology, leading to fat deposition, inflammation, and alterations in sympathetic nerve activity. Bardoxolone methyl (BARD) has been extensively studied for the treatment of chronic diseases. We present for the first time the effects of oral BARD treatment on BAT morphology and associated changes in the brainstem. Three groups (n = 7) of C57BL/6J mice were fed either a high-fat diet (HFD), a high-fat diet supplemented with BARD (HFD/BARD), or a low-fat diet (LFD) for 21 weeks. BARD was administered daily in drinking water. Interscapular BAT, and ventrolateral medulla (VLM) and dorsal vagal complex (DVC) in the brainstem, were collected for analysis by histology, immunohistochemistry and Western blot. BARD prevented fat deposition in BAT, demonstrated by the decreased accumulation of lipid droplets. When administered BARD, HFD mice had lower numbers of F4/80 and CD11c macrophages in the BAT with an increased proportion of CD206 macrophages, suggesting an anti-inflammatory effect. BARD increased phosphorylation of tyrosine hydroxylase in BAT and VLM. In the VLM, BARD increased energy expenditure proteins, including beta 3-adrenergic receptor (β3-AR) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Overall, oral BARD prevented fat deposition and inflammation in BAT, and stimulated sympathetic nerve activity.

Reflex respiratory and cardiovascular effects of stimulation of receptors in the nose of the dog.

PubMed

James, J E; De Burgh Daly, M

1972-02-01

1. In forty-one out of forty-seven dogs under chloralose-urethane or Nembutal anaesthesia, mechanical stimulation of the nasal mucous membrane caused a reduction or inhibition of respiration, bradycardia, variable changes of arterial blood pressure, and a small rise in venous pressure.2. Simultaneous measurements of arterial and venous pressures, and also of blood flow in various arteries by means of an electromagnetic flowmeter indicate that the calculated vascular resistance increases in the intact limb, muscle, and skin, and the vascular beds of the vertebral, superior mesenteric, renal and splenic arteries. No changes in vascular resistance occur in the common carotid circulation.3. Evidence is presented that the increase in vascular resistance is due to vasoconstriction, and occurs in the absence of changes in pulmonary ventilation.4. Stimulation of the nasal mucous membrane causes a reduction in volume of the spleen.5. The respiratory and cardiovascular responses are reflex in nature, being abolished by the application of a local anaesthetic to the nose or by combined division of the maxillary and ethmoidal branches of the trigeminal nerves. The cardiac response is mediated largely by the vagus nerves, and the vascular responses by sympathetic adrenergic fibres.6. Cessation of the stimulus to the nose not infrequently results in the following temporary after-effects: hyperventilation, tachycardia, hypertension, and vasodilatation in the intact limb and in muscle.

Effects of sympathetic nerve stimulation on long posterior ciliary artery blood flow in cats.

PubMed

Koss, Michael C

2002-04-01

A new technique using ultrasonic flowmetry was developed in order to directly measure blood flow in the long posterior ciliary artery (LPCA) of anesthetized cats. Basal LPCA blood flow averaged about 0.6 ml/min and was stable over the experimental period. Electrical stimulation of the cervical preganglionic cervical sympathetic nerve produced frequency-dependent anterior segment ocular vasoconstrictor responses. Ipsilateral nictitating membrane contractions were simultaneously measured as a well-established index of neural sympathetic activation. LPCA frequency-response relationships were shifted to the right in comparison with those for the nictitating membrane. When elicited at two min intervals, submaximal evoked responses of both systems were stable for more than 90 min. Ocular vasoconstrictor and nictitating membrane responses were blocked in a dose-dependent fashion by intravenous treatment with the non-selective a-adrenoceptor antagonist, phentolamine (0.3-3.0 mg/kg), as well as with the selective alpha1-adrenoceptor antagonist, prazosin (3-30 microg/kg). In contrast, neither evoked response was further antagonized by subsequent administration of the alpha2-adrenoceptor antagonist, yohimbine (500 microg/kg). These results demonstrate the usefulness of ultrasonic flowmetry to study mechanisms controlling ocular anterior segment circulation and suggest that, as previously established for the nictitating membrane and anterior choroid, adrenergic neurogenic vasoconstriction in tissues perfused by the LPCA is mediated predominantly by alpha1-adrenoceptors.

Pharmaco-mechanical coupling in the response to acetylcholine and substance P in the smooth muscle of the rat iris sphincter.

PubMed Central

Banno, H.; Imaizumi, Y.; Watanabe, M.

1985-01-01

In the rat iris sphincter muscle contractile responses to transmural stimulation consisted of two components, a fast cholinergic followed by a slow non-adrenergic, non-cholinergic (NANC) one. The magnitude of the latter varied widely and was on average 5% of that of the cholinergic component. Exogenous substance P (1 nM-1 microM) produced a concentration-dependent contraction, the maximum amplitude of which was as large as that produced by acetylcholine (ACh). Capsaicin (10 microM) induced a transient contraction only once in each preparation. After the treatment with capsaicin the NANC component disappeared. Neither nerve nor direct electrical stimulation with short pulses elicited any active change in the membrane potential under physiological conditions, but an action potential was triggered by direct stimulation when the extracellular Ca ion was totally replaced by Ba ion. Under the latter conditions spontaneous spike potentials occurred repetitively. ACh and substance P produced a large contraction without modifying the membrane potential. This was also the case in the presence of 5 mM Ba. These results suggest that substance P-ergic innervation may have a far lesser physiological significance than that which has been described in rabbits and that pure pharmaco-mechanical coupling is characteristic of the responses to acetylcholine, substance P, and nerve stimulation in the rat iris sphincter muscle. PMID:2412624

Central alpha/sub 2/ adrenergic receptors in the rat cerebral cortex: repopulation kinetics and receptor reserve

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adler, C.H.

1986-01-01

The alpha/sub 2/ adrenergic receptor subtype is thought to play a role in the mechanism of action of antidepressant and antihypertensive drugs. This thesis has attempted to shed light on the regulation of central alpha/sub 2/ adrenergic receptors in the rat cerebral cortex. Repopulation kinetics analysis allows for the determination of the rate of receptor production, rate constant of degradation, and half-life of the receptor. This analysis was carried out using both radioligand binding and functional receptor assays at various times following the irreversible inactivation of central alpha/sub 2/ adrenergic receptors by in vivo administration of N-ethoxycarbonyl-2-ethyoxy-1,2-dihydroquinoline (EEDQ). Both alpha/submore » 2/ agonist and antagonist ligand binding sites recovered with a t/sub 1/2/ equal to approximately 4 days. The function of alpha/sub 2/ adrenergic autoreceptors, which inhibit stimulation-evoked release of /sup 3/H-norepinephrine (/sup 3/H-NE) and alpha/sub 2/ adrenergic heteroreceptors which inhibit stimulation-evoked release of /sup 3/H-serotonin (/sup 3/H-5-HT) were assayed. The t/sub 1/2/ for recovery of maximal autoreceptor and heteroreceptor function was 2.4 days and 4.6 days, respectively. The demonstration of a receptor reserve is critical to the interpretation of past and future studies of the alpha/sub 2/ adrenergic receptor since it demonstrates that: (1) alterations in the number of alpha/sub 2/ adrenergic receptor binding sites cannot be extrapolated to the actual function of the alpha/sub 2/ adrenergic receptor; and (2) alterations in the number of alpha/sub 2/ receptors is not necessarily accompanied by a change in the maximum function being studied, but may only result in shifting of the dose-response curve.« less

Platelet alpha 2-adrenergic receptors in major depressive disorder. Binding of tritiated clonidine before and after tricyclic antidepressant drug treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garcia-Sevilla, J.A.; Zis, A.P.; Hollingsworth, P.J.

1981-12-01

The specific binding of tritiated (3H)-clonidine, an alpha 2-adrenergic receptor agonist, to platelet membranes was measured in normal subjects and in patients with major depressive disorder. The number of platelet alpha 2-adrenergic receptors from the depressed group was significantly higher than that found in platelets obtained from the control population. Treatment with tricyclic antidepressant drugs led to significant decreases in the number of platelet alpha 2-adrenergic receptors. These results support the hypothesis that the depressive syndrome is related to an alpha 2-adrenergic receptor supersensitivity and that the clinical effectiveness of tricyclic antidepressant drugs is associated with a decrease in themore » number of these receptors.« less

Do receptors get pregnant too? Adrenergic receptor alterations in human pregnancy.

PubMed

Smiley, R M; Finster, M

1996-01-01

In this review we discuss adrenergic receptor number and function during pregnancy, with emphasis on evidence that pregnancy results in specific receptor alterations from the nonpregnant state. Changes in adrenergic receptor function or distribution in vascular smooth muscle may be in part responsible for the decreased vascular responsiveness seen in human pregnancy, and the lack of the normal alterations may be a part of the syndromes of gestational hypertension, including preeclampsia-eclampsia. The onset of labor may be influenced by adrenergic modulation, and receptor or postreceptor level molecular alterations may trigger or facilitate normal or preterm labor. Human studies are emphasized when possible to assess the role of adrenergic signal transduction regulation in the physiology and pathophysiology of normal and complicated human pregnancy.

Surgical anatomy of the hypoglossal nerve: A new classification system for selective upper airway stimulation.

PubMed

Heiser, Clemens; Knopf, Andreas; Hofauer, Benedikt

2017-12-01

Selective upper airway stimulation (UAS) has shown effectiveness in treating patients with obstructive sleep apnea (OSA). The terminating branches of the hypoglossal nerve show a wide complexity, requiring careful discernment of a functional breakpoint between branches for inclusion and exclusion from the stimulation cuff electrode. The purpose of this study was to describe and categorize the topographic phenotypes of these branches. Thirty patients who received an implant with selective UAS from July 2015 to June 2016 were included. All implantations were recorded using a microscope and resultant tongue motions were captured perioperatively for comparison. Eight different variations of the branches were encountered and described, both in a tabular numeric fashion and in pictorial schema. The examinations showed the complex phenotypic surgical anatomy of the hypoglossal nerve. A schematic classification system has been developed to help surgeons identify the optimal location for cuff placement in UAS. © 2017 Wiley Periodicals, Inc.

Nitric oxide synthase and cyclooxygenase modulate β-adrenergic cutaneous vasodilatation and sweating in young men.

PubMed

Fujii, Naoto; McNeely, Brendan D; Kenny, Glen P

2017-02-15

β-Adrenergic receptor agonists such as isoproterenol induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. Using intradermal microdialysis, we evaluated the roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in β-adrenergic cutaneous vasodilatation and sweating elicited by administration of isoproterenol. We show that while NOS contributes to β-adrenergic cutaneous vasodilatation, COX restricts cutaneous vasodilatation. We also show that combined inhibition of NOS and COX augments β-adrenergic sweating These new findings advance our basic knowledge regarding the physiological control of cutaneous blood flow and sweating, and provide important and new information to better understand the physiological significance of β-adrenergic receptors in the skin. β-Adrenergic receptor agonists such as isoproterenol can induce cutaneous vasodilatation and sweating in humans, but the mechanisms underpinning this response remain unresolved. We evaluated the hypotheses that (1) nitric oxide synthase (NOS) contributes to β-adrenergic cutaneous vasodilatation, whereas cyclooxygenase (COX) limits the vasodilatation, and (2) COX contributes to β-adrenergic sweating. In 10 young males (25 ± 5 years), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites infused with (1) lactated Ringer solution (control), (2) 10 mm N ω -nitro-l-arginine (l-NNA), a non-specific NOS inhibitor, (3) 10 mm ketorolac, a non-specific COX inhibitor, or (4) a combination of l-NNA and ketorolac. All sites were co-administered with a high dose of isoproterenol (100 μm) for 3 min to maximally induce β-adrenergic sweating (β-adrenergic sweating is significantly blunted by subsequent activations). Approximately 60 min after the washout period, three incremental doses of isoproterenol were co-administered (1, 10 and 100 μm each for 25 min). Increases in CVC induced by the first and second 100 μm isoproterenol were attenuated by l-NNA alone, and those in response to all doses of isoproterenol were reduced by l-NNA with co-infusion of ketorolac (all P ≤ 0.05). Ketorolac alone augmented increases in CVC induced by 10 μm and by the second 100 μm isoproterenol (both P ≤ 0.05). While isoproterenol-induced sweating was not affected by the separate administration of l-NNA or ketorolac (all P > 0.05), their combined administration augmented sweating elicited by the first 3 min of 100 μm isoproterenol (P = 0.05). We show that while NOS contributes to β-adrenergic cutaneous vasodilatation, COX restrains the vasodilatation. Finally, combined inhibition of NOS and COX augments β-adrenergic sweating. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Extra- and intramuscular nerve supply of the muscles of the anterior antebrachial compartment: applications for selective neurotomy and for botulinum toxin injection.

PubMed

Lepage, D; Parratte, B; Tatu, L; Vuiller, F; Monnier, G

2005-12-01

Hypertonia of the upper limb due to spasticity causes pronation of the forearm and flexion of wrist and fingers. Nowadays this spasticity is often treated with injections of botulinum toxin and sometimes with selective fascicular neurotomy. To correctly perform this microsurgical technique, it is necessary to get precise knowledge of the extramuscular nerve branching in order to be better able to select the motor branches which supply the muscles involved in spasticity. The same knowledge is required for botulinum toxin injections which must be made as near as possible to the zones where intramuscular nerve endings are the densest, which is also where neuromuscular junctions are the most numerous. Thus, it is necessary to better know these zones, but their knowledge remains today imprecise. The muscles of the anterior compartment of 30 forearms were dissected, first macroscopically, then microscopically, to study the extra- and intramuscular nerve supply and the distribution of terminal nerve ramifications. The results were then linked to surface topographical landmarks to indicate the precise location of motor branches for each muscle with the aim of proposing appropriate surgical approaches for selective neurotomies. Then for each muscle, the zones with the highest density of nerve endings were divided into segments, thus determining the optimal zones for botulinim toxin injections.

Capsaicin modulates acetylcholine release at the myoneural junction.

PubMed

Thyagarajan, Baskaran; Potian, Joseph G; Baskaran, Padmamalini; McArdle, Joseph J

2014-12-05

Transient receptor potential (TRP) proteins are non-selective cation channel proteins that are expressed throughout the body. Previous studies demonstrated the expression of TRP Vanilloid 1 (TRPV1), capsaicin (CAP) receptor, in sensory neurons. Recently, we reported TRPV1 expression in mouse motor nerve terminals [MNTs; (Thyagarajan et al., 2009)], where we observed that CAP protected MNTs from botulinum neurotoxin A (BoNT/A). Phrenic nerve diaphragm nerve muscle preparations (NMP) isolated from isoflurane anesthetized adult mice were analyzed for twitch tension, spontaneous (mEPCs) and nerve stimulus evoked (EPCs) acetylcholine release. When acutely applied to isolated NMP, CAP produced a concentration-dependent decline of twitch tension and produced a significant decline in the amplitude of EPCs and quantal content without any effect on the mEPCs. The suppression of nerve stimulus evoked acetylcholine release by CAP was antagonized by capsazepine (CPZ), a TRPV1 antagonist. CAP did not suppress phrenic nerve stimulus evoked acetylcholine release in TRPV1 knockout mice. Also, CAP treatment, in vitro, interfered with the localization of adapter protein 2 in cholinergic Neuro 2a cells. Wortmannin, (WMN; non-selective phosphoinositol kinase inhibitor), mimicked the effects of CAP by inhibiting the acetylcholine exocytosis. Our data suggest that TRPV1 proteins expressed at the MNT are coupled to the exo-endocytic mechanisms to regulate neuromuscular functions. Copyright © 2014 Elsevier B.V. All rights reserved.

[Clinical and electrophysiological findings in carpal tunnel syndrome].

PubMed

Kohara, Nobuo

2007-11-01

Carpal tunnel syndrome (CTS) is the most common nerve entrapment disorder. The clinical features of CTS are variable, but usually include pain and paresthesia in the thumb, first two fingers, and the radial-half of the ring finger. Paresthesia and sensory deficits might involve the entire palm area in some cases. Pain frequently radiate proximally into the forearm, and occasionally to the shoulder. Many patients experience pain at night and are awakened by abnormal sensations. Shaking hand relief the symptom. The two classic tests for nerve compression at the wrist are the Tinel test and the Phalen maneuver, which diagnostic value is limited. Golden standard for the diagnosis is the combination of the clinical findings and the electrophysiological study. Routine median nerve conduction study is valuable. Prolonged terminal latency of motor or sensory nerve would be found in most CTS hands. If the routine study showed equivocal, more sensitive methods are needed. Those include segmental sensory conduction study across the carpal tunnel by median stimulation at midpalm, a comparison of median and ulnar sensory nerve latencies at ring finger and a comparison of median and radial sensory nerve latencies at thumb. A difference between the median motor latency to the second lumbrical and the ulnar motor latency to the interossei muscles has also diagnostic value in some cases. In addition, inching method can localized the compression site. Using these techniques, the diagnosis of CTS would become more reliable.

Interleukin 13 and the beta-adrenergic blockade theory of asthma revisited 40 years later.

PubMed

Townley, Robert G

2007-09-01

Beta2-Adrenergic agonists are the most potent agents clinically used in inhibiting and preventing the immediate response to bronchoconstricting agents and in inhibiting mast cell mediator release. This raises the possibility that an abnormality in beta-adrenergic receptor function or circulating catecholamine levels could contribute to airway hyperresponsiveness. To link interleukin 13 (IL-13) to the pathogenesis of asthma. Almost 4 decades ago, Andor Szentivanyi published a beta-adrenergic theory of atopic abnormality in bronchial asthma. He proposed 9 characteristics to define bronchial asthma. Because he published these 9 tenets of the beta-adrenergic blockade theory of asthma in 1968, it is appropriate and important to evaluate their relevance in light of advances in pharmacology, inflammation, and immunology. We describe the effects of the allergic reaction on beta-adrenergic responses and airway responsiveness. Both IL-1beta and tumor necrosis factor a have been detected in increased amounts in bronchial lavage fluids in allergic airway inflammation. Both IL-13 and the proinflammatory cytokines IL-1beta and tumor necrosis factor a have been demonstrated in airway smooth muscle to cause a decreased relaxation response to beta-adrenergic agonist. However, IL-13 has been shown to be necessary and sufficient to produce the characteristics of asthma. The decreased adrenergic bronchodilator activity and associated hypersensitivity to mediators put forth by Szentivanyi can be elicited with IL-13 and support its role in the pathogenesis of asthma.

Safety and efficacy of silodosin for the treatment of benign prostatic hyperplasia

PubMed Central

Yoshida, Masaki; Kudoh, Junzo; Homma, Yukio; Kawabe, Kazuki

2011-01-01

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are highly prevalent in older men. Medical therapy is the first-line treatment for LUTS associated with BPH. Mainstays in the treatment of male LUTS and clinical BPH are the α1-adrenergic receptor antagonists. Silodosin is a new α1-adrenergic receptor antagonist that is selective for the α1A-adrenergic receptor. By antagonizing α1A-adrenergic receptors in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. Since silodosin has greater affinity for the α1A-adrenergic receptor than for the α1B-adrenergic receptor, it minimizes the propensity for blood pressure-related adverse effects caused by α1B-adrenergic receptor blockade. In the clinical studies, patients receiving silodosin at a total daily dose of 8 mg exhibited significant improvements in the International Prostate Symptom Score and maximum urinary flow rate compared with those receiving placebo. Silodosin showed early onset of efficacy for both voiding and storage symptoms. Furthermore, long-term safety of silodosin was also demonstrated. Retrograde or abnormal ejaculation was the most commonly reported adverse effect. The incidence of orthostatic hypotension was low. In conclusion, silodosin, a novel selective α1A-adrenergic receptor antagonist, was effective in general and without obtrusive side effects. This review provides clear evidence in support of the clinical usefulness of silodosin in the treatment of LUTS associated with BPH. PMID:21753871

Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation.

PubMed

Baker, Candice N; Gidus, Sarah A; Price, George F; Peoples, Jessica N R; Ebert, Steven N

2015-03-01

As development proceeds from the embryonic to fetal stages, cardiac energy demands increase substantially, and oxidative phosphorylation of ADP to ATP in mitochondria becomes vital. Relatively little, however, is known about the signaling mechanisms regulating the transition from anaerobic to aerobic metabolism that occurs during the embryonic period. The main objective of this study was to test the hypothesis that adrenergic hormones provide critical stimulation of energy metabolism during embryonic/fetal development. We examined ATP and ADP concentrations in mouse embryos lacking adrenergic hormones due to targeted disruption of the essential dopamine β-hydroxylase (Dbh) gene. Embryonic ATP concentrations decreased dramatically, whereas ADP concentrations rose such that the ATP/ADP ratio in the adrenergic-deficient group was nearly 50-fold less than that found in littermate controls by embryonic day 11.5. We also found that cardiac extracellular acidification and oxygen consumption rates were significantly decreased, and mitochondria were significantly larger and more branched in adrenergic-deficient hearts. Notably, however, the mitochondria were intact with well-formed cristae, and there was no significant difference observed in mitochondrial membrane potential. Maternal administration of the adrenergic receptor agonists isoproterenol or l-phenylephrine significantly ameliorated the decreases in ATP observed in Dbh-/- embryos, suggesting that α- and β-adrenergic receptors were effective modulators of ATP concentrations in mouse embryos in vivo. These data demonstrate that adrenergic hormones stimulate cardiac energy metabolism during a critical period of embryonic development. Copyright © 2015 the American Physiological Society.

Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer’s disease and other tauopathies

PubMed Central

Florenzano, Fulvio; Veronica, Corsetti; Ciasca, Gabriele; Ciotti, Maria Teresa; Pittaluga, Anna; Olivero, Gunedalina; Feligioni, Marco; Iannuzzi, Filomena; Latina, Valentina; Maria Sciacca, Michele Francesco; Sinopoli, Alessandro; Milardi, Danilo; Pappalardo, Giuseppe; Marco, De Spirito; Papi, Massimiliano; Atlante, Anna; Bobba, Antonella; Borreca, Antonella; Calissano, Pietro; Amadoro, Giuseppina

2017-01-01

The largest part of tau secreted from AD nerve terminals and released in cerebral spinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting potential extracellular role(s) of NH2 -derived fragments of protein on synaptic dysfunction underlying neurodegenerative tauopathies, including Alzheimer’s disease (AD). Here we show that sub-toxic doses of extracellular-applied human NH2 tau 26-44 (aka NH 2 htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide accumulating in vivo at AD synapses and secreted into parenchyma- acutely provokes presynaptic deficit in K+ -evoked glutamate release on hippocampal synaptosomes along with alteration in local Ca2+ dynamics. Neuritic dystrophy, microtubules breakdown, deregulation in presynaptic proteins and loss of mitochondria located at nerve endings are detected in hippocampal cultures only after prolonged exposure to NH 2 htau. The specificity of these biological effects is supported by the lack of any significant change, either on neuronal activity or on cellular integrity, shown by administration of its reverse sequence counterpart which behaves as an inactive control, likely due to a poor conformational flexibility which makes it unable to dynamically perturb biomembrane-like environments. Our results demonstrate that one of the AD-relevant, soluble and secreted N-terminally truncated tau forms can early contribute to pathology outside of neurons causing alterations in synaptic activity at presynaptic level, independently of overt neurodegeneration. PMID:29029390

Functional interdependence of neurons in a single canine intrinsic cardiac ganglionated plexus

PubMed Central

Thompson, G W; Collier, K; Ardell, J L; Kember, G; Armour, J A

2000-01-01

To determine the activity characteristics displayed by different subpopulations of neurons in a single intrinsic cardiac ganglionated plexus, the behaviour and co-ordination of activity generated by neurons in two loci of the right atrial ganglionated plexus (RAGP) were evaluated in 16 anaesthetized dogs during basal states as well as in response to increasing inputs from ventricular sensory neurites. These sub-populations of right atrial neurons received afferent inputs from sensory neurites in both ventricles that were responsive to local mechanical stimuli and the nitric oxide donor nitroprusside. Neurons in at least one RAGP locus were activated by epicardial application of veratridine, bradykinin, the β1-adrenoceptor agonist prenaterol or glutamate. Epicardial application of angiotensin II, the selective β2-adrenoceptor agonist terbutaline and selective α-adrenoceptor agonists elicited inconsistent neuronal responses. The activity generated by both populations of atrial neurons studied over 5 min periods during basal states displayed periodic coupled behaviour (cross-correlation coefficients of activities that reached, on average, 0·88 ± 0·03; range 0·71–1) for 15–30 s periods of time. These periods of coupled activity occurred every 30–50 s during basal states, as well as when neuronal activity was enhanced by chemical activation of their ventricular sensory inputs. These results indicate that neurons throughout one intrinsic cardiac ganglionated plexus receive inputs from mechano- and chemosensory neurites located in both ventricles. That such neurons respond to multiple chemical stimuli, including those liberated from adjacent adrenergic efferent nerve terminals, indicates the complexity of the integrative processing of information that occurs within the intrinsic cardiac nervous system. It is proposed that the interdependent activity displayed by populations of neurons in different regions of one intrinsic cardiac ganglionated plexus, responding as they do to multiple cardiac sensory inputs, forms the basis for integrated regional cardiac control. PMID:11060132